Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6].[Cl:9][C:10]1[C:11]([F:35])=[N:12][C:13](NCC(OC)=O)=[C:14]([Cl:28])[C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23]C)=[C:19]([CH:25]([CH3:27])[CH3:26])[CH:18]=1>>[Cl:9][C:10]1[C:11]([F:35])=[N:12][C:13]([NH:1][CH2:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6])=[C:14]([Cl:28])[C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH:25]([CH3:27])[CH3:26])[CH:18]=1
Reactant: COC(=O)CNc1nc(F)c(Cl)c(Oc2ccc(OC)c(C(C)C)c2)c1Cl
Reactant: NCCCS(=O)(=O)O
Product: CC(C)c1cc(Oc2c(Cl)c(F)nc(NCCCS(=O)(=O)O)c2Cl)ccc1O

Procedure:
By use of 3-aminopropylsulfonic acid in place of glycine methyl ester ester for the preparation of Compound 1e followed by deprotection as described for example 2.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[CH:10]1([CH2:15]/[CH:16]=[CH:17]/B2OC(C)(C)C(C)(C)O2)[CH2:14][CH2:13][CH2:12][CH2:11]1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[CH:10]1([CH2:15]/[CH:16]=[CH:17]/[C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CC1(C)OB(/C=C/CC2CCCC2)OC1(C)C
Reactant: Nc1ccc(Br)cc1F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(/C=C/CC2CCCC2)cc1F
Temperature: 100 °C
Reaction time: 6 h
Yield: 91.8 %

Procedure:
1,4-Dioxane (5 mL) and water (1.2 mL) were added to 4-bromo-2-fluoroaniline (285 mg, 1.50 mmol), trans-3-(cyclopentyl)propenylboronic acid pinacol ester (425 mg, 1.80 mmol), tris(dibenzylidene acetone)dipalladium (137 mg, 0.15 mmol), tri-2-furylphosphine (210 mg, 0.90 mmol) and cesium carbonate (976 mg, 3.00 mmol). The mixture was heated to an external temperature of 100° C. and stirred for 6 hr, under a nitrogen atmosphere. After cooling, the mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous magnesium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane only→hexane:ethyl acetate=9:1) to afford the title compound as a pale yellow oil (302 mg).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[N:3]1[CH2:12][CH:13]=O.[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:25][N:26]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([CH2:25][N:26]([CH:34]3[CH2:39][CH2:38][N:37]([CH2:13][CH2:12][N:3]4[C:4]5[C:9](=[N:8][CH:7]=[CH:6][CH:5]=5)[CH:10]=[CH:11][C:2]4=[O:1])[CH2:36][CH2:35]3)[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)ccc2ncccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3ncccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
To a solution of 0.62 g of (2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde in 20 mL of dichloromethane, 1.5 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 0.19 mL of acetic acid were added, and the mixture was stirred at room temperature for 30 minutes, and then 1.0 g of sodium triacetoxyborohydride was added to the reaction mixture, and the mixture was stirred at room temperature for 4 days. Thereto were added water, a saturated aqueous sodium hydrogen carbonate solution and chloroform, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=75:1 to obtain 0.70 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a light brown oily substance.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([C:15]([O:17]CC)=[O:16])[N:14]=3)[CH:11]=2)=[CH:2]1.CC(C)(OC(NC1N=C(C2C=CC3N(C=C(C(O)=O)N=3)C=2)C=CC=1)=O)C>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([C:15]([OH:17])=[O:16])[N:14]=3)[CH:11]=2)=[CH:2]1
Reactant: CCOC(=O)c1cn2cc(-c3ccoc3)ccc2n1
Agent: CC(C)(C)OC(=O)Nc1cccc(-c2ccc3nc(C(=O)O)cn3c2)n1
Product: O=C(O)c1cn2cc(-c3ccoc3)ccc2n1
Yield: 83.9 %

