Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([C:11]([O-:13])=[O:12])[C:5]=2[CH:4]=[N:3]1.[Li+].[OH-].Cl>CO.C1COCC1.O>[CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([C:11]([OH:13])=[O:12])[C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc2c1CCCC2C(=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncc2c1CCCC2C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To a solution of 1-methyl-4,5,6,7-tetrahydro-1H-indazole-4-carboxylate (7 g, 36 mmol) in methanol (100 mL), THF (50 mL) and H2O (50 mL) was added LiOH (2.5 g, 108 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified with 1N HCl solution to pH=5-6, and extracted with EA three times. The combined organic layers were washed with brine, dried over Na2SO4. The solvent was concentrated to give 1-methyl-4,5,6,7-tetrahydro-1H-indazole-4-carboxylic acid (6 g, 94%), which was used in the next step directly.
Reaction SMILES: Cl[C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[CH3:23][C:24]1[CH:37]=[CH:36][C:27]([C:28]([NH:30][C:31]2[S:32][CH:33]=[CH:34][N:35]=2)=[O:29])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1>>[CH3:20][S:17]([NH:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:21]=[CH:22][C:2]([C:25]2[CH:26]=[C:27]([C:28](=[O:29])[NH:30][C:31]3[S:32][CH:33]=[CH:34][N:35]=3)[CH:36]=[CH:37][C:24]=2[CH3:23])=[N:3][CH:4]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CS(=O)(=O)Nc1cccc(CNC(=O)c2ccc(Cl)nc2)c1
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1ccc(C(=O)NCc2cccc(NS(C)(=O)=O)c2)cn1

Procedure:
N-(3-Methylsulphonylaminobenzyl)-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-(3-methylsulphonylaminobenzyl)nicotinamide (Intermediate 4) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide (Intermediate 11) using General Method B. LCMS: retention time 2.96 min, MH+ 522. NMR: δH [2H6]-DMSO 10.19,(2H, b), 9.35,(1H, t), 9.17,(1H, s), 8.38,(1H, dd), 8.22,(1H, s), 8.07,(1H, d), 7.84,(1H, d), 7.57,(1H, d), 7.52,(1H, d), 7.31-7.28,(2H, m), 7.22,(1H, s), 7.11,(2H, m), 4.52,(2H, d), 2.99,(3H, s), 2.45,(3H, s).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)=[N:4][NH:5][CH:6]=1.[H-].[Na+].I[CH2:19][CH3:20]>CN(C)C=O>[Br:1][C:2]1[C:3]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)=[N:4][N:5]([CH2:19][CH3:20])[CH:6]=1
Reactant: CCI
Reactant: O=[N+]([O-])c1ccc(-c2n[nH]cc2Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(Br)c(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A 0° C. solution of 4-bromo-3-(4-nitrophenyl)-1H-pyrazole (485 mmol) in N,N-dimethylformamide (1000 mL) was slowly treated with sodium hydride (485 mmol) and then iodoethane (582 mmol). The reaction mixture was stirred for 30 minutes at room temperature and then poured into ice-water (1000 mL). Product precipitated out of solution and was collected by filtration, washed with water (4×500 mL) and dried to provide the title product as a light brown powder (94%). ESMS [M+H]+: 297.2
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([CH:18]1[O:20][CH2:19]1)Br.[H-].[Na+]>CN(C)C=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH:18]2[CH2:19][O:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCCCCc1ccccc1
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CCCCCCCCOCC2CO2)cc1

