Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)#[N:2].Cl.C1(O)C=CC=CC=1.[F:32][C:33]1[CH:40]=[CH:39][C:36](CBr)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O.CN(C)C=O>[C:1]([C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:36]3[CH:39]=[CH:40][C:33]([F:32])=[CH:34][CH:35]=3)=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)#[N:2]
Reactant: COc1ccc(C2(C#N)CCC(=O)CC2)cc1OC1CCCC1
Reactant: Fc1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Oc1ccccc1
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(OCc3ccc(F)cc3)c(OC3CCCC3)c2)CCC(=O)CC1
Temperature: 90 °C
Yield: 61.4 %

Procedure:
A solution of 4-cyano-4-[3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (0.75 g, 2.4 mmol) and concentrated hydrochloric acid (2 mL) in methanol (10 mL) was heated at reflux under an argon atmosphere for 2 h. The mixture was cooled, was diluted with water and was extracted three times with methylene chloride. The organic extract was dried (magnesium sulfate) and was evaporated to the phenol (0.54 g, 92%). A vigorously stirred mixture of this phenol, 4-fluorobenzyl bromide (0.83 mL, 6.6 mmol) and potassium carbonate (0.92 g, 6.6 mmol) in dimethylformamide (12 mL) was heated under an argon atmosphere at 90° C. for 2 h. The mixture was allowed to cool, was diluted with water and was extracted three times with ether. The organic extract was dried (magnesium sulfate) and the solvent was removed in vacuo. Purification by flash chromatography, eluting with 30% ethyl acetate/hexanes, provided a white solid (0.6 g, 78%): m.p. 145°-146° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.[CH2:15]([O:17][C:18]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)=[O:19])[CH3:16]>>[CH3:12][N:11]1[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:24]([C:23]3[CH:27]=[CH:28][C:20]([C:18]([O:17][CH2:15][CH3:16])=[O:19])=[CH:21][CH:22]=3)=[O:25])=[CH:14][C:6]=2[CH2:7][CH2:8][CH2:9][C:10]1=[O:13]
Reactant: CCOC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Product: CCOC(=O)c1ccc(C(=O)Nc2ccc3c(c2)CCCC(=O)N3C)cc1

Procedure:
Analogous to Example 1, from 7-amino-2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-1-benzazepine was reacted with p-ethoxycarbonylbenzoyl chloride to yield ethyl p-[(2,3,4,5-tetrahydro-1-methyl-2-oxo-1H-1-benzazepin-7-yl)carbamoyl]benzoate, m.p. 184°-185° C.
Reaction SMILES: CO[C:3](=[O:24])[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH3:23])[C:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)=[N:11][CH:12]=1)=[O:5].O.[NH2:26][NH2:27]>CCO>[NH:26]([C:3](=[O:24])[C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH3:23])[C:10]([N:13]2[CH2:14][CH2:15][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]2)=[N:11][CH:12]=1)=[O:5])[NH2:27]
Reactant: NN
Reactant: COC(=O)C(=O)Nc1cnc(N2CCC(C(=O)OC)CC2)c(C)c1
Solvent: O
Solvent: CCO
Product: COC(=O)C1CCN(c2ncc(NC(=O)C(=O)NN)cc2C)CC1
Reaction time: 17 h
Yield: 87.6 %

Procedure:
Methyl 1-(5-{[methoxy(oxo)acetyl]amino}-3-methylpyridin-2-yl)piperidine-4-carboxylate (2.01 g; 5.99 mmol) was dissolved in EtOH (140 mL) and treated with dropwise addition of hydrazine hydrate (320 μL; 6.59 mmol). Within a few minutes a flocculent precipitate formed. Vigorous stirring was continued for 17 hrs. A further 32 μL (0.65 mmol) hydrazine hydrate was added and stirring continued at ambient temperature for 24 hrs. The precipitated solid was filtered off, washed with ether on the filter and dried under high vacuum at 60° C. to give the title compound (1.76 g, 88% yield). This was used in the next stage without further purification. 1H NMR δ 1.59-1.80 (m, 2H), 1.83-1.98 (m, 2H), 2.16 (s, 3H), 2.52-2.60 (m, 1H), 2.66-2.84 (m, 2H), 3.22-3.37 (m, 2H), 3.58 (s, 3H), 4.54 (d, 2H), 7.89 (d, 1H), 8.47 (d, 1H), 10.14 (s, 1H), 10.48 (s, 1H). MS m/e MH+ 336.24.
Reaction SMILES: P(Br)(Br)[Br:2].C(Cl)Cl.[Cl:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:10]=1[CH:17](O)[CH3:18]>O>[Br:2][CH:17]([C:10]1[C:9]([Cl:8])=[C:14]([F:15])[CH:13]=[CH:12][C:11]=1[F:16])[CH3:18]
Reactant: CC(O)c1c(F)ccc(F)c1Cl
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(Br)c1c(F)ccc(F)c1Cl
Temperature: 0 °C
Yield: 78 %

