Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[Cl:21][CH2:22][C:23](=O)[CH3:24]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:23]([CH3:24])[CH2:22][Cl:21])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(F)cc2C(c2ccccc2)=NC1
Reactant: CC(=O)CCl
Product: CC(CCl)=NNC1=Nc2ccc(F)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 1, 7-fluoro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine can be reacted with chloropropanone to give 7-fluoro-2-[(2-chloro-1-methylethylidene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:8]([CH3:10])[CH3:9])[S:6][CH:7]=1.C1C[O:14]CC1.O>F[B-](F)(F)F.[Ag+]>[CH3:9][N:8]([C:5]1[S:6][CH:7]=[C:3]([CH2:2][OH:14])[N:4]=1)[CH3:10]
Reactant: CN(C)c1nc(CCl)cs1
Reactant: C1CCOC1
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: O
Product: CN(C)c1nc(CO)cs1
Reaction time: 1 h

Procedure:
A solution of 5.186 g (29 mmol) of 4-(chloromethyl)-2-(dimethylamino)thiazole in 100 ml of 1:1 THF/H2O was cooled to 0° C. and treated dropwise with a solution of 5.73 g (29 mmol) of silver tetrafluoroborate in 50 ml of 1:1 THF/H2O. After being stirred for 1 h, the mixture was filtered, the solid mass was washed with ethyl acetate, and the combined filtrates were concentrated in vacuo. The black residue was purified by silica gel chromatography to provide 0.80 g (17%) of the desired compound (Rf 0.24, 6% methanol in chloroform) as an oil. 1H NMR (CDCl3) δ 2.67 (br, 1H), 3.09 (s, 6H), 4.54 (s, 2H), 6.35 (s, 1H). Mass spectrum: (M+H)+=159.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Br[CH:17]([CH3:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.O>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([CH:17]([CH3:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:12][CH2:11]1
Reactant: CCOC(=O)CC(C)Br
Reactant: COc1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CC(C)N1CCN(c2ccccc2OC)CC1
Temperature: 25 °C
Yield: 41.8 %

Procedure:
A slurry of 1-(2-methoxyphenyl)piperazine hydrochloride (5 g, 21.86 mmol), ethyl 3-bromobutyrate (4.48 g, 22.96 mmol), potassium carbonate (10.57 g, 76.51 mmol) and a catalytic amount of potassium iodide (0.362 g, 2.18 mmol) in acetonitrile (50 mL) was heated at reflux for 18 hrs. After cooling at room temperature, the reaction mixture was added to water (100 mL) and the aqueous phase was extracted with AcOEt (100 mL). The organic phase was washed with water (2×75 mL), brine (75 mL), dried over MgSO4 and evaporated to dryness. The resulting light yellow oil was purified by flash chromatography (Biotage Isolute SI, 40 g column, gradient hexane to 33% ethyl acetate in hexane) and afforded 2.8 g (42%) ethyl 3-[4-(2-methoxyphenyl)piperazin-1-yl]butanoate D11 as a colourless oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][N:5]=[N:4]1.S(C1C=CC(C)=CC=1)(O[CH2:12][C@@H:13]1[CH2:27][C@H:26]2[C@@H:16]([CH2:17][C:18]3[C:28]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]2=4)[NH:20][CH:19]=3)[N:15]([CH3:29])[CH2:14]1)(=O)=O>CN(C)C=O>[CH3:29][N:15]1[C@H:16]2[C@@H:26]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:28]=3[C:18]([CH2:17]2)=[CH:19][NH:20]4)[CH2:27][C@@H:13]([CH2:12][N:3]2[CH:7]=[N:6][N:5]=[N:4]2)[CH2:14]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Reactant: c1nnn[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C[C@H](Cn2cnnn2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
1.7 g of 50% sodium hydride in an oil was added in small portions to a mixture of 5.1 g of tetrazole and 30 ml of dimethylformamide, and the resulting mixture was stirred for 30 minutes. 3.0 g of 6-methylergolin-8β-ylmethyl tosylate was added to the mixture which was then heated on a water bath for 11 hours. The solvent was distilled off under reduced pressure, and the residue was purified by alumina column chromatography (eluted with acetone). The product was recrystallized from acetone to obtain 0.7 g of the titled compound as colorless needles having a melting point of 206°-209° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-:17].[K+].[K+].OO.S([O-])([O-])(=O)=S.[Na+].[Na+]>CS(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([NH2:15])=[O:17])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: N#CC1(c2ccc(N)cc2)CCOCC1
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)C1(c2ccc(N)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 69.8 %

