Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[C:4]([F:11])[CH:3]=1.[CH:12]1([C:17]([OH:30])([C:28]#[CH:29])[CH2:18][C:19]2[O:24][C:23]([CH3:26])([CH3:25])[O:22][C:21](=[O:27])[CH:20]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1.C(NC(C)C)(C)C>CN(C=O)C.CCOC(C)=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:12]1([C:17]([OH:30])([C:28]#[C:29][C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[C:4]([F:11])[CH:3]=2)[CH2:18][C:19]2[O:24][C:23]([CH3:26])([CH3:25])[O:22][C:21](=[O:27])[CH:20]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C#CC(O)(CC1=CC(=O)OC(C)(C)O1)C1CCCC1
Reactant: CC(C)c1ccc(Br)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(C#CC(O)(CC2=CC(=O)OC(C)(C)O2)C2CCCC2)cc1F
Temperature: 90 °C
Yield: 89.2 %

Procedure:
4-Bromo-2-fluoro-1-isopropylbenzene (5.0 g, 23.2 mmol), 6-(2-cyclopentyl-2-hydroxybut-3-ynyl)-2,2-dimethyl-4H-1,3-dioxin-4-one (5.56 g, 21.0 mmol) were dissolved in anhydrous DMF (30 mL). To this solution, CuI (120 mg, 0.63 mmol), Pd(PPh3)2Cl2 (0.59 g, 0.84 mmol), and diisopropylamine (60 mL), were added sequentially. The mixture was then heated at 90° C. for 20 min before it was cooled down to 25° C. The reaction was diluted with EtOAc (150 mL) and washed with aqueous NH4Cl, brine, and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (0-40% EtOAc in hexanes) to give the desired product (7.5 g, 81% yield). 1H NMR (CDCl3, 300 MHz) δ: 1.22-1.28 (m, 8H), 1.69-1.74 (m, 10H), 1.80-1.86 (m, 2H), 2.19-2.26 (m, 1H), 2.62-2.70 (m, 2H), 3.18-3.25 (m, 1H), 5.46 (s, 1H), 7.00 (dd, J=10.61, 1.52 Hz, 1H), 7.09-7.11 (m, 1H), 7.18 (t, J=7.71 Hz, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH3:22])=[N:19]2)=[CH:14][C:13]=1[F:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:24]1CCOCC1>O>[Si:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH:22]=[O:24])=[N:19]2)=[CH:14][C:13]=1[F:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C1COCCO1
Reactant: Cc1ccc2cc(F)c(OCCO[Si](C)(C)C(C)(C)C)cc2n1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCOc1cc2nc(C=O)ccc2cc1F
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of 7-(2-(tert-butyldimethylsilyloxy)ethoxy)-6-fluoro-2-methylquinoline (2.74 g, 8.17 mmol) in dioxane (24 mL) and water (0.24 mL) was added SeO2 (0.997 g, 8.98 mmol). The reaction mixture was heated at reflux for 4 hours. After cooling to ambient temperature, the solid was removed by filtration and washed with DCM. The filtrate was concentrated under reduced pressure and The residue was purified by flash chromatography on silica gel (4:1 hexanes/EtOAc) to give 7-(2-(tert-butyldimethylsilyloxy)ethoxy)-6-fluoroquinoline-2-carbaldehyde (2.69 g, 94%).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6]N=C1)=[O:2].NC1C=[CH:29][C:17]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]([NH:27][CH3:28])=[O:26])[CH:20]=2)=[CH:16][C:15]=1[F:31].[CH3:32][N:33]1[C:41]2[C:36](=CC(N)=[CH:39][CH:40]=2)[CH:35]=[N:34]1>C1C=CC=CC=1.C(Cl)Cl>[F:31][C:15]1[CH:16]=[C:17]([CH:29]=[CH:11][C:12]=1[NH:8][C:1]([NH:3][C:7]1[CH:6]=[C:36]2[C:41](=[CH:40][CH:39]=1)[N:33]([CH3:32])[N:34]=[CH:35]2)=[O:2])[O:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([C:25]([NH:27][CH3:28])=[O:26])[CH:20]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cn1ncc2cc(N)ccc21
Reactant: CNC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1
Solvent: ClCCl
Solvent: c1ccccc1
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc4c(cnn4C)c3)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.7 %