Procedure:
Phosphorus tribromide (1.3 mL) and anhydrous CH2Cl2 (50 mL) were combined and then cooled over ice water for 20 minutes. The cooled solution was then added to a mixture of 1-(2-chloro-3,6-difluorophenyl)ethanol (2.71 g) and methylene chloride (50 mL), and the resulting mixture was stirred at room temperature for two (2) hours. The mixture was then poured into H2O and extracted into CH2Cl2. The organic phase was isolated, dried with magnesium sulfate, filtered, and concentrated to give the title compound (78% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[C:32]([S:51][CH2:52][CH2:53][NH2:54])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([NH:54][CH2:53][CH2:52][S:51][C:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)[nH]2)c1
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To 5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (940 mg, 2.1 mmol) synthesized in Example (18a), 2-(tritylthio)ethaneamine (1.01 g, 3.17 mmol) synthesized in Example (25a) and 4-dimethylaminopyridine (13 mg, 0.1 mmol) were added, followed by dissolution in dichloromethane (50 mL), and subsequently WSCI.HCl (445 mg, 2.3 mmol) was added at room temperature, and stirring was carried out for 1 hour under nitrogen atmosphere. The reaction solution was diluted with dichloromethane (150 mL), washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-55%) to afford the desired product (1.08 g, yield 69%) as a white solid.
Reaction SMILES: [Mg].II.Cl[CH2:5][C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7].[S:15](Cl)([Cl:18])(=[O:17])=[O:16].P([O-])([O-])([O-])=O>C1COCC1>[CH3:7][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:14])[CH2:5][S:15]([Cl:18])(=[O:17])=[O:16]
Reactant: CC(C)(CCl)c1ccccc1
Reactant: O=S(=O)(Cl)Cl
Agent: II
Agent: O=P([O-])([O-])[O-]
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(CS(=O)(=O)Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
In a flask under argon were placed magnesium turnings (0.8 g, 0.036 mol), dry THF (10 mL) and a iodine crystal. Then, 1-chloro-2-methyl-2-phenylpropane (5 mL, 0.031 mol) in THF (15 mL) was added slowly and the reaction mixture was refluxed for 30 min. It was then allowed to cool to room temperature and finally it was cooled to -70° C. and sulfuryl chloride (2.5 mL, 0.031 mol) in THF (10 mL) was added dropwise. The reaction was allowed to warm up to room temperature and was stirred at this temperature overnight. The resulting solution was poured into diluted phosphate buffer and extracted with EtOAc (3×). Evaporation of the solvent afforded the title compound (4.6 g, 65%).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]([CH:20]3[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][CH:9]=2)[N:4]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])[N:3]=1.[CH:28]1([B-](F)(F)F)[CH2:30][CH2:29]1.[K+].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1(C)C=CC=CC=1.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>[CH:20]1([N:12]([CH2:11][C:7]2[CH:6]=[C:5]3[C:10]([C:2]([CH:28]4[CH2:30][CH2:29]4)=[N:3][N:4]3[CH2:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:9][CH:8]=2)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:22][CH2:21]1
Reactant: F[B-](F)(F)C1CC1
Reactant: COCCCn1nc(Br)c2ccc(CN(C(=O)OC(C)(C)C)C3CC3)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COCCCn1nc(C2CC2)c2ccc(CN(C(=O)OC(C)(C)C)C3CC3)cc21
Temperature: 100 °C
Reaction time: 24 h
Yield: 41.7 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (20 mg) was added to a solution of tert-butyl {[3-bromo-1-(3-methoxypropyl)-1H-indazol-6-yl]methyl}cyclopropylcarbamate (150 mg), potassium cyclopropyltrifluoroborate (73 mg) and potassium phosphate (254 mg) in toluene (3 ml)-water (1 ml) under argon atmosphere and the mixture was stirred at 100° C. for 24 hours. Potassium cyclopropyltrifluoroborate (24 mg), potassium phosphate (73 mg) and tetrakis(triphenylphosphine)palladium(0) (20 mg) were added to the reaction mixture and it was stirred further at 100° C. for 24 hours. Water was added to the reaction mixture under ice-cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane to n-hexane/ethyl acetate=2/1) to give tert-butyl cyclopropyl{[3-cyclopropyl-1-(3-methoxypropyl)-1H-indazol-6-yl]methyl}carbamate (57 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:18]([OH:20])=[O:19])[CH2:16][CH2:15][C:14](=[O:17])[O:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23]I.O>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][C:12]1([C:18]([O:20][CH3:23])=[O:19])[CH2:16][CH2:15][C:14](=[O:17])[O:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(NC(=O)OCc2ccccc2)(C(=O)O)O1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(NC(=O)OCc2ccccc2)CCC(=O)O1
Reaction time: 4 h
Yield: 92.9 %