Procedure:
To a solution of 4-(4-aminophenyl)tetrahydro-2H-pyran-4-carbonitrile (500 mg) obtained in Step B of Example 150 and potassium carbonate (1.0 g) in dimethylsulfoxide (10 mL) was added 30% aqueous hydrogen peroxide (0.65 mL), and the mixture was stirred at room temperature for 10 hr. To the reaction mixture was added saturated aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (380 mg).
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]3[CH2:12][CH2:13][O:14][C:15]([CH2:18][C:19]([OH:21])=[O:20])([CH2:16][CH3:17])[C:10]=3[NH:9][C:8]=12.CNC[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O>C(O)C>[CH3:1][CH2:2][C:3]1[C:8]2[NH:9][C:10]3[C@:15]([CH2:18][C:19]([OH:21])=[O:20])([CH2:16][CH3:17])[O:14][CH2:13][CH2:12][C:11]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)O)OCC3
Agent: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCO
Product: CCc1cccc2c3c([nH]c12)[C@@](CC)(CC(=O)O)OCC3
Temperature: 45 °C
Yield: 53.1 %

Procedure:
Racemic etodolac (1148 g) and N-methylglucamine (780.8 g) in ethanol (6.4 litres) were heated to 70° C. with stirring. The solution was cooled to 45° C. and then seeded with crystals of 100% ee (R)-etodolac meglumine salt and the mixture allowed to crystallise for 5 hours. The solid was filtered to provide (R)-etodolac (610 g, 86.4% ee) which could be recycled to racemic etodolac following the procedure in Example 2 below.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>C(COC)OC>[C:18]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCOCC1
Solvent: COCCOC
Product: CC(=O)Nc1cc(C(F)(F)F)ccc1N1CCOCC1
Temperature: 25 °C
Yield: 96 %

Procedure:
A mixture of 40 g. (16 mmoles) of 4-(2-amino-4-trifluoromethylphenyl)morpholine and 2.2 g. (22 mmoles) of acetic anhydride in 40 ml. of dry dimethoxyethane was heated at 70° C. for 10 hours. The reaction mixture was cooled to room temperature and then the solvent removed by evaporation under reduced pressure. The residue was dissolved in 100 ml. of methylene chloride and the solution washed with 5% sodium bicarbonate solution. After drying over anhydrous sodium sulfate, the solution was filtered and evaporated under reduced pressure. The residue was dissolved in n-hexane from which it crystallized to give 4.4 g. (96%) of the desired product melting at 85° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[N:7]=[C:6]([Cl:12])[CH:5]=1.[CH2:14](O)[CH2:15][CH2:16][OH:17]>C1COCC1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([CH:10]2[O:17][CH2:16][CH2:15][CH2:14][O:11]2)[N:7]=[C:6]([Cl:12])[CH:5]=1
Reactant: COC(=O)c1cc(Cl)nc(C=O)c1
Reactant: OCCCO
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)nc(C2OCCCO2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88 %

