Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9](B2OC(C)(C)C(C)(C)O2)[C:8]2[N:7]3[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:6]3=[C:5]([CH3:25])[C:4]=2[CH:3]=1.Br[C:27]1[S:28][C:29]([Cl:32])=[CH:30][CH:31]=1>>[Cl:32][C:29]1[S:28][C:27]([C:9]2[C:8]3[N:7]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:6]4=[C:5]([CH3:25])[C:4]=3[CH:3]=[C:2]([F:1])[CH:10]=2)=[CH:31][CH:30]=1
Reactant: Cc1c2n(c3c(B4OC(C)(C)C(C)(C)O4)cc(F)cc13)CCNC2=O
Reactant: Clc1ccc(Br)s1
Product: Cc1c2n(c3c(-c4ccc(Cl)s4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, light brown solid (15 mg, 22%), MS (ISP) m/z=335.4 [(M+H)+], mp 185° C., was prepared in accordance with the general method of example 171, step B from 8-fluoro-10-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (Example 171, step A) (68.8 mg, 0.2 mmol) and commercially available 2-bromo-5-chlorothiophene (59.2 mg, 0.3 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([NH:9][C:10](=[O:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8][C:4]=2[CH:3]=1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][N:22]=1>C(O)C>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][N:22]=[C:21]2[NH:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]=[C:7]([NH:9][C:10](=[O:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8][C:4]=2[CH:3]=1
Reactant: Nc1ccc2nc(NC(=O)c3ccccc3)oc2c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CCO
Product: COc1cc2ncnc(Nc3ccc4nc(NC(=O)c5ccccc5)oc4c3)c2cc1OC

Procedure:
N-[6-(6,7-Dimethoxyquinazolin-4-ylamino)benzoxazol-2-yl]benzamide was prepared by heating a mixture of N-(6-aminobenzoxazol-2-yl)benzamide (IM 1, 30 mg, 0.118 mmol) and 4-chloro-6,7-dimethoxyquinazoline (Fluorochem, 26.5 mg, 0.118 mmol) in ethanol (3 mL) to 80° C. for 2 h. The resulting precipitate was separated by filtration, washed with ethanol and dried (yellow solid, 38 mg, 85 μmol, 72%). LC/ESI-MS: m/z=442 [M+H]+; m/z=440 [M−H]−; Rt=2.43 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[NH2:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:24]1[N:23]=[CH:22][N:21]=[C:20]([NH2:19])[CH:25]=1)[CH3:2]
Reactant: Nc1cc(Cl)ncn1
Reactant: CCOc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOc1ccccc1-c1cc(N)ncn1
Yield: 96.9 %

Procedure:
To a solution of 2-ethoxyphenylboronic acid (II) (1.73 g, 10.4 mmol) in 30 ml of 1,4-dioxane 10 ml of saturated aqueous sodium carbonate solution were added. Argon gas was purged for 10 min at room temperature. 6-Chloro-pyrimidin-4-ylamine (I) (1.50 g, 11.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.66 g, 0.57 mmol) were added to the reaction mixture simultaneously and argon gas was bubbled in for another 5 min. The reaction mixture was heated to reflux for 12 hours. After completion of the reaction as indicated by TLC the mixture was concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic layer was separated, washed with water and brine, dried over sodium sulfate and concentrated. The obtained crude residue was purified by column chromatography eluting with 15% ethyl acetate in dichloromethane to provide 6-(2-ethoxy-phenyl)-pyrimidin-4-ylamine (III) (2.17 g, 87.3%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11](F)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[SH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH:37]([CH2:42][CH3:43])[CH2:38][CH2:39][CH2:40][CH3:41])=[O:34]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([S:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH:37]([CH2:42][CH3:43])[CH2:38][CH2:39][CH2:40][CH3:41])=[O:34])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Reactant: CCCCC(CC)COC(=O)CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCC(CC)COC(=O)CCSc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-(benzyloxy)-2-fluoro-1-nitrobenzene (2.00 g), potassium carbonate (1.23 g) and DMF (11 mL) was added dropwise 2-ethylhexyl 3-sulfanylpropanoate (2.02 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and washed with saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a yellow liquid (3.60 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:19][C:20]4[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=4)[CH:23]=[O:24])[C:14]3=[O:28])[CH:10]=[N:9]2)=[C:5]([CH3:29])[O:4][N:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:19][C:20]4[CH:27]=[CH:26][CH:25]=[C:22]([CH2:23][OH:24])[CH:21]=4)[C:14]3=[O:28])[CH:10]=[N:9]2)=[C:5]([CH3:29])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(C=O)c3)C2=O)cn1
Agent: [Pd]
Solvent: CCO
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3cccc(CO)c3)C2=O)cn1

