Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=[C:9]1[CH:19](Br)[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:23]>CO>[NH2:23][CH:19]([C:9]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=1)[CH2:20][CH3:21]
Reactant: CCC(Br)c1nc2snc(C)c2c(=O)n1Cc1ccccc1
Reactant: N
Solvent: CO
Product: CCC(N)c1nc2snc(C)c2c(=O)n1Cc1ccccc1
Temperature: 120 °C
Yield: 100 %

Procedure:
A mixture of 32 (160 mg, 0.42 mmol) and 7N ammonia in MeOH (7.5 mL) was heated in a sealed tube at 120° C. for 2 h, and cooled to room temperature. Solvent was removed to give a yellow solid 36 (136 mg, 100%), which was used without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.07–7.28 (m, 5H), 5.39 (s 2H), 4.23 (brs, 2H), 4.15 (t, J=5.99 Hz, 1H), 2.72 (s, 3H), 1.46–1.66 (m, 2H), 0.75 (t, J=7.37 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([CH3:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:49])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[C:40]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)=[CH:39][N:38]=[N:37]2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)[C:11]([CH3:19])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:49])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[C:40]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)=[CH:39][N:38]=[N:37]2)[CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1N1CCCC1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: Cc1cc(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)c(NC(=O)OC(C)(C)C)cc1N1CCCC1

Procedure:
The title compound was prepared from (2-amino-4-methyl-5-pyrrolidin-1-yl-phenyl)-carbamic acid tert-butyl ester acid tert-butyl ester (Example J39) (292 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (401 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (410 mg, 66%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3][N:2]=1.[CH2:14]([O:16][C:17]([C:19]1([NH2:28])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:28][C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=[N:2][CH:3]=2)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: O=C(O)c1cncc2ccccc12
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cncc3ccccc23)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a solution of isoquinoline-4-carboxylic acid (211 mg, 1.22 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (250 mg, 1.22 mmol), HATU (696 mg, 1.83 mmol) in anhydrous DMF (8 mL) is added DIPEA (302 μL, 1.83 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (40 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (51) as white solid (359 mg, 82%).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH:23]3[CH2:26][CH2:25][CH2:24]3)[CH2:18][CH2:17]2)=[O:15])=[C:9]([CH3:27])[CH:8]=1>C1COCC1.O>[CH:23]1([CH2:22][N:19]2[CH2:18][CH2:17][N:16]([C:14](=[O:15])[CH2:13][C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:28])=[O:5])=[CH:8][C:9]=3[CH3:27])[CH2:21][CH2:20]2)[CH2:26][CH2:25][CH2:24]1
Reactant: COC(=O)c1ccc(CC(=O)N2CCN(CC3CCC3)CC2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)O)ccc1CC(=O)N1CCN(CC2CCC2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 63 %

Procedure:
Lithium hydroxide monohydrate (122 mg, 2.9 mmol) was added to a solution of 4-[2-(4-cyclobutylmethyl-piperazin-1-yl)-2-oxo-ethyl]-3-methyl-benzoic acid methyl ester from Example E85.1 (500 mg, 1.4 mmol) in THF (10 ml) and water (5 ml). The mixture was stirred for 20 h at room temperature and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 3% acetic acid:7% methanol:90% chloroform) to yield the title compound (300 mg, 63%).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.Cl>CC(O)C>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: C1CCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCC2)c(Br)c1