Procedure:
To a solution of 1,1′-carbonyldiimidazole (62 mg, 0.38 mmol) in benzene (2 mL) and CH2Cl2 (1 mL) was added 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide (100 mg, 0.38 mmol). The resulting solution was stirred at room temperature for 16 h, then was treated with 1-methyl-5-aminoindazole (56 mg, 0.38 mmol). The reaction continued to stir at room temperature for 18 h. The mixture was concentrated under reduced pressure and the residue was triturated with Et2O. The solid was collected by filtration, and then purified by preparative HPLC to afford 44 mg (27%) of the title product. 1H-NMR (DMSO-d6) δ 2.78 (d, J=4.8, 3H), 4.01 (s, 3H), 7.02-7.07 (m, 1H), 7.14-7.18 (m, 1H), 7.28-7.36 (m, 2H), 7.39 (d, J=2.9, 1H), 7.52-7.59 (m, 1H), 7.89-7.96 (m, 2H), 8.23 (t, J=9.0, 1H), 8.49 (d, J=4.9, 1H), 8.57-8.63 (m, 1H), 8.71-8.81 (m, 1H), 9.06 (s, 1H); MS LC-MS [M+H]+=435.1; mp 231-234° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:31](Cl)(=[O:33])[CH3:32]>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:31](=[O:33])[CH3:32])[CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCCN(C)C)c1
Reactant: CC(=O)Cl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CCN(C)C)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: {2′-[(2-dimethylamino-ethylamino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)(=[O:9])=[O:8].CCN(CC)CC.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[F:49][C:50]([F:60])([F:59])[C:51]1[CH:58]=[CH:57][C:54]([CH2:55][NH2:56])=[CH:53][CH:52]=1>C1COCC1>[S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([NH:56][CH2:55][C:54]1[CH:53]=[CH:52][C:51]([C:50]([F:49])([F:59])[F:60])=[CH:58][CH:57]=1)=[O:15])(=[O:8])=[O:9]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1cccc(S(=O)(=O)Nc2nncs2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1ccc(C(F)(F)F)cc1)c1cccc(S(=O)(=O)Nc2nncs2)c1
Temperature: 35 °C
Reaction time: 18 h

Procedure:
To a solution of 3-[(1,3,4-thiadiazol-2-ylamino)sulfonyl]benzoic acid (100 mg, 0.350, mmol, 1 eq) in THF (1 ml) was added Et3N (0.19 ml, 1.4 mmol, 4 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI HCl, 87 mg, 0.455 mmol, 1.3 eq), 1-hydroxybenzotriazole hydrate (HOBt, 61 mg, 0.455 mmol, 1.3 eq) and 4-(trifluoromethyl)benzylamine (0.075 ml, 0.525 mmol, 1.5 eq) at 0° C. The reaction mixture was stirred at 30-40° C. for 18 hours. The reaction mixture was extracted from 2M HCl into ethyl acetate, washed with sat sodium hydrogen carbonate, brine, dried over magnesium sulphate, filtered and evaporated in vacuo. The crude material was purified by preparative HPLC to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19](/[CH:24]=[CH:25]/[S:26]([CH3:29])(=[O:28])=[O:27])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)([CH2:13][CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([CH2:24][CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)([CH2:13][CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(/C=C/S(C)(=O)=O)cccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(CCS(C)(=O)=O)cccc21
Reaction time: 0.5 h

