Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH2:21]([Sn](CCCC)(CCCC)C=C)[CH2:22]CC>C1(C)C=CC=CC=1>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([S:11]([N:6]2[C:7]3[C:3](=[C:2]([CH:21]=[CH2:22])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:5]2)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Br)cccc32)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cccc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Temperature: 110 °C
Reaction time: 24 h
Yield: 76.7 %

Procedure:
4-bromo-1-[(4-methylphenyl)sulfonyl]-1H-indole (600 mg, 1.71 mmol; Intermediate 3), tributyl(vinyl)stannane (0.550 mL, 1.88 mmol) and Pd(PPh3)2OAc2 (32 mg, 0.043 mmol) were mixed in dry toluene (8 mL) and stirred 24 h at 110° C. using a STEM block, then rt. for 40 h. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (20% DCM in hexane-50% DCM in hexane). This afforded the title compound 390 mg, 77% as a colorless sticky oil. MS (ESI+) for C17H15NO2S m/z 298 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][CH:19]([NH2:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:24](O)(=O)C>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[CH2:24][NH:21][CH:19]([CH3:20])[CH2:18][C:12]2=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(N)Cc1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: CC(=O)O
Agent: C=O
Solvent: CCO
Product: CC1Cc2c([nH]c3ccc(OCc4ccccc4)cc23)CN1
Temperature: 80 °C
Yield: 65.1 %

Procedure:
A mixture of 2-(5-benzyloxy-1H-indol-3-yl)-1-methyl-ethylamine (58 mg, 0.21 mmol), 37% formaldehyde (17 uL, 0.23 mmol) and ethanol (2 ml) was heated in a sealed tube at 80° C. for 2 h. The mixture was cooled to rt and acetic acid (60.6 uL, 1.05 mmol) was added. The mixture was heated again in a sealed tube at 80° C. for 5 h. Evaporation of volatiles yielded 6-benzyloxy-3-methyl-2,3,4,9-tetrahydro-1H-β-carboline (40 mg).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].[N+:28]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)([O-:30])=[O:29]>CN(C=O)C.O>[CH3:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:37][C:34]1[CH:35]=[CH:36][C:31]([N+:28]([O-:30])=[O:29])=[CH:32][CH:33]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCCOCCOc1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 94.7 %

Procedure:
To a stirred solution of 16 (1.83 g, 5.75 mmol) in anhydrous DMF (10 mL) were added K2CO3 (2.39 g, 17.3 mmol) and 4-nitrophenol (0.78 g, 5.59 mmol), and the reaction mixture was heated to 80° C. for 16 h. After cooling, the mixture was diluted in water, extracted three times with DCM, and then dried over MgSO4. The filtrate was concentrated under reduced pressure to give an oily residue, which was purified by flash chromatography over silica gel with Hex/EtOAc (1:2) to afford 17 as a yellow oil (1.51 g, 92%): 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J=9.1 Hz, 2H), 6.97 (d, J=9.1 Hz, 2H), 4.26-3.65 (m, 12H), 3.37 (s, 3H).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=O)=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.Cl.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:32][O:33][C:34]2[CH:35]=[C:36]([NH2:39])[NH:37][N:38]=2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1.C[Al](C)C.C1(C)C=CC=CC=1>>[CH:1]1([N:4]2[CH2:5][CH2:6][N:7]([C:10]3[CH:11]=[CH:12][C:13]([C:14]([NH:39][C:36]4[NH:37][N:38]=[C:34]([O:33][CH2:32][C:26]5[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=[C:24]([O:23][CH3:22])[CH:25]=5)[CH:35]=4)=[O:16])=[CH:19][CH:20]=3)[CH2:8][CH2:9]2)[CH2:2][CH2:3]1
Reactant: COc1cc(COc2cc(N)[nH]n2)cc(OC)c1
Reactant: CCOC(=O)c1ccc(N2CCN(C3CC3)CC2)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1cc(COc2cc(NC(=O)c3ccc(N4CCN(C5CC5)CC4)cc3)[nH]n2)cc(OC)c1
Yield: 3.8 %

