Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[F:28][C:29]1[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Br>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:31][C:30]5[CH:33]=[CH:34][CH:35]=[C:36]([F:37])[C:29]=5[F:28])[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Br)ccc21
Reactant: Fc1cccc(CBr)c1F
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Cc3cccc(F)c3F)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2,3-difluoro-benzyl bromide following a procedure analogous to that described for Intermediate 7. LC (method 4): tR=1.25 min; Mass spectrum (ESI+): m/z=476 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:26])[N:13]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:14]=[C:15]([CH2:16][C:17]([OH:19])=[O:18])[C:5]=3[C:4]=2[CH:3]=1.C([O-])=O.[NH4+].ClCCl>C(O)C.[Pd]>[CH3:11][N:7]1[C:8]2[CH:9]=[CH:10][CH:2]=[CH:3][C:4]=2[C:5]2[C:15]([CH2:16][C:17]([OH:19])=[O:18])=[N:14][N:13]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:12](=[O:26])[C:6]1=2
Reactant: Cn1c2ccc(Cl)cc2c2c(CC(=O)O)nn(-c3ccccc3)c(=O)c21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClCCl
Product: Cn1c2ccccc2c2c(CC(=O)O)nn(-c3ccccc3)c(=O)c21
Yield: 100 %

Procedure:
A solution of 3.3 g (9 mmol) of 8-chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetic acid, of 2.8 g (44 mmol) of ammonium formate and of 1.8 g of 10% palladium-on-charcoal in 500 ml of ethanol is heated at reflux for 5 h. The reaction mixture is cooled, dichloromethane is added, the catalyst is removed by filtration through diatomaceous earth and the solvent is evaporated under reduced pressure. 3 g (9 mmol) of compound are obtained, which compound is used as is in the following stage.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[N:4]=[C:5]([S:32][CH3:33])[C:6]([C:20]1[CH:21]=[C:22]([O:30][CH3:31])[C:23]2OCOC[C:24]=2[CH:29]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.[CH3:35][O:36]C1C=C(C=C(OC)C=1)C=O>>[CH3:1][O:2][C:3](=[O:34])[N:4]=[C:5]([S:32][CH3:33])[C:6]([C:20]1[CH:29]=[C:24]([O:36][CH3:35])[CH:23]=[C:22]([O:30][CH3:31])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc2c(c(OC)c1)OCOC2
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OC)c1

Procedure:
The same procedure was carried out as in Examples (21d) to (21h), except that 3,5-dimethoxybenzaldehyde was used instead of 8-methoxy-4H-benzo[1,3]dioxine-6-carboaldehyde in Example (21d), to give the first eluting enantiomer of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[Br:15]Br>C(O)(=O)C>[Br:15][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[C:10]([CH3:14])([CH3:13])[CH2:9][CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1)C(C)(C)CCC2
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1cc2c(cc1Br)CCCC2(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.7 %

Procedure:
To a solution of 7-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene (0.99 g, 5.2 mmol) in glacial acetic acid (30 mL) at 0° C. was added slowly bromine (0.5 mL, 10.4 mmol), and the resulting solution was allowed to slowly warm to room temperature while being stirred. After 48 h, the reaction mixture was quenched with a saturated solution of Na2S2O3 and extracted with ethyl acetate, and the combined extracts were dried (MgSO4). The solvent was removed under reduced pressure, and the residue was purified by flash column (hexane:ethyl acetate=95:5) to afford 0.5556 g (40%) of the title compound as a clear oil.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][S:7](=[O:10])(=[O:9])[CH2:8][C:4]=2[CH:3]=1.[CH:13]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=C[CH:14]=1.C([Si](C)(C)C)=C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:13]([C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][S:7](=[O:10])(=[O:9])[CH2:8][C:4]=2[CH:3]=1)=[CH2:14]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=S1(=O)Cc2ccc(Br)cc2C1
Agent: [Pd+2]
Agent: C=C[Si](C)(C)C
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: C=Cc1ccc2c(c1)CS(=O)(=O)C2

