Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[S:19](=[O:21])(=[O:20])[CH2:18][CH2:17][C:16]([C:22](O)=[O:23])=[CH:15][C:14]=3[CH:25]=2)=[CH:6][CH:5]=1)[CH3:2].S(Cl)(Cl)=O.[CH2:30]([O:32][CH2:33][CH2:34][CH2:35][N:36]([CH2:38][C:39]1[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=1)[CH3:37])[CH3:31].O>C1COCC1.CN(C=O)C>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[S:19](=[O:21])(=[O:20])[CH2:18][CH2:17][C:16]([C:22]([NH:43][C:42]4[CH:41]=[CH:40][C:39]([CH2:38][N:36]([CH2:35][CH2:34][CH2:33][O:32][CH2:30][CH3:31])[CH3:37])=[CH:45][CH:44]=4)=[O:23])=[CH:15][C:14]=3[CH:25]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCSc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Reactant: CCOCCCN(C)Cc1ccc(N)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCCN(C)Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(SCC)cc4)ccc3S(=O)(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In THF (5.2 ml) was dissolved 7-(4-ethylthiophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (260 mg). To the mixture were added at room temperature thionyl chloride (0.06 ml) and DMF (one drop), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added dropwise to a solution of 4-[[N-(3-ethoxypropyl)-N-methylamino]methyl]aniline (0.58 ml) in THF (5.2 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-(4-ethylthiophenyl)-N-[4-[[N-(3-ethoxypropyl)-N-methylamino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 82) (115 mg).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[N+:21]([C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[N:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(N(c2ccccc2)c2ccccc2)c1
Yield: 61.7 %

Procedure:
A 1 L round bottom flask was charged with diphenylamine (13.29 g, 79.0 mmol), 1-iodo-3-nitrobenzene (19.56 g, 79.0 mmol), palladium (II) acetate (0.70 g, 3.12 mmol), biphenyl-2-dicyclohexylphosphine (2.19 g, 6.25 mmol), sodium tert-butoxide (10.48 g, 109 mmol) and toluene (400 mL). This was stirred at reflux for 18 h. The mixture was then filtered. The filtrate was concentrated in vacuo, and the crude product was chromatographed (silica gel) using a gradient of 10-20% dichloromethane in hexane to give 3-nitro-N,N-diphenylaniline (14.15 g, 62%) as an orange solid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.Cl.C([NH:19][CH:20]([C:22]1([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[CH2:25][CH2:24][CH2:23]1)[CH3:21])C1C=CC=CC=1.[BH4-].[Na+].Cl>C(O)C.O>[ClH:32].[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][NH:19][CH:20]([C:22]2([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=3)[CH2:23][CH2:24][CH2:25]2)[CH3:21])=[CH:3][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(NCc1ccccc1)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(CNC(C)C2(c3ccc(Cl)c(Cl)c3)CCC2)cc1

Procedure:
A stirred mixture of p-anisaldehyde (0.62 ml) and 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine (see Example 1 of published British Patent Specification No. 2098602) in the form of its free base (1.22 g) was heated to 130°-135° for 30 minutes. After cooling the residue was dissolved in ethanol (10 ml) and the solution added to a solution of sodium borohydride (1.5 g) in ethanol (200 ml). The mixture was heated under reflux for one hour. Water (10 ml) and then excess 5N HCl were added and the ethanol removed by evaporation. The residue was basified with aqueous sodium hydroxide solution and an ether extraction performed. The extract was dried and evaporated to give an oil. Hydrogen chloride gas was passed through an ethereal solution of the oil to give N-(4-methoxybenzyl)-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine hydrochloride (m.p. 217°-218° C.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[Cl:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([Cl:17])[C:9]=1[N:18]=[C:19]=S.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([Cl:17])[C:9]=1[N:18]=[C:19]1[NH:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1]1
Reactant: O=[N+]([O-])c1cc(Cl)c(N=C=S)c(Cl)c1
Reactant: NCCCCN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(Cl)c(N=C2NCCCCN2)c(Cl)c1
Temperature: 25 °C
Yield: 30.3 %