Procedure:
Dissolve 2-chloro-6-formyl-isonicotinic acid methyl ester (200 mg, 1.0 mmol) in THF (8 mL). Add Amberlyst® 15 ion exchange resin (0.3 g) and dropwise 1,3-propanediol (0.1 mL, 1.5 mmol). Stir at room temperature for two days. Filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 10:90 ethyl acetate:hexanes) to give the title compound (88%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[Br:1][C:2]1[N:7]=[C:6]([C:8]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cccc(Br)n1
Product: CN1CCN(C(=O)c2cccc(Br)n2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 6-bromo-pyridine-2-carboxylic acid and 1-methyl-piperazine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:24]2[CH:31]=[CH:32][CH:33]=[CH:34][C:23]=2[CH2:22][CH:21]1[OH:35]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:19][CH:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[C:24]3[CH:31]=[CH:32][CH:33]=[CH:34][C:23]=3[CH2:22][CH:21]2[OH:35])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NC1c2ccccc2-c2ccccc2CC1O
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1c2ccccc2-c2ccccc2CC1O

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 5-amino-5,7-dihydro-6H-dibenzo[a,c]cyclohepten-6-ol hydrochloride (Example 2-A), the title compound was prepared as a colorless solid. The product was purified by flash chromatography using 98:2 CHCl3/MeOH.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][CH:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:20][CH2:21][CH3:22])=[O:17])[CH:12]=[CH:11][C:5]=1[C:6](OCC)=[O:7])[CH3:2].[BH4-].[Li+].B(OC)(OC)OC>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][CH:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)[CH2:20][CH2:21][CH3:22])=[O:17])[CH:12]=[CH:11][C:5]=1[CH2:6][OH:7])[CH3:2]
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)OCC)c(OCC)c1)c1ccccc1N1CCCCC1
Agent: COB(OC)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC(NC(=O)Cc1ccc(CO)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared from ethyl 2-ethoxy-4-[N-{1-(2-piperidino-phenyl)-1-butyl}-aminocarbonylmethyl]-benzoate by reduction with lithium borohydride in boiling tetrahydrofuran in the presence of 10% of trimethyl borate.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:7]([O:13][C:14]1[C:15]([C:20]2[CH:25]3[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]3)[CH:21]=2)=[N:16][CH:17]=[CH:18][N:19]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(O)C.O=[Pt]=O>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:7]([O:13][C:14]1[C:15]([CH:20]2[CH:25]3[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]3)[CH2:21]2)=[N:16][CH:17]=[CH:18][N:19]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCOc1nccnc1C1=CN2CCC1CC2
Agent: O=[Pt]=O
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: CCCCCCOc1nccnc1C1CN2CCC1CC2
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of 0.29 g of the free base of (14) (0.001 mol) and 0.15 g PtO2 in 50 ml of ethanol was hydrogenated overnight at 60 psi of H2. The catalyst was filtered off and the solvent evaporated to give 0.22 g of a clear liquid. The oxalate salt (15), 0.15 g, crystallized from ethyl acetate as a floculant colorless solid, mp 137°-138° C. NMR ppm (CDCl3) 0.9 (3H, t), 1.3-1.55 (6H, m), 1.6-1.9 (4H, m), 2.1 (2H, m), 2.45 (1H, m), 3.25 (1H, m), 3.35-3.65 (4H, m), 3.72 (1H, t), 4.25 (1H, q), 4.35 (2H, t), 8.05 (1H, d), 8.1 (1H, d). Anal. C17H27N3O-C2H2O4 requires C: 60.14; H: 7.70; N: 11.07%. Found C: 60.29; H: 7.91; N: 10.85%.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([CH:11]=[CH:12][C:13]2[CH:29]=[CH:28][C:16]([O:17][CH2:18][C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[O:20])=[C:15]([O:30][CH3:31])[CH:14]=2)=[O:10])[CH2:4][CH2:3]1>[C].[Pd].CO>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([CH2:11][CH2:12][C:13]2[CH:29]=[CH:28][C:16]([O:17][CH2:18][C:19]([N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)=[O:20])=[C:15]([O:30][CH3:31])[CH:14]=2)=[O:10])[CH2:4][CH2:3]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCC(=O)N1CCN(C)CC1
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCC(=O)N1CCN(C)CC1

