Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[K+].F[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][C:6]=1[N+:20]([O-:22])=[O:21]>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][C:6]=1[N+:20]([O-:22])=[O:21])#[N:2]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(F)c([N+](=O)[O-])c1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C#N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
134 mg (2.06 mmol) of potassium cyanide were added to a solution of 500 mg (1.87 mmol) of tert-butyl (2E)-3-(4-fluoro-3-nitrophenyl)acrylate in 5.4 ml of DMF. The reaction mixture was stirred at RT overnight and then purified directly by flash chromatography on silica gel (mobile phase cyclohexane/ethyl acetate mixture). This gave 57 mg (11% of theory) of the title compound.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19](O)=[O:20])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[Cl:28][CH2:29][C:30]([NH:32][NH2:33])=[O:31].C(N(CC)CC)C>ClCCl>[Cl:28][CH2:29][C:30]([NH:32][NH:33][C:19]([C:10]1[C:11]2[C:16](=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][CH:12]=2)[N:8]([CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:9]=1)=[O:20])=[O:31]
Reactant: NNC(=O)CCl
Reactant: COc1cccc2c(C(=O)O)cn(CC3CCCCC3)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c(C(=O)NNC(=O)CCl)cn(CC3CCCCC3)c12
Reaction time: 3.5 h
Yield: 30.2 %

Procedure:
To a suspension of 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carboxylic acid (1.0 g, 3.48 mmol) in dichloromethane (20 ml) was added oxalyl chloride (0.6 ml, 6.96 mmol) and the reaction stirred for 3.5 h. The solvent was evaporated under reduced pressure and the resulting residue redissolved in dichloromethane (20 ml). To the solution was added chloroacetic acid hydrazide (1.3 g, 8.97 mmol) and triethylamine (2.9 ml, 20.9 mmol) and the reaction mixture stirred for 4 h and then left to stand overnight. The solvent was evaporated under reduced pressure and the resulting residue purified by flash column chromatography eluting with 50-100% (v/v) ethyl acetate in heptane to give 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carboxylic acid N′-(2-chloroacetyl)hydrazide (397 mg, 1.05 mmol).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C-]#N.[CH3:11][N:12]([S+](N(C)C)N(C)C)C>C(#N)C>[CH2:2]([C:11]#[N:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C)[S+](N(C)C)N(C)C
Reactant: BrCc1ccccc1
Agent: [C-]#N
Solvent: CC#N
Product: N#CCc1ccccc1
Yield: 95 %

Procedure:
A 1.71-g (10 mmole) sample of α-bromotoluene was injected into a solution of 1.90 g (10 mmole) of tris(dimethylamino)sulfonium cyanide in 2.4 ml (1.9 g) acetonitrile, and the mixture was shaken. The mixture became warm. After cooling, analysis by gas chromatography showed that all of the α-bromotoluene had been consumed, benzyl cyanide was formed in 95% yield, and benzyl isocyanide was formed in 5% yield. Crystals of tris(dimethylamino)sulfonium bromide separated from the reaction mixture.
Reaction SMILES: [OH-].[Li+].[CH3:3][N:4]([CH3:25])[C:5](=[O:24])[CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([CH3:17])[CH:14]=[C:15]([CH3:16])[C:10]=2[N:9]([CH2:18][C:19]([O:21]C)=[O:20])[C:8]1=[O:23]>C1COCC1.O>[CH3:25][N:4]([CH3:3])[C:5](=[O:24])[CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([CH3:17])[CH:14]=[C:15]([CH3:16])[C:10]=2[N:9]([CH2:18][C:19]([OH:21])=[O:20])[C:8]1=[O:23]
Reactant: COC(=O)Cn1c(=O)n(CC(=O)N(C)C)c2cc(C)cc(C)c21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c2c(c1)n(CC(=O)N(C)C)c(=O)n2CC(=O)O
Reaction time: 72 h