Procedure:
A solution of 1.76 g (0.02 mol) of 1,4-diaminobutane in 10 mL of toluene was cooled to -10° C. and 2,6-dichloro-4-nitrophenylisothiocyanate (2.45 g, 0.01 mol) in 10 mL of toluene was added dropwise over 30 minutes. The resulting mixture was stirred an additional hour then heated at reflux overnight. The reaction was cooled to room temperature and was treated with 30 mL 1M HCl. The aqueous phase was brought to pH 9 with 1M NaOH and the resulting yellow precipitate was filtered, washed with water then hexane and air dried to give 0.92 g (30%) of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[C:4]([F:17])[CH:3]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:31]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26][C:25]=3[N:24]([CH3:39])[C:23]=2[N:40]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CS(C)=O.CCOCC.C(Cl)Cl.[Cu]I>[ClH:1].[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:19]3[CH:20]=[CH:21][C:22]4[C:31]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26][C:25]=5[N:24]([CH3:39])[C:23]=4[N:40]=3)[C:10](=[O:14])[CH:9]=2)=[C:4]([F:17])[CH:3]=1
Reactant: O=c1cc(OCc2ccc(Cl)cc2F)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)nc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cc5F)cc4=O)nc31)CCNCC2
Temperature: 135 °C
Reaction time: 24 h
Yield: 27.2 %

Procedure:
A suspension of 4-(4-chloro-2-fluorobenzyloxy)pyridin-2(1H)-one (75 mg, 0.30 mmol), tert-butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (91 mg, 0.33 mmol), CuI (67 mg, 0.36 mmol), 8-hydroxyquinoline (9 mg, 0.06 mmol) and Cs2CO3 (106 mg, 0.326 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under N2 and stirred at 135° C. for 24 h. The suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine. Activated carbon was added to the resulting solution, and the resulting suspension was filtered. The filtrate was dried over Na2SO4, and concentrated under reduced pressure. Flash chromatography on silica gel (Et2O/(8:1.9:0.1 Et2O/MeOH/NH4OH) afforded a cream colored solid. 2 N HCl in Et2O (100 mL) was added to a solution of the cream colored solid in CH2Cl2 (5 mL) under N2, and the resulting suspension was stirred at 25° C. for 2 d. The suspension was concentrated, and the resulting residue was dissolved in MeOH (1 mL). Et2O (4 mL) was added, and the resulting suspension was filtered, the solid was washed with Et2O and the solid was put in a vacuum oven at 40° C. for 2 d to afford 20 mg (14%) of the title compound as a white powder: 1H NMR (500 MHz, DMSO-d6) δ 9.00 (br s, 2H), 8.03 (d, J=8.5 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.64 (dd, J=8.0, 8.0 Hz, 1H), 7.54 (dd, J=10.0, 1.5 Hz, 1H), 7.39 (br d, J=8.5 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 6.15 (dd, J=8.0, 3.0 Hz, 1H), 6.05 (d, J=2.5 Hz, 1H), 5.19 (s, 2H), 3.74 (s, 3H), 3.60-3.32 (m, 4H), 3.31-3.26 (m, 2H), 3.17-3.12 (m, 2H); ESI MS m/z 453 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][SH-:7][C:8](=[N:10][C:11]#[N:12])[S-:9])=[CH:4][CH:3]=1.[K+].[K+].[OH:17]O>O>[OH:17][C:11]1[N:10]=[C:8]([S:7][CH2:6][C:5]2[CH:13]=[CH:14][C:2]([Cl:1])=[CH:3][CH:4]=2)[S:9][N:12]=1
Reactant: OO
Reactant: N#CN=C([S-])[SH-]Cc1ccc(Cl)cc1
Agent: [K+]
Solvent: O
Product: Oc1nsc(SCc2ccc(Cl)cc2)n1
Temperature: 65 °C

Procedure:
A mixture of 144 g of potassium S-p-chlorobenzyl-N-cyano-dithioimidocarbonate, 48 ml of 30% hydrogen peroxide and 1000ml of water was heated to 65° C, returned to room temperature and filtered. The filtrate was acidified with 40 ml of concentrated hydrochloric acid and was filtered. The recovered crystals were washed with water and dried to obtain 90 g of 3-hydroxy-5-(p-chlorobenzylthio)-1,2,4-thiadiazole melting at 138° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[N:20]1[CH2:21][CH2:22][N:23]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[N:7]2)[CH2:24][CH2:25]1
Reactant: c1coc(N2CCNCC2)c1
Reactant: ClCCCCn1nnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1coc(N2CCN(CCCCn3nnc4ccccc43)CC2)c1
Temperature: 25 °C
Yield: 71.7 %