Procedure:
Under classical Heck reaction conditions, 5-Bromo-1,3-dihydro-benzo[c]thiophene 2,2-dioxide was transformed with PPh3, Pd(OAc)2, TEA, and vinyltrimethylsilane at 90° C. in DMF. The crude product was extracted with CH2Cl2 and concentrated. Deprotection in CH2Cl2/TFA gave the pure product after purification with flash chromatography (CH2Cl2) in high yields.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C([O-])(=O)C.[NH4+].N[C:16]1([O:25]O)[CH2:21][CH:20]([CH3:22])[CH2:19][C:18]([CH3:24])([CH3:23])[CH2:17]1>C(O)C>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:22][CH:20]1[CH2:19][C:18]([CH3:24])([CH3:23])[CH2:17][C:16](=[O:25])[CH2:21]1
Reactant: CC1CC(C)(C)CC(N)(OO)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CC(=O)c1ccccc1
Product: CC1CC(=O)CC(C)(C)C1
Reaction time: 8 h

Procedure:
To a stirred solution of acetophenone (24.3 g.) in ethanol (50 c.c.) containing ammonium acetate (1.6 g.) and kept at or below 0°C, was added 1-amino-3,3,5-trimethylcyclohexyl hydroperoxide (17.3 g.; pure). The solution was kept at 0°C overnight and then worked up as in the previous Examples to give unreacted acetophenone and dihydroisophorone, and a fraction (4.8 g.), b.p. 126° - 130°C/0.5 mm.Hg. with a peroxide equivalent of 407, shown by mass spectroscopy to contain the peroxide ##SPC59##
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[C:9]1[N:13]2[CH:14]=[C:15]([O:18][C@H:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:22]([NH2:29])[CH2:21][CH2:20]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.CCN(C(C)C)C(C)C.ClC(Cl)(Cl)C[O:42][C:43](=O)[NH:44][C:45]1[N:46]([C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([O:60][CH2:61][CH2:62][O:63][CH:64]3[CH2:69][CH2:68][CH2:67][CH2:66][O:65]3)[CH:55]=2)[N:47]=[C:48]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:49]=1>O1CCOCC1>[C:50]([C:48]1[CH:49]=[C:45]([NH:44][C:43]([NH:29][C@@H:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([N:3]5[C@H:2]([CH3:1])[CH2:7][CH2:6][CH2:5][C@@H:4]5[CH3:8])=[N:10][N:11]=4)[CH:14]=3)[CH2:20][CH2:21]2)=[O:42])[N:46]([C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([O:60][CH2:61][CH2:62][O:63][CH:64]3[CH2:69][CH2:68][CH2:67][CH2:66][O:65]3)[CH:55]=2)[N:47]=1)([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOC5CCCCO5)c4)c4ccccc43)cn12
Temperature: 70 °C

Procedure:
To a solution of Intermediate 96c (100 mg, 0.25 mmol) in 1,4-dioxane (3.00 mL) was added DIPEA (89.0 μL, 0.51 mmol) and Intermediate 39b (133 mg, 0.25 mmol). The reaction was heated to 70° C. overnight then cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC using 0-8% MeOH in DCM to give the title compound. LCMS (Method 4): Rt 4.09 min, m/z 777 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH3:19][C:20]1[C:24]([C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[O:26])=[C:23]([CH3:34])[NH:22][C:21]=1[CH:35]=O>C(O)C.N1CCCCC1>[CH3:19][C:20]1[C:24]([C:25]([N:27]2[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]2)=[O:26])=[C:23]([CH3:34])[NH:22][C:21]=1[CH:35]=[C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:13][C:12]1=[O:18]
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cccc(-c2cccc3c2C(=Cc2[nH]c(C)c(C(=O)N4CCN(C)CC4)c2C)C(=O)N3)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.7 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide 3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (62 mg, 53%)
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[CH2:8]([C@@:15]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([CH2:20][CH:21]=[CH2:22])[CH2:16][C:17]([OH:19])=[O:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCCCCC.CO>[CH2:8]([C@@:15]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([CH2:20][CH:21]=[CH2:22])[CH2:16][C:17]([O:19][CH3:1])=[O:18])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C=CC[C@@](CC(=O)O)(Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CCCCCC
Solvent: CO
Product: C=CC[C@@](CC(=O)OC)(Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A total of 5 ml of a 2 molar solution of trimethylsilyldiazomethane in hexane is added in portions to a solution of 490 mg of (S)-2-benzyl-2-tert-butoxycarbonylaminopent-4-enecarboxylic acid in 8 ml of methanol while stirring at room temperature. After the reaction is complete, the excess trimethylsilyldiazomethane is destroyed by dropwise addition of glacial acetic acid, and the volatile constituents are stripped off in a rotary evaporator at 40° C. The residue is purified on a column (silica gel, mobile phase: methylene chloride:methanol=95:5).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1.[Li]CCCC.C1([C:21](=[O:30])[CH2:22][C:23]2[CH:24]=[C:25](C)[CH:26]=[CH:27][CH:28]=2)C=CC=CC=1>C1COCC1>[Cl:9][C:4]1[CH:3]=[C:2]([C:21](=[O:30])[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:7]=[C:6]([Cl:8])[CH:5]=1
Reactant: Cc1cccc(CC(=O)c2ccccc2)c1
Reactant: Clc1cc(Cl)cc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)c1cc(Cl)cc(Cl)c1
Reaction time: 0.5 h
Yield: 18.3 %