Procedure:
3-((3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,4-dioxoimidazolidin-1-yl)methyl)benzaldehyde (example 10-24) (131 mg, 0.3 mmol) was dissolved in 2 mL ethanol. The solution was passed through the H-Cube instrument at room temperature using 10% Pd/C catalyst at a flow rate of 1 ml/minute. The collected fraction was concentrated, redissolved in 2 mL ethanol and purified by HPLC (10-95% Acetonitrile/Water, 25 minutes). The purified fractions were combined and concentrated to give the title compound. 1H NMR (DMSO, 400 MHz): δ2.123 (s, 3H), 2.388 (s, 3H), 3.978 (s, 2H), 4.516 (s, 2H), 5.182 (s, 2H), 7.242 (m, 4H), 7.779 (s, 1H), 8.172 (s, 1H), 8.505 (s, 1H). MS M+H calculated 396.1; found 396.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.3 uM. Yield: 24 mg, 18%.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[O:12]1[CH:14]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:13]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[Cl:11][C:10]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:13][CH:14]([OH:12])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:7]=[N:6][C:5]=2[CH:9]=1
Reactant: Clc1cc2nc[nH]c2cc1Cl
Reactant: CC(C)(C)C1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)C(O)Cn1cnc2cc(Cl)c(Cl)cc21
Temperature: 160 °C
Yield: 73.3 %

Procedure:
A large (2-5 mL) microwave reactor flask was charged with 5,6-dichlorobenzimidazole (571 mg, 3.1 mmol), 1,2-epoxy-3,3-dimethylbutane (307 mg, 3.1 mmol), powdered anhydrous potassium carbonate (424 mg, 3.1 mmol) and DMF (1.5 mL). The reaction was then heated in a microwave reactor for 6 minutes at 160° C. The reaction was then diluted with ethyl acetate and extracted with water three times. The organics were dried over MgSO4 and the solvent was removed. The residue was crystallized from CH2Cl2 to afford 653 mg (73%) of product as a white solid: 1H NMR (DMSO, 400 MHz) δ 1.06 (s, 9H), 3.47 (dd, 1H, J1=2.0, J2=10.4), 4.08 (dd, 1H, J1=10.5, J2=14.4), 4.47 (dd, 1H, J1=2.0, J2=14.4), 7.75 (s, 1H), 7.79(s, 1H), 8.23 (s, 1H); HPLC-MS calcd. for C21H22Cl2N4O2 (M+H+) 287.1, Found 287.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
1-tert-Butyloxycarbonyl-4-hydroxymethylpiperidine (2.8 g) was dissolved in dimethylformamide (10 ml), followed by stirring for 30 minutes. To the mixture was added p-fluoronitrobenzene (2.1 g), followed by stirring at room temperature overnight. Aqueous saturated solution of sodium bicarbonate was added to the mixture which was extracted with methylene chloride (50 ml×3). The combined organic layer was washed with saturated saline and dried over sodium sulfate. The solvent was distilled off under reduced pressure and the residue thus obtained was purified by silica gel column chromatography (developing solvent: hexane/ethylacetate=5/1 (v/v)) to obtain 1-tert-butyloxycarbonyl-4-[(4-nitrophenyloxy)methyl]piperidine (1.9 g) as pale yellow crystals, m.p. 130°-131° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([N:31]=[C:32]=[S:33])[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1>>[F:19][C:20]([F:34])([F:35])[C:21]1[CH:22]=[C:23]([NH:31][C:32](=[S:33])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:24]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:26]=1
Reactant: FC(F)(F)c1cc(N=C=S)cc(C(F)(F)F)c1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 52.7 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.972 g, 4.00 mmol) and 3,5-di(trifluoromethyl)phenyl isothiocyanate (1.08 g, 3.98 mmol) to afford the product (1.076 g); m.p. 192-193° C.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[NH:17][S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.[N:26]1([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C)C=O>[S:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[S:18]([NH:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[NH:9][C:8]([C:6]1[S:7][C:3]([CH2:2][N:29]3[CH2:28][CH2:27][N:26]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:31][CH2:30]3)=[CH:4][N:5]=1)=[CH:16]2)(=[O:19])=[O:20]
Reactant: O=S(=O)(Nc1cccc2cc(-c3ncc(CCl)s3)[nH]c12)c1cccs1
Reactant: CCOC(=O)CN1CCNCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCN(Cc2cnc(-c3cc4cccc(NS(=O)(=O)c5cccs5)c4[nH]3)s2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 82.8 %