Procedure:
384 mg of ethyl 6-(furan-3-yl)imidazo[1,2-a]pyridine-2-carboxylate are saponified under conditions similar to those described for the preparation of Intermediate 11 (step 11.3) to give 287 mg of 6-(furan-3-yl)imidazo[1,2-a]pyridine-2-carboxylic acid.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[N:22][C:21]([C:24](=[NH:26])[NH2:25])=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.O.[OH-].[Li+].Cl>C1COCC1.CO.O>[C:24]([C:21]1[N:22]=[CH:23][C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:27])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[N:19][CH:20]=1)(=[NH:25])[NH2:26]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cnc(C(=N)N)cn3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2cnc(C(=N)N)cn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.7 %

Procedure:
[6-(5-Carbamimidoyl-pyrazin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (77 mg, 0.21 mmol) was dissolved in THF (3 mL) and methanol (1.2 mL). To this was added lithium hydroxide monohydrate (70 mg, 1.7 mmol) in water (1.2 mL) at 0° C. The reaction was warmed up to room temperature and stirred for 4 h. The reaction mixture was acidified to pH 3 with aqueous HCl (6 N). The solvent was removed. Prep-HPLC separation (C18 column) of the reaction mixture gave the title compound (35 mg, 49%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 8.42 (1H, s), 8.20 (1H, s), 6.85 (1H, s), 6.65 (1H, s), 5.18 (1H, dd), 2.64 (1H, dd), 2.16 (3H, s), 2.15 (1H, m). MS found (electrospray): (M+H)+=343.2.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[CH:28][C:21]=12)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:38](Cl)(=[O:40])[CH3:39]>O1CCCC1>[C:38]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[CH:28][C:21]=12)=[O:13])(=[O:40])[CH3:39]
Reactant: O=C(NCCNCc1ccccc1)c1sccc1Nc1ccnc2[nH]ccc12
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(CCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12)Cc1ccccc1
Yield: 24 %

Procedure:
A solution of 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-benzylamino-ethyl)-amide (95 mg, 0.24 mmol), diisopropylethylamine (84 uL, 0.49 mmol) and acetyl chloride (25 uL, 0.37 mmol) in tetrahydrofuran (2.0 mL) was stirred at room temperature for 18 h. The solution was concentrated in vacuo then purified by ISCO Companion (silica, 10% methanol, methylene chloride, 1% ammonium hydroxide) to afford 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(acetyl-benzyl-amino)-ethyl]-amide (25 mg, 24%). LCMS (ESI) 434 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (1H, br. s.) 10.16-10.43 (1H, m) 8.15 (0H, t, J=5.00 Hz) 8.02 (1H, t, J=2.71 Hz) 7.72-7.86 (1H, m) 7.44-7.54 (1H, m) 7.13-7.39 (6H, m) 6.83 (1H, dd, J=12.23, 5.49 Hz) 6.36-6.50 (1H, m) 4.49-4.61 (2H, m) 3.34-3.50 (4H, m) 1.91-2.19 (3H, m)
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[CH2:9]1
Reactant: c1ccc(CN2CCCC(Nc3ccc4[nH]ncc4c3)C2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: c1cc2[nH]ncc2cc1NC1CCCNC1
Yield: 73.8 %

Procedure:
To a solution of the N-(1-benzylpiperidin-3-yl)-1H-indazol-5-amine (463 mg, 1.51 mmol) obtained in Example 535 in ethanol (10 ml) were added 10% Pd—C (50 mg) and then ammonium formate (952 mg, 15.1 mmol), and the resulting mixture was heated under reflux for 2 hours. The solid was removed by filtration using Celite, and the solvent was distilled off under reduced pressure. Chloroform/aqueous ammonia was added to the residue, followed by extraction with chloroform, and the extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby N-piperidin-3-yl-1H-indazol-5-amine (241 mg, 74%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[N:7]=[C:6]2[C:22](O)=[O:23].Cl.[CH3:26][O:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[CH2:30][CH2:31][NH:32][CH2:33]2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[N:7]=[C:6]2[C:22]([N:32]1[CH2:31][CH2:30][C:29]2[C:34](=[CH:35][CH:36]=[CH:37][C:28]=2[O:27][CH3:26])[CH2:33]1)=[O:23]
Reactant: COc1cc2nc(-c3ccc(F)cc3)nc(C(=O)O)c2cc1OC
Reactant: COc1cccc2c1CCNC2
Agent: Cl
Product: COc1cc2nc(-c3ccc(F)cc3)nc(C(=O)N3CCc4c(cccc4OC)C3)c2cc1OC
Yield: 20.2 %