Procedure:
Lithium hydroxide (131 mg, 3.12 mmol) was added to a solution of methyl {3-[2-(dimethylamino)-2-oxoethyl]-5,7-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetate from Step A (333 mg, 1.04 mmol) in THF (3 mL) and H2O (1 mL). After 72 h, H2O was added and the precipitate was collected by filtration to give the title compound. MS: m/z=306 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.Cl[CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:21]([CH3:23])=[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(CC)ccc3OCC3CC3)ncnc12
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(CC)ccc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a14) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is obtained as yellow viscous oil.
Reaction SMILES: [CH:1]1([O:6][NH:7][S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=2)(=[O:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)C.[Pd]>[NH2:17][C:13]1[CH:12]=[C:11]([S:8]([NH:7][O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:9])=[O:10])[CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)NOC2CCCC2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(S(=O)(=O)NOC2CCCC2)c1
Yield: 100.1 %

Procedure:
A solution of N-(cyclopentyloxy)-3-nitro-1-benzenesulfonamide (2.98 g, 10.41 mmol) in 50 mL of absolute ethanol was combined with 5 wt % Palladium on barium sulfate (300 mg) and reduced under a balloon of hydrogen gas with vigorous agitation for 18 hours. The mixture was filtered, washed with ethanol, and evaporated in vacuo to a residue. The crude product was purified on flash grade silica gel eluting with 4:1 hexane : ethyl acetate. Fractions containing the product were combined, evaporated in vacuo and dried under vacuum to provide 3-amino-N1-(cyclopentyloxy)-1-benzenesulfonamide (2.67 g, 100%) as an oil. Hl-NMR chloroform-D3): 1.62 (m, 8H), 3.92 (bs, 2H), 4.58 (m, 1H), 6.74 (bs, !H), 6.88 (m, 1H), 7.16 (m, 1H), 7.27 (m, 2H). MS(ESI): 257(MH+).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.Cl[C:6]1[C:11]2=[C:12]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[N:13]=[C:14]([CH3:15])[N:10]2[N:9]=[CH:8][N:7]=1.C(=O)(O)[O-].[Na+].COC(C)(C)C>ClCCl>[N:1]1([C:6]2[C:11]3=[C:12]([C:16]4[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=4)[N:13]=[C:14]([CH3:15])[N:10]3[N:9]=[CH:8][N:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C1CNC1
Reactant: Cc1nc(-c2cnn(C)c2)c2c(Cl)ncnn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: Cc1nc(-c2cnn(C)c2)c2c(N3CCC3)ncnn12
Reaction time: 0.08 h

Procedure:
A solution of azetidine (9.21 g, 161 mmol) in dichloromethane (75 mL) was added to a solution of 4-chloro-7-methyl-5-(1-methyl-1H-pyrazol-4-yl)imidazo[5,1-f][1,2,4]triazine (38.14 g, 153.4 mmol) in dichloromethane (310 mL). After stirring for 5 minutes, the reaction was treated with aqueous sodium bicarbonate solution (0.89 M, 260 mL, 231 mmol) and vigorously stirred for 2 hours. After the phases separated, a white solid was collected by filtration and mixed with water and dichloromethane; it did not completely dissolve. Filtration provided a second water/dichloromethane mixture, which was combined with the original filtrate. The layers were separated, and the aqueous layer was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (250 mL), then dried over sodium sulfate and filtered. The filtrate was concentrated on a rotary evaporator at 45° C. until solid began to form in the flask. tert-Butyl methyl ether (400 mL) was added with stirring, and the mixture was granulated for 1 hour. Filtration provided the product as a white solid. Yield: 36.07 g, 133.9 mmol, 87%. 1H NMR (400 MHz, CDCl3) δ 2.23-2.31 (m, 2H), 2.65 (s, 3H), 3.97 (s, 3H), 3.98-4.08 (m, 4H), 7.61 (s, 1H), 7.62 (s, 1H), 7.85 (s, 1H).
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]1[N:11]=[C:10]([Cl:12])[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][C:15]=2[O:22][CH3:23])=[C:8]([CH3:24])[N:7]=1>C(Cl)Cl>[Cl:12][C:10]1[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][Cl:3])=[CH:16][C:15]=2[O:22][CH3:23])=[C:8]([CH3:24])[N:7]=[C:6]([NH2:5])[N:11]=1
Reactant: COc1cc(CO)ccc1Cc1c(C)nc(N)nc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cc(CCl)ccc1Cc1c(C)nc(N)nc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (0.12 mL) was added to a solution of the product from step (i) (0.39 g) in DCM (10 mL) at 0° C. The reaction mixture was stirred at rt for 1 h and then the solvent was evaporated under reduced pressure to give the subtitle compound (0.40 g) which was used without purification.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11](C1CCCCO1)[N:10]=[C:9]2[CH:21]=[O:22])[CH:2]([CH3:4])[CH3:3]>Cl.C(O)C.O1CCOCC1>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[CH:21]=[O:22])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COc1ccc2c(c1)c(C=O)nn2C1CCCCO1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)COc1ccc2[nH]nc(C=O)c2c1
Yield: 60.7 %