Procedure:
A procedure similar to that described in Preparation 46 was repeated, except that 4 g of 8-phenyloctyl alcohol, 3.18 ml of epibromohydrin, 0.85 g of sodium hydride (as a 55% by weight dispersion in mineral oil) and 80 ml of anhydrous dimethylformamide were used, to give 2.42 g of the title compound having an Rf value of 0.51 (on silica gel thin layer chromatography, using a 1:6 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[S:15](=[O:17])(=[O:16])[CH2:14][CH2:13][NH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C=O)C.[H-].[Na+].Cl[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][C:35]=2[F:37])[N:30]=[C:29]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[F:44])[C:28]=1[CH3:45]>CCOC(C)=O>[F:37][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:36]=1[C:27]([N:12]1[C:11]3[CH:18]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH:8]=[CH:9][C:10]=3[S:15](=[O:17])(=[O:16])[CH2:14][CH2:13]1)=[C:28]([CH3:45])[C:29]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[F:44])=[N:30]2
Reactant: O=S1(=O)CCNc2cc(N3CCOCC3)ccc21
Reactant: Cc1c(-c2ccccc2F)nc2cccc(F)c2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccc2F)nc2cccc(F)c2c1N1CCS(=O)(=O)c2ccc(N3CCOCC3)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under a N2 atmosphere, 6-(4-morpholinyl)-3,4-dihydro-2H-1,4-benzothiazine 1,1-dioxide (0.0800 g, 0.298 mmol) was dissolved in DMF (2.00 mL, 26.0 mmol). Sodium hydride (0.0143 g, 0.596 mmol) was added and the reaction was allowed to stir at rt for 10 minutes. 4-Chloro-5-fluoro-2-(2-fluorophenyl)-3-methylquinoline (0.0950 g, 0.328 mmol) was added and the reaction was heated to 140° C. for 2 h. The reaction was diluted with EtOAc and washed with 2% sodium bicarbonate, then brine. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by preparative reverse phase chromatography to afford 4-(5-fluoro-2-(2-fluorophenyl)-3-methyl-4-quinolinyl)-6-(4-morpholinyl)-3,4-dihydro-2H-1,4-benzothiazine 1,1-dioxide. Mass Spectrum (ESI) m/e=522.2 (M+1)
Reaction SMILES: [CH2:1]([C@H:8]([NH:36][C:37](=[O:47])[O:38][C@@H:39]1[C@H:46]2[C@H:42]([O:43][CH2:44][CH2:45]2)[O:41][CH2:40]1)[C@H:9]([OH:35])[CH2:10][N:11]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27]CC2C=CC=CC=2)=[CH:23][CH:22]=1)(=[O:20])=[O:19])[O:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C>[Pd].C(OCC)(=O)C>[CH2:1]([C@H:8]([NH:36][C:37](=[O:47])[O:38][C@@H:39]1[C@H:46]2[C@H:42]([O:43][CH2:44][CH2:45]2)[O:41][CH2:40]1)[C@H:9]([OH:35])[CH2:10][N:11]([O:12][CH:13]([CH2:14][CH3:15])[CH2:16][CH3:17])[S:18]([C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1)(=[O:20])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc(O)cc1
Reaction time: 16 h
Yield: 46.4 %

Procedure:
A solution of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[{[4-(benzyloxy)phenyl]sulfonyl}(1-ethylpropoxy)amino]-2-hydroxypropylcarbamate (222 mg, 0.384 mmol) in 3:1 absolute ethanol:ethyl acetate was combined with Palladium on carbon (10 wt %, 44 mg) and reduced under an atmosphere of Hydrogen gas over 16 hours. The reaction was filtered and evaporated in vacuo. The residue was purified on flash grade silica gel eluting with 3:2 ethyl acetate:hexane. Fractions containing the product were combined and evaporated in vacuo. The residue was triturated with water, filtered and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-{(1-ethylpropoxy)[(4-hydroxyphenyl)sulfonyl]amino}-2-hydroxypropylcarbamate (103 mg, 46%) as a white solid. H1-NMR (chloroform-D3): 0.91 (m, 6H), 1.61 (m, 7H), 2.93 (m, 5H), 3.70 (m, 2H), 3.92 (m, 4H), 4.17 (m, 1H), 4.79 (d, 1H), 5.01 (m, 1H), 5.66 (d, 1H), 6.12 (s, 1H), 6.94 (d, 2H), 7.26 (m, 5H), 7.72 (d, 2H). MS(ESI): 601(M+Na).
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:34][C:35]([F:50])([F:49])[C:36]1[CH:37]=[C:38]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[C:39](O)=[O:40]>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:39](=[O:40])[C:38]2[CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=[C:36]([C:35]([F:34])([F:49])[F:50])[CH:37]=2)[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Fc1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](OCc2cc(F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (28.8 mg) obtained in Example 26 and 3,5-bis(trifluoromethyl)benzoic acid (31.0 mg) were reacted and treated in the same manner as in the method described in Example 33 to obtain the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][C@H:8]([CH3:10])[N:7]([C:11]2[O:12][C:13]3[C:14](=[C:16]([C:20]([O:22]C)=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:15]=2)[C@@H:6]([CH3:24])[CH2:5]1)(=[O:3])[CH3:2].O.[OH-].[Li+:27]>>[C:1]([N:4]1[CH2:9][C@H:8]([CH3:10])[N:7]([C:11]2[O:12][C:13]3[C:14](=[C:16]([C:20]([O-:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:15]=2)[C@@H:6]([CH3:24])[CH2:5]1)(=[O:3])[CH3:2].[Li+:27]
Reactant: COC(=O)c1cccc2oc(N3[C@@H](C)CN(C(C)=O)C[C@@H]3C)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N1C[C@H](C)N(c2nc3c(C(=O)[O-])cccc3o2)[C@@H](C)C1

