Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH2:27][C:28]1[N:32]([CH3:33])[N:31]=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][C:28]2[N:32]([CH3:33])[N:31]=[CH:30][CH:29]=2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: Cn1nccc1N
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: Cn1nccc1NC(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 5-amino-1-methylpyrazole via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(1-methyl-1H-pyrazol-5-yl)terephthalamide. MS (Q1) 466 (M)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[CH3:18][CH:19]([OH:21])[CH3:20]>>[CH:19]([O:21][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1)([CH3:20])[CH3:18]
Reactant: CC(C)O
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: CC(C)Oc1nc(Nc2cc[nH]n2)cc2ccccc12

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and propan-2-ol to give (1-isopropoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 269(MH+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:5]([Cl:20])=[CH:6][C:7]2[NH:11][C:10](=[O:12])[N:9]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:8]=2[CH:19]=1.[O:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.[BH3-]C#N.[Na+]>CO>[Cl:20][C:5]1[C:4]([O:3][CH3:2])=[CH:19][C:8]2[N:9]([CH:13]3[CH2:14][CH2:15][N:16]([CH:24]4[CH2:25][CH2:26][O:21][CH2:22][CH2:23]4)[CH2:17][CH2:18]3)[C:10](=[O:12])[NH:11][C:7]=2[CH:6]=1
Reactant: COc1cc2c(cc1Cl)[nH]c(=O)n2C1CCNCC1
Reactant: O=C1CCOCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(cc1Cl)[nH]c(=O)n2C1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Methoxy-5-chloro-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (D50) (30 mg, 0.1 mmol), Ti(iPrO)4 (0.15 ml, 0.5 mmol), and tetrahydro-4H-pyran-4-one (50 mg, 0.5 mmol) were stirred together at room temperature for 1 h; dry methanol (1 ml) followed by NaBH3CN (30 mg, 0.5 mmol) were added and the mixture was stirred at room temperature for 2 h. The crude mixture was then quenched with methanol and it was purified first by SCX column chromatography followed by silica gel chromatography (10% methanol-NH3-dichloromethane) to afford 5-chloro-6-methoxy-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one. Conversion to the hydrochloride gave the title compound, 10 mg, MH+=366 and 368.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][N:6]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13][C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]1=2.Cl.C(=O)([O-])[O-].[K+].[K+].[CH2:28]([O:30][P:31](Cl)([O:33][CH2:34][CH3:35])=[O:32])[CH3:29]>CN(C=O)C>[CH2:28]([O:30][P:31]([N:2]([CH2:3][CH2:4][CH2:5][N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2)[CH3:1])(=[O:32])[O:33][CH2:34][CH3:35])[CH3:29]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CNCCCN1c2ccccc2CCc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)N(C)CCCN1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Desipramine hydrochloride (1 equivalent, 0.5 gram) was added drop wise to a stirred solution of potassium carbonate (2 equivalents, 0.456 gram) in dry DMF at 0° C. Diethylchlorophosphate (1.2 equivalents, 0.33 ml) which had been dissolved in dry DMF was added drop wise to this mixture and stirred for 12 hours at room temperature. The reaction mixture was quenched with water, extracted with ethyl acetate, the organic layer separated, washed with brine solution and dried over anhydrous sodium sulfate. The dried material was concentrated and purified by column chromatography to provide a pale yellow liquid (yield: 0.33 gram) and analyzed by HPLC (purity 93.1%). The FTIR, MS and 1H NMR spectra were consistent with the assigned with the empirical formula of C22H31N2O3P.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34](/[CH:37]=[C:38](\[F:41])/[CH2:39]O)=[CH:33][CH:32]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([O:10][CH2:39]/[C:38](/[F:41])=[CH:37]/[C:34]1[CH:33]=[CH:32][C:31]([CH2:30][C:26]2[NH:27][CH:28]=[CH:29][N:25]=2)=[CH:36][CH:35]=1)=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: OC/C(F)=C/c1ccc(Cc2ncc[nH]2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C(F)=C/c2ccc(Cc3ncc[nH]3)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
332 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-methyoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid together with 219 mg (1 mM) of (Z)-3-[4-(1-imidazolylmethyl)phenyl]-2-fluoro-2-propen-1-ol, 248 mg (1.2 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled away, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 506 mg (92.5%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.[NH:13]1[CH2:16][CH2:15][CH2:14]1.CCN(CC)CC>C(Cl)Cl>[N:13]1([C:4]([C:3]2[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=2[F:1])=[O:5])[CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: C1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1F)N1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a solution of 2,4-difluorobenzoyl chloride (1.14 g, 6.46 mmol) in CH2Cl2 was added azetidine hydrochloride (1.46 g, 15.6 mmol) and Et3N (2.70 mL, 19.4 mmol). The reaction mixture was stirred at room temperature for 1 hr, quenched with H2O (100 mL), and extracted with CH2Cl2 (2×100 mL). The organic layers were dried over MgSO4 and concentrated to give an off-white solid (896 mg, 76% yield) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.52-7.59 (m, 1 H) 6.91-6.98 (m, 1 H) 6.81-6.87 (m, 1 H) 4.21 (t, J=7.71 Hz, 2 H) 4.11 (t, J=7.71 Hz, 2H) 2.30-2.38 (m, 2 H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([O:19][C:20]([N:22]1[CH2:28][CH:27]=[CH:26][CH2:25][CH2:24][CH:23]1[CH3:29])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH2:12]([O:19][C:20]([N:22]1[CH:23]([CH3:29])[CH2:24][CH2:25][CH:26]2[CH:27]([O:9]2)[CH2:28]1)=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1CCC=CCN1C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CC1CCC2OC2CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 50.4 %

