Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12].B#B>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[CH2:11][OH:12]
Reactant: O=C(O)c1ccccc1CCCCCCCBr
Agent: B#B
Solvent: C1CCOC1
Product: OCc1ccccc1CCCCCCCBr
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 2-(7-bromoheptyl)benzoic acid (8.0 g, 0.027 mole) and distilled tetrahydrofuran (75 ml) was added diborane (40 ml, 0.04 mole) at room temperature under argon. The reaction mixture was stirred at room temperature for approximately 18 hours under argon, cooled to 0° C. and quenched with ethanol. The solvents were evaporated to give a colorless oil which was partitioned between methylene chloride and water. The organic layer was dried over magnesium sulfate and filtered. The resulting oil was flash chromatograhed on silica using 10% ethyl acetate in hexane to give the desired product.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2ccnc3ccc(OC)cc23)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2nccc(-n3cc(C(=O)O)c4ccccc43)c2c1

Procedure:
0.252 g (6 mmol) of lithium hydroxide monohydrate and 8 cm3 of water are added to 0.7 g (2.11 mmol) of 3-methoxycarbonyl-1-(6-methoxyquinol-4-yl)-1H-indole dissolved in 8 cm3 of tetrahydrofuran. After stirring at reflux for 20 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 20 cm3 of water (pH=10). The resulting aqueous solution is washed with 30 cm3 of ethyl acetate, adjusted to pH 6 with N hydrochloric acid and extracted with a mixture of 50 cm3 of ethyl acetate and of 100 cm3 of dichloroethane. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is triturated in 20 cm3 of isopropyl ether and filtered off, resulting in 0.57 g of 3-carboxy-1-(6-methoxyquinol-4-yl)-1H-indole in the form of a white powder. Mass spectrum (EI): m/e 318 (M+•).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([N:9]=[C:10]=[O:11])=O)=[CH:5][CH:4]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][C:16]=1[NH:29][NH:30]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]2[NH:9][C:10](=[O:11])[N:29]([C:16]3[CH:17]=[C:18]([CH:19]=[CH:20][C:15]=3[Cl:14])[CH2:21][NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[N:30]=2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NNc1cc(CNC(=O)C(C)(C)C)ccc1Cl
Reactant: O=C=NC(=O)c1ccc(CBr)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(CBr)cc3)[nH]c2=O)c1
Yield: 49.7 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 4-(bromomethyl)benzoyl isocyanate (0.150 g), tert-Butyl 2-(2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate (Intermediate-94, 0.150 g), DCM (20 mL), and trifluoro acetic acid (5.0 mL) to afford 0.100 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 1.12 (s, 9H), 4.28 (br d, 2H), 4.75 (s, 2H), 7.34 (br d, 2H), 7.43 (br s, 1H), 7.60 (br d, 2H), 7.81 (br d, 2H), 8.17 (br s, 1H), 12.57 (s, 1H).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14].C(=O)(O)[O-].[Na+].Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>ClCCl>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]([C:3]1[N:2]([NH:1][C:22](=[O:23])[O:24][CH2:25][CH3:26])[CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: CCOC(=O)Cl
Reactant: Nn1cccc1C(=O)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)Nn1cccc1C(=O)c1ccccc1Cl
Yield: 120.2 %