Procedure:
To a solution of 1-bromo-3,5-dichlorobenzene (1 g, 4.4 mmol) in anhydrous THF (10 mL) was added n-BuLi (339 mg, 5.3 mmol) at −78° C. After being stirred for 30 minutes, a solution of N-methoxy-N-methyl-2-phenyl-acetamide (prepared following step 1 of Intermediate 4) (790 mg, 4.4 mmol) in THF (5 mL) was added, and the mixture was stirred for 3 hours. When TLC indicated that starting material was consumed, the reaction mixture was diluted with water (50 mL), and extracted with EtOAc (20 mL×3). The combined organic layer was dried over Na2SO4, concentrated in vacuum, and purified by column chromatography (PE: EtOAc=50:1) to afford 1-(3,5-dichlorophenyl)-2-phenylethanone (213 mg, yield 19.4%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:3]=1.[H][H]>COCCO.[Ni]>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:3]=1
Reactant: [H][H]
Reactant: Nc1nc(NCc2ccc(F)cc2)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: COCCO
Product: Nc1ccc(NCc2ccc(F)cc2)nc1N

Procedure:
2-amino-3-nitro-6-(4-fluorobenzylamino)pyridine (ANFP) is dissolved in 2-methoxyethanol and is hydrogenated with hydrogen in the presence of Raney nickel at 5 bar and 60° C. to give 2,3-diamino-6-(4-fluorobenzyl-amino)pyridine. This is acylated with ethyl chloroformate and triethylamine under inert gas to give flupirtine base. The catalyst is filtered off and a solution of isopropanol and maleic acid is added directly to the filtrate which contains triethylamine hydrochloride, crude flupirtine maleate being precipitated with vigorous stirring under an inert-gas atmosphere.
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)[CH:13]=[CH:12][N:11]=2)C=CC=CC=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>O1CCCC1>[N+:23]([C:20]1[CH:19]=[CH:18][C:17]([O:16][C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C:8]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[CH:15]=2)=[CH:22][CH:21]=1)([O-:25])=[O:24]
Reactant: C1COCCN1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)Oc1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
[4-(4-Nitrophenoxy)pyridin-2-yl]carbamic acid phenyl ester (250 mg) was dissolved in tetrahydrofuran (7 ml) under a nitrogen atmosphere, and then morpholine (0.187 ml) was added thereto. The reaction mixture was stirred overnight at room temperature. To the reaction mixture was further added morpholine (0.187 ml), followed by stirring for 2 hrs and 15 min. The reaction mixture was warmed up to 50° C., followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of ammonium chloride. The organic layer was washed with a saturated aqueous solution of ammonium chloride, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:1 to 1:5). Fractions containing the target compound were concentrated under a reduced pressure to give a residue, which was then dried in vacuum to provide the titled compound (152 mg, 61.9%) as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[CH:8][C:7]([OH:21])=[CH:6][CH:5]=2.[CH2:22]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])[CH3:23].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH2:14]([O:13][C:11]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:21][C:26]([C:25]([O:24][CH2:22][CH3:23])=[O:30])([CH3:28])[CH3:27])[CH:8]=2)[NH:3][C:2]=1[CH3:1])=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Cc1[nH]c2ccc(O)cc2c1C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccc2[nH]c(C)c(C(=O)OCc3ccccc3)c2c1
Yield: 49 %