Procedure:
Following general procedure GP-B2, methyl 2-((2S,6S)-4-acetyl-2,6-dimethylpiperazin-1-yl)benzoxazole-4-carboxylate was reacted with lithium hydroxide monohydrate to provide lithium 2-((2S,6S)-4-acetyl-2,6-dimethylpiperazin-1-yl)benzoxazole-4-carboxylate. 1H NMR and MS consistent.
Reaction SMILES: [N:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:52]1[CH:57]=[C:56]([S:58][CH3:59])[N:55]=[C:54]([S:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([F:68])[C:63]=2[F:69])[N:53]=1.[Cl-].[NH4+]>O1CCOCC1.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]>[F:69][C:63]1[C:64]([F:68])=[CH:65][CH:66]=[CH:67][C:62]=1[CH2:61][S:60][C:54]1[N:53]=[C:52]([NH:10][S:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:9])=[O:8])[CH:57]=[C:56]([S:58][CH3:59])[N:55]=1
Reactant: NS(=O)(=O)N1CCOCC1
Reactant: CSc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CSc1cc(NS(=O)(=O)N2CCOCC2)nc(SCc2cccc(F)c2F)n1
Temperature: 100 °C

Procedure:
A mixture of 4-morpholinesulfonamide (prepared according to patent WO 2004/011443, 0.39 g), tris(dibenzylideneacetone)-dipalladium (0) (33 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (17 mg), cesium carbonate (0.58 g) and 4-chloro-2-[(2,3-difluorobenzyl)thio]-6-(methylthio)pyrimidine (the product of example 57, step i) (0.38 g) in dioxane (10 mL) was heated at 100° C. for 18 h. The mixture was cooled and saturated ammonium chloride was added and the resulting mixture extracted with EtOAc. The combined organic extracts were washed with saturated aqueous sodium chloride, dried (MgSO4), filtered and evaporated. The residue was purified by reverse phase HPLC eluting with acetonitrile/aq. 0.1% ammonium acetate mixtures to give the title compound as a white solid. Yield: 30 mg.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10](Br)=[CH:9][N:8]=1.[F:15][C:16]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:17]=1[CH:18]=[O:19].[Cl-].[NH4+]>C(OCC)C.CCCCCC>[Br:6][C:7]1[N:8]=[CH:9][C:10]([CH:18]([C:17]2[C:20]([F:25])=[CH:21][CH:22]=[C:23]([F:24])[C:16]=2[F:15])[OH:19])=[C:11]([CH3:13])[CH:12]=1
Reactant: O=Cc1c(F)ccc(F)c1F
Reactant: Cc1cc(Br)ncc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: Cc1cc(Br)ncc1C(O)c1c(F)ccc(F)c1F
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
A hexane solution of n-butyllithium (1.54 M, 12.2 ml, 18.7 mmol) was added to a solution of 2,5-dibromo-4-methylpyridine (4.27 g, 17.0 mmol) in diethyl ether (200 ml) in an argon atmosphere at −78° C. After stirring the reaction mixture for 30 minutes, 2,3,6-trifluorobenzaldehyde (1.99 ml, 17.0 mmol) was added thereto. After stirring for 30 minutes at the same temperature, saturated aqueous ammonium chloride was added to the mixture at room temperature. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=4:1 was concentrated under reduced pressure to obtain the title compound (4.60 g, 13.9 mmol, 81%) as a pale yellow solid.
Reaction SMILES: C[N:2]([CH3:21])[CH:3]=[C:4]([C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].NC(C(N)=O)[C:24]([NH2:26])=[O:25]>CC(O)=O>[NH2:26][C:24]([C:21]1[NH:2][CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)=[O:25]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)C(N)C(N)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]c(C(N)=O)c1-c1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 83.7 %