Procedure:
1-Amino-2-(2-chlorobenzoyl)pyrrole (32 g, 0.145 mol) was combined with sodium bicarbonate (30.2 g, 0.36 mol) in 400 ml of dichloromethane. To this rapidly stirred mixture was added ethyl chloroformate (18.6 g, 0.172 mol) over 2 minutes and the resultant slurry heated under reflux for 2.5 hours. The reaction mixture was quenched with 300 ml of H2O, separated, washed with H2O, dried (MgSO4), filtered, and evaporated to give 51 g of an oil. This oil was purified by HPLC (silica, 10:1 DCM-ethyl acetate) to give after evaporation 32.8 g (77%) of crystals, m.p. 90°-92°.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1>O=P(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(-c2ccccc2)nc2cc(Cl)ccc12
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Clc1ccc2cnc(-c3ccccc3)nc2c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
7-Chloro-2-phenylquinazolin-4(3H)-one (40 mg, 0.16 mmol) was suspended in POCl3 (2 mL) and heated to 50° C. with stirring for 24 h. Later the reaction was heated to 90° C. for 16 h. With minimum exposure to moisture, the crude mixture was evaporated to dryness under reduced pressure and treated with 2 M NH3/i-PrOH (8 mL) with cooling on ice-H2O bath under Ar. The mixture was partitioned between DCM and H2O and the organic layer was washed (H2O, satd NaHCO3 and brine), dried (Na2SO4) to afford crude material which was used directly in the following de-chlorination step. The crude material (31 mg, 0.113 mmol) and tosyhydrazide (63 mg, 0.34 mmol) were dissolved in anh CHCl3 (10 mL) and heated at 60° C. (overnight, bath temperature) and, then refluxed for 4 h. The solvent was removed under reduced pressure and the solid residue was heated under Ar in anh. PhMe (10 mL) and anh ClCH2CH2Cl (5 mL) at 80° C. (bath temperature) for 63 h: The reaction was cooled to rt and a pale yellow precipitate was collected by filtration and washed with PhMe and DCM (2×). The collected solid in aq Na2CO3 (10%, 10 mL) was placed in a preheated bath at 90° C. After stirring at the temperature for 45 min, the reaction was cooled and left standing at rt overnight. The crude reaction mixture was extracted with DCM (3×), washed (H2O, brine), dried (NazSO4), concentrated under reduced pressure, and purified by flash chromatography (silica gel, 100:0->10:1 EtOAc:hexanes) to afford the title compound as a light orange solid; 1H NMR (400 MHz, CDCl3) δ 9.43 (s, 1H), 8.63-8.56 (m, 2H), 8.09 (d, J=0.8 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.58-7.50 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH3:33])[N:25]=[C:24](Cl)[N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.O>CN1C(=O)CCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH3:33])[N:25]=[C:24]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1c(C)nc(Cl)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)c1c(C)nc(N2CCOCC2)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-2-chloro-6-methylpyrimidine-5-carboxylate (0.6 g, 1.23 mmol) was dissolved in NMP (5 mL), morpholine (0.14 mL) was added and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with water, dried over Na2SO4 and evaporated to give the desired product (0.53 g). 1H NMR (400 MHz, DMSO-d6): δ 10.48 (s, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 4.30 (q, J=6.8 Hz, 2H), 3.75 (s, 2H), 3.64 (m, 4H), 3.46-3.21 (m, 8H), 2.69 (s, 3H), 2.41 (m, 4H), 1.38 (s, 9H), 1.33 (t, J=6.8 Hz, 3H); MS m/z 541.1 (M+1).
Reaction SMILES: C([O:4][P:5]([O:12][CH:13]([CH3:15])[CH3:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(C)C.[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>>[C:16]([P:5]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:4])[O:12][CH:13]([CH3:14])[CH3:15])(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)OP(OC(C)C)c1ccccc1
Product: CC(C)OP(=O)(C(=O)C(C)(C)C)c1ccccc1
Reaction time: 2 h

Procedure:
158 parts of diisopropoxyphenylphosphine are added slowly to 84 parts of pivaloyl chloride at 50°-60° C., with thorough stirring. Stirring is then continued for two hours, after which the mixture is fractionated under reduced pressure. Isopropyl pivaloyl-phenylphosphinate distils at 119°-121° C./0.5 mm.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:6][CH2:7][OH:8])[CH3:5].[CH3:9][O:10][C:11]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[CH:24][C:12]=1[C:13]([NH:15][C:16]1[S:17][CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=1)=[O:14]>CN(C)C=O>[CH3:9][O:10][C:11]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[CH:24][C:12]=1[C:13]([NH:15][C:16]1[S:17][CH:18]=[C:19]([C:21]([O:8][CH2:7][CH2:6][N:4]([CH3:5])[CH3:3])=[O:22])[N:20]=1)=[O:14]
Reactant: COc1cc(OC)c(C(=O)Nc2nc(C(=O)O)cs2)cc1OC
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c(C(=O)Nc2nc(C(=O)OCCN(C)C)cs2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
In 10 ml of N,N-dimethylformamide, 278 mg of sodium hydride was suspended. To the resulting suspension, 620 mg of N,N-dimethylaminoethanol was added dropwise, followed by stirring at room temperature for one hour. In another 10 ml portion of N,N-dimethylformamide, 1.57 g of 2-[N-(2,4,5-trimethoxybenzoyl)amino]-4-(hydroxycarbonyl)-1,3-thiazole was suspended. To the resulting suspension, 827 mg of carbonyl diimiazole was added, followed by stirring at room temperature for one hour. Two reaction mixtures so obtained were combined and were stirred at 100° C. for one hour. The reaction mixture was poured into an ice water and the crystals so precipitated were collected by filtration. The crystals so obtained were recrystallized from isopropyl alcohol, whereby 1.4 g of the title compound was obtained. Yield: 74%.
Reaction SMILES: [N:1]([CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6])=[N+:2]=[N-:3].[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[C:13]#[CH:14])[CH3:10].[Na].C(O)CCC.O>O>[CH2:9]([O:11][CH:12]([O:15][CH2:16][CH3:17])[C:13]1[N:3]=[N:2][N:1]([CH2:4][Si:5]([CH3:8])([CH3:7])[CH3:6])[CH:14]=1)[CH3:10]
Reactant: C[Si](C)(C)CN=[N+]=[N-]
Reactant: C#CC(OCC)OCC
Agent: [Na]
Solvent: CCCCO
Solvent: O
Product: CCOC(OCC)c1cn(C[Si](C)(C)C)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.3 %

