Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.C[C@@:18]1([OH:24])[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:20]2[CH2:21][CH2:22][CH2:23][C@@H:18]([OH:24])[CH2:19]2)=[CH:4][CH:3]=1
Reactant: C[C@@]1(O)CCCNC1
Reactant: BrCc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O[C@@H]1CCCN(Cc2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol), triethylamine (0.84 mL, 6.0 mmol) and (R)-3-methyl-piperidin-3-ol (1.11 g, 8.0 mmol) in THF (20 mL) was stirred at ambient temperature for 16 h. The solvent was evaporated and the resultant residue diluted with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated. The material was purified by flash chromatography (silica, Biotage 50 g column, 50-100% ethyl acetate in cyclohexane) to afford the title compound (0.75 g, 69%). 1H NMR (CDCl3, 300 MHz): 7.46-7.40 (m, 2H), 7.21-7.14 (m, 2,H), 3.85-3.76 (m, 1H), 3.45 (s, 2H), 2.45 (s, 3H), 2.29-2.16 (m, 1H), 1.86-1.70 (m, 1H) 1.67-1.45 (m, 3H) plus 1 exchangeable not observed. LCMS (Method G): RT=2.00 min, M+H+=270.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]([OH:17])=[O:16])(=[O:4])=[O:3].C(N(CC)CC)C.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>ClCCl>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][S:2]([C:5]2[C:6]3[C:11](=[C:10]([C:15]([OH:17])=[O:16])[CH:9]=[CH:8][CH:7]=3)[CH:12]=[CH:13][CH:14]=2)(=[O:4])=[O:3])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1cccc2c(S(=O)(=O)Cl)cccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2cccc3c(C(=O)O)cccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
5-Chlorosulfonyl-naphthalene-1-carboxylic acid 45 (2.00 g, 7.39 mmol) was dissolved in dichloromethane (30 mL). Triethylamine (2.24 g, 3.1 mL, 22.2 mmol) was added followed by 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.63 g, 8.13 mmol). The reaction was stirred overnight at room temperature. The reaction was diluted with dichloromethane (50 mL) and charged to a separatory funnel. The organic layer was washed twice with water and brine and dried over MgSO4. Filtration and concentration in vacuo afforded 46 (3.0 g, 93%) as a yellow foam. 1H NMR (300 MHz, d6-DMSO) δ 9.11 (d, 1H), 8.62 (d, 1H), 8.15 (d, 1H), 7.90 (d, 1H), 7.62 (m, 2H), 3.91 (d, 1H), 3.62 (m, 2H), 3.15 (m, 1H), 2.67 (m, 2H), 1.89 (m, 2H), 1.52 (m, 2H), 1.40 (s, 9H) LC/MS m/z 435 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:11](I)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>O>[CH2:11]([O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCCCCCOc1cccc([N+](=O)[O-])c1

Procedure:
A mixture of 3-nitrophenol (57.0 g, 0.41 mol), n-hexyliodide (87.0 g, 0.41 mol), potassium carbonate (57.0 g, 0.42 mol) and ethylmethylketone (300 ml) was heated at reflux for 18 h. Water (500 ml) was added and the mixture was extracted with ethyl acetate (2×500 ml). The combined extracts were washed with 8% aqueous sodium bicarbonate (2×250 ml) and brine (250 ml) and then dried (MgSO4) and evaporated to afford a dark brown liquid. Distillation under reduced pressure gave the ether (Intermediate 66) as a mobile yellow liquid (70.3 g, 77%).
Reaction SMILES: [CH2:1]([N:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:10][C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C([O-])(=O)C.[Na+].[Br:33]Br>O>[CH2:1]([N:8]1[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:10]([Br:33])[C:9]1=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(OCc2ccccc2)cc(=O)n1Cc1ccccc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(OCc2ccccc2)c(Br)c(=O)n1Cc1ccccc1

Procedure:
The product from example 35, 1-benzyl-4-(benzyloxy)-6-methylpyridin-2(1H)-one (4.2 mmol, 1.3 g), acetic acid (50 mL), and sodium acetate (5.0 mmol, 0.41 g) were stirred at room temperature. Bromine (4.2 mmol, 0.67 g) was added drop wise with stirring. After M hour, water (100 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate solution and brine. After drying over magnesium sulfate and concentrating, the mixture was purified by flash column chromatography eluting with ethyl acetate:hexanes (12). The appropriate fractions were concentrated to yield a light oil. (1.0 g, 62%): 1H NMR (DMSO-d6/300 MHz) 7.4-7.0 (m, 10H), 6.5 (s, 1H), 5.29 (s, 2H), 5.27 (s, 2H), 2.2 (s, 3H). ES HRMS m/z 384.057 (M+H, C20H18NO2Br requires 384.060).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH3:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:14]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CNc1c(N)cnc2ccccc12
Reactant: O=Cc1ccccc1
Product: Cn1c(-c2ccccc2)nc2cnc3ccccc3c21