Procedure:
A solution of 5-iso-butoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (250 mg, 0.83 mmol, 1.00 equiv) in 12N hydrochloric acid (3 mL), ethanol (3 mL) and 1,4-dioxane (6 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum and the pH value of the solution was adjusted to 8 with saturated sodium bicarbonate solution. The resulting mixture was extracted with 3×50 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 60-100% of ethyl acetate in petroleum ether to yield 110 mg (61%) of 5-iso-butoxy-1H-indazole-3-carbaldehyde as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 10.16 (s, 1H), 7.61 (d, J=9.0 Hz, 1H), 7.48 (d, J=2.1 Hz, 1H), 7.14 (dd, J=9.0 Hz, 2.1 Hz, 1H), 3.80 (d, J=6.6 Hz, 1H), 2.10-2.05 (m, 1H), 1.01 (d, J=6.6 Hz, 6H) ppm. LCMS (method D, ESI): RT=1.50 min, m/z=219.1 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]12(O)[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2.[OH:17][C:18]1[CH:23]=[C:22]([CH3:24])[O:21][C:20](=[O:25])[C:19]=1[SH:26]>>[C:6]12([S:26][C:19]3[C:20](=[O:25])[O:21][C:22]([CH3:24])=[CH:23][C:18]=3[OH:17])[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: Cc1cc(O)c(S)c(=O)o1
Agent: O=S(=O)(O)O
Product: Cc1cc(O)c(SC23CC4CC(CC(C4)C2)C3)c(=O)o1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Ice (22 g.) was slowly added to 90 g. of concd. sulfuric acid with stirring, keeping the temperature below 35°C. by means of an ice-salt bath. 1-Adamantanol (18.2 g., 0.120 mole) was added followed by the slow addition of 15.8 g. (0.100 mole) of 4-hydroxy-3-mercapto-6-methyl-2-pyrone, keeping the temperature of the reaction mixture between 0° and 5°C. The ice bath was then removed from the reaction vessel, and the reaction mixture was warmed to 30°-40°C. with vigorous stirring for 1.5 hours. The mixture was then poured into ice water and allowed to stand for about 15 hours. The crude, solid product was collected on a filter, dried in vacuo over calcium chloride and recrystallized from ethanol (Darco) to give 8.3 g. (28 percent) of colorless needles, m.p. 175.5°-176.5°C. A second recrystallization from ethanol gave the pure product as colorless needles, m.p. 176°-177°C.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C@H:23]3[CH2:28][CH2:27][C@H:26]([C:29]([O:31]CC)=[O:30])[CH2:25][CH2:24]3)=[CH:18][CH:17]=2)=[O:15])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.O>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14]([C:16]2[CH:17]=[CH:18][C:19]([NH:22][C@H:23]3[CH2:28][CH2:27][C@H:26]([C:29]([OH:31])=[O:30])[CH2:25][CH2:24]3)=[CH:20][CH:21]=2)=[O:15])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@H]1CC[C@H](Nc2ccc(C(=O)Nc3nnc(Cc4ccccc4)s3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1nnc(Cc2ccccc2)s1)c1ccc(N[C@H]2CC[C@H](C(=O)O)CC2)cc1
Reaction time: 18 h