Procedure:
1-(4-chlorobutyl)-1H-benzotriazole (7.55 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(2-furyl)piperazine (4.6 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 7.0 g compound (I-43) with a yield of 71.3%. ESI-MS [M+H]+: m/z 325.2.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:10])=[CH:6][C:7]=1[CH2:8][CH3:9].[CH3:11]C(O)=O.S(=O)(=O)(O)O.[NH4+].[NH4+].[O-]S(OOS([O-])(=O)=O)(=O)=O.[OH-].[NH4+]>O.[N+]([O-])([O-])=O.[Ag+]>[Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:10])=[C:6]([CH3:11])[C:7]=1[CH2:8][CH3:9]
Reactant: CC(=O)O
Reactant: CCc1cc(Cl)nnc1Cl
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: O
Product: CCc1c(Cl)nnc(Cl)c1C
Temperature: 72.5 °C

Procedure:
To a suspension of 3,6-dichloro-4-ethylpyridazine (1 eq), AgNO3 (0.7 eq) and AcOH (2.8 eq) in H2O (9.4 mL, 0.6M) was added a solution of cone, sulfuric acid (6.6 eq) in H2O (9.4 mL, 0.6 M) at 50° C., followed by addition of a solution ammonium peroxodisulfate (5.4 eq) in H2O (9.4 mL, 0.6 M) at 60° C. for 20 min. The reaction mixture was heated at 70-75° C. for 30 min. After cooling, the reaction mixture was adjusted to pH 7 with a 25% ammonium hydroxide solution, and extracted with Et2O. The extracts were washed with H2O and dried (Na2SO4) and solvent was removed under high vacuum. The residue was purified by silica gel chromatography, eluting with 9:1 petroleum ether:EtOAc, to afford the desired product as colourless crystals. 1H NMR (400 MHz, CDCl3) δ: 2.85 (2H, q, J=7.6 Hz), 2.45 (3H, s), 1.21 (3H, t, J=7.6 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5](OS(C(F)(F)F)(=O)=O)[CH:4]=1.[CH3:21][CH:22]([CH3:26])[CH2:23][C:24]#[CH:25]>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.[Cu]I>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:25]#[C:24][CH2:23][CH:22]([CH3:26])[CH3:21])[CH:4]=1
Reactant: C#CCC(C)C
Reactant: COC(=O)c1ccc(OC)cc1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: COC(=O)c1ccc(OC)cc1C#CCC(C)C
Yield: 98.3 %

Procedure:
Coupling of methyl 4-(methyloxy)-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate (77) (1.0 g, 3.18 mmol) with 4-methyl pentyne (0.78 mL, 6.36 mmol) using Pd(PPh3)2Cl2 and CuI gave 0.77 g (98%) of compound 102 as a brown oil. 1H NMR (400 MHz, CDCl3): δ 1.06 (d, J=6.8 Hz, 6H), 1.90-2.00 (m, 1H), 2.37 (d, J=6.4 Hz, 2H), 3.83 (s, 3H), 3.87 (s, 3H), 6.82 (dd, J1=8.8 Hz, J2=2.8 Hz, 1H), 7.00 (d, J=2.7 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H). LCMS (ESI): m/z 247 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:14][C:15]1[NH:16][N:17]([C:21]2[CH:38]=[CH:37][C:24]3[NH:25][C:26]([C:28]4[CH:36]=[CH:35][C:31]([C:32]([O-])=[O:33])=[CH:30][CH:29]=4)=[N:27][C:23]=3[CH:22]=2)[C:18](=[O:20])[CH:19]=1>>[CH3:14][C:15]1[NH:16][N:17]([C:21]2[CH:38]=[CH:37][C:24]3[NH:25][C:26]([C:28]4[CH:36]=[CH:35][C:31]([C:32]([NH:11][C:10]5[CH:12]=[CH:13][C:7]([N:4]6[CH2:3][CH2:2][O:1][CH2:6][CH2:5]6)=[CH:8][CH:9]=5)=[O:33])=[CH:30][CH:29]=4)=[N:27][C:23]=3[CH:22]=2)[C:18](=[O:20])[CH:19]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: Cc1cc(=O)n(-c2ccc3[nH]c(-c4ccc(C(=O)[O-])cc4)nc3c2)[nH]1
Product: Cc1cc(=O)n(-c2ccc3[nH]c(-c4ccc(C(=O)Nc5ccc(N6CCOCC6)cc5)cc4)nc3c2)[nH]1

