Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].O1CCCC1.CC(C)([O-])C.[K+].[Cl:18][C:19]1[CH:28]=[CH:27][C:22]([C:23](=[O:26])[CH2:24]Br)=[CH:21][CH:20]=1>O.[Cl-].[Na+].O.CCCCCC.C(OCC)(=O)C>[Cl:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([CH2:24][CH:3]([C:1]#[N:2])[C:4]([NH2:6])=[O:5])=[O:26])=[CH:21][CH:20]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: N#CCC(N)=O
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#CC(CC(=O)c1ccc(Cl)cc1)C(N)=O
Yield: 19.7 %

Procedure:
To a stirred mixture of cyanoacetamide (2.5 g, 0.030 mol) and tetrahydrofuran (160 mL) is slowly added potassium tert-butoxide (3.3 g, 0.030 mol) followed by p-chlorophenacyl bromide (7.0 g, 0.030 mol). The reaction is slightly exothermic and, after a short time, TLC shows none of the p-chlorophenacyl bromide present. The reaction mixture is diluted with water and brine and extracted with ether. The ether extract is dried and concentrated in vacuo to give a red oil. Upon addition of a hexane/ethyl acetate mixture (3:1) to the oil a solid forms and is collected by filtration to give the title product as a light yellow solid (1.4 g, 20%, mp 160°-161° C.) which is identified by IR and NMR spectral analyses.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([CH:17]=O)[N:14]=[CH:13]2)=[CH:8][CH:7]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:16]=[C:15]([CH:17]3[O:4][CH2:1][CH2:2][O:3]3)[N:14]=[CH:13]2)=[CH:10][CH:11]=1
Reactant: O=Cc1cn(-c2ccc(Cl)cc2)cn1
Reactant: OCCO
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: Clc1ccc(-n2cnc(C3OCCO3)c2)cc1
Temperature: 25 °C
Yield: 41.2 %

Procedure:
A solution of ethane-1,2-diol (0.081 mL, 1.45 mmol, 1.5 equiv), 1-(4-chlorophenyl)-1H-imidazole-4-carbaldehyde (200 mg, 0.968 mmol), and camphorsulfonic acid (45 mg, 0.19 mmol, 0.2 equiv) in toluene (10 mL) was heated at reflux with a Dean-Stark apparatus for 1 hour. The reaction was cooled to room temperature and quenched with saturated aqueous sodium bicarbonate (30 mL). The mixture was extracted with ethyl acetate (30 mL) and the organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. Silica gel column chromatography (EtOAc with 7% methanol) provided 1-(4-chlorophenyl)-4-(1,3-dioxolan-2-yl)-1H-imidazole (0.100 g, tan solid) in 41% yield. 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.36 (s, 1H), 7.33 (d, J=8.4 Hz, 2H), 5.96 (s, 1H), 4.20 (m, 2H), 4.05 (m, 2H). MS m/z 251.0 (M+H)+; Rt-0.53 min.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[CH:11][C:10]=1[CH2:19][C:20]#[N:21])C1C=CC=CC=1>[C].[Pd].O1CCCC1>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[CH:11][C:10]=1[CH2:19][C:20]#[N:21]
Reactant: COCOc1ccc(OCc2ccccc2)c(CC#N)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COCOc1ccc(O)c(CC#N)c1
Yield: 93.5 %

