Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[C:13]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22](O)=[O:23])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>ClCCl>[C:16]([O:15][C:13]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([NH:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])=[O:23])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1c(N)cccc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Solvent: ClCCl
Product: Cc1c(NC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cccc1C(=O)O
Reaction time: 18 h
Yield: 45 %

Procedure:
HCl salt (3.1 g, 16.6 mmol) was added to a suspension of 3-amino-2-methylbenzoic acid (2.5 g, 16.6 mmol) and N-Boc-L-proline (3.5 g, 16.6 mmol) in dichloromethane (40 mL). The reaction mixture was stirred under nitrogen for 18 h, diluted with solvent (1 vol) and washed with 1N HCl, brine, and dried (MgSO4). Concentration gave a foam with was applied to a 40 M Biotage SiO2 column, and eluted by gradient 20%-60% B (1000 mL); A=1% acetic acid/hexanes; B=1% acetic acid/ethyl acetate to give J.36 (S)-3-(1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)-2-methylbenzoic acid 2.6 g (45%). 1H NMR (300 MHz, DMSO-d6) δ: 12.5 (br. s, 1H), 9.52/9.46 (s, 1H), 7.57 (d, J=7.3 Hz, 1H), 7.44-7.40 (m, 1H), 7.29-7.24 (m, 1H), 4.32-4.28 (m, 1H), 3.47-3.48 (m, 1H), 3.34-3.29 (m, 1H), 2.33 (s, 3H), 1.93-1.80 (m, 4H), 1.41/1.36 (s, 9H). LC (Cond.-J1): 1.55 min; LCMS: Anal. Calcd. for [M+H]+ C18H25N2O5: 349.18; found 349.33.
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([CH:25]=O)=[CH:10][N:11]2[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Br:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([CH:25]=[CH2:1])=[CH:10][N:11]2[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1
Reactant: [Li]CCCC
Reactant: COc1ccc(Cn2cc(C=O)c3c(Br)cccc32)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cn(Cc2ccc(OC)cc2)c2cccc(Br)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Methyltriphenylphosphonium bromide (1.14 g) was suspended in tetrahydrofuran (6.0 mL), and to this solution was added n-butyl lithium (in 2.64 M hexane solution of 1.16 mL) at −78° C. The mixture was stirred at 0° C. for 1 hour and then a solution of compound (48a) (0.91 g) in tetrahydrofuran (2.0 mL) was added thereto, followed by stirring at room temperature for 1 hour. The reaction solution was partitioned with ethyl acetate and water, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by evaporation. The residue was purified by neutral silica gel column chromatography (hexane/ethyl acetate) to obtain compound (48b) (0.864 g, 95%) as a colorless oily substance.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C@@H:21]([CH3:22])[CH2:20][N:19]([C:23]([NH:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32]C(OC(C)(C)C)=O)[N:27]=3)=[O:24])[C@H:18]([CH3:40])[CH2:17]2)=[CH:12][C:11]=1[C:41]([F:44])([F:43])[F:42])#[N:9]>ClC(Cl)C>[NH2:32][C:28]1[N:27]=[C:26]([NH:25][C:23]([N:19]2[CH2:20][C@H:21]([CH3:22])[N:16]([C:13]3[CH:14]=[CH:15][C:10]([C:8]#[N:9])=[C:11]([C:41]([F:44])([F:43])[F:42])[CH:12]=3)[CH2:17][C@H:18]2[CH3:40])=[O:24])[CH:31]=[CH:30][N:29]=1
Reactant: C[C@@H]1CN(c2ccc(C#N)c(C(F)(F)F)c2)[C@@H](C)CN1C(=O)Nc1ccnc(NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: C[C@@H]1CN(c2ccc(C#N)c(C(F)(F)F)c2)[C@@H](C)CN1C(=O)Nc1ccnc(N)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.2 %