Procedure:
To a solution of (E)-methyl 2-(4-chlorophenyl)-2-(4-(2-(methylsulfonyl)vinyl)-1H-indol-1-yl)butanoate (1.18 g, 2.73 mmol) in EtOAc (50 mL) was added Pd/C (10% on carbon, 0.2 g). The mixture was stirred under H2 atmosphere for 30 min. Then the reaction mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo. The residue was purified via column chromatography (0-30% EtOAc/hexanes) to provide the title compound. LC/MS m/z=434.1[M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.Br[C:32]1[C:33]2[C:34]3[CH:47]=[CH:46][S:45][C:35]=3[C:36](=[O:44])[NH:37][C:38]=2[CH:39]=[CH:40][C:41]=1[O:42][CH3:43]>>[CH3:43][O:42][C:41]1[CH:40]=[CH:39][C:38]2[NH:37][C:36](=[O:44])[C:35]3[S:45][CH:46]=[CH:47][C:34]=3[C:33]=2[C:32]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#CC1(c2ccc(Br)cc2)CC1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C2(C#N)CC2)cc1
Yield: 24.2 %

Procedure:
Following General Procedure B, 1-(4-bromophenyl)cyclopropanecarbonitrile (1.5 g, 7.1 mmol) was reacted with bis(pinacolato)diboron (2.7 g, 10 mmol) to afford the crude boronic ester which was reacted with 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (1.3 g, 4.2 mmol) to afford the desired product (378 mg, 29%) as a white solid: ESI MS m/z 373 [C22H16N2O2S+H]+.
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[O:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl.N1C=CC=CC=1>[O:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[S:18]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][S:18]([C:10]1[O:9][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=1)(=[O:19])=[O:20])(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: Nc1ccccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccccc1NS(=O)(=O)c1cc2ccccc2o1)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.9 %

Procedure:
To a solution of benzene-1,2-diamine (0.5 mmol) in DCM (2 mL) and pyridine (0.5 mL) at 0° C., benzofuran-2-sulfonyl chloride (1.1 mmol; prepared as in Example 12) was added at 0° C. in small portions over 10-15 min. The reaction mixture was then gradually warmed to RT with stirring continued for 6 h. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% aqueous HCl (5 mL), water (5 mL), and brine (5 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM followed by EtOAc/DCM (1% to 3%) to give 117 mg of N-{2-[(1-benzofuran-2-ylsulfonyl)amino]phenyl}-1-benzofuran-2-sulfonamide. Tr 1.18 min; MS: 469.7 (M+1)+.
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[C:6]1([OH:16])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1>N1C=CC=CC=1>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:16][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[P:1]([Cl:5])(=[O:2])([O:16][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)[O:16][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: Oc1cccc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: O=P(Cl)(Cl)Oc1cccc2ccccc12
Product: O=P(Cl)(Oc1cccc2ccccc12)Oc1cccc2ccccc12
Yield: 3.4 %
Yield: 94.6 %

Procedure:
To a mixture of 113 g. phosphoryl chloride and 0.8 g. pyridine there is added 72 g. alpha-napthol over a one and 1-half hour period at a temperature of 100°C. The temperature is held at 105°-110°C. for one and one-half hours and stripped. Distillation affords 94.6 percent naphthyl phosphorodichloridate and 3.4 percent dinaphthyl phosphorochloridate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH2:13]([CH2:15][NH2:16])[OH:14]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8]([NH:16][CH2:15][CH2:13][OH:14])(=[O:10])=[O:9])[CH:7]=1
Reactant: NCCO
Reactant: Cc1ccc(Br)cc1S(=O)(=O)Cl
Product: Cc1ccc(Br)cc1S(=O)(=O)NCCO
Yield: 57.8 %

Procedure:
Prepared by general procedure III from 5-Bromo-2-methyl-benzenesulfonyl chloride (1.6 g, 6 mmol, synthesized according to J. Am. Chem. Soc., 1940, 62, 511-514) and ethanolamine (1.0 mL, 17 mmol) to give the title compound (1.02 g, 58%) as a pale-yellow solid. MS (ISP) 294.1 [(M+H)+], 296.2 [(M+2+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2[C:24]1[N:29]=[C:28]([O:30][C@H:31]2[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36][CH2:35][C:32]32[CH2:34][CH2:33]3)[CH:27]=[N:26][CH:25]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C1(P(C2CCCCC2)C2C(OC)=CC=C(OC)C=2C2C(OC(C)C)=CC(OC(C)C)=CC=2OC(C)C)CCCCC1>[C:2]1([NH:1][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[N:13]=[C:12]3[C:24]2[N:29]=[C:28]([O:30][C@H:31]3[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36][CH2:35][C:32]43[CH2:34][CH2:33]4)[CH:27]=[N:26][CH:25]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Reactant: Nc1ccccc1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(OC(C)C)cc(OC(C)C)cc1OC(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Nc5ccccc5)cc34)n2)C1
Temperature: 70 °C
Yield: 59.6 %