Procedure:
50 mg of ethyl trans-4-[4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenylamino]cyclohexanecarboxylate (0.11 mmol, 1 eq.) are placed in 1 mL of tetrahydrofuran. 9 mg of lithium hydroxide monohydrate (0.22 mmol, 2 eq.) dissolved in 1 mL are added and stirring is continued for 18 hours. The reaction medium is diluted with water, washed with ethyl acetate and acidified with aqueous 6% sulfur dioxide solution. The solid obtained is filtered off by suction, and washed successively with water, ethanol and diethyl ether. 13 mg of trans-4-[4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenylamino]cyclohexanecarboxylic acid are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([CH3:30])=[CH:24][C:25]=2[C:26]([F:29])([F:28])[F:27])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[ClH:34]>O1CCOCC1.C(OCC)C>[ClH:34].[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([CH3:30])=[CH:24][C:25]=2[C:26]([F:27])([F:28])[F:29])=[CH:18][CH:19]=1)[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1
Reaction time: 4 h
Yield: 92 %

Procedure:
To a solution of N-[(1,1-dimethylethoxyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester (132 mg, 0.33 mmol) in dioxane (3 mL) was added 4 N HCl solution in dioxane (4.5 mL) at room temperature. The solution was stirred for 4 h as a white solid was formed. The mixture was diluted with diethyl ether (50 mL) and solid was collected by filtration washing with diethyl ether. After drying under high vacuum, 315 mg (92% yield) of 4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester hydrochloride salt was obtained as an amorphous white solid. ES-HRMS m/e calcd for C18H19F3N2O3 (M+Na) 391.1241. found 391.1241. e) Preparation of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C:9]=3[NH:10]2)=[CH:6][C:5]=1[F:24].[CH3:25]I>CN(C=O)C>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:13][C:9]=3[N:10]2[CH3:25])=[CH:6][C:5]=1[F:24]
Reactant: CC(C)(C)OC(=O)N1CCc2c([nH]c3cc(Br)c(F)cc23)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2c(c3cc(F)c(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
Sodium hydride (60% weight dispersion in mineral oil, 25 mg, 0.60 mmol) was added to a solution of tert-butyl 7-bromo-6-fluoro-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (150 mg, 0.40 mmol) in DMF (10 mL) at room temperature under N2 and stirred for 1 h at ambient temperature. Methyl iodide (230 mg, 0.16 mL, 0.60 mmol) was added, and the reaction mixture was stirred for 1 h. The resulting mixture was concentrated under reduced pressure to approximately ⅓ of initial volume and treated with water (20 mL). The resulting precipitate was collected by filtration, washed with water and diethyl ether and dried under vacuum to afford the title compound (140 mg, 91%) as a yellow powder: ESI MS m/z 383 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][CH2:15][OH:16])[CH2:9][CH2:8]2)[S:5][CH:6]=1.[CH3:17][C:18]1([CH3:37])[C:27]2[CH:26]=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=[CH:23][C:22]=2[CH2:21][CH2:20][CH2:19]1.Cl>>[CH3:17][C:18]1([CH3:37])[C:27]2[CH:26]=[C:25]([C:2]3[N:3]=[C:4]([N:7]4[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][CH2:15][OH:16])[CH2:9][CH2:8]4)[S:5][CH:6]=3)[CH:24]=[CH:23][C:22]=2[CH2:21][CH2:20][CH2:19]1
Reactant: OCCNC1CCN(c2nc(Br)cs2)CC1
Reactant: CC1(C)CCCc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: Cl
Product: CC1(C)CCCc2ccc(-c3csc(N4CCC(NCCO)CC4)n3)cc21