Procedure:
A 15 ml portion of trifluoroacetic acid was added to 60 ml of dichloroethane solution containing 2.8 g of (2R,5S)-4-(4-cyano-3-trifluoromethylphenyl)-N-[2-(1,1-dimethylethoxycarbonyl)amino-4-pyrimidyl]-2,5-dimethylpiperazine-1-carboxamide synthesized in Example 6-2, and the mixture was stirred at room temperature for about 12 hours. The reaction solution was evaporated under reduced pressure, and the thus obtained residue was mixed with saturated sodium bicarbonate solution and extracted with chloroform. The thus obtained organic layer was washed with water and dried over anhydrous magnesium sulfate, and then the crude product obtained by evaporating the solvent was subjected to a silica gel column chromatography to obtain 1.97 g of the title compound from chloroform-methanol (30:1, v/v) eluate. Thereafter, this was crystallized from ethyl acetate-hexane to obtain 1.51 g of the title compound as crystals.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH:12]([O:15][C:16]1[NH:20][N:19]=[C:18]([NH2:21])[CH:17]=1)([CH3:14])[CH3:13].C(N(CC)CC)C>C(#N)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:21][C:18]2[CH:17]=[C:16]([O:15][CH:12]([CH3:14])[CH3:13])[NH:20][N:19]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CC(C)Oc1cc(N)n[nH]1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)Oc1cc(Nc2nc(Cl)ccc2[N+](=O)[O-])n[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61 %

Procedure:
A mixture of 2,6-dichloro-3-nitropyridine (0.5 g) and 5-isopropoxy-1H-pyrazol-3-amine (Intermediate 6, 0.35 g) in acetonitrile (10 mL) with triethylamine (2 mL) was stirred at room temperature for 24 hours, The resulting mixture was concentrated, and the resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to afford 0.45 g desired product. MS (electrospray): 298 (M+1) for C11H12ClN5O3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[N:15]3)[NH:12][S:11](=[O:21])(=[O:20])[C:10]1[C:5]2=[CH:6][C:7]([C:22]([OH:24])=[O:23])=[CH:8][CH:9]=1.[CH:25]1(O)[CH2:29][CH2:28][CH2:27][CH2:26]1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH:25]1([O:23][C:22]([C:7]2[CH:6]=[C:5]3[C:10]([S:11](=[O:21])(=[O:20])[NH:12][C:13]4[C:4]3=[CH:3][C:2]([Cl:1])=[C:19]3[C:14]=4[N:15]=[CH:16][CH:17]=[CH:18]3)=[CH:9][CH:8]=2)=[O:24])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: OC1CCCC1
Reactant: O=C(O)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(OC1CCCC1)c1ccc2c(c1)-c1cc(Cl)c3cccnc3c1NS2(=O)=O
Yield: 28.4 %