Procedure:
2-Methyl-3-benzyloxycarbonyl-5-hydroxyindole (10.0 g, 35.54 mmol, 1.0 eq) was dissolved in acetonitrile (250 mL), followed by ethyl-2-bromo-isobutyrate (7.63 g, 39.10 mmol, 2.0 eq). Potassium carbonate (9.82 g, 71.08 mmol, 8.7 eq) was also added followed by potassium iodide (catalytic amount). The reaction mixture was refluxed for 24 hours. The reaction mixture was washed with brine and extracted with ethyl acetate (3×100 mL) and dried over sodium sulfate. The product was chromatographed in a hexane to hexane/ethyl acetate 7:3. 6.88 g of the product was obtained, 48% yield.
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].O[CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[C:28]3[CH2:27][C:26]4[C:21](=[CH:22][C:23](=[O:29])[CH2:24][CH:25]=4)[S:20][C:19]=3[CH:18]=[CH:17][C:16]=2[N:30]=1>CN(C=O)C.C(Cl)Cl>[Cl:3][CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[C:28]3[CH2:27][C:26]4[C:21](=[CH:22][C:23](=[O:29])[CH2:24][CH:25]=4)[S:20][C:19]=3[CH:18]=[CH:17][C:16]=2[N:30]=1
Reactant: O=C1C=C2Sc3ccc4nc(CO)ccc4c3CC2=CC1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1C=C2Sc3ccc4nc(CCl)ccc4c3CC2=CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 438.2 %

Procedure:
A solution of cyanuric chloride (0.29 g, 0.16 mmol) in DMF (1 mL) was stirred for 0.5 hrs, resulting in a white precipitate. Dichloromethane (30 mL) was added, followed by a solution of 3-hydroxymethylpyridothioxanthone (0.25 g, 1.0 mmol) in DCM (20 mL). The solution was stirred at r.t. overnight, then washed with hydrochloric acid (0.5 M, 30 mL) and water, and then dried over sodium sulfate. The mixture was purified by column chromatography on silica gel with DCM/hexane (2:3) as the eluant, yielding 3-chloromethylpyridothioxanthone (0.22 g, 82%). 1H-NMR (CDCl3): 8.88 (1H, d, J 8.4, H1), 8.61 (1H, d, J 8.1, H8), 7.73-7.64 (3H, m, H2+H5+H6), 7.57-7.52 (1H, m, H7), 4.76 (2H, s)). m/z (ES+): 262 [M+H]+, 284 [M+Na]+, 545 [2M+Na]+.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH:5][C:6]1[CH:7]=[CH:8][C:9]2[CH:13]=[C:12]([S:14](=[O:17])(=[O:16])[NH2:15])[S:11][C:10]=2[CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH:13]=[C:12]([S:14](=[O:16])(=[O:17])[NH2:15])[S:11][C:10]=2[CH:18]=1)[CH:2]=[CH2:3]
Reactant: NS(=O)(=O)c1cc2ccc(O)cc2s1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCOc1ccc2cc(S(N)(=O)=O)sc2c1
Reaction time: 24 h

Procedure:
Allyl bromide (2.07 ml, 24.0 mmol) was added dropwise to a stirred solution of 6-hydroxy-2-sulfamoylbenzo[b]thiophene (5.0 g, 22.0 mmol) in dimethylsulfoxide (15.0 ml). A solution of K2CO3 (3.34 g, 24.0 mmol) in water (7.5 ml) was added dropwise to the reaction solution at 25° C. After 24 hours, the reaction mixture was diluted with water (50 ml). The solid that formed was collected and dried, 3.75 gm (13.9 mmol), m.p. 101°-102° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[NH:17][CH:18]2[CH2:23][CH2:22][N:21]([CH2:24][C:25]#[N:26])[CH2:20][CH2:19]2)=[CH:4][CH:3]=1.N.[H][H]>[Ni].CO>[NH2:26][CH2:25][CH2:24][N:21]1[CH2:22][CH2:23][CH:18]([NH:17][C:9]2[N:8]([CH2:7][C:5]3[O:6][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)[CH2:19][CH2:20]1
Reactant: [H][H]
Reactant: Cc1ccc(Cn2c(NC3CCN(CC#N)CC3)nc3ccccc32)o1
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1ccc(Cn2c(NC3CCN(CCN)CC3)nc3ccccc32)o1