Procedure:
5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.2, 1 g, 2.53 mmol), pyrrolidine (0.544 g, 5.06 mmol), DIPEA (1.325 mL, 7.58 mmol) and iPrOH (2.53 mL) were added to a MW vial and subjected to MW irradiation at 140° C. for 1 h. The mixture was treated with aqueous HCl (40 mL of 0.5 M) was added and extracted with EtOAc The combined extracts were washed with 0.5 M HCl (40 mL) and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue was crystallized from cyclohexane/EtOAc to yield the title compound as an off-white solid. UPLC-MS (Condition 3) tR=1.34 min, m/z=430.1/432.1 [M+H]+, m/z=428.3/430.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.76-2.01 (m, 4H) 3.60-3.80 (m, 4H) 7.33 (d, J=8.20 Hz, 2H) 7.72-7.91 (m, 2H) 8.32 (d, J=1.95 Hz, 1H) 8.66 (d, J=1.95 Hz, 1H) 10.20 (s, 1H).
Reaction SMILES: [CH2:1](OS(C)(=O)=O)[CH2:2][C:3]#[CH:4].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>CCOCC>[CH2:1]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH2:2][C:3]#[CH:4]
Reactant: C#CCCOS(C)(=O)=O
Reactant: C1COCCN1
Solvent: CCOCC
Product: C#CCCN1CCOCC1
Temperature: 100 °C

Procedure:
A mixture of methanesulfonic acid but-3-ynyl ester (10.1 g, 68 mmol) and morpholine (12.5 mL, 143 mmol) was heated to 100° C. for 1 h. The mixture was diluted with Et2O (50 mL) and filtered. The solid residue was discarded, and the mother liquor extracted with 3N HCl. The aqueous layer was basified with NaOH, and back-extracted into EtOAc. Drying (Na2SO4), concentration, and distillation (short-path, b.p.=130° C. at ˜5 mm Hg) gave the title compound as a colorless oil. 1H NMR (CDCl3) δ 3.72 (t, 4H), 2.60 (t, 2H), 2.48 (t, 4H), 2.39 (td, 2H), 2.00 (t, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[O:8]=[C:9]1[C@@H:16]2[C@@H:12]([CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15]2)[CH2:11][CH2:10]1>>[OH:8][C:9]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[C@@H:16]2[C@@H:12]([CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15]2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CCC(=O)[C@H]2C1
Reactant: Brc1cccnc1
Product: CC(C)(C)OC(=O)N1C[C@H]2CCC(O)(c3cccnc3)[C@H]2C1
Yield: 26.6 %

Procedure:
3-Bromopyridine (4.36 g, 27.6 mmol) and the product from Example 44A (2.07 g, 9.19 mmol) were processed as described in Example 1E to afford the title compound (0.743 g, 27%). MS (DCI/NH3) m/z 305 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-])=O)[C:5](OC)=[O:6].[H][H]>[Pd].C(OCC)(=O)C>[F:15][C:13]1[CH:14]=[C:9]2[C:10](=[CH:11][CH:12]=1)[NH:16][C:5](=[O:6])[CH:4]2[C:3]([O:2][CH3:1])=[O:19]
Reactant: COC(=O)C(C(=O)OC)c1cc(F)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C1C(=O)Nc2ccc(F)cc21
Yield: 92.9 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer and a gas inlet tube and having an inner volume of 100 ml were charged 3.93 g (14.2 mmol) of dimethyl -2-(5-fluoro-2-nitrophenyl)malonate synthesized according to Example 1 with a purity of 98%, 0.5 g (0.12 mmol as a palladium atom) of 5% by weight palladium/carbon (49% hydrated product) and 50 ml of ethyl acetate under argon atmosphere. Then, the inner system was replaced with hydrogen, and the mixture was reacted under a hydrogen pressure of 0.15 MPa at 20° C. for 2 hours. After completion of the reaction, the catalyst was filtered off by filtrating the reaction mixture and then the filtrate was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (filler: Daisogel 1002w, eluent: chloroform) to obtain 2.76 g (isolation yield: 92%) of 5-fluoro-3-methoxycarbonyloxindole as white crystals with a purity of 99% (areal percentage by high performance liquid chromatography).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:19](=O)[CH3:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:22][OH:23].Cl.N1C=CC=CC=1>CCO>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:19](=[N:22][OH:23])[CH3:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: CC(=O)c1ccc(-c2ccccc2)c(-c2ccccc2)n1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NO)c1ccc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 70 °C