Procedure:
In a similar fashion using route 54 general procedure 123, 12-chloro-6,6-dioxo-5,6-dihydro-6λ*6*-thia-4,5-diaza-chrysene-9-carboxylic acid 524 (150 mg, 0.41 mmol), cyclopentanol (0.19 ml, 2.0 mmol), EDC.HCl (88 mg, 0.45 mmol), DMAP (6 mg, 0.04 mmol) and DMF (1 ml) gave the title compound (50 mg, 28%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH:19]1([CH2:22][CH:23]=[O:24])[CH2:21][CH2:20]1>O1CCCC1>[CH:19]1([CH2:22][CH:23]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=2)[OH:24])[CH2:21][CH2:20]1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: O=CCC1CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)CC2CC2)cc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a −40° C. solution of methyl 4-iodobenzoate (0.39 g, 1.5 mmol) in tetrahydrofuran (7.5 mL) was added isopropylmagnesium chloride lithium chloride (1.5 mL, 1.3 M in THF, 1.95 mmol) dropwise. After stirring for 30 minutes at −40° C., 2-cyclopropylacetaldehyde (190 mg, 2.26 mmol) was added dropwise. The resulting mixture was then stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated ammonium chloride and partitioned between water and ethyl acetate. The layers were separated and the aqueous was extracted again with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave (+/−)-methyl 4-(2-cyclopropyl-1-hydroxyethyl)benzoate (150 mg, 45%). 1HNMR (400 MHz, CDCl3, δ): 7.89 (d, 2H), 7.32 (d, 2H), 4.75-4.72 (m, 1H), 3.79 (s, 3H), 1.60-1.51 (m, 2H), 0.60-0.51 (m, 1H), 0.49-0.25 (m, 2H), 0.07-−0.12 (m, 2H).
Reaction SMILES: Cl.CN.[C:4]([O:8][C:9]([NH:11][C@@H:12]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]=O)[CH:26]=2)=[CH:21][CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])([CH3:7])([CH3:6])[CH3:5].[C:33]([BH3-])#[N:34].[Na+]>CO>[C:4]([O:8][C:9]([NH:11][C@@H:12]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][NH:34][CH3:33])[CH:26]=2)=[CH:21][CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: [BH3-]C#N
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2cccc(C=O)c2)cc1)NC(=O)OC(C)(C)C
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)[C@H](Cc1ccc(-c2cccc(CNC)c2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
21.2 g (314 mmol) of methylamine hydrochloride are introduced into a solution containing 25 g (63.0 mmol) of ethyl (S)-2-tert-butoxycarbonylamino-3-(3′-formylbiphenyl-4-yl)propionate in 200 ml of methanol. After stirring for 30 min at ambient temperature, 6.0 g (95.4 mmol) of sodium cyanoborohydride are added portionwise. The reaction medium is stirred for 16 h and the solvents are evaporated off. The residue is dissolved in ethyl acetate, and the organic phase is washed with water and then dried over magnesium sulfate and concentrated.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=4)[NH2:22])[CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>ClCCl>[CH2:37]([O:36][C:34](=[O:35])[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][CH:8]3[CH2:7][CH2:6][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:10][CH2:9]3)[CH2:18][CH2:17]2)[CH:20]=1)[CH3:38]
Reactant: Nc1cccc(N2CCN(CCC3CCC4(CC3)OCCO4)CC2)c1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Nc1cccc(N2CCN(CCC3CCC4(CC3)OCCO4)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
To a cooled solution of 1 g (3 mmol) of 3-{4-[2-(1,4-dioxaspiro[4.5]dec-8-yl)ethyl]piperazin-1-yl}aniline in 30 mL of dichloromethane and 0.3 g (3 mmol) of triethylamine, is slowly added 0.32 g (3 mmol) of ethyl chloroformate. The mixture is stirred overnight at room temperature then concentrated under reduced pressure. The product is dissolved in ethyl acetate, washed twice with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The oily residue is purified over 10 g of silica gel (eluant dichloromethane/methanol 95/5) to give 0.35 g (29%) of (3-{4-[2-(1,4-dioxaspiro[4.5]dec-8-yl)ethyl]piperazin-1-yl}phenyl)carbamic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][SH:16])=[CH:13][CH:12]=1.[Na]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:15]([S:16][CH:8](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: SCc1ccc(Cl)cc1
Reactant: C#Cc1ccc(Cl)cc1
Agent: [Na]
Product: Clc1ccc(/C=C\C(SC(/C=C\c2ccc(Cl)cc2)c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1

Procedure:
A solution of 4-chlorophenylacetylene (0.02 mol) and 4-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to Procedure 2 to form (Z)-4-chlorostyryl 4-chlorobenzylsulfide. The title compound was obtained in 76% yield following oxidation. 1HNMR (CDC13) δ4.62 (2H, s), 6.68 (1H, d, JH,H=11.92), 7.18-7.60 (8H aromatic+1H ethylenic).
Reaction SMILES: C([NH:4][C:5]1[C:14]([Cl:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:16][CH:17]([C:19]#[C:20][CH3:21])[CH3:18])[CH:6]=1)(=O)C.C(=O)([O-])O.[Na+]>CO.S(=O)(=O)(O)O>[NH2:4][C:5]1[C:14]([Cl:15])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:16][CH:17]([C:19]#[C:20][CH3:21])[CH3:18])[CH:6]=1
Reactant: CC#CC(C)Oc1cc(NC(C)=O)c(Cl)cc1C(=O)OC
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: CC#CC(C)Oc1cc(N)c(Cl)cc1C(=O)OC
Temperature: 25 °C
Yield: 105 %