Procedure:
A mixture of 6 parts of 4-[[1-[(5-methyl-2-furanyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidineacetonitrile and 200 parts of methanol, saturated with ammonia was hydrogenated at normal pressure and at room temperature with 2 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 6 parts of N-[1-(2-amino-ethyl)-4-piperidinyl]-1-[(5-methyl-2-furanyl)methyl]-1H-benzimidazol-2-amine as a residue (int. 37).
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[C:6]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:5]=1.[CH2:20]([O:22][C:23](=[O:28])[CH2:24][C:25](O)=[O:26])[CH3:21].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(#N)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:25](=[O:26])[CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:28])[CH2:12][CH2:11]2)=[C:6]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:5]=1
Reactant: CCOC(=O)CC(=O)O
Reactant: CC(C)(C)c1cc(Br)ccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)N1CCN(c2ccc(Br)cc2C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.4 %

Procedure:
A suspension of 1-(4-bromo-2-tert-butylphenyl)piperazine dihydrochloride (Reference Example 9, 0.300 g, 0.81 mmol), 3-ethoxy-3-oxopropanoic acid (0.128 g, 0.97 mmol), EDCI (0.186 g, 0.972 mmol), HOBt (0.131 g, 0.972 mmol) and triethylamine (339 4.05 mmol) in acetonitrile (10 mL) was stirred at room temperature for 16 h. The reaction mixture was poured into saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate solution and brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to give the crude product. The product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=80:20 to 50:50) to provide ethyl 3-[4-(4-bromo-2-tert-butylphenyl)piperazin-1-yl]-3-oxopropanoate (0.308 g, 93%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6](O)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38]1(=[O:48])[NH:42][C:41](=[O:43])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([N:42]2[C:38](=[O:48])[C:39]3[C:40](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:41]2=[O:43])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:3]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC1(C)CC(c2ccncc2[N+](=O)[O-])=CC(O)C1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)CC(c2ccncc2[N+](=O)[O-])=CC(N2C(=O)c3ccccc3C2=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a homogeneous solution of 5,5-dimethyl-3-(3-nitropyridin-4-yl)cyclohex-2-enol (1.0 eq), triphenyl phosphine (1.5 eq), and phthalimide (1.5 eq) in THF (0.2 M) cooled to 0° C., ditertbutyl azodicarboxylate (1.5 eq) in THF was added to the solution. The mixture was stirred at 0° C. for 2 hours. The reaction was concentrated in vacuo. The residue was purified by column (5% methanol in 1:1 ethyl acetate and hexanes) to give 2-(5,5-dimethyl-3-(3-nitropyridin-4-yl)cyclohex-2-enyl)isoindoline-1,3-dione (99%). LC/MS (m/z): MH+=378.2, Rt=1.10.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26].[CH2:27]([CH2:29][NH2:30])[OH:28]>N1C=CC=CC=1>[CH2:27]([CH2:29][NH2:30])[OH:28].[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:30][CH2:29][CH2:27][OH:28])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: c1ccncc1
Solvent: NCCO
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NCCO)c(Cl)c32)c(F)cc1F
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 76.5 %

Procedure:
1-(6-Amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (300 mg) and ethanolamine (300 mg) were added to pyridine (1,300 mg), and the mixture was stirred at 50° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (2 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Ethanol (4 ml) was added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (290 mg) as a colorless powder.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.C(N(CC)CC)C.[C:18]([NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C(O)C>[C:21]([O:20][C:18](=[O:19])[NH:25][CH:26]1[CH2:31][CH2:30][N:29]([C:2]2[N:7]=[CH:6][N:5]=[C:4]3[NH:8][N:9]=[CH:10][C:3]=23)[CH2:28][CH2:27]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: Clc1ncnc2[nH]ncc12
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(c2ncnc3[nH]ncc23)CC1
Temperature: 80 °C
Yield: 26.5 %

Procedure:
To a solution of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (J. Amer. Chem. Soc. 1957, 79, 6407-6413) (59 mg, 0.38 mmol) in ethanol (2 ml) was added triethylamine (100 μl, 0.72 mmol) and 4-(N-Boc-amino)piperidine (134 mg, 0.67 mmol). The solution was heated at 80° C. for 3 hours, and then cooled to room temperature. The solution was evaporated to dryness and the residue purified by recrystallisation (isopropanol) to yield the product (32 mg, 26% yield).