Procedure:
m-Chloro-perbenzoic acid (1.05 g, 57-86% pure) was added to a solution of 2-methyl-2,3,4,7-tetrahydro-azepine-1-carboxylic acid benzyl ester (0.83 g, 3.34 mmol) in CH2Cl2 at 0 degrees C. The reaction mixture was stirred for half an hour, then was warmed to RT. Additional m-chloro-perbenzoic acid (0.3 g, 57-86% pure) was added and the reaction was stirred 2 h. The reaction mixture was concentrated in vacuo by rotary evaporation, then 80 ml of 9:1 hexanes/EtOAc was added and the reaction mixture was filtered. The filtrate was concentrated in vacuo by rotary evaporation, then was chromatographed (silica gel, 20% EtOAc:hexanes) to give racemic (1S,4R,7S)-4-methyl-8-oxa-3-aza-bicyclo[5.1.0]octane-3-carboxylic acid benzyl ester (0.44 g, 50%) and the title compound as a racemic mixture of the title compound (0.15 g, 17% yield): 1H NMR: 7.42-7.22 (m, 5H), 5.13 (2H, s), 4.50-4.15 (m, 2H), 3.27 (1H, d), 3.12-2.95 (1H, m), 2.15-1.70 (m, 2H), 1.47 (m, 2H), 1.12 (3H, d); Liquid Chromatgraphy/Electrospray mass spec: M+H+=262.0.
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[CH:3]=1.[C:9]1([CH3:18])[C:10]([N:15]=[C:16]=[O:17])=[CH:11][CH:12]=[CH:13][CH:14]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:16]([NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH3:18])=[O:17]
Reactant: Cc1ccccc1N=C=O
Reactant: Cc1cc(O)n(C)n1
Solvent: Cc1ccccc1C
Product: Cc1ccccc1NC(=O)c1c(C)nn(C)c1O

Procedure:
A mixture of 22.4 g (0.2 mol) 5-hydroxy-1,3-dimethyl-1H-pyrazole [K. Auwers, J.Prakt.Chem., 110, 153 (1925)], 26.6 g (0.2 mol) o-tolylisocyanate in 150 ml xylene containing 1 ml triethylamine is heated to reflux for 1.5 hours.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:12].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>C(#N)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][Br:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCc1ccccc1
Reactant: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CO
Product: BrCCCCc1ccccc1
Reaction time: 0.17 h
Yield: 106.3 %

Procedure:
To a solution of 4-phenyl-1-butanol (21.75 g) in acetonitrile (300 mL) was added triphenylphosphine dibromide (67.23 g) in portions with stirring over 10 min. After stirring over night under nitrogen, methanol (4 mL) was added and after 1.5 h, the solvent was removed under reduced pressure. Hexanes (200 mL) and ˜75 g silica gel were added to the residue and the mixture was filtered and the filter cake was eluted with hexanes. The clear filtrate was concentrated to give 32.8 g of clear colorless liquid. This product was again eluted through silica gel using 1.5 L hexanes to give the title compound (24.7 g) as a colorless liquid.
Reaction SMILES: [N:1]1([C:6]2[N:10]([CH2:11][C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=3)[C:9]3[CH:22]=[CH:23][CH:24]=[CH:25][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>O.CO.Cl>[N:1]1([C:6]2[N:10]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=3)[C:9]3[CH:22]=[CH:23][CH:24]=[CH:25][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(Cn2c(N3CCCC3)nc3ccccc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(Cn2c(N3CCCC3)nc3ccccc32)cc1
Reaction time: 0.25 h