Procedure:
General Procedure P. 1-(5,6-Diphenyl-pyridin-2-yl)-ethanone (Compound 75, 119 mg, 0.44 mmol), NH2OH—HCl (103 mg, 1.48 mmol) and pyridine (272 mg, 0.27 mmol) was dissolved in EtOH (2 ml), and the mixture was heated to 70° C. under nitrogen for 3 hours. The reaction was quenched with water, and the product was extracted with ethyl acetate. The combined organic layers were washed with brine, and dried over Na2SO4. The filtered solvents were concentrated in vacuo, and the residue was purified by silica gel chromatography (15% ethyl acetate in hexane) to give title compound as an oil.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[CH2:15][N:16]=[C:17]=[S:18]>C(O)C>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[CH2:15][NH:16][C:17]([NH:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[S:18]
Reactant: COc1cccc(CN=C=S)c1
Reactant: CCCCCCCCN
Solvent: CCO
Product: CCCCCCCCNC(=S)NCc1cccc(OC)c1
Temperature: 4 °C

Procedure:
N-Octyl amine (3.09 g, 23.9 mmol) in 83 ml ethanol at 40° C. was reacted with an excess of 3-methoxybenzyl isothiocyanate (4.7 g, 26.2 mmol) for 2 h under N2 with stirring, then transferred to a 100 ml beaker, cooled to 4° C. and the crystals filtered off using Whatman 541 filter paper. The filtrate was evaporated to 20 ml and cooled to 4° C. to obtain a second crop of crystals. The remaining supernatant was dried and weighed. The first and second crop of crystals yielded 6.32 g, or 85.5% of the theoretical amount of 1-(3-methoxybenzyl-3-octyl thiourea. Calculated elemental analysis of 1-(3-methoxybenzyl)-3-octyl thiourea: C, 66.19; H, 9.15; N, 9.08; S, 10.39. Found: C, 66.21; H, 9.04; N, 9.07; S, 10.59.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:13])=O.CN(C=O)C>C(Cl)Cl>[OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccccc1O
Temperature: 60 °C

Procedure:
2-Hydroxy benzoic acid (1 g, 7.2 mmol) is dissolved in DCM (14 mL). To this mixture, thionyl chloride (1.57 mL, 22 mmol) and a catalytic amount of dry DMF are added. The resulting mixture is heated to 60° C. overnight, after which the resulting mixture is evaporated to give the desired product that is used as such.
Reaction SMILES: F[C:2]1[C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[CH3:19][O-:20].[Na+].CO>CN(C)C=O>[CH3:19][O:20][C:2]1[C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: Fc1c(OC(F)(F)F)cccc1C1CCNCC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1c(OC(F)(F)F)cccc1C1CCNCC1

Procedure:
Preparation according to preparation 34: 4-[2-fluoro-3-(trifluoromethoxy)phenyl]piperidine (1.23 g, 4.7 mmol), N,N-dimethylformamide (20 ml), sodium methoxide in methanol (30%, 2.35 ml, 13.2 mmol). Yield: 1.32 g.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C.CCOC(C)=O>[CH2:28]([O:27][CH2:26][CH2:25][CH2:24][N:11]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[S:8]([C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=S(=O)(NC1CCCC1)c1ccc(Cl)nc1
Reactant: BrCCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(Cl)nc1)N(CCCOCc1ccccc1)C1CCCC1
Temperature: 40 °C
Yield: 105.1 %