Procedure:
A mixture of 2-(2-benzyloxy-5-methoxymethoxyphenyl)acetonitrile (2.95 g), 5% palladium carbon (2.0 g) and tetrahydrofuran (100 mL) was subjected to catalytic hydrogenation at room temperature and 4.8 atm. After filtering off the catalyst, the solvent was evaporated under reduced pressure to give crystals (1.88 g, 94%) of 2-(2-hydroxy-5-methoxymethoxyphenyl)acetonitrile. Recrystallization from ethyl acetate-hexane gave pale-brown prism crystals. melting point: 68-69° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([SH:7])([CH3:6])[CH3:5].C([O:10][C:11](=[O:35])[CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22](F)=[CH:21][C:20]=2[CH2:26][N:27]([C:30]([CH:32]2[CH2:34][CH2:33]2)=[O:31])[CH2:28][CH3:29])[CH:18]=1)C>CN(C=O)C.O.N#N>[C:4]([S:7][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[CH:18]=[C:13]([CH2:12][C:11]([OH:35])=[O:10])[CH:14]=[N:15][CH:16]=2)=[C:20]([CH2:26][N:27]([C:30]([CH:32]2[CH2:34][CH2:33]2)=[O:31])[CH2:28][CH3:29])[CH:21]=1)([CH3:6])([CH3:5])[CH3:3]
Reactant: CCOC(=O)Cc1cncc(-c2ccc(F)cc2CN(CC)C(=O)C2CC2)c1
Reactant: CC(C)(C)S
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(Cc1cc(SC(C)(C)C)ccc1-c1cncc(CC(=O)O)c1)C(=O)C1CC1
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% in mineral oil; 0.042 g, 1.04 mmol) was suspended in DMF (5 mL). After stirring for 10 minutes, 2-methyl-2-propanethiol (0.13 mL, 1.15 mmol) was added, and the mixture was stirred for 30 minutes. (5-{2-[(N-Cyclopropanecarbonyl-N-ethyl-amino)-methyl]-4-fluoro-phenyl}-pyridin-3-yl)-acetic acid ethyl ester (0.20 g, 0.52 mmol) was added, and the reaction was stirred at 90° C. overnight. The mixture was diluted with H2O, and N2 was bubbled through the solution into a bleach trap until all odor was removed. The aqueous layer was washed with EtOAc, and then acidified to pH 4 and extracted with EtOAc. The combined organic layers were concentrated, and the residue was purified by preparative HPLC to give Compound 22.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C@H:5]1[CH2:9][N:8]([CH3:10])[C@H:7]([CH2:11][O:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:6]1.CO>C1COCC1>[CH3:3][O:4][CH:5]1[CH2:9][N:8]([CH3:10])[C@H:7]([CH2:11][O:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:6]1
Reactant: CO[C@@H]1C[C@@H](COc2cccnc2)N(C)C1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COC1C[C@@H](COc2cccnc2)N(C)C1

Procedure:
To the compound from step 47a above, dissolved in 4 mL of THF, was added 3.39 mL of BH3 and the mixture was heated at reflux for 2 hours. Methanol was added to the reaction mixture and evaporated. The residue was dissolved in anhydrous ethanol. Cesium fluoride was added, and the resultant solution was stirred under reflux for 16 hr. Evaporation of the solvent provided a white solid which was purified on a silica gel column. MS (DCI/NH3) m/e: 223 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.34 (m, 1H), 8.23 (t, J=3 Hz, 1H), 7.22 (m, 1H), 3.93-4.10 (m, 3H), 3.44-3.54 (m, 1H), 3.32 (s, 3H), 3.03-2.87 (m, IF), 2.51 (s, 3H), 2.44-2.33 (m, 11H), 2.11-1.92 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:28][CH3:29])=[CH:6][C:7]([O:23][CH2:24][CH:25]([F:27])[F:26])=[C:8]([CH:22]=1)[C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([F:21])([F:20])[F:19])[CH2:14][CH2:13]1)=[O:10])([O-])=O.[H][H]>[Pd]>[NH2:1][C:4]1[C:5]([NH:28][CH3:29])=[CH:6][C:7]([O:23][CH2:24][CH:25]([F:26])[F:27])=[C:8]([CH:22]=1)[C:9]([NH:11][C@H:12]1[CH2:13][CH2:14][C@H:15]([C:18]([F:21])([F:20])[F:19])[CH2:16][CH2:17]1)=[O:10]
Reactant: [H][H]
Reactant: CNc1cc(OCC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CNc1cc(OCC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N

Procedure:
The sub-title compound was prepared from 5-nitro-2-(2,2-difluoroethoxy)-4-(methylamino)-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-benzamide, hydrogen and Pd/C in analogy to example 86c.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH:23]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[Cl:22][C:7]1[C:8]([NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:23]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH:11]=[CH:10]2
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: C1CNCCNC1
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CCCNCC3)ccc12
Yield: 40.4 %

