Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C@H:5]1[C@@H:9]([CH3:10])[C:8](=[O:11])[N:7]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[CH2:6]1)=[O:4].COC([C@H]1[C@H](C)C(=O)N(CC2C=CC(OC)=CC=2OC)C1)=O.C[O-].[Na+].O>CO>[CH3:22][O:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[CH2:12][N:7]1[C:8](=[O:11])[C@@H:9]([CH3:10])[C@H:5]([C:3]([OH:4])=[O:2])[CH2:6]1
Reactant: COC(=O)[C@@H]1CN(Cc2ccc(OC)cc2OC)C(=O)[C@@H]1C
Agent: COC(=O)[C@@H]1CN(Cc2ccc(OC)cc2OC)C(=O)[C@H]1C
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(CN2C[C@@H](C(=O)O)[C@H](C)C2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of a mixture of (cis)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid methyl ester and (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid methyl ester (14.2 g) in methanol (150 ml) was added sodium methoxide (about 5M solution in methanol, 28 ml), and the mixture was stirred at room temperature for 16 hours, and then heated to 55° C. and stirred for 3 hours. To this reaction solution was added sodium methoxide (about 5M solution in methanol, 10 ml), and the mixture was stirred at 55° C. for additional 2 hours. This reaction solution was cooled to room temperature, and then water (50 ml) was added thereto, and the mixture was stirred overnight. The reaction solution was concentrated under reduced pressure to remove methanol. To the resulting residue was added a 2M aqueous solution of hydrochloric acid (105 ml), and the mixture was extracted with ethyl acetate (300 ml). The resulting organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product of the titled compound (14.0 g).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([OH:10])[C:4]=2[CH:3]=[N:2]1.[N+:11]([C:14]1[CH:39]=[CH:38][C:17](C(O[C@H]2CC[C@@H](N3C(=O)C4C(=CC=CC=4)C3=O)CC2)=O)=[CH:16][CH:15]=1)([O-])=O.O[C@@H]1CC[C@H](N2C(=O)C3C(=CC=CC=3)C2=O)CC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC1C=CC=CC=1)=O)=NC(OCC1C=CC=CC=1)=O.ClCCl>O1CCCC1>[NH:1]1[C:9]2[C:4](=[C:5]([O:10][C@H:17]3[CH2:38][CH2:39][C@H:14]([NH2:11])[CH2:15][CH2:16]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: Oc1cccc2[nH]ncc12
Reactant: O=C(O[C@H]1CC[C@@H](N2C(=O)c3ccccc3C2=O)CC1)c1ccc([N+](=O)[O-])cc1
Agent: O=C(N=NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@@H](O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: N[C@H]1CC[C@H](Oc2cccc3[nH]ncc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the 1H-indazol-4-ol (131 mg, 0.977 mmol) obtained in Example 320, (b) in tetrahydrofuran (10 ml) were added dropwise cis-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (215 mg, 0.879 mmol), triphenylphosphine (283 mg, 1.07 mmol) and 40%-dibenzyl azodicarboxylate-dichloromethane solution (0.672 ml, 1.17 mmol) at 0° C. The resulting mixture was warmed up to room temperature 30 minutes after the addition. After stirring overnight, the reaction solution was concentrated under reduced pressure and the resulting residue was dissolved in chloroform (50 ml) and washed with a 1M-aqueous sodium hydroxide solution (20 ml). Extraction with chloroform (20 ml) was carried out again, and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate). To the resulting mixture was added 30%-methylamine/ethanol (2 ml) at room temperature, and the resulting mixture was refluxed for 15 minutes. After 4 hours, the reaction solution was concentrated under reduced pressure at room temperature and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=10/1→chloroform/methanol/(1%-aqueous ammonia)=10/1) to obtain trans-4-(1H-indazol-4-yloxy)-cyclohexanamine (11 mg, 5.6%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([C:12]1[C:13](=[O:25])[N:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:15]([CH3:18])[C:16]=1[CH3:17])=[O:11].CC([O-])(C)C.[K+].[Cl:32][C:33]1[C:34](C(N)=O)=[N:35][CH:36]=[CH:37][C:38]=1Cl.CCOC(C)=O.C[N:50](C=O)C>O>[NH2:50][C:34]1[C:33]([Cl:32])=[C:38]([O:8][C:6]2[CH:5]=[CH:4][C:3]([NH:9][C:10]([C:12]3[C:13](=[O:25])[N:14]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:15]([CH3:18])[C:16]=3[CH3:17])=[O:11])=[C:2]([F:1])[CH:7]=2)[CH:37]=[CH:36][N:35]=1
Reactant: NC(=O)c1nccc(Cl)c1Cl
Reactant: Cc1c(C(=O)Nc2ccc(O)cc2F)c(=O)n(-c2ccccc2)n1C
Reactant: CN(C)C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3Cl)cc2F)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A mixture of N-(2-fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (300 mg, 0.879 mmol) and t-BuOK (118 mg, 1.05 mmol) in DMF (3 mL) was stirred at rt for 30 minutes, then 3,4-dichloropicolinamide (201 mg, 1.05 mmol) was added. The reaction mixture was heated to 120° C. and stirred for 12 hours. EtOAc (1 mL) and H2O (20 mL) were added, and the resulted mixture was stirred at rt overnight. Filtered to give the title compound as a brown solid (379 mg, 87.0%).