Procedure:
Aniline (0.019 ml, 0.205 mmol), dicyclohexyl(2′,4′,6′-triisopropoxy-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (brettphos) (5.00 mg, 8.55 μmol), brettphosprecatalyst (7.24 mg, 8.55 μmol), and (4R)-tert-butyl 4-((6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)oxy)-6-azaspiro[2.5]octane-6-carboxylate (0.100 g, 0.171 mmol) were combined in 0.37 mL THF under argon. Lithium bis(trimethylsilyl)amide, 1.0 m solution in THF (0.376 ml, 0.376 mmol) was added. The dark red solution was sealed and heated in a 70° C. bath for 5 h. The reaction was cooled partitioned between saturated aqueous NH4Cl and DCM. The aqueous layer was extracted with DCM 3 times, and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (25 g column) using 0-30% EtOAc/hexane. The product-containing fractions were combined and concentrated to give (4R)-tert-butyl 4-((6-(5-(phenylamino)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)oxy)-6-azaspiro[2.5]octane-6-carboxylate (0.061 g, 0.102 mmol, 59.8% yield) as a sticky brown oil. MS (ESI, pos. ion) m/z: 597 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[OH:11].C([O:14][CH2:15][CH3:16])C.[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([O:11][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[Br:1])[N:8]([C:15](=[O:14])[CH3:16])[N:7]=[CH:6]2)(=[O:19])[CH3:18]
Reactant: CCOCC
Reactant: CC(=O)OC(C)=O
Reactant: Oc1cc2cn[nH]c2cc1Br
Product: CC(=O)Oc1cc2cnn(C(C)=O)c2cc1Br
Temperature: 110 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A mixture of 6-bromo-5-hydroxy-1H-indazole (25 g, 117 mmol) in acetic acid anhydride (75 mL) is heated at 110° C. with stirring for 2 hours. After it is cooled, diethyl ether (100 mL) is added. The precipitate is collected by filtration, washed with diethyl ether (30 mL), and dried under vacuum to afford the product (34 g, 98% yield). MS (m/z): 297.0 (M+H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([OH:10])=O)[CH:4]=1.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:26][C@@H:27]([CH3:43])[CH2:28][N:29]1[CH:33]=[CH:32][C:31]([C:34]2[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[C:36]([Cl:42])[CH:35]=2)=[N:30]1>C(Cl)Cl>[Br:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([NH:26][C@@H:27]([CH3:43])[CH2:28][N:29]2[CH:33]=[CH:32][C:31]([C:34]3[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[C:36]([Cl:42])[CH:35]=3)=[N:30]2)=[O:10])[CH:4]=1
Reactant: O=C(O)c1cc(CBr)on1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(CBr)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
5-(Bromomethyl)isoxazole-3-carboxylic acid (1.027 g, 4.99 mmol) and DCC (1.029 g, 4.99 mmol) were dissolved in dry DCM under nitrogen atmosphere and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (1.0 g, 3.84 mmol) was added. The mixture was stirred overnight at RT and a precipitate was filtered. The filtrate was washed with water, dried and evaporated to dryness. The evaporation residue was purified by Flash-chromatography to give the title compound. Yield 83%. 1H-NMR (400 MHz; DMSO): δ 1.17 (d, 3H), 4.32 (d, 2H), 4.40-4.50 (m, 1H), 4.86 (s, 2H), 6.81 (s, 1H), 6.94 (d, 1H), 7.82 (d, 1H), 7.91 (dd, 1H), 7.97 (dd, 1H), 8.08 (dd, 1H). 8.85 (d, 1H)
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]3[CH2:13][CH2:12]3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Br[CH2:15][C:16]1[CH:37]=[CH:36][C:19]2/[C:20](=[C:30](/[CH:33]3[CH2:35][CH2:34]3)\[C:31]#[N:32])/[C:21]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=3[O:23][CH2:24][C:18]=2[CH:17]=1>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH:11]3[CH2:13][CH2:12]3)[N:7]([CH2:15][C:16]3[CH:37]=[CH:36][C:19]4/[C:20](=[C:30](/[CH:33]5[CH2:34][CH2:35]5)\[C:31]#[N:32])/[C:21]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=5[O:23][CH2:24][C:18]=4[CH:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: N#C/C(=C1\c2ccc(CBr)cc2COc2cc(F)ccc21)C1CC1
Reactant: Clc1cccc2[nH]c(C3CC3)nc12
Product: N#C/C(=C1\c2ccc(Cn3c(C4CC4)nc4c(Cl)cccc43)cc2COc2cc(F)ccc21)C1CC1
Yield: 74.8 %