Procedure:
The preparation is carried out as described above starting from 100 mg (0.27 mmol) of 2-[1-(4-bromothiazol-2-yl)piperidin-4-ylamino]ethanol and 98 mg (0.30 mmol) of 2-(8,8-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The product is in the form of the hydrochloride.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH:3]=[CH:2]1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[CH:13]2>C1COCC1>[CH3:8][O:9][C:10]1[CH:18]=[CH:17][C:16]2[NH:15][C:14]3[CH2:19][CH:20]([C:21]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:22])[CH:2]4[C:1](=[O:7])[NH:5][C:4](=[O:6])[CH:3]4[C:13]=3[C:12]=2[CH:11]=1
Reactant: COc1ccc2[nH]c(/C=C/C(=O)OCc3ccccc3)cc2c1
Reactant: O=C1C=CC(=O)N1
Solvent: C1CCOC1
Product: COc1ccc2[nH]c3c(c2c1)C1C(=O)NC(=O)C1C(C(=O)OCc1ccccc1)C3
Temperature: 25 °C
Yield: 83 %

Procedure:
Maleimide (4.82 g, 0.050 mol) was added to a solution of benzyl (2E)-3-(5-methoxy-1H-indol-2-yl)-2-propenoate, (12.71 g, 0.041 mol) prepared as in example 1 in THF (150 mL) in a 250 mL flat-bottomed flask and the mixture was stirred until homogeneous. The THF was removed in vacuo and the residue dried under high vacuum for 30 min. The flask was immersed in a 175° C. oil bath and the mixture was stirred at this temperature for 3 h. The solid melt was cooled to room temperature and ethyl acetate (100 mL) was added. The solid mass was partially broken up with a spatula and the mixture was stirred vigorously overnight, after which time the product (3) was present as a cream precipitate. Filtration followed by washing with diethyl ether gave benzyl 9-methoxy-1,3-dioxo-1,2,3,3a,4,5,6,10c-octahydropyrrolo[3,4-c]carbazole-4-carboxylate (13.76 g, 83%), mp 179–181° C. 1H NMR δ [(CD3)2SO] 10.98 (br s, 1H), 10.87 (s, 1H), 7.45–7.32 (m, 5H), 7.20 (d, J=2.4 Hz, 1H), 7.17 (d, J=8.7 Hz, 1H), 6.69 (dd, J=8.7, 2.4 Hz, 1H), 5.21 (s, 1H), 4.22 (br d, J=7.8 Hz, 1H), 4.14 (dd, J=7.8, 4.2 Hz, 1H), 3.75 (s, 3H), 3.19–3.13 (m, 1H), 3.00 (dd, J=16.5, 4.8 Hz, 1H), 2.79–2.70 (m, 1H).
Reaction SMILES: I[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=[N:4][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:31][C:32]1[C:37](B(O)O)=[CH:36][CH:35]=[CH:34][N:33]=1>O1CCOCC1.O.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>[F:31][C:32]1[CH:37]=[C:36]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)=[N:4][N:5]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=3)[CH:6]=2)[CH:35]=[CH:34][N:33]=1
Reactant: COc1ccc(Cn2cc(I)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Reactant: OB(O)c1cccnc1F
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Cn2cc(-c3ccnc(F)c3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
1 g (2.3 mmol) of 4-iodo-1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazole (prepared as described in Example 27) were dissolved in a mixture of 20 ml of dioxane and 5 ml of water in a nitrogen atmosphere. 750 mg (2.3 mmol) of cesium carbonate, 350 mg (0.3 mmol) of palladium tetrakis and 486 mg (3.45 mmol) of 2-fluoro-pyridyl boronic acid were added and the reaction stirred at 100° C. for 4 hours. The mixture was then filtered through a celite pad and the filtrate evaporated under reduced pressure. The residue was re-dissolved with dichloromethane and washed with water. The organic layer was dried over sodium sulphate and evaporated. 680 mg (73%) of the title compound crystallized from diethylether.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:25])[C:9]4[CH:21]=[CH:20][C:19]([C:22]([OH:24])=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[NH2:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29]>>[OH:29][CH2:28][CH:27]([NH:26][C:22]([C:19]1[CH:20]=[CH:21][C:9]2[C:8](=[O:25])[C:7]3[C:6]4[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[NH:13][C:12]=3[C:11]([CH3:17])([CH3:16])[C:10]=2[CH:18]=1)=[O:24])[CH2:30][OH:31]
Reactant: CC1(C)c2cc(C(=O)O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: NC(CO)CO
Product: CC1(C)c2cc(C(=O)NC(CO)CO)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B3-15, the title compound was prepared from Compound B2-28 and 2-aminopropane-1,3-diol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:14])[C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].[C:15](N1C=CN=C1)([N:17]1C=CN=C1)=O.CN>O1CCCC1>[N+:11]([C:10]1[C:2]([CH3:1])=[CH:3][C:4]([C:5]([NH:17][CH3:15])=[O:6])=[CH:8][C:9]=1[CH3:14])([O-:13])=[O:12]
Reactant: Cc1cc(C(=O)O)cc(C)c1[N+](=O)[O-]
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cc(C)c([N+](=O)[O-])c(C)c1
Reaction time: 3 h
Yield: 93.8 %