Procedure:
A mixture of 1 g (3.84 mmol) of 6-chloro-N-cyclopentylpyridine-3-sulfonamide, 1.32 g (9.59 mmol) of K2CO3 and 0.88 mL (4.99 mmol) of [(3-bromopropoxy)methyl]benzene in 8 mL of anhydrous DMF is heated for 12 hours at 40° C. After cooling to room temperature, the medium is taken up in 300 mL of EtOAc, washed successively with water (2×100 mL), saturated NaHCO3 solution (100 mL) and brine (100 mL), dried over Na2SO4 and then concentrated under reduced pressure and purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc gradient of 0 to 10% EtOAc. 1.65 g of N-[3-(benzyloxy)propyl]-6-chloro-N-cyclopentylpyridine-3-sulfonamide are thus obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([C:14]1[C:22]3[C:17](=[C:18]([CH2:23][S:24][CH3:25])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=1)([CH3:13])[CH2:5][CH2:6][O:7]2.ClCCl.ClC1C=CC=C(C(OO)=[O:37])C=1>CO>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([C:14]1[C:22]3[C:17](=[C:18]([CH2:23][S:24]([CH3:25])=[O:37])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=1)([CH3:13])[CH2:5][CH2:6][O:7]2
Reactant: CSCc1cccc2c(C3(C)CCOc4cc(F)cc(F)c43)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: CS(=O)Cc1cccc2c(C3(C)CCOc4cc(F)cc(F)c43)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
75 mg (0.21 mmol) of the compound from Example 193 were introduced into 10 ml of dichloromethane at 0° C., 51 mg (0.21 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient).
Reaction SMILES: [Li]C(C)(C)C.[C:6]1([NH:12][C:13]2[N:14]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=[CH:16][N:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:37][O:38][C:39]1[CH:40]=[C:41]([CH:45]=[C:46]([O:50][CH3:51])[C:47]=1[O:48][CH3:49])[C:42](Cl)=[O:43]>C1COCC1>[C:6]1([NH:12][C:13]2[N:14]([C:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:15]=[C:16]([C:42]([C:41]3[CH:45]=[C:46]([O:50][CH3:51])[C:47]([O:48][CH3:49])=[C:39]([O:38][CH3:37])[CH:40]=3)=[O:43])[N:17]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: c1ccc(Nc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c(Nc3ccccc3)n2)cc(OC)c1OC
Reaction time: 8 h
Yield: 43.6 %

Procedure:
At −78° C., t-BuLi in THF (1.7 M, 0.34 mL, 0.58 mmol) was added to a solution of trityl protected compound (d) (116 mg, 0.289 mmol) in THF. Then 3,4,5-trimethoxybenzoyl chloride (66.5 mg, 0.289 mmol) was added and stirred overnight. The reaction mixture was quenched with saturated NR4Cl, and dried with MgSO4. Filtration and evaporation of the solvent followed by chromatography afforded compound (e) (75 mg, 43.7%). 1H NMR (500 MHz, CDCl3) δ 7.55-7.41 (m, 5H), 7.32 (s, 1H), 7.28-7.18 (m, 15H), 6.94 (s, 2H), 3.78 (s, 6H), 3.70 (s, 3H). MS: 594.2 (M−H)−; 596.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]([NH2:14])=[O:13])=[CH:6][CH:5]=1.[Cl:17][CH:18](Cl)[C:19](=O)[CH3:20]>C1(C)C=CC=CC=1>[Cl:17][CH2:18][C:19]1[N:14]=[C:12]([CH:11]=[CH:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:15])([F:16])[F:1])=[CH:9][CH:8]=2)[O:13][CH:20]=1
Reactant: NC(=O)C=Cc1ccc(OC(F)(F)F)cc1
Reactant: CC(=O)C(Cl)Cl
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc(C=Cc2nc(CCl)co2)cc1