Procedure:
Compound 451 was prepared from 4-morpholinoaniline and 4-(5-(3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-1H-benzimidazol-2-yl)benzoate by standard conditions. [M+H]+ calcd for C28H26N6O3: 495.22; found: 495.01.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].O.[OH-].[Na+].[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](Cl)=[O:16]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH:7][NH:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:16]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CC(C)(C)NN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)NNC(=O)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a suspension of t-butyl hydrazine hydrochloride (6.2 g, 0.05 mole), water (30 mL) and toluene (60 mL) at 0° C. to 5° C. was added 50% sodium hydroxide (4.0 g, 0.05 mol). To the above reaction mixture was then added, separately and simultaneously, 50% sodium hydroxide (4.0 g, 0.05 mol) and 3-chlorobenzoyl chloride (8.8 g, 0.05 mol) from two dropping funnels. After addition was completed, the reaction mixture was stirred at 0° C. for 30 minutes and room temperature for 30 minutes. The resultant precipitate was collected by suction-filtration and washed with water (100 mL) and dried in air to give 9.0 g (79% yield) of 1-(3chlorobenzoyl)-2-t-butyl hydrazine as a white solid. mp 116°-118° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[CH:22][S:23](Cl)(=[O:25])=[O:24])=[C:17]([O:27][CH3:28])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[S:23]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][C:3]=2[S:10]([NH2:13])(=[O:11])=[O:12])(=[O:24])=[O:25])=[C:17]([O:27][CH3:28])[CH:16]=1
Reactant: N#Cc1ccc(N)c(S(N)(=O)=O)c1
Reactant: COc1cc(Cl)ccc1C=CS(=O)(=O)Cl
Product: COc1cc(Cl)ccc1/C=C/S(=O)(=O)Nc1ccc(C#N)cc1S(N)(=O)=O
Yield: 27 %

Procedure:
The title compound was synthesized as described for Example 178 in 27% yield, starting from 2-amino-5-cyanobenzenesulfonamide and 2-(4-chloro-2-methoxy-phenyl)-ethenesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][C:23]([CH2:26]O)=[CH:22][CH:21]=1.C(C=P(CCCC)(CCCC)CCCC)#N.CCCCCC>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH2:26][C:23]2[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: OCc1ccncc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(Cl)cc1)C(Cc1ccncc1)c1cc(F)ccc1F
Yield: 31.4 %

Procedure:
Under an argon atmosphere, the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (200 mg, 0.660 mmol) obtained in Example 5 and 4-pyridylmethanol (144 mg, 1.32 mmol) were dissolved in toluene (6 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (318 mg, 1.32 mmol). The resulting mixture was heated under reflux for 15 hours under an argon atmosphere. The reaction mixture was then concentrated. The residue thus obtained was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=1:2 elulate was concentrated. The solid thus obtained was recrystallized from ethyl acetate, whereby the title compound (81.4 mg, 0.207 mmol, 31%) was obtained as colorless needle crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8](Br)[CH2:9][F:10])[N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]([CH:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:9][F:10])[CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: FCC(Br)c1cccc(Br)n1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: FCC(c1cccc(Br)n1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-6-(1-bromo-2-fluoroethyl)pyridine (70 mg, 0.25 mmol), morpholine (0.022 mL, 0.25 mmol) and DIPEA (0.048 mL, 0.27 mmol) were stirred in DMF (1 mL) at room temperature for 4 hours. Additional morpholine (10.78 μL, 0.12 mmol) and DIPEA (0.024 mL, 0.14 mmol) were added and the resulting solution stirred at room temperature overnight. Water was added and the reaction mixture was extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel column chromatography (6-50% EtOAc-hexanes) gave the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N+:14]([O-])=O)=[C:11]([CH:13]=2)[NH2:12])=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>[Pd].CO>[F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:13]=[C:11]([NH2:12])[C:10]([NH2:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Nc1cc(Oc2ccc(F)cc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1ccc(Oc2ccc(F)cc2)cc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.8 %