Procedure:
3,5-Dimethyl-4-nitrobenzoic acid (1 g, 5.12 mmol) is suspended in dry tetrahydrofuran (10 mL) and 1,1′-carbonyldiimidazole (0.91 g, 5.64 mmol) is added. The mixture is stirred for 3 hours then methylamine (2 M solution in tetrahydrofuran, 7.7 mL, 15.4 mmol) is added and the mixture stirred for 30 minutes. The solvent is removed, the residue suspended in EtOAc and washed with 0.2 M aqueous HCl solution, saturated sodium bicarbonate solution and brine, dried and the solvent removed under vacuum to give the title compound (Yield 1.0 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][C:13]1[CH:14]=[C:15]([C:24]([O:26]CC)=[O:25])[C:16](=[O:23])[N:17]3[C:22]=1[CH:21]=[CH:20][CH:19]=[CH:18]3)[CH2:6][CH2:5]2.[CH3:29][Zn]C>C1COCC1.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>[CH3:29][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][C:13]1[CH:14]=[C:15]([C:24]([OH:26])=[O:25])[C:16](=[O:23])[N:17]3[C:22]=1[CH:21]=[CH:20][CH:19]=[CH:18]3)[CH2:6][CH2:5]2
Reactant: CCOC(=O)c1cc(CN2CCc3cc(Br)ccc3C2)c2ccccn2c1=O
Reactant: C[Zn]C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)CCN(Cc1cc(C(=O)O)c(=O)n3ccccc13)C2
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl 1-[(6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)methyl]-4-oxo-4H-quinolizine-3-carboxylate (0.045 g, 0.10 mmol) in 1 mL THF under nitrogen was added 1.0 M dimethylzinc solution in THF (0.112 mL, 0.112 mmol), and tetrakis(triphenylphosphine)palladium (0) (10 mol %). The reaction mixture was stirred at 60° C. for 4 hours, quenched with 1 mL of saturated aqueous ammonium chloride, then cooled to rt and concentrated in vacuo. To a solution of the resultant brown residue in 1 mL DMSO was added saturated aqueous lithium hydroxide (0.3 mL). After 2 hours, the reaction was acidified with 1 N HCl to pH ˜2, filtered and subjected to purification via reverse phase HPLC to provide the title compound which gave a mass ion (ES+) of 349.0. 1H NMR (400 MHz, DMSO) δ 10.07 (br s, 1H), 9.46 (d, J=6.8 Hz, 1H), 8.70 (s, 1H), 8.53 (d, J=8.4 Hz, 1H), 8.22-8.19 (m, 1H), 7.76 (t, J=6.6 Hz, 1H), 7.20-6.97 (m, 3H), 4.89 (s, 2H), 4.40-4.34 (m, 2H), 3.76-3.60 (m, 2H), 3.10-3.02 (m, 2H), 2.26 (s, 3H).