Procedure:
To the suspension of methyl 4-acetoamido-5-chloro-2-{(3-pentyn-2-yl)oxy}benzoate (73.3 g) in methanol (700 ml), concentrated sulfuric acid (73 ml) was dropwisely added at 0° C. The temperature of the reaction mixture was raised to room temperature. After the reaction mixture was stirred over night at room temperature, the reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution (5 l) gradually. Crystal thus precipitated was recovered by filtration, washed with water and dried to obtain 66.5 g of the title compound as colorless crystal.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:12])[CH2:7]2.CO.[BH4-].[Na+]>C(O)(=O)C>[C:2]1([OH:1])[C:3]2[CH2:4][CH2:5][CH:6]([OH:12])[CH2:7][C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: O=C1CCc2c(O)cccc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Oc1cccc2c1CCC(O)C2
Reaction time: 2.5 h

Procedure:
A 3.7 g. (0.0235 mole) sample of 5-hydroxy-3,4-dihydro-2(1H)-naphthalenone in 125 ml. of methanol is added to a cooled solution of 1.0 g. (0.025 mole) of sodium borohydride in 25 ml. of methanol. After 150 minutes at 0°, 7.2 g. of acetic acid is added and the solvent removed in vacuo. Partitioning between water and methylene chloride gives 3.54 g. of crude product after further extraction, drying and solvent removal. Recrystallization from hexane-ethyl acetate gives 2.92 g., m.p. 126°-128.5°. (lit. m.p. 127°-128°) JACS, 80, 2887 (1958).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[S:11][CH:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([OH:15])=O.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Cl:8][C:7]1[C:6]([O:9][CH3:10])=[CH:5][C:4]2[C:13](=[O:15])[CH:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:11][C:3]=2[C:2]=1[Cl:1]
Reactant: COc1ccc(SC(C(=O)O)c2ccccc2)c(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O=S(Cl)Cl
Product: COc1cc2c(c(Cl)c1Cl)SC(c1ccccc1)C2=O
Temperature: 0 °C

Procedure:
A solution of 1.17 g of α-(2,3-dichloro-4-methoxyphenylthio)-α-phenylacetic acid in 25 ml of carbon disulfide is refluxed with 0.5 g of thionyl chloride until the solution becomes clear. The solution is cooled to 5° and to it is added, in small portions, 340 mg of aluminum chloride. The mixture is stirred at reflux for 3 additional hours. Ice-water (20 g) is added to quench the reaction mixture and the product is extracted into dichloromethane. The dichloromethane extract is washed with sodium bicarbonate solution, water, dried and concentrated to give a syrup. The oily residue is triturated with 2 ml of acetone and allowed to stand at room temperature. Crystals slowly deposit and are collected after 2 days. Recrystallization from chloroform gives 6,7-dichloro-5-methoxy-2-phenylbenzo[b]thiophen-3(2H)-one as a yellowish solid, mp 228°-229° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([N+:25]([O-])=O)[CH:16]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CO.[Pd]>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([NH2:25])[CH:16]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N)cc(C(F)(F)F)c2)CC1