Procedure:
Using 4-chloro-2-cyclopropyl-1H-benzo[d]imidazole (EP1988091, 60 mg, 0.31 mmol) and (E)-2-(8-bromomethyl-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene)-2-cyclopropylacetonitrile (120 mg, 0.31 mmol) obtained in Reference Example 6, and in the same manner as in Reference Example 1A, the title compound (115 mg, 74%) was obtained.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH:4]([CH:7]=[CH:8][C:9](=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:3][CH:2]=1.[OH:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([CH3:24])[CH:18]=1.[CH3:25]N(C)C=O>>[CH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:21]([C:20]3[CH:22]=[CH:23][C:17]([OH:16])=[CH:18][C:19]=3[CH3:24])[CH:25]=[C:10]([C:9](=[O:15])[CH:8]=2)[C:11]([O:13][CH3:14])=[O:12])[CH2:3][CH:2]=1
Reactant: Cc1cc(O)ccc1N
Reactant: CN(C)C=O
Reactant: COC(=O)CC(=O)C=CC1CC=CCC1
Product: COC(=O)c1cn(-c2ccc(O)cc2C)c(C2CC=CCC2)cc1=O
Temperature: 25 °C

Procedure:
In 30 ml of N,N-dimethylformamide was dissolved 2.0 g of methyl 5-(cyclohexen-4-yl)-3-oxo-4-pentenoate and 1.4 g of N,N-dimethylformamidodimethylacetal was added thereto. They were reacted at 70° C. for 1.5 hours. To the reaction mixture was then added 1.3 g of 4-hydroxy-2-methylaniline at 70° C., and the resulting mixture was subjected to reaction at 80° C. for 2 hours and at 140° C. for 3 hours. After completion of this reaction, the reaction mixture was cooled to room temperature, and the solvent was removed by distillation under reduced pressure. The residue was dissolved in 20 ml of dioxane, and a solution of 2.4 g of 2,3,5,6-tetrachloro-p-benzoquinone in 15 ml of dioxane was added dropwise thereto at 80° C., followed by reaction at the same temperature for one hour. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was suspended in 30 ml of chloroform and 30 ml of water. After adjusting the pH of the suspension to 7.5 with sodium hydrogencarbonate, the organic layer was separated, washed successively with 10 ml of water and 20 ml of a saturated aqueous solution of sodium chloride, and then dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 1.3 g of methyl 6-(cyclohexen-4-yl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinate having a melting point of 250° C. or more.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]2[CH2:15][O:14][NH:13][C:12]2=[O:16])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:18]1([C:24]([O:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH:22]=[CH:21][C:20](=[O:23])[O:19]1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[C:1]1([CH2:7][C:8]([NH:10][C@H:11]2[CH2:15][O:14][N:13]([C:18]3([C:24]([O:26][CH:27]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[O:25])[CH:22]=[CH:21][C:20](=[O:23])[O:19]3)[C:12]2=[O:16])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C=CC(Cl)(C(=O)OC(c2ccccc2)c2ccccc2)O1
Reactant: O=C(Cc1ccccc1)N[C@H]1CONC1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)N[C@H]1CON(C2(C(=O)OC(c3ccccc3)c3ccccc3)C=CC(=O)O2)C1=O
Yield: 71.8 %