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:20]=[CH:19][C:12]([CH:13]=[CH:14][C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26]Cl.O>CN(C)C=O>[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][O:1][CH:2]([C:9]1[CH:10]=[CH:11][C:12]([CH:13]=[CH:14][C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CN(C)CCCl
Reactant: COC(=O)C=Cc1ccc(C(O)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C=Cc1ccc(C(OCCN(C)C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.9 %

Procedure:
3.04 g (11.33 mmol) of methyl 4-(α-hydroxybenzyl)cinnamate was dissolved in 35 ml of N,N-dimethylformamide, thereafter 0.45 g (11.33 mmol) of 60% sodium hydride was added thereto, and the mixture was stirred overnight at room temperature. 2.44 g (22.66 mmol) of 2-dimethylaminoethyl chloride was then added thereto. The resulting mixture was heated at 80° C. and stirred for 5 hours. After cooling, the reaction mixture was poured into water, the obtained mixture was extracted twice with ethyl acetate, and the extract was washed with brine. The organic phase was dried (MgSO4) and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (chloroform:methanol =50:1 (v/v)) followed by alumina column chromatography (n-hexane:ethyl acetate=5:1 (v/v)) to obtain 0.19 g (0.560 mmol) of methyl 4-[α-(2-dimethylaminoethoxy)benzyl]cinnamate as a pale yellow oily substance. Its spectroscopic data are as follows:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27][C:26]=2[CH:33]=1.C(O)(C)C>Cl.O1CCOCC1.O>[Cl:20][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]3[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27][C:26]=3[CH:33]=2)=[N:3][CH:4]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCC(=O)CC2
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)CCC(=O)CC3)ncc1Cl
Yield: 90 %

Procedure:
Into a microwave vial was placed N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (50 mg, 0.0001 mol) and 2-amino-5,6,8,9-tetrahydro-benzocyclohepten-7-one (34 mg, 0.00019 mol) in isopropyl alcohol (5 mL, 0.06 mol) along with 3-4 drops of 4 M HCl in dioxane-water. The mixture was subjected microwaves at 130° C. for 10 minutes. The reaction mixture was resubjected to the same conditions for complete conversion of starting materials. The resulting solid was collected by filtration and washed with cold methylene chloride and dried in a vacuum oven at 50° C. overnight to give N-{(1R,2R)-2-[5-chloro-2-(7-oxo-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as an off-white solid (43 mg, 60%). MP: 146-153° C.; 1HNMR (400 MHz, DMSO-d6) δ 9.34 (broad s, 1H), 7.98 (s, 1H), 7.65 (s, 1H), 7.44 (d, 1H, J=8.8 Hz), 7.18 (d, 1H, J=8 Hz), 7.14 (d, 1H, J=8 Hz), 6.99 (broad s, 1H), 3.85 (m, 1H), 3.57 (m, 1H), 2.94 (s, 3H), 2.84 (dd, 4H, J=7 Hz), 2.54 (m, 4H), 2.06 (m, 2H), 1.70 (d, 2H, J=11 Hz), 1.19-1.38 (m, 4H); MS (m/e) 478 (M+1).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.CON(C)[C:16](=[O:28])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1.CC(O)=O>C1(C)C=CC=CC=1.O>[CH3:4][O:3][P:2]([CH2:1][C:16](=[O:28])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=1)(=[O:7])[O:5][CH3:6]
Reactant: COP(C)(=O)OC
Reactant: CON(C)C(=O)Cc1cccc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: COP(=O)(CC(=O)Cc1cccc(C(F)(F)F)c1)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of dimethyl methylphosphonate (9.4 g, 75.8 mmol) in toluene (80 mL) at −78° C. was slowly added n-BuLi (2.5M in hexanes, 28 mL, 70 mmol). The reaction mixture was stirred for 1 h and a solution of N-methoxy-N-methyl-2-(3-trifluoromethyl-phenyl)-acetamide (14.39 g) in toluene (50 mL) was slowly added. The reaction mixture was stirred for 2.5 h and AcOH (40 mL) was added. The reaction mixture was warmed to room temperature and water was added. The organic layer was washed with water followed by brine. The organic solution was dried (MgSO4), filtered and concentrated in vacuo. Medium pressure chromatography (CH2Cl2 to 2% MeOH in CH2Cl2) provided the title compound of Preparation 10 (9.37 g). 1H NMR (CDCl3) δ7.52 (m, 1H), 7.44 (m, 2H), 7.37 (m, 1H), 3.96 (s, 2H), 3.87 (s, 3H), 3.76 (s, 3H), 3.12 (d, 2H).