Procedure:
A 3 L round bottomed flask was charged with ethyl 3-(dimethylamino)-2-(4-nitrobenzoyl)acrylate (63.59 g, 217.5 mmol) and 2-aminomalonamide (33.12 g, 282.8 mmol) and AcOH (800 mL). The reaction mixture was heated to 80° C. over night. The starting material appeared consumed by TLC. The AcOH was removed under reduced pressure and TFA (400 mL) was added. The mixture was heated over night at 60° C. The reaction was cooled to room temperature and the TFA was removed under reduced pressure. The orange oil was washed with saturated aqueous NaHCO3 (1 L) and solid NaHCO3 was added until the solution was neutral. The solids were filtered and placed in a 1 L erlenmeyer flask. The solids were washed with H2O (3×1 L) and the water was decanted off through the filter. On the last washing the solids were poured onto the filter and allowed to air dry. The solids were once again removed from the filter and washed with Et2O (4×500 mL). The Et2O was decanted off through the filter and on the final washing the solids were transferred to the filter. An addition portion of Et2O (200 mL) was used to wash the flask and the filter cake. The product was dried in a vacuum oven at 40° C. over P2O5 for 4 h affording ethyl 5-(aminocarbonyl)-4-(4-nitrophenyl)-1H-pyrrole-3-carboxylate as a tan solid (55.2 g, 182 mmol, 83.7%). 1H-NMR (DMSO-d6) δ 12.33 (br s, 1H), 8.19-8.15 (m, 2H), 7.57 (d, J=3.6 Hz, 1H), 7.53-7.49 (m, 2H), 7.29 (br s, 1H), 6.41 (br s, 1H), 3.99 (q, J=7.2 Hz, 2H), 1.03 (t, J=7.2 Hz, 3H); LCMS RT=2.79 min; MS {M+H]+=304.2.
Reaction SMILES: [CH3:1][N:2]([S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)(=[O:30])=[O:29])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[C:23](OCC)=[O:24])[CH2:15][N:16]=1)=[CH:8]2.[BH4-].[Li+].C(=O)([O-])O.[Na+]>O1CCCC1.CO>[OH:24][CH2:23][C:19]1[N:18]([CH2:17][CH:14]2[S:13][C:12]([C:9]3[NH:10][C:11]4[C:7]([CH:8]=3)=[CH:6][CH:5]=[CH:4][C:3]=4[N:2]([CH3:1])[S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)(=[O:29])=[O:30])=[N:16][CH2:15]2)[CH:22]=[CH:21][N:20]=1
Reactant: CCOC(=O)c1nccn1CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4ccccn4)c3[nH]2)S1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1cccc2cc(C3=NCC(Cn4ccnc4CO)S3)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
Ethyl 1-[(2-{7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)methyl]-1H-imidazole-2-carboxylate (220 mg) was dissolved in a mixed solvent of tetrahydrofuran (8 mL) and methanol (4 mL), lithium borohydride (27 mg) was added, and the mixture was stirred at room temperature for 1 hr. Lithium borohydride (20 mg) was added, and the mixture was stirred at room temperature for 24 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The residue was silica gel column chromatography (methanol:ethyl acetate=0:100-15:85) to give the title compound (38 mg, yield 19%) as a white solid. MS: 482(MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[Br-].[CH:12]1([Zn+])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C1COCC1.C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:12]1([C:2]2[CH:3]=[CH:4][C:5]3[O:9][CH:8]=[CH:7][C:6]=3[CH:10]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: [Zn+]C1CCCCC1
Reactant: Brc1ccc2occc2c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1cc2cc(C3CCCCC3)ccc2o1
Temperature: 100 °C
Yield: 42.5 %

Procedure:
5-bromobenzofuran (500 mg, 2.55 mmol) was dissolved in a THF solution of cyclohexyl zinc(II) bromide (0.5M, 15 mL, 7.40 mmol) in a microwave reaction tube. Pd(PtBu3)2 (65 mg, 0.128 mmol, 0.05 eqv.) was added to this solution. The mixture was purged with N2 gas for 3-5 min and heated at 100° C. for 30 min under microwave irradiation. Upon completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with 1N HCl aqueous solution, brine, filtered through Celite. The filtrate was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (ISCO system, 5% EtOAc in hexanes) to give 0.217 g desired product (43% yield): 1H NMR (400 MHz, CDCl3) δ 7.57 (d, 1H), 7.41 (d, 2H), 7.15 (d, 1H), 6.72 (d, 1H), 2.58 (m, 1H), 1.92-1.74 (m, 4H), 1.51-1.35 (m, 4H), 1.31-1.25 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH:14]2[CH2:16][CH2:15]2)=[N:4][N:3]=1.[NH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH2:20][CH2:19]1>>[CH:14]1([C:5]2[C:6]3[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=3)[C:2]([NH:17][CH:18]3[CH2:19][CH2:20][N:21]([CH2:24][C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH:26]=4)[CH2:22][CH2:23]3)=[N:3][N:4]=2)[CH2:16][CH2:15]1
Reactant: NC1CCN(Cc2ccc3ccccc3c2)CC1
Reactant: COc1ccc2c(C3CC3)nnc(Cl)c2c1
Product: COc1ccc2c(C3CC3)nnc(NC3CCN(Cc4ccc5ccccc5c4)CC3)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting 1-chloro-4-cyclopropyl-7-methoxyphthalazine with 4-amino-1-(naphthalen-2-ylmethyl)piperidine.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[N+:12]([O-:14])=[O:13].[C:15]1([S:21]([O-:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Na+]>CN(C)C=O>[N+:12]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[CH:3][C:2]([S:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:23])=[O:22])=[CH:11]2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc2cc(I)cnc12
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2cc(S(=O)(=O)c3ccccc3)cnc12
Temperature: 65 °C
Yield: 57.6 %