Procedure:
In 2.5 ml of dichloromethane suspension of 35 mg of (4S)-4-phenylacetamido-3-isoxazolidinone and 50 mg of diphenylmethyl 2-chloro-5-oxo-2,5-dihydro-2-furancarboxylate obtained in Example 49 was added under ice-cooling and stirring, 0.025 ml of triethylamine. The reaction solution was stirred at room temperature for 30 minutes, which was diluted with ethyl acetate, followed by washed with water and drying (Na2SO4). The solvent was evaporated off, and the residue was subjected to a silica gel column chromatography, followed by elution with hexane-ethyl acetate (1:1) to give 56 mg of the subject Compound (51) as colorless crystals. Recryslallization from dichloromethaneethylether afforded colorless prisms, m.p. 168°-169° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=3)[CH2:12][CH2:11][CH2:10][C:9]2=[O:22])=[CH:4][CH:3]=1.C(Cl)Cl.S(Cl)(Cl)(=O)=[O:27].C(=O)([O-])O.[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]([C:14]3[CH:15]=[CH:16][C:17]([S:20]([CH3:21])=[O:27])=[CH:18][CH:19]=3)[CH2:12][CH2:11][CH2:10][C:9]2=[O:22])=[CH:4][CH:3]=1
Reactant: CSc1ccc(C2CCCC(=O)N2c2ccc(Cl)cc2)cc1
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CS(=O)c1ccc(C2CCCC(=O)N2c2ccc(Cl)cc2)cc1
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a stirred mixture of 7.7 g of 1-(4-chlorophenyl)-6-(4-methylthiophenyl)-2-piperidone, 80 ml of methylene chloride, 3 g of silica gel, and 2.2 g of water was added 3.44 g of sulfuryl chloride at 15° to 25° C., and the mixture was stirred at 15° to 25° C. for 2 hours. The reaction mixture was poured into a cold aqueous sodium hydrogen carbonate solution. The methylene chloride solution was washed with a saturated aqueous sodium chloride solution, dried, and concentrated. The residue was purified by silica gel column chromatography (solvent; ethyl acetate:ethanol=10:1) and recrystallization from ethyl acetate to give 7.69 g of 1-(4-chlorophenyl)-6-(4-methylsulfinylphenyl)-2-piperidone as colorless prisms.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=3)[N:10]([CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[C:27]4=[O:34])[CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][CH:3]=1.CS(C)=O.[ClH:39]>O>[Cl:39][C:9]1[N:10]([CH:18]2[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][N:28]([CH:31]([CH3:32])[CH3:33])[C:27]3=[O:34])[CH2:22][CH2:23]2)[C:11]2[C:16]([C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2
Reactant: Cl
Reactant: Cc1ccc2c(c1)c(-c1ccc(F)cc1)cn2C1CCN(CCN2CCN(C(C)C)C2=O)CC1
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc2c(c1)c(-c1ccc(F)cc1)c(Cl)n2C1CCN(CCN2CCN(C(C)C)C2=O)CC1
Temperature: 60 °C

Procedure:
A mixture of 3-(4-Fluorophenyl)-5-methyl-1-[1-[2-[3-(2-propyl)imidazolidin-2-on-1yl]ethyl]-4-piperidyl)-1H-indole 4h (3.0 g), dimethylsulphoxide (0.51 g) and conc. aqueous HCl (1 ml) was heated to 60° C. for 0.5 h under stirring. The reaction mixture was cooled to room temperature and water was added. The solution was extracted with ethyl acetate (2×50 ml). The combined organic phases were washed with 4N aqueous NaOH and brine. Evaporation of the solvent gave an oil which was purified by column chromatography on silica gel (eluted with ethyl acetate/heptane 1:3). This afforded the title compound which crystallized from diethyl ether. Yield 0.4 g, mp 127°-130° C.