Procedure:
Prepared according to the method of example 2 using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1 (a)) (200 mg) and homopiperazine (600 mg). Recrystallisation from acetonitrile afforded the title compound as a solid (96 mg).
Reaction SMILES: [CH2:1]([NH:8][CH:9]([C:12]1([C:15]([O:17]CC)=O)[CH2:14][CH2:13]1)[C:10]#[N:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N.[H][H]>[Ni]>[CH2:1]([NH:8][CH:9]1[C:12]2([CH2:14][CH2:13]2)[C:15](=[O:17])[NH:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(C(C#N)NCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Product: O=C1NCC(NCc2ccccc2)C12CC2

Procedure:
An autoclave was charged with 61.3 mg of 1-(1-benzylamino-1-cyanomethyl)-1-ethoxycarbonylcyclopropane, 0.2 ml of Raney nickel and 2.0 ml of ammonia-saturated ethanol, and the contents were stirred at room temperature for 2 hours in an atmosphere of hydrogen under a pressure of 30 kg/cm2. After completion of the reaction, the catalyst was removed by filtration and the resulting filtrate was concentrated under a reduced pressure to obtain 51.3 mg (quantitative) of the title compound in the form of light yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)#[N:2].[Br:18]Br.C(OCC)(=O)C>CN(C=O)C.[Cl-].[Na+].O>[Br:18][C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])[CH:10]=2)[NH:14][CH:13]=1
Reactant: N#Cc1ccccc1-c1ccc2[nH]ccc2c1
Reactant: BrBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccccc1-c1ccc2[nH]cc(Br)c2c1
Yield: 92.7 %

Procedure:
5-(2-Cyanophenyl)indole (1.38 mmoles, 300 mg) was dissolved in DMF (1 ml). A solution of bromine (1.4 moles, 0.074 ml) in 0.5 ml DMF was added. The reaction was poured into ethyl acetate and brine. The organic phase was washed with water, dried over sodium sulfate, and concentrated. The intermediate was chromatographed over silica gel eluted with 50 % ether in hexane to yield 380 mg of 3-bromo-5-(2-cyanophenyl)indole (MS)
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[CH:20]#[N:21].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O1CCCC1.CO>[NH2:9][CH:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:20]#[N:21]
Reactant: C#N
Reactant: N#CCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: N#CC(N)Cc1ccccc1
Temperature: 0 °C
Yield: 70 %

Procedure:
1 millimole (0.117 g ) of benzyl cyanide is dissolved in 1 ml of anhydrous toluene at 0° C., under an argon atmosphere. 1.5 millimoles of a toluenic solution 1.5M of diisobutylaluminum hydride (1 m) are added dropwise at this temperature. The reaction mixture is maintained at 0° C. for 1 hour, then a solution of hydrocyanic acid (in excess) in tetrahydrofuran is added to this mixture, which is then maintained at room temperature for 3 hours, then hydrolyzed with 4 ml of methanol and pasty sodium sulfate. After an acid-base extraction, there are obtained 0.107 g of 2-amino-3-phenyl-propionitrile, in the form of a pale-yellow oil, with a yield of 70%,
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[CH:5]2.[C-:14]#[N:15].[K+].[OH-].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:14]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[CH:5]2)#[N:15]
Reactant: [C-]#N
Reactant: COc1ccc2cc(Br)ccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2cc(C#N)ccc2n1