Procedure:
Using 0.2 g of 1-{4-{2-[N-(trans-4-methylcyclohexyl) carbamoyl]vinyl}-2-methoxyphenoxyacetyl}-4-methylpiperazine (Example 188 ), 0.01 g of 10% palladium-carbon, and 30 ml of methanol, a reaction similar to that conducted in Example 147 was carried out. As a result, 0.13 g of 1-{4-{2-[N-(trans-4-methylcyclohexyl) carbamoyl]ethyl}-2methoxyphenoxyacetyl}-4-methylpiperazine (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1.C1(C)C=CC=CC=1>C(OCC)C>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)=[S:27])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1ccc(F)cc1F
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Fc1ccc(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)c(F)c1

Procedure:
A mixture of 2-amino-3-(2,4-difluorobenzyloxy)pyridine (2.10 g, 0.009 mol), 4chlorophenyl isothiocyanate (1.81 g, 0.01 mol) and toluene (10 ml) was refluxed for 3.5 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield2.94 g (81%), m.p.154°-156 ° C.
Reaction SMILES: [O:1]1[CH:5]=[N:4][C:3]([C:6]([NH:9]C(=O)OC(C)(C)C)([CH3:8])[CH3:7])=[N:2]1.[ClH:17]>C(OCC)(=O)C>[ClH:17].[CH3:7][C:6]([NH2:9])([C:3]1[N:4]=[CH:5][O:1][N:2]=1)[CH3:8]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ncon1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(N)c1ncon1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
tert-Butyl 2-(1,2,4-oxadiazol-3-yl)propan-2-ylcarbamate (0.668 g, 2.9 mmol) was dissolved in in ethyl acetate saturated with hydrochloride (10 mL) and stirred at room temperature for 0.5 h. Then it was concentrated to give product (0.45 g, 94%); MS (EI): m/e=128.2 [M+H]+.
Reaction SMILES: [C:1]([S:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]([O:17][CH3:18])=[O:16])=[S:13])=[C:7]([N+:19]([O-])=O)[CH:6]=1)(=[O:3])[NH2:2].CO>[Fe].O>[NH2:19][C:7]1[CH:6]=[C:5]([S:4][C:1](=[O:3])[NH2:2])[CH:10]=[CH:9][C:8]=1[NH:11][C:12]([NH:14][C:15]([O:17][CH3:18])=[O:16])=[S:13]
Reactant: COC(=O)NC(=S)Nc1ccc(SC(N)=O)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CO
Solvent: O
Product: COC(=O)NC(=S)Nc1ccc(SC(N)=O)cc1N

Procedure:
1.5 G. of 4-carbamoylthio-1-(3-methoxycarbonyl-2-thioureido)-2-nitrobenzene is treated for four hours in a refluxing mixture of 160 ml. methanol and 40 ml. water and with 4 g. iron powder (added in two portions) and 1 g. ferrous sulfate. The mixture is filtered, and the filtrate concentrated. The residue is dissolved in chloroform and washed with water, then the solvent evaporated affording 2-amino-4-carbamoylthio-1-(3-methoxycarbonyl-2-thioureido)-benzene.
Reaction SMILES: [OH-].[Na+].O.[NH2:4][CH2:5][C:6]([OH:8])=[O:7].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18](Cl)=[O:19])=[CH:12][CH:11]=1>O1CCOCC1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]([NH:4][CH2:5][C:6]([OH:8])=[O:7])=[O:19])=[CH:14][CH:15]=1
Reactant: O=C(Cl)CCc1ccc(Cl)cc1
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CNC(=O)CCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of 26 mmol sodium hydroxide in 7 ml water 8.7 mmol of glycine were added. The mixture was cooled in an ice-bath and a solution of 8.7 mmol 3-(4-chloro-phenyl)-propionyl chloride (CA [52085-96-8]) in 10 ml dioxane was slowly added over a period of 20 minutes. After stirring overnight at room temperature, the mixture was extracted with diethyl ether. The aqueous phase was acidified by addition of diluted hydrochloric acid and filtered. Trituration of the solid in diethyl ether yielded the title compound as a colorless solid. Yield=42%.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[CH2:16]([Li])CCC.CI.ClCCl>C1COCC1.O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH:5]([CH3:16])[C:4]=2[CH:3]=1
Reactant: [Li]CCCC
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CC1c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 70.3 %