Procedure:
Following the general method of Example 195, Step B, 3-amino-4-(methylamino)quinoline was reacted with benzaldehyde to provide 1-methyl-2-phenyl-1H-imidazo[4,5-c]quinoline, melting point 168-170° C. Analysis: Calculated for C17H13N3 : % C, 78.7; % H, 5.1; % N, 16.2. Found: % C, 78.9; % H, 5.0; % N, 16.1.
Reaction SMILES: [F:1][CH2:2][C:3](Cl)=[O:4].[N:6]1[N:7]=[C:8]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[C:18]([O:25][CH2:26][C:27]([CH3:31])([CH3:30])[CH2:28][NH2:29])[CH:19]=[CH:20][CH:21]=3)[N:16]=2)[N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[N:6]1[N:7]=[C:8]([C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[C:18]([O:25][CH2:26][C:27]([CH3:31])([CH3:30])[CH2:28][NH:29][C:3](=[O:4])[CH2:2][F:1])[CH:19]=[CH:20][CH:21]=3)[N:16]=2)[N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12
Reactant: CC(C)(CN)COc1cccc2ccc(-c3nnc4ccccn34)nc12
Reactant: O=C(Cl)CF
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(CNC(=O)CF)COc1cccc2ccc(-c3nnc4ccccn34)nc12
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
2-Fluoroacetyl chloride (12 mg, 0.13 mmol) was added to a stirred solution of 3-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-2,2-dimethylpropan-1-amine (prepared according to Example 18; 30 mg, 0.086 mmol) and diisopropylethyl amine (45 μL, 0.26 mmol) in DCM (2 mL) at 0° C. After 30 minutes, the reaction was quenched with saturated aqueous bicarbonate (5 mL), extracted into EtOAc, washed with water, dried over Na2SO4 followed by concentration in vacuo. The resulting oil was purified by flash column chromatography (silica gel), eluting with 100% EtOAc (Biotage) to give the desired product (12 mg, 0.029 mmol, 34% yield) as a white solid. MS ESI (+) m/z 408.2 (M+1) detected.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][NH:6][C:7](=[O:34])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH:28]2[CH2:31][C:30]([CH3:33])([CH3:32])[CH2:29]2)[NH:15][C:16]2[C:25]([CH3:26])=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:27])[CH:22]=3)[N:17]=2)=[CH:10][CH:9]=1.[OH-].[Na+]>CO.C1COCC1>[CH3:32][C:30]1([CH3:33])[CH2:31][CH:28]([CH:14]([NH:15][C:16]2[C:25]([CH3:26])=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:27])[CH:22]=3)[N:17]=2)[C:11]2[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:35])=[O:2])=[O:34])=[CH:13][CH:12]=2)[CH2:29]1
Reactant: COC(=O)CCNC(=O)c1ccc(C(Nc2nc3ccc(F)cc3cc2C)C2CC(C)(C)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2cc(F)ccc2nc1NC(c1ccc(C(=O)NCCC(=O)O)cc1)C1CC(C)(C)C1

Procedure:
The title compound was prepared by treating 3-{4-[(3,3-Dimethyl-cyclobutyl)-(6-fluoro-3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid methyl ester, isomer 1, (intermediate 74) with 1N NaOH (2.5 eq.) in methanol/THF in a similar manner as described in Example 19 to provide the title compound. Analytical chiral SFC: (Chiralpak IC column, 4.6 mm×25 cm, 25% methanol/carbon dioxide eluent, 2.5 mL/min flow rate, 4.33 retention time); 1H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 8.38 (br. s., 1H), 7.63-7.76 (m, 3H), 7.55 (d, J=7.8 Hz, 2H), 7.39-7.50 (m, 1H), 7.30-7.39 (m, 1H), 7.21-7.30 (m, 1H), 6.45-6.60 (m, 1H), 5.11-5.28 (m, 1H), 3.41 (dd, J=12.7, 7.1 Hz, 2H), 2.75-2.91 (m, 1H), 2.46 (t, J=7.1 Hz, 2H), 2.29 (s, 3H), 1.92-2.00 (m, 1H), 1.56-1.67 (m, 2H), 1.42-1.55 (m, 1H), 1.12 (s, 3H), 1.07 (s, 3H); MS (M+1): 464.3.
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[CH:4]([CH3:8])[CH2:5][CH2:6][CH:7]=1.[NH3:10]>[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH2:10]
Reactant: N
Reactant: CC1=CCCC(C)C1=O
Agent: [Pd]
Product: Cc1cccc(C)c1N
Reaction time: 4 h
Yield: 63 %

