Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)C(C)C)C.[CH3:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14].Cl.[CH3:21][O:22][C:23]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[CH2:30][CH2:29][C@H:28]2[NH2:34])=[O:24]>C(Cl)Cl.C(OCC)(=O)C>[CH3:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:34][C@H:28]1[C:27]2[C:31](=[CH:32][CH:33]=[C:25]([C:23]([O:22][CH3:21])=[O:24])[CH:26]=2)[CH2:30][CH2:29]1)=[O:14]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1C)CC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 70 %

Procedure:
N-Ethyl-diisopropylamine (2.5 eq.) and 2-methylbenzoyl chloride (1.2 equiv.) were added to an ice-cold solution of (3R)-3-amino-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester hydrochloride (A-03 HCl) (0.88 mmol, 1 equiv.) in methylene chloride at 0° C. under an inert atmosphere and the mixture was then stirred at room temperature for 2 d. The reaction mixture was diluted with ethyl acetate and the organic phase was washed with 10% NH4Cl solution, sat. NaHCO3 solution and sat. NaCl solution. The organic phase was dried over Na2SO4 and concentrated to obtain the crude product, which was purified by column chromatography (silica, cyclohexane/ethyl acetate 4:1). Yield: 70%
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:9](=O)[CH2:8][CH2:7][CH2:6]1)=[O:4].C([O-])=O.[NH4+:14]>CO>[NH2:14][C:9]1[CH2:8][CH2:7][CH2:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)C1CCCC1=O
Reactant: [NH4+]
Agent: O=C[O-]
Solvent: CO
Product: COC(=O)C1=C(N)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a solution of 10.00 g (70.35 mmol) of methyl cyclopentanone-2-carboxylate in 100 ml of methanol, 22.18 g (351.74 mmol) of ammonium formate was added, and the resulting mixture was heated under reflux for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. To the residue, 50 ml of ethyl acetate and 30 ml of water were added, and the mixture was stirred at room temperature for 30 minutes. Then, the organic layer was separated, and the aqueous layer was extracted with 50 ml of ethyl acetate. The organic layers were combined, washed twice with each 30 ml of water and once with 30 ml of a brine successively and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was recrystallized from methanol to give the objective methyl 2-amino-1-cyclopentenecarboxylate (7.34 g, white crystals). The yield was 73.9%.
Reaction SMILES: Cl[CH:2]1[NH:7][C:6]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:10][C:5]=2[C:4](=[O:17])[N:3]1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1.[CH3:25][NH:26][CH3:27].C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([N:3]2[C:4](=[O:17])[C:5]3[S:10][CH:9]=[C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:6]=3[N:7]=[C:2]2[N:26]([CH3:27])[CH3:25])=[CH:19][CH:20]=1
Reactant: O=C1c2scc(-c3ccccc3)c2NC(Cl)N1c1ccc(Cl)cc1
Reactant: CNC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)c1nc2c(-c3ccccc3)csc2c(=O)n1-c1ccc(Cl)cc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
The thus synthesized compound 2-chloro-3-(4-chlorophenyl)-7-phenyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (22.7 mg, 0.06 mmol) was mixed with a solution of N,N-dimethylamine (3 ml) and diisopropylethylamine (0.01 ml, 0.06 mmol) in THF. The mixture was heated with stirring at 65° C. overnight. After the completion of the reaction was confirmed by TLC, the reaction mixture was cooled to room temperature and separated with water and dichloromethane. The extracted organic layer was washed with brine, dried over anhydrous MgSO4, and filtered. The filtrate was distilled under reduced pressure. The concentrate was purified by silica gel column chromatography (EtOAc:Hex=1:5) to give 14.1 mg (0.037 mmol, 62% yield) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1.[CH3:16][NH:17][C@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19].O>CS(C)=O>[CH3:11][C:8]1[N:6]2[N:7]=[C:2]([N:17]([CH3:16])[C@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2=[N:10][N:9]=1
Reactant: CN[C@@H](C)c1ccccc1
Reactant: COC(=O)c1cc(Cl)nn2c(C)nnc12
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc(N(C)[C@@H](C)c2ccccc2)nn2c(C)nnc12