Procedure:
2,7-dibromofluorene (30 g, 92.59 mmol) was dissolved in anhydrous THF (300 mL) under nitrogen and cooled to −78° C. To solution at −78° C., added n-butyllithium (40.36 mL, 100.9 mmol) over 5 minutes and allowed reaction stir for another 10 minutes. To reaction, then add methyl iodide (6.29 mL, 100.9 mmol) and allowed reaction to stir at −78° C. for 2.0 hours. The reaction was poured into a mixture of dichloromethane and water. The organic layer was collected, and the water layer was further extracted with dichloromethane. Combined all organic layers and removed solvent via vacuo. The crude material was triturated with hexanes and filtered using Buchner funnel to give white solids (22 g, 70%). 1H NMR (500 MHz, CDCl3): δ=7.62 (s, 2H), 7.56-7.58 (d, 2H), 7.48-7.50 (dd, 2H), 3.90-3.94 (q, 1H), 1.49-1.51 (d, 3H).
Reaction SMILES: C([C:5]1[CH:6]=[C:7]([NH:21][C:22](=[O:25])[CH2:23][Cl:24])[C:8]([O:19]C)=[C:9]([S:11]([NH:14]C(C)(C)C)(=[O:13])=[O:12])[CH:10]=1)(C)(C)C.[Cl-].[Al+3].[Cl-].[Cl-].C1(C)C=CC=C(C)C=1.C(OCC)C>O>[Cl:24][CH2:23][C:22]([NH:21][C:7]1[C:8]([OH:19])=[C:9]([S:11]([NH2:14])(=[O:12])=[O:13])[CH:10]=[CH:5][CH:6]=1)=[O:25]
Reactant: COc1c(NC(=O)CCl)cc(C(C)(C)C)cc1S(=O)(=O)NC(C)(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1cccc(C)c1
Solvent: CCOCC
Solvent: O
Product: NS(=O)(=O)c1cccc(NC(=O)CCl)c1O
Temperature: 95 °C
Reaction time: 16 h

Procedure:
A mixture of 5-t-butyl-2-methoxy-3-(chloroacetamido) phenyl-N-t-butyl-sulfonamide (8.0 g), aluminium chloride (16.4 g) and m-xylene (80 ml) was heated at 95° C. with stirring for 16 hours under nitrogen. The mixture was then poured into a beaker containing diethyl ether (300 ml) and water (300 ml) and stirred at ambient temperature for 15 minutes. The organic layer is separated and dried over sodium sulphate and concentrated under vacuum in order to remove all diethyl ether. The residual solution was cooled and hexane added to precipitate the title compound (4.7 g).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:9]2=[O:12])=[CH:4][C:3]=1[F:22].C([O-])([O-])=O.[K+].[K+].[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[F:22][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:9](=[O:12])[N:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc(Cn2ccc3cc(F)c(Br)cc3c2=O)cc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2ccc3cc(F)c(-c4ccccc4)cc3c2=O)cc1
Temperature: 100 °C

Procedure:
453 mg (1.25 mmol) 7-bromo-6-fluoro-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (313), 432 mg (3.125 mmol) K2CO3 and 190.5 mg (1.56 mmol) phenylboronic acid were dissolved in 12.5 mL toluene. Under Argon, 72 mg (0.062 mmol) Pd(Ph3)4 were added and the solution was stirred at 100° C. After complete conversion, the solvent is removed i. vac. and saturated sodium bicarbonate solution is added. The aqueous solution is extracted three times with dichloromethane and the organic layers are dried with MgSO4. After evaporation, the crude product is purified by preparative HPLC. Rt=1.80 min (Method C). Detected mass: 360.4 (M+H+).
Reaction SMILES: [Li].[Cl:2][C:3]1[CH:4]=[C:5]([C:9]([O-])=[CH:10][C:11](=O)[C:12]([O:14]CC)=[O:13])[CH:6]=[N:7][CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[Cl:42][C:43]1[CH:44]=[C:45]([NH:50][NH2:51])[CH:46]=[CH:47][C:48]=1[F:49]>>[Cl:42][C:43]1[CH:44]=[C:45]([N:50]2[C:9]([C:5]3[CH:6]=[N:7][CH:8]=[C:3]([Cl:2])[CH:4]=3)=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[N:51]2)[CH:46]=[CH:47][C:48]=1[F:49]
Reactant: NNc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cncc(Cl)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cncc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1