Procedure:
In 100 ml of dimethylformamide was dissolved 27.93 g of 2-benzyloxycarbonylamino-5-oxo-2-tetrahydrofurancarboxylic acid prepared by the method described in Journal of Organic Chemistry, 6, 878 (1941). To the solution was added 4.0 g of sodium hydride (60% oil), to which was then added 28.4 g of methyl iodide, followed by allowing the reaction to proceed at room temperature for 4 hours. To the resultant was added 28.4 g of methyl iodide, and the mixture was stirred for further 3 hours. The reaction mixture was added to water, which was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, successively, then dried (MgSO4). The solvent was distilled off, and precipitating crystals were collected by filtration, followed by washing with ether to give 27.25 g of methyl 2-benzyloxycarbonylamino-5-oxo-2-tetrahydrofurancarboxylate as colorless crystals, m.p. 134°-134.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](F)=[N:6][CH:7]=1.[OH-].[NH4+:11]>>[NH2:11][C:5]1[C:4]([F:9])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1
Reactant: [NH4+]
Reactant: Fc1cc(Cl)cnc1F
Agent: [OH-]
Product: Nc1ncc(Cl)cc1F
Temperature: 150 °C
Yield: 76 %

Procedure:
To a 20 mL microwave vial equipped with a stir bar was added 5-chloro-2,3-difluoropyridine (2.0 g, 41 mmol). Ammonium hydroxide (ca 12 mL) was then added and the mixture was stirred until homogeneous. The solution was capped and heated in the microwave reactor at 150° C. for three 20 minute increments until a white solid precipitated out of solution. The white solid was filtered, washed with water, and dried to afford 2-amino-5-chloro-3-fluoropyridine (1.5 g, 76% yield), characterized by 1H NMR (d6-DMSO).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:15]([CH3:27])[CH:16]2[CH2:26][CH2:25][C:19]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.[C:28]([CH2:30][C:31](O)=[O:32])#[N:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[C:3]([N:15]([CH3:27])[CH:16]2[CH2:26][CH2:25][C:19]3([CH2:24][CH2:23][N:22]([C:31](=[O:32])[CH2:30][C:28]#[N:29])[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CCC2(CCNCC2)CC1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1CCC2(CC1)CCN(C(=O)CC#N)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.6 %

Procedure:
To a suspension 5-chloro-N4-methyl-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(3-azaspiro [5.5]undecan-9-yl)pyrimidine-2,4-diamine (165 mg, 0.42 mmol) and 2-cyanoacetic acid (107.18 mg, 1.26 mmol) in a mixture of DCM and N,N-dimethylformamide (8 mL/2 mL) were added O-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (85.75 mg, 0.63 mmol) and N,N-diethylethanamine (127.50 mg, 1.26 mmol). The mixture was stirred at rt overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=100/1 to 10/1) to give the title compound as a yellow solid (30 mg, 15.54%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[N:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[CH2:20][CH2:19]2)=[N:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:29]2[CH2:28][CH2:27][N:26]([C:24]([CH:21]3[CH2:22][CH2:23][N:18]([C:15]4[CH:16]=[CH:17][N:12]=[CH:13][N:14]=4)[CH2:19][CH2:20]3)=[O:25])[CH2:31][CH2:30]2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: O=C(C1CCN(c2ccncn2)CC1)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)N2CCN(C(=O)C3CCN(c4ccncn4)CC3)CC2)cc1
Yield: 46.2 %