Procedure:
Reaction of 6,7-dimethoxy-2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 5-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 110 (20.2% yield). 1H NMR (400 MHz, DMSO-d6) δ 2.67 and 2.92 (2t, 2H), 3.51-4.09 (m, 11H), 4.47 and 4.98 (2s, 2H), 6.47-7.28 (m, 4H), 7.38-7.42 (m, 1H), 7.51-7.55 (2s, 1H), 7.59-7.63 (m, 1H), 8.15-8.20 (m, 1H), 8.30-8.35 (m, 1H); 19F (376 MHz, DMSO-d6) 6-113.0; MS (ESI) m/z 474 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([NH:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=4)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH3:42].B(Br)(Br)Br>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([NH:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=4)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH3:42]
Reactant: COc1ccc(CNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(-c4ccccc4C)c(C)c2)C3)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4ccc(O)cc4)n3Cc3ccccc32)cc1C
Temperature: 25 °C
Yield: 128.9 %

Procedure:
To a solution of 10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-N-(4-methoxybenzyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 8 (243 mg, 0.437 mmol) in dichloromethane (1.5 mL) at 0° C. under nitrogen was added a solution of boron tribromide in dichloromethane (1.0 M, 1.5 mL, 1.5 mmol) dropwise over 5 minutes. After 10 minutes at 0° C. the cooling bath was removed and the solution allowed to warm slowly to room temperature over 1.5 hours. The reaction was quenched by the addition of saturated aqueous sodium hydrogen carbonate solution (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with a saturated aqueous sodium hydrogen carbonate solution (20 mL) and brine (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a reddish oil (305 mg). Purification by flash chromatography using a solvent gradient of 0 to 2% methanol in dichloromethane gave the title compound (119 mg, 52%) as a white solid. MS [(+)ESI, m/z]: 542 [M+H]+.HRMS [(+)ESI, m/z]: 542.24405. Calcd for C35H32N3O3: 542.24437. Anal. Calcd for C35H31N3O3: C, 77.61; H, 5.77; N, 7.76. Found: C, 77.54; H, 5.79; N, 7.72.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9]([CH2:14][C@@H:15]([OH:19])[C:16]([OH:18])=[O:17])[CH:10]=[CH:11][C:12]=1[OH:13].[CH3:20]O>>[Br:6][C:7]1[CH:8]=[C:9]([CH2:14][C@@H:15]([OH:19])[C:16]([O:18][CH3:20])=[O:17])[CH:10]=[CH:11][C:12]=1[OH:13]
Reactant: O=C(O)[C@H](O)Cc1ccc(O)c(Br)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)[C@H](O)Cc1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.5 mL concentrated sulphuric acid were added to a solution of 53.6 g (154 mmol) (R)-3-(3-bromo-4-hydroxy-phenyl)-2-hydroxy-propionic acid in 250 mL MeOH and the reaction mixture was stirred for 4 h at RT. The mixture was evaporated down i.vac., the residue was taken up in 250 mL EtOAc, the organic phase was washed twice with 100 mL saturated NaHCO3 solution and saturated NaCl solution and dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was further reacted without purification.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[OH:8][CH2:9][CH2:10][N:11]1[C:15]([NH2:16])=[CH:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>C(O)=O>[OH:8][CH2:9][CH2:10][N:11]1[C:15]([NH:16][CH:1]=[O:3])=[CH:14][CH:13]=[N:12]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccnn1CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=CO
Product: O=CNc1ccnn1CCO
Temperature: 25 °C