Procedure:
To a 100 ml round bottom flask equipped with a magnetic stir bar were added (azidomethyl)(trimethyl)silane (1.000 g, 7.740 mmol), 3,3-diethoxyprop-1-yne (0.992 g, 7.740 mmol), freshly made 1.0N sodium asorbate (0.774 ml, 7.740 mmol), and 1.0N Cu2SO4 (0.774 ml, 7.740 mmol) into 30.0 ml of a mixed solvent BuOH/H2O (1:1). The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum to give the crude title compound as a light yellow liquid (1.620 g, 81% crude). ES-MS [M+1]+: 258.1 (M+H). This intermediate was carried over to the next step without further purifications and characterizations.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[C:12](=[O:29])[NH:13][C:14](=[O:28])[C:15]=1[C:16]1[CH:17]=[C:18]2[C:23]3=[C:24]([CH:26]=[CH:27][N:22]3[CH2:21][CH2:20][CH2:19]2)[CH:25]=1.[Mg].Cl>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C@H:11]1[C@H:15]([C:16]2[CH:17]=[C:18]3[C:23]4=[C:24]([CH:26]=[CH:27][N:22]4[CH2:21][CH2:20][CH2:19]3)[CH:25]=2)[C:14](=[O:28])[NH:13][C:12]1=[O:29]
Reactant: O=C1NC(=O)C(c2c[nH]c3ccc(Br)cc23)=C1c1cc2c3c(ccn3CCC2)c1
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: CO
Product: O=C1NC(=O)[C@@H](c2c[nH]c3ccc(Br)cc23)[C@@H]1c1cc2c3c(ccn3CCC2)c1
Yield: 18 %

Procedure:
To a solution of 3-(5-bromo-1H-indol-3-yl)-4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-pyrrole-2,5-dione (250 mg, 0.559 mmol) in methanol (35 ml) was added magnesium turnings (354 mg, 14.57 mmol) portionwise over 20 minutes and the mixture was heated to reflux for 6 hours. The mixture was cooled and diluted with water (50 ml) and acidified with 2M aqueous hydrochloric acid. The mixture was extracted with dichloromethane (3×50 ml) and the combined organic extracts were dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified (Xterra C18, reverse phase column, eluted with acetonitrile-water system with 0.1% trifluoracetic acid as modifier) to provide (±)-trans-3-(5-bromo-1H-indol-3-yl)-4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-pyrrolidine-2,5-dione as a brown solid (45 mg). M.p.=195-200° C.; 400 MHz 1H NMR (DMSO-d6) δ: 11.41 (s, 1H), 11.24 (s, 1H), 7.99 (d, J=2.0 Hz, 1H), 7.47 (d, J=2.0 Hz, 1H), 7.30 (m, 3H), 7.17 (dd, J=8.4 and 2.0 Hz, 1H), 6.83 (s, 1H), 4.53 (d, J=7.6 Hz, 1H), 4.38 (d, J=7.6 Hz, 1H), 4.13 (m, 2H), 2.90 (t, J=6.0 Hz, 2H), 2.11 (m, 2H); LCMS: 448 and 450 [M+H].
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1.CCN(C(C)C)C(C)C.Cl.Cl.[N:37]1([CH:42]2[CH2:46][CH2:45][NH:44][CH2:43]2)[CH2:41][CH2:40][CH2:39][CH2:38]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:44]4[CH2:45][CH2:46][CH:42]([N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[CH2:43]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1
Reactant: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: C1CCN(C2CCNC2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(N3CCC(N4CCCC4)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-1-hydroxycyclohexylmethyl)-amide, DIPEA and 3-pyrrolidin-yl-pyrrolidine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1H), 7.48 (2H), 6.69 (1H), 4.59 (s, 1H), 3.89 (m, 1H), 3.70 (m, 1H), 3.45 (m, 1H), 3.26 (m, 2H), 2.85 (m, 1H), 2.54 (m, 4H), 2.15 (m, 1H), 2.06 (m, 2H), 1.85 (m, 3H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 494 [M+H]
Reaction SMILES: [CH3:1]I.[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[S:13])[S-:12].[NH4+]>O>[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[S:12])[S:13][CH3:1]
Reactant: CI
Reactant: Nc1ccccc1NC(=S)[S-]
Agent: [NH4+]
Solvent: O
Product: CSC(=S)Nc1ccccc1N
Yield: 90 %