Procedure:
A solution of 4-cyanobenzoyl chloride (298 mg) in methylene chloride (10 ml) was added to a stirred mixture of 1-[1(4-pyrimidinyl) piperidin-4-ylcarbonyl]piperazine (412.5 mg) and triethylamine (0.28 ml) in methylene chloride (15 ml) and the resultant mixture was stirred at ambient temperature for 2 hours. The mixture was partitioned between methylene chloride and water. The organic phase was washed with water, dried (Na2SO4) and evaporated. The residue was purified by column chromatography using 0.5% methanol in methylene chloride. Recrystallisation from ethyl acetate/hexane gave, as a solid 1-(4-cyanobenzoyl)-4-[1-(4-pyrimidinyl)piperidin-4-ylcarbonyl] piperazine (280 mg): mpt 192-193° C.;
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1.[CH3:14][N:15]([CH3:29])[C:16]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[ClH:48].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C1COCC1.ClCCCl.CC(=O)CC.C(O)C>[ClH:48].[ClH:48].[CH3:14][N:15]([CH3:29])[C:16]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:17][CH2:18][CH:19]([N:2]2[CH2:3][CH2:4][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:12][C:13]=3[CH2:1]2)[CH2:20][CH2:21]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(N2CCc3c([nH]c4ccccc34)C2)CC1
Reaction time: 0.25 h

Procedure:
2,3,4,9-Tetrahydro-1H-β-carboline (345 mg) and 4-dimethylamino-4-phenylcyclohexanone (435 mg) were dissolved in a mixture of THF (10 ml) and 1,2-dichloroethane (15 ml) under argon, and acetic acid (120 mg, 2 mmol.) was added thereto. After 15 minutes, NaBH(OAc)3 (600 mg) was added, stirring was carried out for 68 hours, the reaction mixture was concentrated and the residue was taken up in 1N hydrochloric acid (20 ml) and washed with ether (2×20 ml). The aqueous solution was rendered alkaline with 1M NaOH (30 ml) and extracted with ether (3×30 ml). After drying and concentration of the combined extracts, a semi-solid crude product was obtained which, after separation by column chromatography with methanol/NH3 (500:3), yielded the nonpolar diastereomer (334 mg, m.p. 147-150° C.) which, dissolved with heating in 2-butanone (20 ml) and ethanol (10 ml), was converted with 3.3M ethanolic hydrochloric acid (0.8 ml) into the corresponding dihydrochloride (335 mg; 264-269° C.).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.C[N:23]([CH3:26])C=O>NC1C2C(=CC=CC=2)CC1.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:23][CH:26]4[C:20]5[C:5](=[CH:4][CH:3]=[CH:2][CH:21]=5)[CH2:6][CH2:9]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: CN(C)C=O
Agent: NC1CCc2ccccc21
Solvent: CCO
Product: O[C@H](CNC1CCc2ccccc21)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 1-aminoindan in ethanol, essentially as described above in Example 70. Purity by LC/MS=94%, [M+H]+=419.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]1.CCN(CC)CC>CC(O)C.CCOC(C)=O>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16][CH2:15]1)[N:11]=[CH:10]2
Reactant: COc1ccc2nc(Cl)ncc2c1
Reactant: COC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: COC(=O)C1CCN(c2ncc3cc(OC)ccc3n2)CC1
Temperature: 50 °C
Yield: 101.4 %

Procedure:
A mixture of 2-chloro-6-methoxyquinazoline (Intermediate 8, 700 mg, 3.60 mmol), methyl 4-piperidinecarboxylate (2.58 g, 18.0 mmol) and Et3N (729 mg, 7.20 mmol) in iPrOH (15 mL) was heated to 50° C. for 16 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with H2O (30 mL×2) and brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by prep-HPLC (0.1% TFA as additive). Most of CH3CN was removed under reduced pressure and the remaining solvent was removed by lyophilization to give the product (1.10 g, yield: 73%).
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH2:11])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:12]([O:16][C:17](=[O:27])[NH:18][C:19]1[C:20]([CH:25]=O)=[N:21][CH:22]=[CH:23][CH:24]=1)([CH3:15])([CH3:14])[CH3:13].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:12]([O:16][C:17](=[O:27])[NH:18][C:19]1[C:20]([CH2:25][NH:11][CH:9]2[C:10]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7][CH2:8]2)=[N:21][CH:22]=[CH:23][CH:24]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: NC1CCCc2cccnc21
Reactant: CC(C)(C)OC(=O)Nc1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccnc1CNC1CCCc2cccnc21