Yield: 15 %

Procedure:
A solution of methyl 6-chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate (2.0 g, 8.85 mmol) and (S)-N-methyl-1-phenylethanamine (2.39 g, 17.7 mmol; commercially available from Aldrich) in DMSO (20 mL) was heated at 130° C. in a microwave tube for 30 min. Water (100 mL) was added to the reaction mixture, and the product was extracted with EtOAc (3×100 mL). The combined EtOAc layers were concentrated and the residue was purified by flash chromatography (silica gel, 1% to 10% MeOH in CH2Cl2) to give the (S)-methyl 3-methyl-6-(methyl(1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate (400 mg, 15% yield). LRMS [M+H]+: 325 m/z.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:15]=[C:14]([N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)[CH:13]=[CH:12][C:11]=1[C:21]1[N:26]=[N:25][C:24]([O:27][CH:28]2[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]2)=[CH:23][CH:22]=1.[OH-].[Na+]>C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:15]=[C:14]([N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)[CH:13]=[CH:12][C:11]=1[C:21]1[N:26]=[N:25][C:24]([O:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1
Reactant: COc1cc(-n2cccn2)ccc1-c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-n2cccn2)ccc1-c1ccc(OC2CCNCC2)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
Trifluoroacetic acid (1 mL) was added to tert-butyl 4-((6-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)pyridazin-3-yl)oxy)piperidine-1-carboxylate (0.18 g, 0.40 mmol) in DCM (3 mL) at 0° C. The reaction was stirred for 1 h at RT. The reaction mixture was added to an aqueous solution of NaOH (1 M) and the aqueous phase was extracted with chloroform/propan-2-ol (3:1). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 3-(2-methoxy-4-(1H-pyrazol-1-yl)phenyl)-6-(piperidin-4-yloxy)pyridazine (0.14 g, 100%) as a colorless solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[CH:26][CH:27]=5)[C:22]([CH2:39][C:40]([O:42]C)=[O:41])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O1CCCC1>CO>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:26][CH:27]=5)[C:22]([CH2:39][C:40]([OH:42])=[O:41])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCCOc1ccc2c(c1)c(CC(=O)OC)cn2Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1csc(-c2cc3cc(Cn4cc(CC(=O)O)c5cc(OCCCCC(=O)O)ccc54)ccc3o2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.6 %

Procedure:
A mixture of methyl 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(4-ethoxycarbonylbutoxy)indole-3-acetate (0.2 g) and 1N-sodium hydroxide (1.66 ml) in a mixed solvent of tetrahydrofuran (2 ml) and methanol (1 ml) was stirred at room temperature for 4 hours. After removal of solvents, the aqueous solution was acidified with diluted hydrochloric acid. The resulting precipitates were collected by filtration and washed with water to give 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-(4-carboxybutoxy)indole-3-acetic acid (0.15 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([Br:24])[C:15]2[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(Cl)=O)C(C)C.[CH2:33]([NH:35][CH2:36][CH3:37])[CH3:34]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([Br:24])[C:15]2[CH:16]=[CH:17][C:18]([C:21](=[O:22])[N:35]([CH2:36][CH3:37])[CH2:33][CH3:34])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)c2ccc(C(=O)O)cc2)CC1
Reactant: CCNCC
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(C(Br)=C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C

Procedure:
To a solution of compound 51 (1.0 g, 2.5 mmol) in dry dichloromethane (10 mL) at −20° C. was added iso-butylchloroformate (450 mg, 3.3 mmol). After 20 min at −20° C. diethylamine (4 mL) was added and the reaction was allowed to warm to room temperature. After 1.5 hrs the solvent was evaporated and the reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate was washed with water and brine and dried over MgSO4 and removed by evaporation. The crude product was purified by silica gel chromatography (0-60% ethyl acetate in heptanes) to give the product (compound 52) as white needles (800 mg, 73%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:19](=O)[C@@H:20]([O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[CH3:21].[C:30](OCC)(=O)C.CCCCCC>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[C:19]([C@@H:20]([O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[CH3:21])=[CH2:30]