Procedure:
4-(4-Cyclopropylpiperazin-1-yl)-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]benzamide was prepared following the procedure as outlined for Example 100, starting from ethyl 4-(4-cyclopropylpiperazin-1-yl)benzoate (0.329 g, 1.2 mmol), 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine hydrochloride (0.343 g, 1.20 mmol) and 2M trimethylaluminium in toluene (1.500 mL, 3.00 mmol). The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.022 g, 3.84%) as a white solid. 1H NMR (500.13 MHz, DMSOd6) δ 0.34-0.40 (2H, m), 0.45-0.50 (2H, m), 1.67-1.75 (1H, m), 2.67-2.73 (4H, m), 3.24-3.32 (4H, m), 3.78 (6H, s), 5.08 (2H, s), 5.68 (1H, s), 6.42-6.46 (1H, m), 6.58-6.61 (2H, m), 6.95 (2H, d), 7.83 (2H, d), 10.30 (1H, s), 11.01 (1H, s). MS: m/z 478 (MH+).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]2[CH:13]=[CH:12][N:11]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:6]=2[C:7](=[O:10])[NH:8][CH:9]=1.I[CH3:25].O>CN(C)C=O>[Br:3][C:4]1[C:5]2[CH:13]=[CH:12][N:11]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:6]=2[C:7](=[O:10])[N:8]([CH3:25])[CH:9]=1
Reactant: CI
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Br)c[nH]c(=O)c32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Br)cn(C)c(=O)c32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
Sodium hydride (0.875 g, 36.5 mmol, 1.46 g of a 60% in oil dispersion) was added to a stirring solution of 4-bromo-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (11.2 g, 30.4 mmol) in dimethylformamide (217 mL) under nitrogen. After 30 minutes, iodomethane (2.27 mL, 36.5 mmol) was added and the solution was stirred at room temperature for 3 h. Upon addition of water (250 mL) a precipitate formed. The precipitate was collected by vacuum filtration, rinsed with water (50 mL) and dried in a vacuum oven at 55° C. overnight to provide 11.2 g of 4-bromo-6-methyl-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-one (96%).
Reaction SMILES: Cl[CH:2]([Cl:4])[CH3:3].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[S:16]1C2C(=O)[CH:22]=[CH:21][NH:20][C:19]=2[CH:18]=[CH:17]1>ClCCl>[Cl:4][C:2]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:18]=[CH:17][S:16][C:3]=12
Reactant: O=c1cc[nH]c2ccsc12
Reactant: CC(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Clc1ccnc2ccsc12

Procedure:
30 ml of dichloromethane and 20 ml of dichloroethane in 250 ml round bottom flask were added with dimethylformamide (1.8 ml, 23.28 mmol) and oxalylchloride (2.9 ml, 33.86 mmol) was slowly dropped to the mixture at 0° C. After 4H-thieno[3,2-b]pyridine-7-one (1.6 g, 10.58 mmol) was added, the mixture was refluxed for 6 hours. After lowering the temperature to room temperature, the title compound of yellowish solid (1.7 g, 90%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].Cl.[C:47]([N:49]=[C:50]([NH2:52])[NH2:51])#N.C(=O)([O-])O.[Na+]>O>[NH:49]([C:47]1[NH:1][C:2]2[C:3]([C:4]([NH:6][C:7]3[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=4[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[O:28])=[O:12])=[CH:9][C:8]=3[O:39][CH3:40])=[O:5])=[CH:41][CH:42]=[CH:43][C:44]=2[N:45]=1)[C:50]([NH2:52])=[NH:51]
Reactant: N#CN=C(N)N
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2nc(NC(=N)N)[nH]c12
Yield: 45.1 %

Procedure:
To a suspension of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (200 mg) in water (5 ml) was added 1N hydrochloric acid (1.3 ml) and then dicyandiamide (545 mg) was added to the stirred reaction mixture. The solution was heated under reflux for 24 hours. After cooling, aqueous sodium hydrogen carbonate was added to the mixture and extracted with ethyl acetate. The extract was washed with brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (SiO2, 30 g, 15% methanol in chloroform) to give 4-[2-guanidinobenzimidazol-4-yl]carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (100 mg) as yellow amorphous.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]([OH:15])=[O:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][CH:6]=2.[CH3:16]C1C=CC(S(O)(=O)=O)=CC=1.C(OC)(OC)OC.C([O-])(O)=O.[Na+]>CO.OS(O)(=O)=O>[OH:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[CH:7][CH:6]=2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)c1cc2cccc(O)c2cc1O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: COC(=O)c1cc2cccc(O)c2cc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 4404.1 %

Procedure:
To a solution of 3,5-dihydroxy-2-naphthoic acid (5.05 g) in MeOH (100 mL) was added TsOH (93 mg). Tho reaction mixture was stirred at reflux for 18 hours and then CH(OMe)3 (1 mL) was added. The reaction mixture was stirred at reflux for an additional 5 hours, at which point H2SO4 (10 drops) was added. After an additional 18 h, the reaction mixture was cooled to rt, poured into saturated aqueous NaHCO3 and extracted with EtOAc. The extract was dried over MgSO4 and concentrated in vacuo to give the title compound as a yellow-white solid (5.19 g, 96%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@@H:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+].[NH2:29]O.Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@@H:13]([C:15]3[O:22][NH:29][C:17](=[O:18])[CH:16]=3)[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(F)c(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(F)c(F)c1
Temperature: -40 °C
Reaction time: 0.67 h
Yield: 71.2 %