Procedure:
Methyl 4-[(2-pyrrolidinyl-1H-benzimidazol-1yl)methyl]benzoate (2.5 g, 7.5 mmol) was added to a solution of sodium hydroxide (1.8 g, 45 mmol) in water (30 mL) and methanol (10 mL). The mixture was heated on a steam bath until all of the ester dissolved. Heating was continued for an additional 15 minutes and then the solution was diluted with an equal volume of water and neutralized with hydrochloric acid. The resulting precipitate was isolated by filtration, washed with water and dried to provide 1.9 g of crude product. This material was recrystallized from N,N-dimethylformamide to provide 4-[(2-pyrrolidinyl-1H-benzimidazol-1yl)methyl]benzoic acid. Analysis: Calculated for C19H19N3O2: %C, 71.01; %H, 5.96; %N, 13.07; Found: %C, 70.01; %H, 6.14; %N, 13.32.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]([C@H:5]1[C@H:9]([CH3:10])[CH2:8][N:7](C(OCC2C=CC=CC=2)=O)[CH2:6]1)=[O:4].C(Cl)CCl.CNC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][N:2]([CH3:21])[C:3]([C@H:5]1[C@H:9]([CH3:10])[CH2:8][NH:7][CH2:6]1)=[O:4]
Reactant: C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1C(=O)N(C)C
Agent: CN(C)c1ccncc1
Agent: CNC
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@@H]1CNC[C@H]1C(=O)N(C)C

Procedure:
A solution of commercially available phenylmethyl (trans)-3-[(dimethylamino)carbonyl]-4-methyl-1-pyrrolidinecarboxylate (1.06 g, 3.4 mmol), DMAP (0.63 g, 5.2 mmol), and EDC (1.0 g, 5.2 mmol) in DCM (18 mL) was stirred for 5 min and dimethylamine (1.9 mL, 3.8 mmol, 2M in THF) was added. The reaction was allowed to stir until it was judged to be complete by LCMS and was quenched with 1 M HCl. A standard work-up provided the desired amide intermediate. This material was immediately dissolved in degassed MeOH (20 mL) and 10% Pd/C (120 mg) was added. The reaction mixture was allowed to stir under a hydrogen balloon until complete deprotection was observed by LCMS. The catalyst was removed by filtration to yield (trans)-N,N,4-trimethyl-3-pyrrolidinecarboxamide. LCMS: (M+H)+: 157.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]([NH2:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C(N(CC)C(C)C)(C)C.Cl[C:24]([O:26][CH2:27][CH:28]1[C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:34]2[C:29]1=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25]>ClCCl>[CH:39]1[C:40]2[CH:28]([CH2:27][O:26][C:24]([NH:12][C@H:4]([C:5]3[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=3)[C:3]([O:2][CH3:1])=[O:13])=[O:25])[C:29]3[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]=2[CH:36]=[CH:37][CH:38]=1
Reactant: COC(=O)C(N)c1ccc(O)cc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 0° solution of 2.50 g (11.48 mmol) of amino-(4-hydroxy-phenyl)-acetic acid methyl ester (from Example 178) in 125 mL of dichloromethane was added 10 mL of N,N-diisopropylethylamine followed by 2.97 g (11.48 mmol) of 9-fluorenylmethyl chlorformate and the resulting mixture was stirred at 0° for 2 h and room temperature for 2 h. The reaction mixture was then concentrated and the residue was diluted with ethyl acetate and water. The organics were washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:3) to provide methyl(2R)-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}(4-hydroxyphenyl)ethanoate as a white solid. Electrospray Mass Spec 404.1 (M+H)+.
Reaction SMILES: [CH:1]1([S:4]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)(=[N:6][S:7]([CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])(=[O:9])=[O:8])=[O:5])[CH2:3][CH2:2]1.Cl.[OH-].[Na+].C(OCC)(=O)C>O1CCCC1.[Cl-].[Ti+3].[Cl-].[Cl-]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([S:4]([CH:1]2[CH2:3][CH2:2]2)(=[N:6][S:7]([CH2:10][CH2:11][Si:12]([CH3:14])([CH3:15])[CH3:13])(=[O:8])=[O:9])=[O:5])=[CH:17][CH:18]=1
Reactant: C[Si](C)(C)CCS(=O)(=O)N=S(=O)(c1ccc([N+](=O)[O-])cc1)C1CC1
Agent: [Ti+3]
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCS(=O)(=O)N=S(=O)(c1ccc(N)cc1)C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.8 %