Procedure:
A mixture of 6-bromo-2-methoxyquinoline (0.476 g), potassium cyanide (0.26 g), potassium hydroxide (0.05 mg) and palladium (II) acetate (0.067 g) in DMF (2.0 cm3) were heated at 135° for 3 hours. The cooled solution was then partitioned between water (20 cm3) and chloroform (50 cm3) and the aqueous phase was further extracted with chloroform (2×25 cm3). The combined and dried (MgSO4) extracts were evaporated in vacuo and the residue was chromatographed on silica (Merck "MK 60.9385") eluting with toluene to afford, after collection and evaporation of appropriate fractions, 6-cyano-2-methoxyquinoline, m.p. 163°-165°, (0.216 g).
Reaction SMILES: Br[C:2]1[N:6]([CH:7]2[CH:11]([OH:12])[CH:10]([OH:13])[CH:9]([CH2:14][OH:15])[CH2:8]2)[C:5]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:4]=2[N:3]=1.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([NH:26][C:2]1[N:6]([CH:7]2[CH:11]([OH:12])[CH:10]([OH:13])[CH:9]([CH2:14][OH:15])[CH2:8]2)[C:5]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:4]=2[N:3]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: OCC1CC(n2c(Br)nc3cc(Cl)c(Cl)cc32)C(O)C1O
Reactant: CC(C)(C)N
Product: CC(C)(C)Nc1nc2cc(Cl)c(Cl)cc2n1C1CC(CO)C(O)C1O
Temperature: 90 °C

Procedure:
A solution of (±)-(1R*, 2S*, 3S*, 5S*)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol (750 mg, 1.44 mmole) was stirred in tert-butylamine (Aldrich, 98%, 25 mL) in a Parr bomb maintained at 90° C. (oil bath) for 6 days. Volatiles were evaporated in vacuo and the residual solids refluxed in ethanol (30 mL) with aqueous dimethylamine (Aldrich, 40%, 2 mL) for one hour. Volatiles were evaporated and the residual solids chromatographed on silica gel. Elution with 10% methanol-ethyl acetate gave title compound as colorless glass. Solidification from water gave (±)-(1R*, 2S*, 3S*, 5S*)-5-[2-(tert-butylamino )-5,6-dichloro-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol as a white powder (150 mg, 26%); m.p. 130°-132° C.; 1H-NMR(DMSO-d6) identical with that of the enatiomer described in Example 82.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[CH3:17])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]([O:20][CH3:21])=[O:19])[CH:8]=2)[N:3]=1.CC1(C)OB([C:28]2[CH:32]=[CH:31][N:30]([Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])[CH:29]=2)OC1(C)C.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:17][C@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[C:11]1[C:2]([C:28]2[CH:32]=[CH:31][N:30]([Si:33]([CH:37]([CH3:39])[CH3:38])([CH:40]([CH3:42])[CH3:41])[CH:34]([CH3:35])[CH3:36])[CH:29]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:18]([O:20][CH3:21])=[O:19])=[CH:6][CH:5]=2
Reactant: COC(=O)c1ccc2nc(Cl)c(N3CCC[C@@H]3C)nc2c1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B2OC(C)(C)C(C)(C)O2)c1
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: O
Solvent: COCCOC
Product: COC(=O)c1ccc2nc(-c3ccn([Si](C(C)C)(C(C)C)C(C)C)c3)c(N3CCC[C@@H]3C)nc2c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
To a solution of methyl 2-chloro-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylate (180 mg, 0.59 mmol) in ethylene glycol dimethyl ether (6 ml) and water (2 ml) was added 3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[tris(propan-2-yl)silyl]-1H-pyrrole (618 mg, 1.77 mmol), sodium carbonate (188 mg, 1.77 mmol) and Pd(PPh3)4 (34 mg, 0.03 mmol) with stirring for 1 h at 95° C. in an oil bath maintained under an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to give a residue, which was purified via silica gel chromatography (2% ethyl acetate in petroleum ether) to afford methyl 3-[(2S)-2-methylpyrrolidin-1-yl]-2-[1-[tris(propan-2-yl)silyl]-1H-pyrrol-3-yl]quinoxaline-6-carboxylate as a light yellow solid (150 mg, 52%).
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[ClH:17]>O.Cl[Cu]>[Cl:17][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: Nc1ccc2c(c1)C(=O)CCC2
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C1CCCc2ccc(Cl)cc21
Yield: 98 %