Procedure:
Using General Procedure B: Reaction of 5,6,7,8-tetrahydro-quinolin-8-ylamine in CH2Cl2 with (2-formyl-pyridin-3-yl)-carbamic acid tert-butyl ester and NaBH(OAc)3 gave {2-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-pyridin-3-yl}-carbamic acid tert-butyl ester as a yellow oil. 1H NMR (CDCl3) δ 1.51 (s, 9H), 1.85-1.94 (m, 2H), 1.98-2.08 (m, 2H), 2.78-2.84 (m, 2H), 3.82-3.86 (m, 1H), 4.19 (s, 2H), 7.11-7.19 (m, 2H), 7.42 (d, 1H, J=7.1 Hz), 8.15-8.17 (m, 1H), 8.28 (d, 1H, J=8.0 Hz), 8.44 (d, 1H, J=3.0 Hz), 10.17 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[C:5]([NH2:15])[NH:4][N:3]=1.[C:16]1([C:22](=O)[CH2:23][C:24](OCC)=[O:25])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[C:2]([CH3:1])=[N:3][N:4]3[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:23][C:24](=[O:25])[NH:15][C:5]=23)=[CH:12][CH:11]=1
Reactant: COc1ccc(-c2c(C)n[nH]c2N)cc1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(-c2c(C)nn3c(-c4ccccc4)cc(=O)[nH]c23)cc1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
3-Methyl-4-(4-methoxyphenyl)-1H-pyrazol-5-amine (200 mg) and ethyl 3-phenyl-3-oxopropanoate (227 mg) are stirred overnight in a pyridine (10 mL) solvent at 95° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and 270 mg of the target compound is yielded by column chromatography.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[CH2:11]O.[Cl:13]CCl>S(Cl)(Cl)=O>[Cl:13][CH2:11][C:3]1[C:2]([F:1])=[C:7]([O:8][CH3:9])[CH:6]=[CH:5][C:4]=1[F:10]
Reactant: ClCCl
Reactant: COc1ccc(F)c(CO)c1F
Solvent: O=S(Cl)Cl
Product: COc1ccc(F)c(CCl)c1F

Procedure:
A solution of 120 mg (0.689 mmol) of 2,6-difluoro-3-methoxyphenyl)methanol from Example 132A in 3 ml of dichloromethane and 1 ml of thionyl chloride was stirred at room temperature overnight. The solvent was evaporated off under reduced pressure and the residue was purified by flash chromatography using a prepacked silica gel cartridge (eluent:cyclohexane-ethyl acetate 10:1 to 1:1), which gave 50 mg (38% of theory) of the target compound.
Reaction SMILES: [C:1]1([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=[C:5]2[C:10]=1[C:9]1[CH:11]=[CH:12][NH:13][C:8]=1[CH:7]=[CH:6]2.[H-].[Na+].Cl[C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1>CN(C)C=O>[S:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[N:13]1[C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[C:1]([NH2:15])[N:2]=[C:3]([NH2:14])[N:4]=3)[C:9]=2[CH:11]=[CH:12]1
Reactant: Clc1nc2ccccc2s1
Reactant: Nc1nc(N)c2c(ccc3[nH]ccc32)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc(N)c2c(ccc3c2ccn3-c2nc3ccccc3s2)n1
Reaction time: 11 h

Procedure:
To 3.98 g. 7H-pyrrolo[3,2-f]quinazoline-1,3-diamine dissolved in 250 ml. dry dimethylformamide are added, with stirring under nitrogen, 1.15 g. ca. 50% sodium hydride-mineral oil dispersion. After stirring for 1.5 hours, 3.90 g. 2-chlorobenzothiazole are added and the mixture is heated at 95° for 3 hours. An additional 1.29 g. 2-chlorobenzothiazole are added and heating at 95° is continued for 11 hours. A third portion of 2-chlorobenzothiazole (1.29 g.) is added and heating at 95° is continued for 8 hours. The reaction mixture is processed as in Example 69 and the crude product is recrystallized (twice) from dimethylformamide and is thoroughly dried to yield 2.30 g. title compound, m.p. 326° (dec).