Procedure:
320 mg of (RS)—S-cyclopropyl-S-(4-nitrophenyl)-N-[2-(trimethylsilyl)ethyl-sulfonyl]sulfoximide is dissolved in 5 ml of tetrahydrofuran. While being cooled with ice, 7.2 ml of an approximately 10% by weight solution of titanium(III) chloride in 20-30% by weight of hydrochloric acid is added in drops. The solution is stirred for 16 hours at room temperature and poured onto ice. The pH is set at 8-9 with 15% sodium hydroxide solution. After ethyl acetate is added, the mixture is vigorously stirred. The precipitate is suctioned off and washed with 100 ml of ethyl acetate. The filtrates are combined, dried and concentrated by evaporation. After purification by flash chromatography, 215 mg of (RS)—S-(4-aminophenyl)-S-cyclopropyl-N-[2-(trimethylsilyl)ethylsulfonyl]sulfoximide is obtained.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C(=O)=[O:12].[C:14]([O:18][C:19](=[O:33])[N:20]([CH2:22][CH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([CH2:30][C:31]#N)[CH2:26][CH2:25]1)[CH3:21])([CH3:17])([CH3:16])[CH3:15].Cl>C(Cl)Cl>[C:14]([O:18][C:19](=[O:33])[N:20]([CH3:21])[CH2:22][CH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([CH2:30][CH:31]=[O:12])[CH2:26][CH2:25]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: O=C=O
Reactant: CN(CC[C@H]1CC[C@H](CC#N)CC1)C(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: CN(CC[C@H]1CC[C@H](CC=O)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
90.4 ml (108.5 mmol) of diisobutylaluminium hydride (1.2M in toluene) were dropped under stirring and dry-ice-cooling at −70° C. to −78° C., within 20 minutes, to a solution of 10.14 g (36.17 mmol) of crude trans-[2-(4-cyanomethyl-cyclohexyl)-ethyl]-methyl-carbamic acid tert-butyl ester in 90 ml of methylenechloride. The reaction mixture was stirred for 4 hours at −70° C. to −78° C. To this reaction mixture was then carefully added 40 ml of 4N HCl (in water), within 10 minutes at −78° C. The temperature was slowly raised to room temperature. After stirring for 10 minutes at room temperature, the reaction mixture was partitioned between ether, 1N HCl and water. The ether-phase was dried over sodium sulfate and concentrated under reduced pressure giving 10.14 g of crude trans-methyl-{2-[4-(2-oxo-ethyl)-cyclohexyl]-ethyl}-carbamic acid tert-butyl ester as colorless oil, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]2=[C:13]3[C:3]=1[O:4][CH2:5][CH2:6][N:7]3[C:8]([CH:14]([NH2:16])[CH3:15])=[N:9]2.Cl[C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2[CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[CH:12]=[CH:11][C:10]2=[C:13]3[C:3]=1[O:4][CH2:5][CH2:6][N:7]3[C:8]([CH:14]([NH:16][C:18]1[N:26]=[CH:25][N:24]=[C:23]3[C:19]=1[N:20]=[CH:21][N:22]3[CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH3:15])=[N:9]2
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CC(N)c1nc2ccc(F)c3c2n1CCO3
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c3c2n1CCO3
Temperature: 100 °C
Yield: 82 %