Procedure:
Cis-methyl 2-(3,4-difluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (5.23 g, 14.16 mmol) was dissolved in MeOH (50 mL) and cooled to −40° C. Sodium hydroxide (3.73 mL, 14.16 mmol) dissolved in water (5.00 mL) was added and the reaction stirred at −40° C. for 40 min. Hydroxylamine (0.868 mL, 14.16 mmol) was added and stirring continued for 3.5 h at −40° C. The reaction mixture was then added to a prewarmed 80° C. solution of 6 M hydrogen chloride (73.2 mL, 438.95 mmol) and stirred for 20 min. The solvent was concentrated in vacuo. DCM (200 mL) and water (150 mL) were added, shaken and the phases separated. The aqueous phase was extracted with DCM (150 mL). The combined organic phases were dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 20-60% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. Cis-methyl 2-(3,4-difluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (3.41 g, 71.2%) was isolated as a white solid. 1H NMR (600 MHz, CDCl3) δ 1.81-1.88 (m, 1H), 2.08-2.18 (m, 1H), 2.19-2.28 (m, 1H), 2.30-2.38 (m, 1H), 3.02-3.11 (m, 1H), 3.32-3.40 (m, 1H), 3.67 (s, 3H), 4.09-4.18 (m, 1H), 5.02-5.08 (m, 1H), 5.56 (s, 1H), 6.86-6.92 (m, 1H), 6.95-7.01 (m, 1H), 7.03-7.10 (m, 1H). MS m/z 339 (M+H)+.
Reaction SMILES: C(O[C:4]1[CH2:8][CH:7]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:6][N:5]=1)C.Cl.[NH2:20][NH:21][C:22]([NH2:24])=[S:23]>C(O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][S:9][CH:7]2[CH2:6][NH:5][C:4](=[N:20][NH:21][C:22]([NH2:24])=[S:23])[CH2:8]2)=[CH:12][CH:13]=1
Reactant: NNC(N)=S
Reactant: CCOC1=NCC(SCc2ccc(OC)cc2)C1
Agent: Cl
Solvent: CCO
Product: COc1ccc(CSC2CNC(=NNC(N)=S)C2)cc1
Yield: 21.8 %

Procedure:
A solution of 2-ethoxy-4-p-methoxybenzylthio-1-pyrroline (900 mg) and thiosemicarbazide hydrochloride (433 mg) in ethanol (30 ml) was refluxed under heating for 1.5 hours. The reaction solution was evaporated to dryness under reduced pressure, then the residue was distributed between ethyl acetate and 5% aqueous solution of sodium hydroxide and the organic phase was dried over Na2SO4 before the solvent was distilled off under reduced pressure. The resultant residue was passed through a column packed with 25 g of silica gel and eluted with ethyl acetate and thus 230 mg of the objective compound was obtained as colorless foam.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[C:16]([C:24](=[O:26])[CH3:25])[CH:17]=[CH:18][C:19]=2[S:20]([CH3:23])(=[O:22])=[O:21])[C:3]=1[CH3:27].[O:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[C:36]([NH2:40])[CH:37]=[N:38][CH:39]=2)[CH2:30][CH2:29]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:40][C:36]1[CH:37]=[N:38][CH:39]=[C:34]([N:31]3[CH2:32][CH2:33][O:28][CH2:29][CH2:30]3)[CH:35]=1)=[C:3]([CH3:27])[C:4]([C:14]1[CH:15]=[C:16]([C:24](=[O:26])[CH3:25])[CH:17]=[CH:18][C:19]=1[S:20]([CH3:23])(=[O:21])=[O:22])=[N:5]2
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: CC(=O)c1ccc(S(C)(=O)=O)c(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(S(C)(=O)=O)c(-c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)c1