Procedure:
Methyl iodide (99.4 g.) is added to a solution of ammonium 2-aminophenyl-dithiocarbamate (141 g.) in water (1050 cc.), whilst keeping the temperature at about 20° C. The mixture is stirred for a further hour after the end of the exothermic reaction. The precipitate obtained is filtered off and is then recrystallized moist from ethanol. Methyl 2-aminophenyl-dithiocarbamate (125 g.), m.p. 114° C., is thus obtained.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[N:11]3[N:19]=[C:20]([C:22]([OH:24])=[O:23])[N:21]=[C:10]3[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:26](O)[CH3:27]>>[CH2:26]([O:23][C:22]([C:20]1[N:21]=[C:10]2[CH2:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[N:11]2[N:19]=1)=[O:24])[CH3:27]
Reactant: CCO
Reactant: O=C(O)c1nc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: Cl
Product: CCOC(=O)c1nc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
6.77 g (0.020 mole) of 6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxylic acid [cp. Example 1(a), (b) and (c)] is suspended in 250 ml of abs. ethanol. While being stirred and refluxed, the solution is saturated with hydrogen chloride gas. The obtained clear solution is refluxed for a further 10 hours, and afterwards concentrated at 40° in vacuo. The residue is dissolved in 100 ml of ice-cold 5% sodium bicarbonate solution and 100 ml of methylene chloride; the organic phase is separated, washed with water, dried over sodium sulphate and concentrated at 40° in vacuo. The crude greasy residue is refluxed for one hour with 100 ml of ether, whereby crystallisation occurs. After cooling to 0°, the crystals are filtered off under suction and washed with ether. 6-Phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxylic acid ethyl ester, M.P. 137°-138°, is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][C:3]=1[O:23][CH3:24].N1C=CC=CC=1.[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[CH2:36][C:37](Cl)=[O:38]>ClCCl>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:37](=[O:38])[CH2:36][C:32]4[S:31][CH:35]=[CH:34][CH:33]=4)=[C:3]([O:23][CH3:24])[CH:4]=3)=[CH:9][N:10]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)Cc1cccs1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1NC(=O)Cc1cccs1
Reaction time: 8 h
Yield: 32.3 %

Procedure:
5-(4-Amino-3-methoxyphenyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (31 mg, 0.096 mmol) was dissolved in dichloromethane (1 mL). Pyridine (1 mL) was added followed by 2-(2-thienyl)ethanoyl chloride (14 uL, 0.113 mmol). After stirring overnight, another 14 uL of 2-(2-thienyl)ethanoyl chloride was added and the reaction mixture was stirred overnight. The solvent was removed and the residue was purified by preparative thin layer chromatography eluting with dichlormethane/methanol (95:5) to give N1-[4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]-2-(2-thienyl)acetamide (14 mg, 0.031 mmol). 1H NMR (DMSO-d6) δ 1.89 (m, 6H), 2.25 (m, 2H), 3.82 (s, 3H), 3.99 (s, 2H), 5.19 (bs, 2H), 5.21 (m, 1H), 6.93 (s, 1H), 6.94 (s, 1H), 7.06 (m, 3H), 7.31 (m, 1H), 8.02 (s, 1H), 8.32 (s, 1H), 8.42 (d, J=8.22 Hz, 1H). LC/MS MH+=448.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])=[N:3]1.[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br>>[Br:15][C:16]1[CH:17]=[C:18]([CH2:19][CH2:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:4]2[O:5][CH2:6][C:2]([CH3:14])([CH3:1])[N:3]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: BrCc1cccc(Br)c1
Reactant: Cc1ccccc1C1=NC(C)(C)CO1
Product: CC1(C)COC(c2ccccc2CCc2cccc(Br)c2)=N1