Reaction SMILES: C1([Li])C=CC=CC=1.C(NC(C)C)(C)C.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C(OCC)C>[Si:22]([CH2:21][C:17]1[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: Cc1cccnc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Li]c1ccccc1
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Cc1cccnc1
Reaction time: 1 h
Yield: 89.9 %

Procedure:
In a 500 ml 3 neck round bottomed flask stirring under N2 was charged 33.1 ml of 2M phenyl lithium, in 70/30 cyclohexane diethyl ether, (0.0662 moles, 1.0 eq.), to which 6.70 g of diisopropylamine (1.0 eq. 0.0662 moles) in 10 ml of diethylether was pipetted into the flask followed by rapid addition of 6.16 g of 3-picoline (1.0 eq., 0.066 moles) in 10 ml of diethylether and 10.0 g of tert-butyldimethylsilylchloride (1.0 eq., 0.0662 moles) in 10 ml diethyl ether. The temperature of the reaction was maintained below 35° C. with an ice bath during the additions. After 1 hour of stirring GLC indicated the reaction was complete. The reaction was quenched by adding 100 ml of water, extracted with 250 ml of diethylether and washed with 2×100 ml of water. The ether was dried over magnesium sulfate and concentrated to give 12.3 g of an orange oil. GLC indicated the crude mixture was 96% product. A 7.0 g portion was purified by flash chromatography with 1:4 ethyl acetate/hexane and afforded 3.8 g (48.7% yield based on chromatographic portion) of 3-(tert-butyldimethylsilyl)pyridine.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14]C(=O)C)[NH:10][CH:9]=[CH:8]2)(=O)C.C(OC1C=C2C(=CC=1OCC1C=CC=CC=1)NC=C2)C1C=CC=CC=1>[Fe].C(O)(=O)C>[OH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[OH:14])[NH:10][CH:9]=[CH:8]2
Reactant: CC(=O)Oc1cc2cc[nH]c2cc1OC(C)=O
Agent: [Fe]
Agent: c1ccc(COc2cc3cc[nH]c3cc2OCc2ccccc2)cc1
Solvent: CC(=O)O
Product: Oc1cc2cc[nH]c2cc1O

Procedure:
In a first stage, 5,6-diacetoxyindole and 5,6-dibenzyloxyindole are prepared by means of a cyclizing reduction. In the case of 5,6-dibenzyloxyindole the cyclizing reduction is carried out using iron in the presence of acetic acid. In a second stage, 5,6-dihydroxyindole is obtained:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39].[CH3:40][C:41]([NH:44][CH2:45][CH2:46][CH2:47][NH2:48])([CH3:43])[CH3:42]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:48][CH2:47][CH2:46][CH2:45][NH:44][C:41]([CH3:43])([CH3:42])[CH3:40])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39]
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CC(C)(C)NCCCN
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(NCCCNC(C)(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 81 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (20 mg, 0.036 mmol) in THF(3 mL) was added N-(1,1-dimethylethyl)-1,3-propanediamine (0.028 mL, 0.177 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (18 mg, 80%). LC-MS m/z 618 (M+H)+; 1H-NMR (MeOD) δ 1.11 (s, 9H), 1.58 (m, 2H), 2.34 (s, 3H), 2.48 (m, 2H), 3.15 (m, 2H), 4.13 (s, 2H), 7.15 (m, 4H), 7.53 (m, 2H), 7.72 (m, 2 H), 7.82 (s, 1H), 7.98 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][C:5]=1[C:13]1[NH:14][CH2:15][C:16]2[N:21]([CH3:22])[N:20]=[C:19]([CH2:23][CH2:24][CH3:25])[C:17]=2[N:18]=1)[CH3:2].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.Cl.CN(C)CCCN=C=NCC.[OH:45]N1C2C=CC=CC=2N=N1>ClCCl>[CH2:1]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)=[O:10])=[CH:6][C:5]=1[C:13]1[NH:14][C:15](=[O:45])[C:16]2[N:21]([CH3:22])[N:20]=[C:19]([CH2:23][CH2:24][CH3:25])[C:17]=2[N:18]=1)[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CCCc1nn(C)c2c1N=C(c1cc(C(=O)O)ccc1OCC)NC2