Procedure:
A solution of 19.7 g (0.158 mole) of 2,6-dimethyl-cyclohex-2-en-1-one in 180 ml of conc. ammonia is heated, after the addition of 4.0 g of palladium on charcoal (5%), in a hydrogenating autoclave for 4 hours at 280°-290° C., whereby a pressure of 20 bars is established, and is then maintained under these conditions for 5 hours. Cooling and pressure release are then carried out; the contents are again heated for about 5 hours and the pressure is again released. In order to effect the complete removal of hydrogen, the procedure of heating and pressure release is carried out in all three times. An addition is then made of 150 ml of ether and the catalyst is filtered off. The filter residue is washed three times alternately with 100 ml of ether and water, respectively. The mother liquor is extracted, after separation of the ether phase, five times with 150 ml of ether each time. The combined ether phases are dried over magnesium sulphate. After the ether has been distilled off, there remains 17.0 g of crude 2,6-dimethylaniline, from which is obtained, by distillation in a water-jet vacuum, 12.0 g (63% of theory) of pure 2,6-dimethylaniline; b.p. 103° C./ 18 Torr.
Reaction SMILES: [CH:1]1([N:4]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:5](=[O:18])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[C:8]([F:17])[CH:7]=2)[CH2:3][CH2:2]1.Cl[C:26]1[N:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][N:27]=1>>[CH:1]1([N:4]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[N:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[C:5](=[O:18])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[C:8]([F:17])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCc1cnc(Cl)nc1
Reactant: O=C(c1ccc(-c2cnco2)c(F)c1)N(C1CCNCC1)C1CC1
Product: CCc1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)c(F)c3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from N-cyclopropyl-3-fluoro-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 2-chloro-5-ethyl-pyrimidine following a procedure analogous to that described in Example 19. LC (method 1): tR=1.16 min; Mass spectrum (ESI+): m/z=436 [M+H]+.
Reaction SMILES: N[C@H:2](C(O)=O)CC1C=CC=CC=1.[NH2:13][C@H:14]([C:17]([OH:19])=[O:18])[CH2:15][OH:16].[ClH:20]>CO>[ClH:20].[CH3:2][O:18][C:17](=[O:19])[C@H:14]([CH2:15][OH:16])[NH2:13]
Reactant: N[C@@H](CO)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H](N)CO
Yield: 83.8 %

Procedure:
The same esterification procedure as in Example 1 was followed with the exception that the L-phenylalanine was replaced with 105.6 g of L-serine and that 105.6 g of methanol and 50.5 g of hydrochloric acid were used. Following cooling to deposit the crystals, which were collected by filtration and then dried to obtain 134.4 g (83.8% yield) of L-serine methyl ester hydrochloride having a purity of 97.0% and containing 0.2% of water and 0.7% of L-serine.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[C:15]([CH3:21])=[N:16]C(C)=[CH:18][CH:19]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.[Li]CCCC.CC1C(C=O)=C(C)[O:43]N=1>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[C:15]([CH3:21])=[N:16][O:43][C:19]=3[CH3:18])[OH:13])[CH:10]=2)[N:5]=[C:4]([O:22][CH3:23])[C:3]=1[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=1
Reactant: Cc1noc(C)c1C=O
Reactant: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3c(C)noc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.03 h