Procedure:
4.28 g (18.5 mmol) 3-(4-Trifluoromethoxy-phenyl)-acrylamide, 2.80 g (22.2 mmol) dichloro acetone and 30.0 ml toluene were kept at reflux temperature for 16 h with continuous removal of water by use of a Dean-Stark trap. After removal of solvents in vacuo, the residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 20:1). All fractions containing the product were concentrated to a volume of 10 ml and the crystallized material isolated by filtration, washed with cold heptane and dried. 1.75 g (31%) 4-Chloromethyl-2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazole.
Reaction SMILES: Br[C:2]1[C:3]([O:31][CH3:32])=[C:4]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:21][CH2:22]3)=[CH:18][CH:17]=2)[CH:5]=[C:6]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:9]2=[O:15])[CH:7]=1.[O:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1>>[O:15]=[C:9]1[NH:10][C:11](=[O:14])[CH:12]=[CH:13][N:8]1[C:6]1[CH:7]=[C:2]([C:35]2[CH:36]=[CH:37][O:33][CH:34]=2)[C:3]([O:31][CH3:32])=[C:4]([C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:21][CH2:22]3)=[CH:18][CH:17]=2)[CH:5]=1
Reactant: COc1c(Br)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2c(c1)CC=C2CNS(C)(=O)=O
Reactant: OB(O)c1ccoc1
Product: COc1c(-c2ccoc2)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2c(c1)CC=C2CNS(C)(=O)=O
Yield: 45 %

Procedure:
The product from Example 63, Part A (25.9 mg, 0.050 mmol) was reacted with furan-3-yl boronic acid (7.2 mg, 0.064 mmol) as described in Example 63, Part B to give the title compound as an off-white solid (10.6 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ 11.46 (s, 1H) 7.84 (d, J=8.09 Hz, 1H) 7.80 (t, J=1.84 Hz, 1H) 7.68-7.75 (m, 2H) 7.54-7.64 (m, 2H) 7.50 (t, J=6.07 Hz, 1H) 7.35 (d, J=2.57 Hz, 1H) 7.08 (d, J=1.47 Hz, 1H) 6.57 (s, 1H) 5.68 (d, J=8.09 Hz, 1H) 3.47 (s, 2H) 3.30 (s, 3H) 2.96 (s, 3H).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][NH2:21])[CH:14]=1>C(O)C>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:21][CH2:20][CH2:19][C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1)=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NCCc1cccnc1
Solvent: CCO
Product: Nc1ccccc1C(=O)NCCc1cccnc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of 4.89 g of isatoic anhydride, 3.66 g of 2-(3-pyridinyl)ethylamine and 40 ml of ethanol was stirred at room temperature for 22 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and cooled. The desired product was isolated by filtration, mp 126°-128° C.
Reaction SMILES: [CH3:1][O:2][C:3]1C=C(O)[CH:6]=[CH:7][CH:8]=1.[CH2:10]([O:12][C:13](=[O:28])[C:14]([C:26]#[N:27])=[CH:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[CH:17]=1)[CH3:11]>>[C:26]([C:14]1[C:13](=[O:28])[O:12][C:10]2[C:6]([C:15]=1[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[CH:17]=1)=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:11]=2)#[N:27]
Reactant: CCOC(=O)C(C#N)=Cc1cc(OC)cc(OC)c1
Reactant: COc1cccc(O)c1
Product: COc1cc(OC)cc(-c2c(C#N)c(=O)oc3cc(OC)ccc23)c1
Yield: 4.2 %

Procedure:
The title compound was prepared from 3-methoxyphenol and 2-cyano-3-(3,5-dimethoxy-phenyl)-acrylic acid ethyl ester by a procedure similar to that described for Example 1 in 4.2% yield. 1H NMR (CDCl3): 7.36 (d, J=9.0, 1H), 6.89-6.83 (m, 2H), 6.65-6.63 (m, 1H), 6.55-6.54 (m, 2H), 3.93 (s, 3H), 3.85 (s, 6H).
Reaction SMILES: C([O:8][C:9]1[C:14]([N:15]([CH2:20][CH3:21])[S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][N:12]2[N:22]=[C:23]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:24]([C:25]([NH:27][CH3:28])=[O:26])=[C:11]2[CH:10]=1)C1C=CC=CC=1.B(Cl)(Cl)Cl>ClCCl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:20]([N:15]([C:14]1[C:9]([OH:8])=[CH:10][C:11]2[N:12]([N:22]=[C:23]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[C:24]=2[C:25]([NH:27][CH3:28])=[O:26])[CH:13]=1)[S:16]([CH3:19])(=[O:17])=[O:18])[CH3:21]
Reactant: CCN(c1cn2nc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1OCc1ccccc1)S(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: CCN(c1cn2nc(-c3ccc(F)cc3)c(C(=O)NC)c2cc1O)S(C)(=O)=O
Temperature: -78 °C
Reaction time: 14 h