Procedure:
1.70 g (4.24 mmol) of the compound of Example 14A is reacted analogously to the synthesis of the compound of Example 20A with 1.25 g (6.36 mmol) of 3-chloro-4-fluorophenylhydrazine hydrochloride. After hydrolysis, 896 mg (60% of theory) of the title compound is obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=1.C(N(CC)CC)C.[Cl:25][C:26]1[N:31]=[CH:30][C:29]([CH:32]=[CH:33][C:34](O)=[O:35])=[CH:28][CH:27]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C1COCC1.CCOC(C)=O>[Cl:25][C:26]1[N:31]=[CH:30][C:29]([CH:32]=[CH:33][C:34]([NH:2][CH2:3][C:4]2[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([C:16]#[CH:17])[CH:5]=2)=[O:35])=[CH:28][CH:27]=1
Reactant: C#Cc1cc(CN)cc(F)c1NS(C)(=O)=O
Reactant: O=C(O)C=Cc1ccc(Cl)nc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#Cc1cc(CNC(=O)C=Cc2ccc(Cl)nc2)cc(F)c1NS(C)(=O)=O
Reaction time: 0.17 h
Yield: 23.4 %

Procedure:
N-(4-Aminomethyl-2-ethynyl-6-fluoro-phenyl)-methanesulfonamide HCl salt (78.3 mg, 0.272 mmol) was suspended in THF and treated with triethylamine (30 mg, 0.299 mmol) and then the resulting mixture was stirred for 10 mins. 3-(6-chloro-pyridin-3-yl)-acrylic acid (50 mg, 0.272 mmol) was added to the reaction mixture followed by DMTMM (82 mg, 0.299 mmol) after 10 mins. The resulting mixture was stirred overnight at ambient temperature and then diluted with EtOAc. The resulting solution was washed successively with water, sat'd NaHCO3 (×2), brine, and then dried over anhyd. Na2SO4, filtered and concentrated under reduced pressure. The crude residue was recrystallized (CH2Cl) to yield the title compound (26 mg, 23%).
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][C@@H:5]([N:11]1[C:17](=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:6]([N:8]([CH3:10])[CH3:9])=[O:7].[Cl:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)/[CH:23]=[CH:24]/[C:25](O)=[O:26].C(N(CC)CC)C>>[Cl:19][C:20]1[CH:21]=[C:22](/[CH:23]=[CH:24]/[C:25]([N:14]2[CH2:15][CH2:16][C:17](=[O:18])[N:11]([C@H:5]([CH2:4][CH2:3][OH:2])[C:6]([N:8]([CH3:10])[CH3:9])=[O:7])[CH2:12][CH2:13]2)=[O:26])[CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)/C=C/c1cccc(Cl)c1
Reactant: CN(C)C(=O)[C@@H](CCO)N1CCNCCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)[C@@H](CCO)N1CCN(C(=O)/C=C/c2cccc(Cl)c2)CCC1=O
Yield: 72 %

Procedure:
In analogy to the procedure described in example 1, (R)-4-hydroxy-N,N-dimethyl-2-(7-oxo-[1,4]diazepan-1-yl)-butyramide hydrochloride and (E)-3-chlorocinnamic acid with 1.1 eq. of triethylamine gave the titled compound in 72% yield as white foam. MS: 408.1 (MH+, 1Cl).