Procedure:
To a flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (2.0 g, 4.64 mmol, Intermediate 12: step d) was added THF (65 mL) and the solution was cooled to −78° C. n-BuLi (2.5 M in hexanes, 2.1 mL, 5.25 mmol) was added dropwise producing a dark reddish-brown mixture. After 2 minutes, a THF solution of 3,5-dimethylisoxazole-4-carbaldehyde (700 mg, 5.63 mmol in 2 mL THF) was introduced. The reaction mixture immediately became a homogeneous yellow solution. After 25 minutes the mixture was quenched with aqueous NH4Cl solution and the aqueous portion was extracted with EtOAc (3×50 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness. Chromatography on silica gel (100% DCM increasing to 20% CH3CN/DCM) provided the titled compound an off white amorphous solid.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([CH2:21][CH2:22][CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].CO>C(OCC)(=O)C>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:27]3[CH2:28][CH2:29][CH:24]([CH2:23][CH2:22][CH2:21][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:25][CH2:26]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Reactant: c1cc(OCC2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(CCCc2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(3-phenylpropyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 73% overall yield. FDMS m/e=392 (M+ of free base). α[D]589 =-13.53 (c=0.58, methanol).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.[F:17][C:18]([F:37])([F:36])[C:19]1[CH:20]=[C:21]([C:29]2[O:30][CH:31]=[C:32]([CH2:34]Cl)[N:33]=2)[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1>>[F:37][C:18]([F:17])([F:36])[C:19]1[CH:20]=[C:21]([C:29]2[O:30][CH:31]=[C:32]([CH2:34][N:3]3[C:4]4[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=4)[CH:10]=[C:2]3[CH3:1])[N:33]=2)[CH:22]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:24]=1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: FC(F)(F)c1cc(-c2nc(CCl)co2)cc(C(F)(F)F)c1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1coc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 2-[3,5-bis(trifluoromethyl)phenyl]-4-(chloromethyl)-1,3-oxazole: MS (ES) m/z 518 (M+1).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[CH3:11]>>[CH2:10]([O:12][C:13](=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])[CH:16]=1)[CH3:11]
Reactant: CCOC(=O)Cc1cccc(N)c1
Reactant: O=C(O)c1ccc(Br)s1
Product: CCOC(=O)Cc1cccc(NC(=O)c2ccc(Br)s2)c1

Procedure:
5-Bromothiophene-2-carboxylic acid (232 mg, 1.1 mmol) was coupled with ethyl ester (6) (201 mg, 1.1 mmol) following Method C to give the title compound.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27]([OH:31])[CH2:28][CH2:29][CH3:30]>O>[CH2:27]([O:31][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCO
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCCOc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 100 °C

Procedure:
A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.27 g of potassium carbonate and 3 ml of butanol was stirred while heating at 100° C. for six hours. To the mixture, 0.14 g of potassium carbonate was added, and the reaction mixture was stirred while heating at 100° C. for further four hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.24 g of 2-(3-butoxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 72”).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:5]([CH2:15][CH2:16][N:17]2[C:22]3[CH:23]=[C:24]([C:27]#[N:28])[CH:25]=[CH:26][C:21]=3[O:20][CH2:19][C:18]2=[O:29])[CH2:4][CH2:3]1.[O:30]=[C:31]1[CH2:36][O:35][C:34]2[CH:37]=[CH:38][C:39]([CH:41]=O)=[N:40][C:33]=2[NH:32]1.[BH3-]C#N.[Na+]>CO>[C:27]([C:24]1[CH:25]=[CH:26][C:21]2[O:20][CH2:19][C:18](=[O:29])[N:17]([CH2:16][CH2:15][C@H:5]3[CH2:4][CH2:3][C@H:2]([NH:1][CH2:41][C:39]4[CH:38]=[CH:37][C:34]5[O:35][CH2:36][C:31](=[O:30])[NH:32][C:33]=5[N:40]=4)[CH2:7][N:6]3[C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[C:22]=2[CH:23]=1)#[N:28]
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)CC[C@@H]1CCN1C(=O)COc2ccc(C#N)cc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](NCc2ccc3c(n2)NC(=O)CO3)CC[C@@H]1CCN1C(=O)COc2ccc(C#N)cc21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl(2R,5S)-5-amino-2-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidine-1-carboxylate (Intermediate 183, 0.14 g), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (75 mg) and 3 Å molecular sieves powder (70 mg) in methanol (8 mL) was heated at 80° C. for 1 hour. The solution was cooled to 0° C. and NaCNBH3 (33 mg) was added. After stirring at room temperature overnight, the reaction was filtered and concentrated. The residue was purified chromatography on silica gel with a gradient of 0-5% methanol in methylene chloride to give 0.14 g.
Reaction SMILES: [F:1][C:2]1[C:3]([C:33]([F:36])([F:35])[F:34])=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:25]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][C:20]=4[NH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[ClH:37]>C(Cl)Cl.CCOCC>[ClH:37].[F:1][C:2]1[C:3]([C:33]([F:35])([F:34])[F:36])=[C:4]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[C:25]4[CH2:24][CH2:23][NH:22][CH2:21][C:20]=4[NH:19][N:18]=3)=[O:16])[CH2:13][CH2:14]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(C(=O)N3CCC(c4cc(F)cc(F)c4C(F)(F)F)CC3)n[nH]c2C1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2cc(F)cc(F)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
To a solution of tert-butyl 3-(4-(3,5-difluoro-2-(trifluoro-methyl)phenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (59, 94 mg, 0.19 mmol) in CH2Cl2 (3 mL) was added HCl (2.0 N solution in Et2O, 3 mL). The mixture was stirred for 18 h at ambient temperature. The reaction mixture was diluted with Et2O (20 mL) and the mixture concentrated under reduced pressure to yield (4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone hydrochloride (60) as a white solid (80 mg, 97%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[CH:19]=[CH:20][NH:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1.[C:23](O)(=[O:25])[CH3:24]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[CH:19]=[CH:20][N:21]([C:23](=[O:25])[CH3:24])[C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1
Reactant: CC(=O)O
Reactant: CC1c2[nH]ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1
Product: CC(=O)n1ccc2c1C(C)N(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-methyl-1,4,5,7-tetrahydro-pyrrolo[2,3-c]pyridin-6-yl)-methanone is reacted with acetic acid to provide the title compound.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]1COCC1.[Cl-].[NH4+].CO>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[C:2]1([C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH2:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: Cc1ccccc1
Product: C=C(c1ccccc1)c1ccccc1
Reaction time: 13 h