Procedure:
Essentially prepared according to Procedure H using 1-(3-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-4-(methylsulfonyl)phenyl)ethanone (150.0 mg, 0.35 mmol) and 5-morpholinopyridin-3-amine in toluene to give 1-(3-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)-4-(methylsulfonyl)-phenyl)ethanone. 1H NMR (CDCl3) δ ppm 8.17-8.35 (3H, m), 7.94-8.13 (2H, m), 7.76 (1H, s), 7.54-7.66 (1H, m), 7.17 (1H, ddd, J=13.0, 8.5, 2.4 Hz), 6.73 (1H, s), 3.72-3.88 (4H, m), 3.18-3.33 (4H, m), 3.10 (3H, s), 2.70 (3H, s), 1.96 (3H, s). Mass Spectrum (ESI) m/e=553.2 (M+1).
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:18][CH:19]=[C:20]([C:22]([O:24]C)=[O:23])[N:21]=3)=[CH:13][CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1COCC1.[OH-].[Na+]>CO>[N:1]1([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:18][CH:19]=[C:20]([C:22]([OH:24])=[O:23])[N:21]=3)=[CH:15][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1coc(-c2ccc(Cn3ccc4ccccc43)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1coc(-c2ccc(Cn3ccc4ccccc43)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
A solution of methyl 2-[4-(1H-indol-1-ylmethyl)phenyl]-1,3-oxazole-4-carboxylate (1.52 g; 4.57 mmol) in (1:1) MeOH:THF was treated with sodium hydroxide (4.57 g, 4.57 mmol) stirred at room temperature overnight and concentrated under reduced pressure. The resultant concentrate was diluted with 1N sodium hydroxide (50 mL), washed with EtOAc, acidified with concentrated HCl and extracted with EtOAc. The extracts were combined, dried over MgSO4 and concentrated to dryness to give the title product in 91% yield, identified by NMR and mass spectral analyses. LCMS (ESI−) 317 (MH−).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]([C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:12][CH:11]=1)[C:6]([O:8]C)=[O:7])[CH3:3].[OH-].[K+:24]>C1COCC1.CO>[C:17]([O:16][C:14]([C:13]1[CH:21]=[CH:22][C:10]([CH:5]([CH2:4][N:2]([CH3:3])[CH3:1])[C:6]([O-:8])=[O:7])=[CH:11][CH:12]=1)=[O:15])([CH3:19])([CH3:18])[CH3:20].[K+:24]
Reactant: COC(=O)C(CN(C)C)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CC(C(=O)[O-])c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-{1-[(dimethylamino)methyl]-2-methoxy-2-oxoethyl}benzoate (859 mg, 2.79 mmol) in THF (9 mL) and MeOH (3 mL) was added KOH (1N, 2.93 mL, 2.93 mmol). The reaction was stirred at room temperature for 30 minutes. An additional 100 μL of 1N KOH was added, and the solution was stirred for another 30 minutes. Concentration of the reaction mixture to dryness yielded potassium 2-[4-(tert-butoxycarbonyl)phenyl]-3-(dimethylamino)propanoate as a white solid that was carried on without purification. MS (EST) calcd [M+H]+ 294.1, found 294.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([F:22])=[CH:20][C:19]([Cl:23])=[CH:18][N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2ncc(Cl)cc2F)c1-c1ccc(Cl)cc1
Product: Cc1nnc(Cl)c(-c2ncc(Cl)cc2F)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 69.7 %

Procedure:
0.3 g of 5-(4-chlorophenyl)-4-(5-chloro-3-fluoro-2-pyridyl)-6-methyl-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed. The mixture was stirred for 1.5 hours on an oil bath of 110° C. The reaction mixture was allowed to cool to room temperature, the, concentrated under reduced pressure. To the resultant residue were added ethyl acetate and ice-cooled sodium bicarbonate water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-separated. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 0.3 g of the resultant residue was subjected to silica gel column chromatography, to obtain 0.22 g of 3-chloro-5-(4-chlorophenyl)-4-(5-chloro-3-fluoro-2-pyridyl)-6-methylpyridazine (hereinafter, described as compound (14) of the present invention.).
Reaction SMILES: C(O[C:4]([N:6]1[CH2:18][C@H:17]2[C@H:9]([CH2:10][C:11]3[C:16]2=[CH:15][C:14]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][C:12]=3[CH3:27])[CH2:8][CH2:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:20]([NH:19][C:14]1[CH:15]=[C:16]2[C:11](=[C:12]([CH3:27])[CH:13]=1)[CH2:10][C@H:9]1[C@@H:17]2[CH2:18][N:6]([CH3:4])[CH2:7][CH2:8]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)N1CC[C@H]2Cc3c(C)cc(NCc4ccccc4)cc3[C@H]2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(NCc2ccccc2)cc2c1C[C@@H]1CCN(C)C[C@H]21
Yield: 8.9 %