Procedure:
To a solution of N-{2-[5-(chloromethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}thiophene-2-sulfonamide (0.460 g) in N,N-dimethylformamide (12 ml) were added ethyl piperazin-1-ylacetate (0.385 g) and triethylamine (0.31 ml), and the mixture was stirred at room temperature for 15 hr. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from tetrahydrofuran-hexane to give the title compound (0.507 g, yield 83%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]#[N:12])=[CH:4][C:3]=1[N+:13]([O-])=O.CO>[Fe].O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]#[N:12])=[CH:4][C:3]=1[NH2:13]
Reactant: N#CCCSc1ccc(N)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CO
Solvent: O
Product: N#CCCSc1ccc(N)c(N)c1
Reaction time: 2 h

Procedure:
2.3 G. of 1-amino-2-nitro-4-(2-cyanoethylthio)benzene in 30 ml. of methanol and 6 ml. of water is treated with 2.5 g. of ferrous sulfate and 3.3 g. of iron powder at reflux. After 2 hours, 1.25 g. of ferrous sulfate and 3.3 g. of iron powder are added and heating is continued for four hours. The mixture is poured into 600 ml. of hot tetrahydrofuran and filtered. 1,2-Diamino-4-(2-cyanoethylthio)benzene is obtained from the filtrate by evaporation.
Reaction SMILES: [C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH:18]=[CH:19][CH2:20][CH:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>O.C(Cl)(Cl)Cl>[C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH:18]4[O:29][CH:19]4[CH2:20][CH:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(c1ccccc1)N1CC2CC=Cc3cccc1c32
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(c1ccccc1)N1CC2CC3OC3c3cccc1c32
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution was prepared from 2.71 g. of 1-benzoyl-1,2,2a,3-tetrahydrobenz[cd]indole in 100 ml. of chloroform. A second solution containing 2.1 g. of 85% m-chloroperbenzoic acid in 100 ml. of chloroform was added. The reaction mixture was stirred at ambient temperature for 41/4 hours. TLC of an aliquot of the solution indicated that most of the starting material had been comsumed. The reaction mixture was diluted with water and the organic layer washed with 1N aqueous sodium hydroxide, with water and with saturated aqueous sodium chloride. The organic layer was dried and the solvent removed therefrom by evaporation in vacuo. The resulting residue containing 1-benzoyl-4,5-epoxy-1,2,2a,3,4,5-hexahydrobenz[cd]indole formed in the above reaction was dissolved in chloroform and the chloroform solution filtered through florisil. The chloroform was evaporated from the filtrate and the resulting residue crystallized from a mixture of ether and hexane, yielding 1-benzoyl-4,5-epoxy-1,2,2a,3,4,5-hexahydrobenz[cd]indole melting in the range 103°-115° C. (the above procedure is based upon that of Kornfeld et al., J. Am. Chem. Soc., 78, 3101 (1956))
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4].[C:12]([O:15][C:16](=O)C)(=O)[CH3:13].C(OC(OCC)OCC)C>>[CH2:12]([O:15][CH:16]=[C:6]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CCCC(=O)CC(=O)OCC
Solvent: CCOC(OCC)OCC
Product: CCCC(=O)C(=COCC)C(=O)OCC