Procedure:
The subtitle compound was prepared from the product of step (i) (1 g) and 3-bromobenzylbromide (1.32 g) according to the method of example 21 step (ii). Purification was by chromatography eluting with 5-10% ethyl acetate inisohexane. Yield 0.64 g.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].O1CCCC1.[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22]I)=[O:16])([CH3:13])([CH3:12])[CH3:11].[NH4+].[Cl-]>C(OCC)C.[Cu]I>[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][CH:1]=[CH2:2])=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: C=C[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CI
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: -36 °C
Reaction time: 6 h

Procedure:
Under a nitrogen atmosphere, a solution of vinylmagnesium bromide, 1.0 M in tetrahydrofuran (2.0 mL, 2.0 mmol) was slowly added to a suspension of copper(I) iodide (244.9 mg, 1.28 mmol) in dry diethyl ether (10 mL) at −78° C. Upon completion of the addition, the mixture was warmed to −36° C. for 5 min and was then cooled to −78° C. A solution of (2S)-N-(tert-butoxycarbonyl)-2-(iodomethyl)pyrrolidine (200.0 mg, 0.64 mmol) in dry diethyl ether (5 mL) was added over a period of 10 min. The reaction mixture was warmed to −36° C. and was stirred at −36° C. for 6 h. The resulting dark mixture was treated with saturated aqueous NH4Cl solution (5 mL) and was stirred while warming to ambient temperature. The reaction mixture was extracted with diethyl ether (4×10 mL). The combined ether extracts were dried (Na2SO4), filtered and concentrated under vacuum to yield a pale-yellow oil (200 mg). The product was purified by column chromatography, eluting with hexane:ethyl acetate (1:1). Fractions containing the product were combined and concentrated under vacuum to afford 100 mg (73.6%) of an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([O:14][C:15]3[C:20]4[N:21]=[C:22]([NH2:24])[S:23][C:19]=4[CH:18]=[CH:17][CH:16]=3)[CH:9]=2)=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([O:14][C:15]3[C:20]4[N:21]=[C:22]([NH:24][C:25](=[O:27])[CH3:26])[S:23][C:19]=4[CH:18]=[CH:17][CH:16]=3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc2c(Oc3cc(-c4ccc(Br)cc4)ncn3)cccc2s1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(Br)cc4)ncn3)cccc2s1
Temperature: 90 °C

Procedure:
To a 50 mL, round-bottomed flask containing 4-[6-(4-bromo-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-ylamine, (Example 129(c)), (0.050 g, 0.13 mmol) was added anhydrous toluene (3 mL) and acetic anhydride (0.010 mL, 0.39 mmol, Aldrich). The mixture was heated at 90° C. and the progress of the reaction was monitored by TLC (developed in 50% EtOAc/hexanes). After reaching completion, the reaction mixture was allowed to cool to room temperature, the white precipitate was collected by filtration, washed with MeOH (5 mL), and dried under vacuum to obtain the title compound as a white solid. Mp: 271–272° C. MS (ESI, pos. ion.) m/z: 441 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:19][CH:20]1[CH2:22][CH2:21]1)[CH:13]([OH:18])[C:14]([O:16]C)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1.O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:19][CH:20]1[CH2:21][CH2:22]1)[CH:13]([OH:18])[C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(O)[C@H](CC1CC1)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@@H](CC1CC1)C(O)C(=O)O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of the methyl ester of Step 2 (400 mg; 1.3 mmol) in THF (8 mL) and water (6.63 mL) was added LiOH (1 N, 1.37 mL). The reaction mixture was stirred for 30 minutes and then acidified with 1.0 N HCl to pH=3˜4. The mixture was extracted with EtOAc (20 mL, twice). The combined organic layer was washed with water, brine, and then concentrated in vacuo to afford the title compound (370 mg). (M+1) 294.