Procedure:
A mixture of 5-(4-fluorophenoxy)-2-nitroaniline (410 mg, 1.65 mmol), ammonium formate (520 mg, 8.26 mmol), 10% palladium on carbon (123 mg, 0.116 mmol) and methanol (10 mL) was stirred at ambient temperature for 30 minutes. The mixture was filtered and filtrate was concentrated. Product was purified from the residue by silica gel column chromatography (eluted with a 2:3→1:2 of hexane/EtOAc) to give 4-(4-fluorophenoxy)benzene-1,2-diamine (370 mg, quant) as a brown oil.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:6])[O-:5])[CH3:2].O[C:8]1[C:9]([Cl:21])=[CH:10][C:11]2[CH:12]([CH3:20])[CH:13]3[CH2:17][NH:16][CH2:15][CH:14]3[C:18]=2[CH:19]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(CC)CC>CO.CS(C)=O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([NH:3][C:4](=[O:5])[O-:6])[CH3:2].[Cl:21][C:9]1[CH:8]=[CH:19][C:18]2[CH:14]3[CH2:15][NH:16][CH2:17][CH:13]3[CH:12]([CH3:20])[C:11]=2[CH:10]=1
Reactant: CC1c2cc(Cl)c(O)cc2C2CNCC12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCNC(=O)[O-]
Solvent: CO
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC1c2cc(Cl)ccc2C2CNCC12
Temperature: 80 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
To a mixture of N-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole, o-trifluoromethanesulfonate (60 mg, 0.14 mmol), palladium(II) acetate (6 mg, 0.028 mmol) and 1,3-bis(diphenylphosphino) propane (12 mg, 0.035 mmol) in MeOH (0.5 mL) and DMSO (0.5 mL) was added Et3N (0.2 mL, 1.4 mmol). The resulting mixture was stirred for 2 hours at 80° C. then cooled to room temperature. The reaction mixture was diluted with EtOAc (5 mL) and then washed with H2O (2 mL). The organic extract was dried over MgSO4 and concentrated to afford 15 mg (35% yield) of the subtitle compound, which was used without further purification. MS calculated for C15H18ClNO2+H: 280, observed: 280.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([O:15][C:16]([NH:18][CH:19]1[C:25](=[O:26])[NH:24][C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[NH:21][CH2:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>C1COCC1.C(OCC)(=O)C>[CH3:36][O:35][C:33](=[O:34])[CH2:32][N:24]1[C:25](=[O:26])[C@@H:19]([NH:18][C:16]([O:15][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:17])[CH2:20][NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]1=2
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Reactant: COC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A 1.0 M solution of lithium bis(trimethylsilyl)amide (3.4 ml, 3.4 mmol) in THF was added dropwise to a −78° C. solution of 3-tert-butoxycarbonylamino-1,3,4,5-tetrahydrobenzo[b][1,4]diazepin-2-one (0.94 g, 3.38 mmol) in 20 ml of anhydrous tetrahydrofuran and stirred for 30 minutes. Methyl bromoacetate (o0.44 ml, 4 mmol) was added dropwise to the reaction mixture then warmed to room temperature. The reaction was diluted with 100 ml of ethyl acetate and washed with 0.3N potassium hydrogen sulfate (50 ml), water (2×50 ml), and brine. The combined organics were dried over anhydrous sodium sulfate, filtered, and evaporated to afford a gum that was purified by flash chromatography eluting with 3:7 EtOAc/Hex. to give 0.98 g (83%) of the title compound as a white solid. 1H NMR (CDCl3) δ7.15-7.07 (2H, m), 6.98-6.94 (1H, m), 6.88-6.84 (1H, d), 5.62-5.55 (1H, d), 4.71-4.65 (1H, d), 4.65-4.6 (1H, m), 4.33-4.27 (1H, d), 3.96-3.90 (1H, m), 3.78 (3H, s), 3.44-3.37 (1H, m), 1.4 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19]>C(Cl)(Cl)Cl>[OH:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([NH:1][C:18](=[O:20])[CH3:19])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(CO)cc1N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(CO)ccc1C

Procedure:
The solution of 11.3 g of (3-amino-4-methylphenyl)methanol in 500 ml of chloroform is cooled to 0° C. with stirring and admixed with 13.4 ml of triethylamine. 6.03 ml of acetyl chloride are slowly added dropwise. Subsequently, the mixture is stirred at 0° C. over 2 hours. The reaction mixture is poured onto water (1 l) and extracted with dichloromethane (2×350 ml). The organic phases are washed with brine (350 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a slightly brownish solid from the residue by means of flash chromatography (SiO2 60F). Rf=0.10 (1:2 dichloromethane-diethyl ether); Rt=2.14.