Procedure:
A mixture of ethyl butyrylacetate (105.1 g), acetic anhydride (126 ml) and triethylorthoformate (117 ml) was stirred and boiled under reflux for 1.5 hours. The low boiling materials were distilled off under reduced pressure and the residue distilled under high vacuum to give ethyl 2-(ethoxymethylene)-3-oxohexanoate, b.p. 109°-120° C. (0.4 mmHg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2].Br[CH2:15][CH:16]1[CH2:18][CH2:17]1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[N:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])=[O:5])[CH3:2]
Reactant: BrCC1CC1
Reactant: CCOC(=O)c1n[nH]cc1[N+](=O)[O-]
Product: CCOC(=O)c1c([N+](=O)[O-])cnn1CC1CC1
Yield: 23 %

Procedure:
The product was obtained according to the method described in example 4, step 2 starting from 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester and bromomethyl-cyclopropane as a mixture of regioisomers which were separated by silica gel chromatography using a heptane/ethyl acetate gradient to yield 179 mg (46%) of the desired regioisomer and 88 mg (23%) of 2-cyclopropylmethyl-4-nitro-2H-pyrazole-3-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br.Br[CH:11]([C:13]1[CH:14]=[C:15]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[CH:16]=[C:17]2[C:22]=1[O:21][C:20]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[CH:19][C:18]2=[O:29])[CH3:12]>>[CH3:33][N:32]([CH3:34])[C:30]([C:15]1[CH:16]=[C:17]2[C:22](=[C:13]([CH:11]([N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH3:12])[CH:14]=1)[O:21][C:20]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[CH:19][C:18]2=[O:29])=[O:31]
Reactant: CNc1ccccc1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: CC(c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1ccccc1
Yield: 36.4 %

Procedure:
N-methylaniline (153 mg, 1.43 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (175 mg, 0.36 mmol) using an analogous procedure to the one described in Example 3.03 to give N,N-dimethyl-8-(1-(methyl(phenyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide (57 mg, 37%) as a white solid. Mass Spectrum: M+H+ 436. NMR Spectrum (DMSOd6): 1.57 (d, 3H), 2.65 (s, 3H), 2.90 (bs, 3H), 3.00 (bs, 3H), 3.16-3.22 (m, 2H), 3.23-3.31 (m partially hidden by H2O, 2H), 3.36-3.42 (m, 2H), 3.42-3.49 (m, 2H), 5.52 (s, 1H), 5.55 (q, 1H), 6.66 (t, 1H), 6.84 (d, 2H), 7.19 (t, 2H), 7.67 (d, 1H), 7.87 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:44]=[C:45]([S:50](Cl)(=[O:52])=[O:51])[CH:46]=[C:47]([Cl:49])[CH:48]=1>C(#N)C>[Cl:49][C:47]1[CH:46]=[C:45]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:52])[CH:44]=[C:43]([Cl:42])[CH:48]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3cc(Cl)cc(Cl)c3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 44 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0332 g, 0.0719 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0600 mL, 0.432 mmol) and 3,5-dichlorobenzenesulfonylchloride (0.0530 g, 0.216 mmol) to obtain 4-(3,5-dichlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0212 g, yield 44%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:7]([NH2:8])=[C:6]([CH3:14])[CH:5]=1.[CH3:15]I.O>CN(C=O)C>[Br:3][C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:7]([NH:8][CH3:15])=[C:6]([CH3:14])[CH:5]=1
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1N
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNc1c(C)cc(Br)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
3.80 g (86.6 mmol) sodium hydride (55%, suspension in mineral oil) were added batchwise to 20.0 g (86.6 mmol) 4-bromo-2-methyl-6-nitroaniline in 250 mL DMF with slight cooling and the mixture was stirred for 30 min. Then 5.40 mL (86.6 mmol) methyl iodide were slowly added dropwise, the cooling was stopped and the mixture was stirred overnight at RT. Then water was slowly added while the mixture was cooled and it was extracted several times with EtOAc. The organic phases were combined, dried on sodium sulphate, filtered and evaporated down i.vac. The residue was recrystallised from DIPE, cooled and the precipitate was suction filtered and dried.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:29]([O:31][CH3:32])=[O:30])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]([C:21](OC)=[O:22])[CH2:18][C:17]4[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[BH4-].O.Cl>C1COCC1>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:29]([O:31][CH3:32])=[O:30])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]([CH2:21][OH:22])[CH2:18][C:17]4[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)OC)Cc1ccccc1-3
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CO)Cc1ccccc1-3
Temperature: 0 °C
Yield: 85 %