Procedure:
3-Iodo-8-nitroquinoline (D3) (135 g, 0.45 mol), was suspended in dimethylformamide (2.4 L) in a 5 L 3-necked flask fitted with an overhead stirrer, under an argon atmosphere. This mixture was treated successively with anhydrous sodium phenylsulfinate (99.6 g 0.608 mol), and bis-(copper(I)triflate)benzene complex (170 g, 0.338 mol). The resulting slurry was heated to 65° C. for 18 h. The mixture was cooled, filtered and the solvent evaporated in vacuo. Acetone (2.5 L) was added to the residue and the solution filtered. The filtrate was evaporated in vacuo, a further 2.5 L of acetone added and the mixture filtered again. The solvent was evaporated in vacuo and the residue dissolved in chloroform (3 L) and washed with 10% aqueous ammonia (2×2 L), and the organic phase was dried over magnesium sulphate and the solvent evaporated in vacuo. The dark brown residue was purified using a Biotage flash-150 chromatography apparatus (5 kg silica gel) eluting with hexane and increasing proportions of ethyl acetate to give the title compound (D4) (81.5 g, 58%) as a yellow solid;
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][C:14]([Cl:16])=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:16][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCBr
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCCCCl)cc1

Procedure:
A solution of 4′-hydroxyacetophenone (20 mmol, 2.72 g), 3-bromopropionyl chloride (21 mmol, 2.07 mL) and potassium carbonate (4.14 g, 30.0 mmol) in acetone (50 mL) was heated at reflux for overnight. The salt was filtered off. The solvent was evaporated. After drying in vacuo, the title compound (4.24 g) was collected.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:14]=[CH:15][C:16](=[O:18])[CH3:17].[H][H]>[C].[Pd].C(OCC)(=O)C>[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:14][CH2:15][C:16](=[O:18])[CH3:17]
Reactant: CC(=O)C=Cc1ccc2c(c1)Cc1ccccc1-2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)CCc1ccc2c(c1)Cc1ccccc1-2
Yield: 56.3 %

Procedure:
To 350 ml of ethyl acetate were added 17 grams of 4-(2-fluorenyl)-3-buten-2-one and 2 grams of 10% palladium carbon powder, the mixture was warmed at 40°-50° C., and hydrogen was introduced in under ordinary pressure. When the absorption of hydrogen ceased, the catalyst was removed by filtration, the filtrate was concentrated, and ethyl acetate was removed therefrom. Crystals separated out therefrom were recrystallized from methanol to give 9.65 grams of 4-(2-fluorenyl)-butan-2-one, white crystals, m.p. 99°-101° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Na+].[Cl-].[S:14](=O)(=[O:17])([OH:16])[OH:15]>>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][C:5]=1[S:14]([OH:17])(=[O:16])=[O:15]
Reactant: O=S(=O)(O)O
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Agent: [Cl-]
Agent: [Na+]
Product: O=[N+]([O-])c1cc(S(=O)(=O)O)c(Cl)cc1Cl
Temperature: 50 °C

Procedure:
2,4-Dichloronitrobenzene (122 g (0.635 moles)) in 20% fuming sulfuric acid was heated at a temperature of 120° C. to 130° C. for 5 hours with stirring. After completion of the reaction, the reaction mixture was added portionwise to 1.5 l of ice water. The resulting aqueous solution was warmed to 50° C. and 400 g of NaCl was added thereto followed by cooling to room temperature. Crystals which separated out were collected by filtration, washed with water and with acetonitrile and dried.