Procedure:
A mixture of acetic anhydride (44.5 ml) and formic acid (22.3 ml) was stirred at ambient temperature for an hour. To this mixture was added 1-(2-hydroxyethyl)-5-aminopyrazole (30 g) at 0°-10° C., and the mixture was stirred under ice-cooling for 30 minutes. The mixture was poured into ice-cold water, adjusted to pH 10.5 with 40% aqueous potassium carbonate, and stirred under ice-cooling for 30 minutes. The mixture was extracted with a mixture of tetrahydrofuran and ethyl acetate 6 times. The organic layer was dried over magnesium sulfate and evaporated in vacuo to give 1-(2-hydroxyethyl)-5-formamidopyrazole (30.8 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][O:7][B:8]([OH:9])[C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:15][CH3:16].Cl>CN(C=O)C>[CH2:15]([O:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][O:7][B:8]([OH:9])[C:4]=2[CH:3]=1)[CH3:16]
Reactant: OB1OCc2ccc(O)cc21
Reactant: CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc2c(c1)B(O)OC2
Temperature: 0 °C
Reaction time: 24 h
Yield: 65.4 %

Procedure:
H181 (110 mg, 0.73 mmol) was dissolved in DMF (6.0 mL) and cooled to 0° C. with ice bath. To this solution under nitrogen were added in sequence NaH (60% in mineral oil, 117 mg, 2.93 mmol) and bromoethane (0.22 mL, 2.93 mmol). The reaction mixture was stirred for 1 d then treated with 1.0 M HCl (10.0 mL). After extraction with ethyl acetate, the organic phase was washed with water and brine, and dried over anhydrous Na2SO4. The residue after rotary evaporation was purified by column chromatography over silica gel to give the title compound (85 mg, 65% yield). 1H NMR (300 MHz, DMSO-d6): δ 9.13 (s, 1H), 7.29 (d, J=8.1 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 7.03 (dd, J=8.1 & 2.4 Hz, 1H), 4.91 (s, 2H), 4.02 (q, J=7.0 Hz, 2H) and 1.33 (t, J=7.2 Hz, 3H) ppm; Mp: 80-82° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](Cl)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:36]1(=[O:46])[C:45]2[C:40](=[CH:41][N:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][NH:37]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C@@H:6]([C:12]1[C:27]([CH3:28])=[CH:26][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:37]4[CH:38]=[CH:39][C:40]5[C:45](=[CH:44][CH:43]=[N:42][CH:41]=5)[C:36]4=[O:46])[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=c1[nH]ccc2cnccc12
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-n4ccc5cnccc5c4=O)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (26.0 mg, 0.049 mmol) in anhydrous THF (0.6 mL) was added 2,6-naphthyridin-1(2H)-one (11.0 mg, 0.074 mmol), Xantphos (4.0 mg, 0.006 mmol), Cs2CO3 (27.0 mg, 0.084 mmol) and Pd2(dba)3 (2.0 mg, 0.002 mmol). The reaction was degassed for 5 minutes with N2 and then heated at 100° C. overnight. After cooling, the reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 90% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C35H32ClN4O4S: 639.2; found: 639.3.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:32])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:31])([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)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.Cl.FC1C=CC(C(=O)CCC[N:45]2[CH2:50][CH2:49][CH:48](C(O)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:47][CH2:46]2)=CC=1.[I-].[K+]>N1CCCCC1>[OH:31][C:18]([CH:15]1[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)=[CH:3][CH:4]=2)=[O:32])[CH2:13][CH2:14]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(CCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1)c1ccc(F)cc1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: C1CCNCC1
Product: O=C(CCCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1)c1ccc(N2CCCCC2)cc1