Reactant: C[C@H](OC1CCCCO1)C(=O)c1ccc(F)cc1F
Reactant: CCOC(C)=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(c1ccc(F)cc1F)[C@H](C)OC1CCCCO1
Temperature: 8 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A mechanically stirred mixture of methyl triphenylphosphonium bromide (169.2 g, 0.474 moles) in 350 ml of dry tetrahydrofuran was cooled to 8° C. A solution of lithium bis (trimethylsilyl) amide (84.8 g, 0.507 moles) in 500 ml tetrahydrofuran was added to the above mixture at a rate so that the temperature of the mixture remained at 23° C. After stirring for 1 hour at room temperature the contents were cooled to 31 70° C. and stirred for 1/2 hour. Then a solution of compound 4a, (2S)-2',4'-Difluoro-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propiophenone, (100 g, 0.370 moles) in 250 ml of tetrahydrofuran was added slowly to maintain the temperature of the mixture below -70° C. The resulting mixture was stirred at 7° C. for 17 hours. Added 65 ml of ethyl acetate to the above mixture followed by the addition of 3.9 L of hexane and allowed to stand for 15 minutes. The solid was removed by suction-filtration and washed thoroughly with 650 ml of hexane. The filtrate was washed with 1:1 mixture of methanol: water (2×1300 ml) and brine (1300 ml) then dried over MgSO4. The solvent was evaporated to give the title compound 5a as an oil (91.5 g, 92%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[C:13]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:12]2)[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.[C:39]([N:43]=[C:44]=[O:45])([CH3:42])([CH3:41])[CH3:40]>C(Cl)Cl>[Cl:31][C:28]1[S:27][C:26]([S:23]([NH:22][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[N:11]([CH2:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][NH:2][C:44]([NH:43][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:45])[CH:5]=3)[N:12]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Reactant: CC(C)(C)N=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(=O)NC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride (for a preparation see Intermediate 4) (55 mg, 0.11 mmol) in dry DCM (0.5 mL) was added triethylamine (0.015 mL, 0.11 mmol), followed by tert-butyl isocyanate (0.013 mL, 0.11 mmol). The reaction mixture was stirred at room temperature for 1.5 h. LCMS showed mainly required product with 6% SM. The reaction mixture was diluted with DCM and methanol and then concentrated in vacuo. The resultant residue was dissolved in 1:1 MeOH:DMSO (1 mL) and purified by MDAP (supelcosil ABZ+Plus column) eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid). The solvent was evaporated in vacuo to give the title compound (52 mg, 84%). LCMS (System A) RT=1.15 min, ES+ve m/z 562/564 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[N:24][N:23]=2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:45][CH2:46][O:47][CH3:48]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:45][CH2:46][O:47][CH3:48])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[N:24][N:23]=2)=[CH:19][CH:20]=1
Reactant: COc1cc2c(Oc3ccc(Nc4nnc(-c5ccccc5)c5ccccc45)cc3)ccnc2cc1O
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1cc2nccc(Oc3ccc(Nc4nnc(-c5ccccc5)c5ccccc45)cc3)c2cc1OC
Reaction time: 0.08 h

Procedure:
6-Methoxy-4-(4-(4-phenylphthalazin-1-ylamino)phenoxy)quinolin-7-ol (45 mg, 92 μmol) and cesium carbonate (33 mg, 102 μmol) were combined in DMF (2 Ml) and stirred for 5 min. 1-Bromo-2-methoxyethane (9.6 μl, 204 μmol) was added and the mixture was stirred at RT for 12 hours. DMF was then removed under vacuum overnight. The crude material was purified by silica gel chromatography using 0 to 100% ethyl acetate in hexane to afford the titled product. MS: M+H+=545.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C1COCC1>[Si:21]([O:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:7]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: Oc1ccc(NCc2cccnc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(NCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-(4-hydroxyphenyl)pyridin-3-ylmethylamine (1.0 equiv.) in THF (0.1 M) was cooled to 0° C. and treated with imidazole (1.0 equiv.) and t-butyldimethylsilyl chloride (1.1 equiv.). The reaction was warmed to ambient temperature and stirred overnight. The THF was removed in vacuo. The residue was dissolved in ethyl acetate and washed with 0.1 N HCl, saturated aqueous NaHCO3, water, and brine. The residue was purified via preparative HPLC eluting with 80:20 to 68:32 DCM/ethyl acetate to give N-(4-(t-butyldimethylsilyloxy)phenyl) pyridin-3-ylmethylamine. Anal Calcd for C18H26N2OSi: C, 68.74; H, 8.33; N, 8.91. Found: C, 68.62; H, 8.28; N, 8.74. 1H NMR (400 MHz) 0.15 (6H, s), 0.96 (9H, s), 3.77 (1H, bs), 4.30 (2H, s), 6.53 (2H, m), 6.70 (2H, m), 7.26 (1H, m), 7.70 (1H, td, J=1.9, 7.7 Hz), 8.53(1H, dd, J=1.4, 4.6 Hz), 8.62 (1H, d, J=1.6 Hz). MS found 315.2 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:39]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[OH:51])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]([N:42]2[CH2:41][CH2:40][N:39]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[OH:51])[CH2:44][CH2:43]2)=[O:15])=[C:11]([CH3:16])[O:10][N:9]=1
Reactant: Oc1ccccc1N1CCNCC1
Reactant: Cc1onc(-c2ccccc2F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Cc1onc(-c2ccccc2F)c1C(=O)N1CCN(c2ccccc2O)CC1
Yield: 61.4 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 3-(2-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 2-(piperazine-1-yl)phenol (424 mg, 1.84 mmol), a white solid required compound (433 mg, 1.13 mmol, 62%) was obtained.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([N:14](CC3C=CC(OC)=CC=3OC)[C:15]3[S:19][N:18]=[CH:17][N:16]=3)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH3:31])[CH:3]=1.[CH3:32][N:33]1[C:37]([C:38]2[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[CH:40][C:39]=2B(O)O)=[CH:36][CH:35]=[N:34]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(Cl)(=O)C>>[CH3:31][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([S:11]([NH:14][C:15]3[S:19][N:18]=[CH:17][N:16]=3)(=[O:12])=[O:13])[CH:6]=2)[C:2]([C:39]2[CH:40]=[CH:41][C:42]([C:44]([F:47])([F:45])[F:46])=[CH:43][C:38]=2[C:37]2[N:33]([CH3:32])[N:34]=[CH:35][CH:36]=2)=[CH:3]1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Reactant: Cn1nccc1-c1cc(C(F)(F)F)ccc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)Cl
Product: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1cn(C)c2cc(S(=O)(=O)Nc3ncns3)ccc12
Temperature: 90 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
A microwave vial was charged with 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (Intermediate D) (48.17 mg, 0.092 mmol), (2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)boronic acid (Intermediate G) (32.3 mg, 0.120 mmol), potassium phosphate (58.6 mg, 0.276 mmol), and Pd(AmPhos)2Cl2 (3.26 mg, 4.60 μmol). The vial was flushed with Ar, then 1,4-dioxane (0.4 mL) and water (0.125 mL) were added in sequence. The vial was sealed and heated in a microwave reactor at 90° C. for 20 min. The mixture was diluted with water, then extracted with EtOAc (3×). The combined organic extracts were concentrated. The residue was taken up in MeOH (1 mL), and cooled in an ice bath for 5 min. Acetyl chloride (65.4 μl, 0.920 mmol) was added dropwise, and the resulting mixture was stirred for 2 h. The mixture was concentrated under vacuum to remove excess HCl, and the residue was taken up in 2N ammonia in methanol. The resulting mixture was again concentrated under vacuum. The crude product was purified by chromatography on silica gel (0 to 10% MeOH/DCM) to give 1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (35.38 mg, 0.068 mmol, 74.1% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=8.37 (s, 1 H), 7.97-7.83 (m, 3 H), 7.77 (d, J=1.9 Hz, 1 H), 7.60-7.53 (m, 1 H), 7.47-7.36 (m, 2 H), 7.17 (s, 1 H), 6.35 (d, J=1.9 Hz, 1 H), 3.81 (s, 3 H), 3.22 (s, 3 H). m/z (ESI) 519.2 (M+H)+.