Procedure:
A mixture of 1-(6-fluoro-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2-yl)ethylamine (85 mg, 0.38 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (92 mg, 0.38 mmol) and DIPEA (132 μL, 0.76 mmol) in IPA (1 mL) was heated for 18 h at 100° C. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si—PPC, gradient 0-5% MeOH in DCM) to afford the title compound as a pale yellow oil (132 mg, 82%). LCMS (Method J): RT=2.22 min, [M+H]+=424
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][CH:24]=[C:23]4[CH3:29])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:30][CH3:31])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CN(C=O)C>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][CH:24]=[C:23]4[CH3:29])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:30][CH3:31]
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
A mixture of 7-benzyloxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (7.76 g, 18.9 mmol), ammonium formate (17.82 g, 282 mmol) and 10% palladium on charcoal (800 mg) in DMF (350 ml) was stirred at ambient temperature for 1 hour. The catalyst was filtered off through celite and the cake washed with DMF. The solvent was removed in vacuo and the residue stirred with a saturated solution of sodium hydrogen carbonate for 2 hours. The suspension was then filtered, washed with water and dried to give 7-hydroxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (5.49 g, 91%).
Reaction SMILES: [CH2:1]([C:9]1[C:10]([C:22]([F:25])([F:24])[F:23])=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:14]3[CH:13]=[CH:12]2)[CH:17]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[CH3:27][N:28]([CH3:33])[CH2:29][C:30](O)=[O:31].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C1COCC1>[CH3:27][N:28]([CH3:33])[CH2:29][C:30]([CH:20]1[NH:19][CH2:18][C:16]2=[C:15]3[C:11](=[C:10]([C:22]([F:25])([F:24])[F:23])[C:9]([CH2:1][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:17]2)[CH:12]=[CH:13][N:14]3[CH2:21]1)=[O:31]
Reactant: CN(C)CC(=O)O
Reactant: FC(F)(F)c1c(CCc2ccccc2)cc2c3c1ccn3CCNC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CC(=O)C1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1
Reaction time: 8 h

Procedure:
To 6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (prepared as described in Example 2 above, 37 mg, 0.1 mmol) and N,N-dimethylglycine hydrochloride (14 mg, 0.1 mmol) in THF (7 mL) was added triethylamine (50 mg, 0.5 mmol), and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU; 43 mg, 0.1 mmol). The resulting mixture was stirred overnight, then partitioned between ethyl acetate and water. The organic phase was washed sequentially with NaHCO3 and brine, then dried and concentrated. The residue was purified by reverse-phase chromatography (acetonitrile/water/trifluoroacetic add) to yield 2-(dimethylamino)-1-(6-phenethyl-7-(trifluoromethyl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indol-2(1H)-yl)ethanone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.CO[CH:13](OC)[CH2:14][NH2:15].S(=O)(=O)(O)O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:7]([CH:13]=[CH:14][N:15]=[CH:5]2)=[CH:8][C:9]=1[F:10]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: COC(CN)OC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1cc2ccncc2cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 3-bromo-4-fluorobenzaldehyde (1.70 g, 8.37 mmol) (Aldrich, Cat. #339547) and aminoacetaldehyde dimethyl acetal (0.917 mL, 8.37 mmol) (Aldrich, Cat. #121967) in toluene (17.0 mL) was stirred at r.t. overnight. The mixture was then added to sulfuric acid (10 mL) and phosphorus pentoxide (2.38 g, 8.37 mmol) at 160° C. The mixture was stirred at 160° C. for 1 h. After cooled to r.t., the mixture was poured onto crushed ice. The acidic mixture was adjusted to pH=8 by the careful addition of NaOH in water with stirring and external cooling. The basic mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-40%) to afford the desired product. Analytic LCMS (M+H)+: m/z=225.9/227.9.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([CH2:12][C:13]2[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=2)[C:3]1=[O:20]>CC(O)=O.[Zn]>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH2:12][C:13]1[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[C:3](=[O:20])[CH2:2]2
Reactant: O=C1N(Cc2cccnc2F)c2ccc(Cl)cc2C1(Br)Br
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1Cc2cc(Cl)ccc2N1Cc1cccnc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 9.1 %

Procedure:
In a 50 ml, three-necked flask fitted with a magnetic stirrer under inert atmosphere, 3,3-dibromo-5-chloro-1-[(2-fluoropyridin-3-yl)methyl]-1,3-dihydro-2H-indol-2-one x73 (1.79 g, 4.12 mmol) is dissolved in AcOH (20 ml) and, at 0° C., powdered zinc (2.7 g, 41.2 mmol) is added. The mixture is stirred for 10 min at room temperature, filtered on Celite and concentrated to dryness. The residue is purified by chromatography on silicagel (Hexane/AcOEt:6/4 (v/v)) to give 104 mg of 5-chloro-1-[(2-fluoropyridin-3-yl)methyl]-1,3-dihydro-2H-indol-2-one 227.