Procedure:
1-Boc-4-(3-nitro-5-trifluoromethyl-phenoxy)-piperidine (470 mg) was dissolved in MeOH (12 ml) and Pd/C (10 mg) was added. After sparging briefly with H2, the mixture was stirred under H2 for 6H. The catalyst was removed by filtration and the MeOH solution was concentrated in vacuo to yield 1-Boc-4-(3-amino-5-trifluoromethyl-phenoxy)-piperidine as an off-white foam.
Reaction SMILES: [CH:1]([C@H:4]1[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)OC(=O)[NH:5]1)([CH3:3])[CH3:2].[H][H]>CO.CC(O)=O.[Pd]>[NH2:5][C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)[C@@H]1NC(=O)OC1(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)[C@H](N)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
A solution of (S)-4-isopropyl-5,5-diphenyl-2-oxazolidinone (3) (2.9 g, 10.31 mmol) in MeOH/AcOH and a 10% Pd (435 mg, 4.09 mmol) on activated carbon was shaken for 68 h under 4–5 atm pressure of hydrogen at room temperature. The catalyst was filtered off over Hyflo Super Cell and organic solvents were evaporated under reduced pressure. The resulting residue was treated with HCl (2.0 M, 50 ml), stirred for 2 h at room temperature, made basic with NaOH pellets, and saturated with K2CO3 and NaCl. Organic compounds were then extracted into AcOEt (3×100 ml), dried over MgSO4/K2CO3 and concentrated under reduced pressure to obtain a crude product. Re-crystallisation from petroleum ether gave the title compound (4) (1.79 g, 72%) as a light-brown solid. m.p. 71–72° C. [α]D25=−4.19° (c, 0.1097 in CHCl3). δH 0.78 (3H, d, 3J=6.60 Hz, CH3), 0.91 (3H, d, 3J=7.20 Hz, CH3), 1.26 (2H, broad s, NH2), 1.62 (1H, ds, CHMe2), 3.45 (1H, dd, 3J=10.5 and 2.40 Hz, CH—NH2), 3.70 (1H, d, 3J=10.5 Hz, CH—Ph2), 7.00–7.40 (10H, m, Ar—H). δC 14.2 and 21.5 (CH3), 28.9 (CH—Me2), 58.1 and 58.9 (CH—NH2 and CH—Ph2), 126.5, 126.7, 128.2, 128.5, 128.8 and 129.0 (o-, m- and p-Ar), 143.5 (2×α-Ar). Anal. Calcld for C17H21N: C 85.30; H 8.84; N 5.85. Found: C 85.12; H 8.91; N 5.96. ir 3361 (NH2). m/e (CI—CH4) 240 (MH+, 8%), 72 (100%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([I:9])[CH:5]=[C:4]([CH2:10][OH:11])[N:3]=1.[H-].[Na+].[CH2:14](Br)[CH:15]=[CH2:16]>CN(C=O)C.CCOC(C)=O>[CH2:16]([O:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([CH2:10][OH:11])=[CH:5][C:6]=1[I:9])[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: OCc1cc(I)c(O)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1c(I)cc(CO)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
2-Chloro-6-(hydroxymethyl)-4-iodo-3-pyridinol (C2) (7.14 g, 25.0 mmol) is dissolved in DMF (50 mL) in a dry flask under N2, sodium hydride (60% dispersion in mineral oil) (1.0 g, 25.0 mmol) is added, and the reaction is stirred for 1 h at rt. Allyl bromide (2.38 mL, 27.5 mmol) is added, and the reaction mixture is stirred 48 h at rt. The mixture is diluted with EtOAc (50 mL) and washed 4×25 mL of a 50% saturated solution of 1:1 NaCl/NaHCO3. The organic layer is dried over MgSO4, filtered and concentrated in vacuo to a white solid. The solid is washed with hexane and dried to afford 3-(allyloxy)-2-chloro-6-(hydroxymethyl)-4-iodopyridine (C50) as a white solid (68% yield). MS (EI) for C9H9Cl/NO2, m/z: 325 (M)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([NH:8][NH2:9])=[O:7].[O:15]([C:22]1[C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=[CH:24][N:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[O:15]([C:22]1[C:27]([C:28]([NH:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][CH:12]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=2)=[O:29])=[CH:26][CH:25]=[CH:24][N:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1cccnc1Oc1ccccc1
Reactant: NNC(=O)c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: O=C(NNC(=O)c1cccnc1Oc1ccccc1)c1cccc(C(F)(F)F)c1
Yield: 53.3 %

Procedure:
A solution of 3-(trifluoromethyl)benzhydrazide (102.1 mg, 0.5 mmol), 2-phenoxypyridine-3-carbonyl chloride (117 mg, 0.5 mmol) in pyridine (5 mL) was refluxed for 2 h. It was evaporated in vacuo and the residue was purified by column chromatography (silica gel, EtOAc/CH2Cl2=4:1) to give 107 mg (54%) of the title compound. 1H NMR (CDCl3): 10.88 (d, J=6.3 Hz, 1H), 9.80 (d, J=6.3 Hz, 1H), 8.60 (m, 1H), 8.30 (m, 1H), 8.17 (s, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.61 (t, J=7.2 Hz, 1H), 7.51–7.46 (m, 2H), 7.34–7.17 (m, 4H).
Reaction SMILES: [OH:1][C@:2]([C:32]1[CH:36]=[C:35]([CH3:37])[O:34][N:33]=1)([CH3:31])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[O:14][CH2:13][CH2:12][N:11]3[C:15]([C:21]([NH:23][CH:24]4CCOCC4)=[O:22])=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=[C:10]3[C:9]=2[CH:30]=1.CN[CH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>>[OH:1][C@:2]([C:32]1[CH:36]=[C:35]([CH3:37])[O:34][N:33]=1)([CH3:31])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[O:14][CH2:13][CH2:12][N:11]3[C:15]([C:21]([NH:23][CH2:24][CH:40]4[CH2:41][CH2:42][O:43][CH2:44][CH2:45]4)=[O:22])=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=[C:10]3[C:9]=2[CH:30]=1
Reactant: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NC4CCOCC4)n2CCO3)no1
Reactant: CNC1CCOCC1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NCC4CCOCC4)n2CCO3)no1