Procedure:
7-Amino-1-tetralone (500 mg, 3.1 mmol) was suspended in 3 mL of water and treated with 3 mL of concentrated hydrochloric acid with stirring. The mixture was cooled in an ice bath and treated dropwise with vigorous stirring with a solution of 241 mg of sodium nitrite in 1.5 mL of water (3.5 mmol, 1.1eq). The mixture was stirred at 0°-5° for 15 minutes then added dropwise to a cold solution of 366 mg of CuCl (3.7 mmol, 1.2 eq) in 6 mL of concentrated hydrochloric acid. The mixture was stirred for 5 minutes at 0° and 1 hour at room temperature. The mixture was extracted with methylene chloride (3×15 mL); the combined extracts were washed with brine, dried over magnesium sulfate, filtered and evaporated to dryness under vacuum at room temperature to give 550 mg (3.05 mmol, 98%) of the product, 1H NMR (300MHz, CDCl3): 2.16 (m,2H), 2.67 (t,6Hz,2H), 2.95 (t,6Hz,2H), 7.22 (d,8Hz,1H), 7.44 (dd;2,8Hz;1H), 8.01 (d,2Hz,1H). FAB-MS: calculated for C10H9C10 180; found 181 (M+H,10%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[Br:22][C:23]1[CH:24]=[C:25]2[CH2:31][C:30](=[O:32])[NH:29][C:26]2=[N:27][CH:28]=1>>[Br:22][C:23]1[CH:24]=[C:25]2[C:31](=[CH:20][C:3]3[NH:4][C:5]4[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]5[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]5)[C:7](=[O:19])[C:6]=4[C:2]=3[CH3:1])[C:30](=[O:32])[NH:29][C:26]2=[N:27][CH:28]=1
Reactant: O=C1Cc2cc(Br)cnc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3ncc(Br)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 65.1 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-bromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one as starting materials to give 2-(5-bromo-2-oxo-1,2-dihydro-pyrrolo[2,3-b]pyridin-3-ylidenemethyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (32 mg, 65.1%) as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Br:11]Br.C(=O)(O)[O-].[Na+]>C(OCC)C>[Br:11][CH2:9][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1cccc(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: Cc1cccc(C(=O)CBr)c1

Procedure:
To a solution of 1-(3-methylphenyl)ethanone (2 g) in ethyl ether (20 mL) is added bromine (726 μL) at 0° C. The mixture is treated with an aqueous solution of sodium bicarbonate, extracted with ethyl ether, dried over magnesium sulfate, concentrated and purified on silica gel (ethyl acetate/cyclohexane 0/100) to give the desired compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH:10]3[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:5]([CH3:23])[O:4][N:3]=1.Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:5]([CH3:23])[O:4][N:3]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccccc1)C(=O)N2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)CC1(c2ccccc2)C(=O)Nc2ccc(-c3c(C)noc3C)cc21
Temperature: 60 °C
Yield: 60.3 %

Procedure:
A mixture of 5-(3,5-dimethylisoxazol-4-yl)-3-phenyl indolin-2-one (260 mg, 0.85 mmol), ethyl bromoacetate (172 mg, 1.0 mmol), potassium iodide (171 mg, 1.0 mmol) and potassium carbonate (260 mg, 1.88 mmol) in acetone (10 mL) was heated at 60° C. for 15 hours in a capped pressure tube. The mixture was then cooled to room temperature and diluted with ethyl acetate (30 mL) and extracted with water (2×30 mL) and brine (20 mL). Aqueous layers were back washed with ethyl acetate (30 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (dichloromethane, then 5% ethyl acetate in dichloromethane as solvent) to give product (200 mg, 59.9%). 1H NMR (400 MHz, DMSO-d6): δH 10.61 (s, 1H), 7.21-7.39 (m, 7H), 6.97 (d, J=8.0 Hz, 1H), 3.82-3.85 (m, 2H), 3.41 (s, 3H), 2.36 (s, 3H), 2.19 (s, 3H), 0.90 (t, J=6.8 Hz, 1H). MS (ESI) m/e [M+1]+ 391.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([CH3:13])[C:3]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:2]2[N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1nc2ccc(I)cc2c(Cl)c1S(C)(=O)=O
Reactant: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2ccc(I)cc2c(N2CCCCC2)c1S(C)(=O)=O
Yield: 54.4 %