Procedure:
To this reaction mixture was added dropwise a liquid mixture of 182.2 g (1.1 mol) of benzophenone (8a; Ar=R=Ph) and 365 ml of dry THF at 35° to 40° C. over a period of 30 minutes. This mixture was stirred at that temperature for 2 hours and for further 13 hours to complete the reaction. The reaction mixture was poured into 1.4 kg of cooled 10% aqueous ammonium chloride solution with cooling with ice. This mixture was stirred for 30 minutes, allowed to stand, and then subjected to liquid separation, followed by washing with aqueous common salt solution, drying with magnesium sulfate, and concentration to obtain 200.2 g of a crude carbinol (theoretical yield based on the benzophenone, 98.6%). Into a 1-liter reaction flask were introduced 200.2 g of the crude carbinol, 400 ml of toluene, and 1 g of p-toluenesulfonic acid (PTSA). Azeotropic dehydration was conducted for 2 hours with toluene refluxing (94°-116° C.). After cooling, this reaction mixture was washed with water, with 2% aqueous soda ash solution, and then with water, dried with magnesium sulfate, and concentrated to obtain 190.1 g of crude 1,1-diphenylethylene. This crude reaction product was distilled with a Claisen flask equipped with a vigreux to obtain 174.1 g of 1,1-diphenylethylene (9a; Ar=R=Ph). b.p., 103° C./1 mmHg.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[Na+].[Na+].[Cl:7][C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([O:18][CH:19]([F:21])[F:20])[CH:17]=1)[S:14][CH2:13][CH2:12][C@:11]2([OH:24])CO>O.[Pt]>[Cl:7][C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([O:18][CH:19]([F:20])[F:21])[CH:17]=1)[S:14][CH2:13][CH2:12][C@@:11]2([C:1]([OH:2])=[O:4])[OH:24]
Reactant: OC[C@@]1(O)CCSc2c(OC(F)F)cc(Cl)cc21
Reactant: O=C([O-])[O-]
Agent: [Pt]
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@@]1(O)CCSc2c(OC(F)F)cc(Cl)cc21
Temperature: 95 °C
Reaction time: 30 h
Yield: 74.9 %

Procedure:
Sodium carbonate (0.72 g, 6.7 mmol) and 5% Pt/C (1.50 g, 75% weight of reactant) were added to a solution of (R)-6-chloro-8-difluoromethoxy-4-hydroxy-4-hydroxymethylthiochromane (2.0 g, 6.7 mmol; from step (v) above) in H2O (180 mL). The mixture was vigorously stirred at ca. 95° C. for 20-40 h with air being directly bubbled into the reaction mixture. The reaction was cooled to room temperature and filtered through a pad of Celite with saturated Na2CO3 solution (ca. 100 mL). The resulting liquid was slowly acidified with 2 N HCl (ca. 200 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (75 mL), dried (Na2SO4), filtered, and concentrated in vacuo to afford 1.56 g (ca. 75%) of the sub-title compound as a brown oil which was used without further purification.