Procedure:
Prepared as described for (R)-10-(3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-N3-(tetrahydro-2H-pyran-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide replacing 4-aminotetrahydropyran with 4-(methylamino)tetrahydropyran. Off-white solid (19.4 mg, 7%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)=[C:4]([N+:16]([O-])=O)[CH:3]=1.Cl[Sn]Cl>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)=[C:4]([NH2:16])[CH:3]=1
Reactant: Cc1cccc(Sc2ccc(C)cc2[N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Product: Cc1cccc(Sc2ccc(C)cc2N)c1

Procedure:
The product from Example 48a was reduced with SnCl2 following the procedure from Example 1f giving the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]1[CH:24]=[C:25]2[N:31]=[N:30][N:29]([C:32]3[CH:33]=[CH:34][C:35]([C:38](O)=[O:39])=[N:36][CH:37]=3)[C:26]2=[N:27][CH:28]=1>>[Cl:1][C:2]1[C:3]([N:8]([C:38]([C:35]2[CH:34]=[CH:33][C:32]([N:29]3[C:26]4=[N:27][CH:28]=[C:23]([CH3:22])[CH:24]=[C:25]4[N:31]=[N:30]3)=[CH:37][N:36]=2)=[O:39])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ncccc2Cl)C1
Reactant: Cc1cnc2c(c1)nnn2-c1ccc(C(=O)O)nc1
Product: Cc1cnc2c(c1)nnn2-c1ccc(C(=O)N(c2ncccc2Cl)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc1
Yield: 43.2 %

Procedure:
Prepared according to General Procedure A and C starting from Preparation 1 tert-butyl (3R)-3-[(3-chloropyridin-2-yl)amino]piperidine-1-carboxylate (3.22 g, 10.3 mmol) and Preparation 8 5-(6-methyl-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)pyridine-2-carboxylic acid (2.51 g, 9.83 mmol) to provide 2.33 g (43%) of the product as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[F:10][C:11]([F:20])([F:19])[C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.Cl>CCO>[ClH:8].[Cl:9][C:3]1[N:4]=[CH:5][N:6]=[C:7]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([C:11]([F:10])([F:19])[F:20])=[CH:13][CH:14]=2)[C:2]=1[NH2:1]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Nc1c(Cl)ncnc1Cl
Agent: Cl
Solvent: CCO
Product: Nc1c(Cl)ncnc1Nc1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Yield: 70.1 %

Procedure:
A mixture of 5-amino-4,6-dichloropyrimidine (10.0 g, 61.0 mmol, 1.0 eq), 4-trifluoromethylaniline (8.34 mL, 67.1 mmol, 1.1 eq), EtOH (80 mL), and concentrated HCl (2.5 mL, 30.5 mmol, 0.5 eq) was heated to 80° C. for 24 h and then cooled to rt. The resulting precipitate was collected by filtration, rinsed with EtOH, and dried under vacuum at 50° C. for 18 h to provide the title compound as a white solid (13.9 g, 70%). MS (ESI): mass calcd. for C11H9ClF3N4 [M+H]+, 289.0; m/z found, 289.0. 1H NMR (d6-DMSO): 9.26 (s, 1H), 8.01 (d, J=8.5 Hz, 2H), 7.94 (s, 1H), 7.67 (d, J=8.6 Hz, 2H), 6.41 (br s, 3H).