Procedure:
4-Chloro-6-iodo-3-methanesulfonyl-2-methyl-quinoline (compound of example D.2) (300 mg, 0.786 mmol), piperidine (74 mg, 0.865 mmol) and N,N-diisopropyl ethyl amine (0.148 mL, 0.865 mmol) were heated in dry N,N-dimethylformamide (3 mL) for 4 h at 100° C. N,N-Dimethylformamide was evaporated at 40° C./0.1 mbar, and the residue directly purified by chromatography on silica gel in dichloromethane. One obtained 184 mg (54%) of white crystals. MS: m/z=431 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH2:22])[CH:10]=[C:11](S([O-])(=O)=O)[C:12]=3[OH:17])[C:7](=[O:23])[C:6]=2[C:5]([OH:24])=[C:4](S([O-])(=O)=O)[CH:3]=1.[Na+].[Na+].[CH2:31]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:32][CH2:33][CH3:34]>B(O)(O)O.S(=O)(=O)(O)O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([NH2:22])[CH:10]=[CH:11][C:12]=3[OH:17])[C:7](=[O:23])[C:6]=2[C:5]([OH:24])=[CH:4][C:3]=1[C:39]1[CH:40]=[CH:41][C:36]([O:35][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:37][CH:38]=1
Reactant: Nc1cc(S(=O)(=O)[O-])c(O)c2c1C(=O)c1c(O)c(S(=O)(=O)[O-])cc(N)c1C2=O
Reactant: CCCCOc1ccccc1
Agent: O=S(=O)(O)O
Agent: OB(O)O
Agent: [Na+]
Product: CCCCOc1ccc(-c2cc(O)c3c(c2N)C(=O)c2c(O)ccc(N)c2C3=O)cc1
Temperature: 80 °C

Procedure:
4.0 g of sodium 4,8-diamino-1,5-dihydroxy-anthraquinone-2,6-disulfonate is dissolved in a mixture of 2.0 g of boric acid and 30 ml concentrated sulphuric acid heated to 80° C. The blue solution obtained is cooled to a temperature of 0° to 5° C., and 2.8 g of butoxybenzene is stirred in drop by drop, the colour then changing from blue to reddish brown. The mixture is agitated for a further two hours at 0° to 10° C., then poured onto ice. The suspension obtained is heated on reflux for 4 hours to destroy the boric ester, and a violet precipitate is filtered off after cooling, corresponding to 4,8-diamino-1,5-dihydroxy-3-p-butoxyphenyl-anthraquinone-6-sulphonic acid. The moist precipitate is dissolved hot in a mixture of 24 ml of 33% ammonia and 160 ml of water, and the sulphonic groups are separated by adding 2.2 g of sodium dithionate in stages. The mixture is finally heated to 95° C. for approximately 2 hours, then cooled and filtered. The precipitate thus obtained is washed with slightly acidified water, then with a great excess of water, and dried. The desired product may further be purified by crystallisation or chromatography if necessary.
Reaction SMILES: [C:1]1(=O)N[C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]1(=[O:18])[NH:16][C:15](=[O:17])[CH:14]=[CH:13]1>>[C:15]1(=[O:17])[N:16]([CH:4]2[C:3]3=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]3[CH2:1]2)[C:12](=[O:18])[CH:13]=[CH:14]1
Reactant: O=C1C=CC(=O)N1
Reactant: O=C1NC(=O)c2ccccc21
Product: O=C1C=CC(=O)N1C1Cc2ccccc21

Procedure:
An alternative process is that wherein a 3- or 4-halobenzocyclobutene reactant is treated with a phthalimide or maleimide to produce a 3- or 4-phthalimido-or maleimidobenzocyclobutene. When phthalimide or maleimide is monomeric, for example, phthalide or maleimide themselves, the product can be cleaved by reaction with an amine to produce a corresponding aminobenzocyclobutene. A preferred amine for this purpose is hydrazine, preferably hydrazine hydrate.