Reaction SMILES: Cl[Mg][CH2:3][C:4]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH2:5].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[C@@H:22]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][C@@:23]([OH:27])([CH2:3][C:4](=[CH2:5])[CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:22]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)[C@@H]1c1ccccc1
Reactant: C=C(COc1ccccc1)C[Mg]Cl
Solvent: C1CCOC1
Product: C=C(COc1ccccc1)C[C@]1(O)CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A tetrahydrofuran solution of 3-(chloromagnesio)-2-(phenoxymethyl)-1-propene (0.91 M, 3 ml) (Louw et. al. Tetrahedron, 48, 6087-6104, 1992, prepared from 2.74 mmol of 3-chloro-2-(phenoxymethyl)-1-propene) was slowly added to a solution of (2S)-1-tert-butoxycarbonyl-2-phenylpiperidin-3-one (Desc.1) in THF (3 ml). The solution was stirred at room temperature for 1 hour, quenched by addition of saturated ammonium chloride solution (20 ml) and extracted with ethyl acetate (20 ml). The organic phase was washed (saturated brine), dried (MgSO4), evaporated to a small volume and purified by chromatography on silica gel eluting with hexane containing increasing proportions of ethyl acetate between 0% to 20%. Evaporation of the fractions gave (2S,3R)-1-tert-butoxycarbonyl-3-hydroxy-3-(2-methylene-3-phenoxypropyl)-2-phenylpiperidine. MS (ES+) m/z 424 (M+H), 324 (M+2H-tBuOCO--), 368 (M+2H-tBu). 1H NMR (360 MHz, CDCl3) δ 7.48 (2H, d, J 6.9 Hz), 7.35-7.2 (6H, m) 6.9-6.88 (3H, m), 5.4 (1H, s), 5.15 (2H, d, J 13.7 Hz), 4.61 (2H, s), 4.11 (2H, m), 3.17 (1H, m), 2.66 and 2.59 (2H, AB d, J 14.0 Hz), 1.95 (2H, m), 1.79 (2H, m), 1.36 (9H, s).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[CH:15][C:16]4[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][C:19]([C:25]([OH:27])=O)=[CH:18][C:17]=4[CH:28]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:51][N:52]([CH2:59][C:60]1[CH:66]=[CH:65][C:63]([NH2:64])=[CH:62][CH:61]=1)[CH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>CN(C=O)C.CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH3:51][N:52]([CH2:59][C:60]1[CH:61]=[CH:62][C:63]([NH:64][C:25]([C:19]2[CH2:20][CH2:21][S:22](=[O:24])(=[O:23])[C:16]3[CH:15]=[CH:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([N:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)=[CH:12][CH:11]=4)=[CH:28][C:17]=3[CH:18]=2)=[O:27])=[CH:65][CH:66]=1)[CH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: O=C(O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2S(=O)(=O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(N5CCOCC5)cc4)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reaction time: 1 h
Yield: 11.9 %

Procedure:
To a solution of 7-(4-morpholinophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (177 mg; purity: about 50%) and 1-hydroxybenzotriazole (HOBt) (90 mg) in DMF (5 ml) was added at room temperature 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (WSC) (127 mg), and the mixture was stirred for 1 hour. To the mixture were added a solution of 4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]aniline (107 mg) and triethylamine (0.12 ml) in DMF (5 ml) and a piece of 4-dimethylaminopyridine, and the mixture was stirred for 64 hours. The mixture was concentrated under reduced pressure, and to the residue was added water. The mixture was extracted with dichloromethane, and the organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with column chromatography (ethanol/ethyl acetate=1:1) and recrystallized from ethanol/diethylether to give yellow crystals of N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7-(4-morpholinophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 1) (31.6 mg).