Procedure:
5-(Benzyloxy)-6-(N-ethylmethylsulfonamido)-2-(4-fluorophenyl)-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide (2.5 g, 5 mmol, 1 eq) was dissolved in dichloromethane and cooled to −78° C. Tetrabutylammonium iodide (0.19 g, 0.5 mmol, 0.1 eq) was added to the above mixture followed by slow dropwise addition of BCl3 (25 ml) at −78° C. The above solution was stirred at room temperature for 14 h. The solution was quenched with 10% sodium bicarbonate solution and the product was extracted with dichloromethane. The dichloromethane solution was evaporated to get off-brown solid. Yield: 1.6 g (79%). 1HNMR (400 MHz, DMSO-d6): δ 1.08 (t, J=7.14 Hz, 3H), 2.71 (d, J=4.52 Hz, 3H), 3.11 (s, 3H), 3.62 (q, J=6.92 Hz, 2H), 7.14 (s, 1H), 7.30 (t, J=8.86 Hz, 2H), 7.57 (d, J=4.56 Hz, 1H), 7.81-7.82 (m, 2H), 8.72 (s, 1H), 11.32 (br s, 1H). LCMS: (ES+) m/z=407.0 (M+H).
Reaction SMILES: [CH:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10]([O-])=[O:11])=[CH:8][C:7]=2[C:15]([F:18])([F:17])[F:16])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[BH4-].Cl>O1CCOCC1>[CH:1]1([C:6]2[CH:14]=[CH:13][C:9]([CH2:10][OH:11])=[CH:8][C:7]=2[C:15]([F:16])([F:17])[F:18])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C([O-])c1ccc(C2CCCC2)c(C(F)(F)F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1COCCO1
Product: OCc1ccc(C2CCCC2)c(C(F)(F)F)c1
Temperature: 85.5 °C
Reaction time: 5.5 h
Yield: 54.7 %

Procedure:
To a solution of 4-cyclopentyl-3-(trifluoromethyl)benzoat (224 g, 823 mmol) in 1,4-dioxane (600 mL), LiBH4 (494 mL, 987 mmol, 2 M solution in THF) was added dropwise at 22° C. The resulting suspension was stirred at 85.5° C. for 5.5 h. The dark brown solution was cooled to 0° C. and the pH adjusted to 5 by slowly adding 6 N HCl (130 mL). The layers were separated and to the aqueous phase H2O (250 mL) and NaCl (20 g) were added. The combined aqueous layers were extracted with EtOAc (2×250 mL). The EtOAc layer was added to the previously separated organic phase and the combined organics were concentrated under reduced pressure. The resulting suspension was filtered through a pad of Celite®/Na2SO4 and the solids were washed with EtOAc (3×400 mL). The combined organics were rotary evaporated and the dark brown oily residue was subjected to chromatography on silica to give the title compound as colorless liquid (110 g). LCMS m/z=243.3 [M−H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.67-1.55 (m, 2H), 1.82-1.69 (m, 2H), 1.95-1.83 (m, 2H), 2.19-2.04 (m, 2H), 3.39 (quintet, J=8.0 Hz, 1H), 4.72 (s, 2H), 7.55-7.46 (m, 2H), 7.62 (s, 1H).