Procedure:
Dimethyl 13-cyclohexyl-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylate (prepared according to International patent application publication WO 2006/020082) was dissolved in anhydrous THF (0.02 M) and after cooling at 0° C. BH3THF complex (1.5 eq.) was added followed by LiBH4 (1 eq.) and water (4 eq.). The mixture was left stirring at RT for 2h, then 1N hydrochloric acid was slowly added. The crude was extracted twice with EtOAc, dried over Na2SO4, filtered, and all volatiles were removed in vacuo to obtain desired compound as a yellow solid (85%) that was used in the next step without purification. (ES+) m/z 404 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]=1[CH2:12][C:13]#[N:14].[CH2:15](N)[CH2:16][NH2:17]>C(=S)=S>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]=1[CH2:12][C:13]1[NH:14][CH2:15][CH2:16][N:17]=1
Reactant: NCCN
Reactant: CC1=C(CC#N)CCc2ccccc21
Solvent: S=C=S
Product: CC1=C(CC2=NCCN2)CCc2ccccc21
Temperature: 120 °C

Procedure:
To a mixture of 60 g (0.33 mole) of 3,4-dihydro-1-methyl-2-naphthaleneacetonitrile and 30 ml of ethylenediamine was added 3 ml of carbon disulfide. The reaction mixture was stirred under nitrogen and heated in an oil bath at 120° C. for 21 hours, and then cooled to room temperature and concentrated in vacuo to remove volatile substances. The solid material was collected, dissolved in 600 ml of chloroform and dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was triturated with ether and dissolved in ethanol. The ethanol solution was acidified with ethanolic hydrogen chloride and ether was added until the solution became cloudy. The solid product which crystallized was collected and dried in vacuo to give 28.7 g of 2-[(3,4-dihydro-1-methyl-2-naphthalenyl)methyl]-4,5-dihydro-1H-imidazole in the form of its mono-hydrochloride salt, m.p. 223°-224° C. A recrystallization from the same solvent mixture gave a sample with m.p. 226°-229° C.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:14]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:13]2[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:12]=2[N:11]=1.[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=1[F:38]>>[C:34]([C:33]1[CH:36]=[CH:37][C:30]([NH:29][C:3](=[O:28])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:10]2[N:14]([CH2:15][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)[C:13]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:12]=3[N:11]=2)=[C:31]([F:38])[CH:32]=1)#[N:35]
Reactant: COC(=O)c1ccccc1-c1nc2cc(F)c(F)cc2n1CC1CCCCC1
Reactant: N#Cc1ccc(N)c(F)c1
Product: N#Cc1ccc(NC(=O)c2ccccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 85, from 2-(1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazol-2-yl)-benzoic acid methyl ester and 4-amino-3-fluoro-benzonitrile (CAS Reg. No. 63069-50-1). Off-white powder (65%). MS (Turbo Spray): m/z=489.6 (M+H).