Procedure:
A mixture of 15 g (0.035 mole) of 4'-fluoro-4-[4-(α-hydroxy-α-phenylbenzyl)piperidino]butyrophenone, the free base of the compound of Example 1, and a small amount of potassium iodide in 100 ml of piperidine was refluxed for 22 hours. The unreacted piperidine was removed under vacuum, and the remaining residue was triturated with water, the water decanted, and the residue dissolved in methanol and added to a large amount of water. The resulting precipitate was dissolved in a large volume of ether, dried over magnesium sulfate, treated with charcoal and filtered. The filtrate was concentrated to a 50 ml volume and cooled, yielding a product which was recrystallized from ether to give the title compound, M.P. 137.5°-139° C.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH2:5]1[S:9](=[O:11])(=[O:10])[O:8][CH2:7][CH2:6]1>CO>[OH:2][CH2:1][CH2:3][NH:4][CH2:7][CH2:6][CH2:5][S:9]([OH:11])(=[O:10])=[O:8]
Reactant: O=S1(=O)CCCO1
Reactant: NCCO
Solvent: CO
Product: O=S(=O)(O)CCCNCCO
Reaction time: 2 h

Procedure:
N-(β-hydroxyethyl)-3-aminopropanesulfonic acid, ##STR9## was prepared as follows: 366 parts ethanolamine and 1000 parts methanol were cooled to 10° C. in a three-necked, round-bottom flask which was fitted with a stirring bar, thermometer, and a dropping funnel. 244 parts propane sultone dissolved in 1000 parts methanol were added via the dropping funnel at such a rate that the flask temperature did not increase above 20° C. After the addition was completed, the contents of the flask were stirred for two hours, concentrated to a thick slurry, and then added to 2400 parts isopropyl alcohol. The resulting solid was filtered, rinsed with 500 parts isopropyl alcohol and dried to give 240 parts of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[CH3:13][CH:14]1[CH:19](O)[CH2:18][CH2:17][N:16]([C:21]2[N:22]=[N:23][CH:24]=[CH:25][N:26]=2)[CH2:15]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[O:12][CH:19]1[CH2:18][CH2:17][N:16]([C:21]2[N:22]=[N:23][CH:24]=[CH:25][N:26]=2)[CH2:15][CH:14]1[CH3:13]
Reactant: CC1CN(c2nccnn2)CCC1O
Reactant: Oc1cc(C(F)(F)F)ccc1Cl
Product: CC1CN(c2nccnn2)CCC1Oc1cc(C(F)(F)F)ccc1Cl

Procedure:
Compound 37 is prepared from 2-chloro-5-trifluoromethylphenol and intermediate 5c according to synthesis method 3 under the operating conditions described for example 8 (38% yield).
Reaction SMILES: [C:1]([C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][CH:25]([C:29]([O:31][CH3:32])=[O:30])[C:26](O)=[O:27])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:41][NH2:42]>ClCCl>[C:1]([C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][CH:25]([C:26]([NH:42][CH3:41])=[O:27])[C:29]([O:31][CH3:32])=[O:30])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)C(=O)O
Reactant: CN
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CNC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)C(=O)OC
Reaction time: 1 h

Procedure:
The compound obtained in Example 63 is dissolved in anhydrous dichloromethane and then 1.5 equivalents of thionyl chloride are added and the mixture is heated at reflux for 1 hour 30 minutes. The reaction mixture is then cooled using an ice bath, and 1.2 equivalents of methylamine are added via the top of the condenser. The reaction mixture is stirred for one hour and is then extracted with dichloromethane. The organic phases are washed with a sodium carbonate solution, and with water, and are then filtered, dried over magnesium sulphate and evaporated under reduced pressure. The resulting residue is purified by flash chromatography using an ethyl acetate/cyclohexane mixture as eluant. The resulting title product is recrystallised from a toluene/cyclohexane mixture.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[CH:40][N:39]=[N:38]2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[CH:40][N:39]=[N:38]2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCCC2)c(Cl)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCCC2)c(Cl)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-piperidin-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example J14) 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) according to the general procedure M. Obtained as a yellow foam (257 mg).