Procedure:
The title compound (5.0 mg, 0.016 mmol) was prepared by following the procedure of step B of example 17 from crude cis-6-benzylamino-8-methyl-1,2,4,4a,9,9a-hexahydro-3-aza-fluorene-3-carboxylic acid ethyl ester (66 mg, 0.18 mmol) and LiAlH4 (27 mg, 0.73 mmol) in THF (1 mL): MS (ES) 307.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2([C:31](O)=[O:32])[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH:34][NH:35]C(C1CCN(CC2C=CC(C3C=CC=CN=3)=CC=2)C(S(C2C=CC(OC)=CC=2)(=O)=O)C1)=O>>[OH:34][NH:35][C:31]([C:12]1([S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:10])=[O:11])[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:23][CH:24]=2)[CH2:14][CH2:13]1)=[O:32]
Reactant: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(-c4ccccn4)cc3)CC2)cc1
Reactant: COc1ccc(S(=O)(=O)C2CC(C(=O)NO)CCN2Cc2ccc(-c3ccccn3)cc2)cc1
Product: COc1ccc(S(=O)(=O)C2(C(=O)NO)CCN(Cc3ccc(-c4ccccn4)cc3)CC2)cc1
Yield: 33 %

Procedure:
Starting from 4-(4-methoxy-benzenesulfonyl)-1-(4pyridin-2-yl-benzyl)-piperidine-4-carboxylic acid (1.32 g, 2.83 mmol) and following the procedure outlined in example 83, 480 mg of 4-(4-methoxy-benzenesulfonyl-1-(4pyridin-2-yl-benzyl)-piperidine-4-carboxylic acid hydroxyamide was isolated as a HCl salt, a white powder. Yield 33%; mp 214° C.; MS: 482.0 (M+H)+; 1H NMR (300 MHz, DMSO-d6): δ2.30 (m, 2H), 2.80 (m, 2H), 3.42 (d, J=12.5 Hz, 2H), 3.75 (m, 2H), 3.88 (s, 3H), 4.36 (s, 2H), 7.15 (d, J=8.9 Hz, 2H), 7.59-7.74 (m, 4H), 7.84-7.95 (m, 3H), 8.55 (d, J=8.1 Hz, 1H), 8.79 (s, 1H), 9.14 (s, 1H), 10.68 (s, 1H), 11.17 (s, 1H)
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]([C:12]1[S:13][C:14]([S:32][CH3:33])=[C:15]([S:17]([C:20]2[CH:25]=[C:24]([O:26]C(C)(C)C)[CH:23]=[C:22]([Br:31])[CH:21]=2)(=[O:19])=[O:18])[CH:16]=1)=[O:11]>C(Cl)Cl>[CH3:8][O:9][C:10]([C:12]1[S:13][C:14]([S:32][CH3:33])=[C:15]([S:17]([C:20]2[CH:25]=[C:24]([OH:26])[CH:23]=[C:22]([Br:31])[CH:21]=2)(=[O:18])=[O:19])[CH:16]=1)=[O:11]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cc(Br)cc(OC(C)(C)C)c2)c(SC)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(S(=O)(=O)c2cc(O)cc(Br)c2)c(SC)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of 4-(3-bromo-5-tert-butoxy-benzenesulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester ((Example 12: step c) 240 mg, 0.5 mmol) in DCM (5 mL). The solution was stirred at rt for 2 h and the solvents were removed in vacuo, yielding 214 mg of an oil (quantitative) which was used without further purification.
Reaction SMILES: F[C:2](F)(F)C(O)=O.NN=CNC1C=C(C(NCC([NH:24][CH:25]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[CH2:26][C:27]([OH:29])=[O:28])=O)=O)C=CC=1.[ClH:40].O1CCOCC1>CO>[ClH:40].[NH2:24][CH:25]([C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1)[CH2:26][C:27]([O:29][CH3:2])=[O:28]
Reactant: NN=CNc1cccc(C(=O)NCC(=O)NC(CC(=O)O)c2ccc3ccccc3c2)c1
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)CC(N)c1ccc2ccccc2c1
Reaction time: 8 h

Procedure:
A suspension of the product of Step A (2.5 g) in methanol (100 ml) was treated with 4N HCl/dioxane (10 ml). The resulting solution was stirred overnight. The excess solvent was removed under reduced pressure and the semi solid was purified by HPLC (RP--CH3CN/H2O). The solid was dissolved in CH3CN/H2O, treated with 20% aqueous HCl (5 ml) and lyophilized to give methyl β-aminonaphthalene-2-propanoate hydrochloride (1.1 g). MS and 1H-NMR were consistent with the structure.