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(C(=O)N4CCN(C)CC4)ccc3OCC)nc12
Yield: 25.3 %

Procedure:
A solution of 4-ethoxy-3-(1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-5-yl)benzoic acid (0.095 g, 0.00027 mol), 1-methylpiperazine (0.265 g, 0.00265 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.77 g, 0.0004 mol) and 1-hydroxybenzotriazole (0.054 g, 0.0004 mol) in dichloromethane (25 ) was stirred at room temperature for 18 hours. The reaction solution was washed with water (25 ml), dried (MgSO4) and evaporated under vacuum, and then the resulting residue crystallised from ethyl acetate-hexane to give the title compound as colourless crystals (0.03 g, 25%), m.p. 196°-197° C. Found C,63.12; H,6.81; N,18.96. C23H30N6O3 requires C,62.99; H,6.90; N,19.16%.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].O.OC1C2N=NNC=2C=CC=1.C(N=C=NCCCN(C)C)C.[F:32][C:33]([F:51])([F:50])[C:34]1[CH:35]=[CH:36][C:37]([NH:40][C@@H:41]2[CH2:49][N:44]3[CH2:45][CH2:46][NH:47][CH2:48][C@@H:43]3[CH2:42]2)=[N:38][CH:39]=1>ClCCl.CN(C)C=O>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([N:47]1[CH2:46][CH2:45][N:44]2[CH2:49][C@@H:41]([NH:40][C:37]3[CH:36]=[CH:35][C:34]([C:33]([F:51])([F:32])[F:50])=[CH:39][N:38]=3)[CH2:42][C@H:43]2[CH2:48]1)=[O:6]
Reactant: FC(F)(F)c1ccc(N[C@H]2C[C@H]3CNCCN3C2)nc1
Reactant: O=C(O)CCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: O=C(CCC(F)(F)F)N1CCN2C[C@@H](Nc3ccc(C(F)(F)F)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solutions of 4,4,4-trifluorobutanoic acid (99 mg, 0.7 mmol) and hydroxybenzotriazole hydrate (54 mg, 0.35 mmol) in dichloromethane (4 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (163 mg, 1.05 mmol) in dichloromethane (1 mL). After 5 minutes, a solution of Example 20 (200 mg, 0.7 mmol) in dimethylformamide (1.5 mL) was added. The mixture was stirred at room temperature for 3 days and then concentrated. The residue was purified by chromatography on silica gel (ethyl acetate/methanol=10:1) to give the title compound. 1H NMR(400 MHz, DMSO-d6) δ ppm 1.30 (m, 1H), 1.80-2.10 (m, 2H), 2.35-2.70 (m, 6H), 2.80-2.97 (m, 3H), 3.10 (m, 1H), 3.82-4.00 (m, 1H), 4.30 (m, 1H), 4.35-4.50 (m, 1H), 6.60 (d, 1H, J=7 Hz), 7.55 (m, 1H), 7.60 (d, 1H, J=7 Hz), 8.28 (s, 1H); MS (ESI) m/z 411 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]2[CH2:8][N:9](C)[CH2:10][CH2:11][CH:12]=2)=[N:5][S:4][N:3]=1.ClC(OC(Cl)=O)C>ClCCCl>[ClH:1].[Cl:1][C:2]1[C:6]([C:7]2[CH2:8][NH:9][CH2:10][CH2:11][CH:12]=2)=[N:5][S:4][N:3]=1
Reactant: CN1CCC=C(c2nsnc2Cl)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: Cl
Product: Clc1nsnc1C1=CCCNC1
Temperature: 40 °C

Procedure:
To a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine (670 mg, 3.1 mmol) in 1,2-dichloroethane (20 ml) was added a solution of 1-chloroethyl-chloroformate (440 mg, 3.1 mmol) in 1,2-dichloroethane at 0° C. The reaction mixture was heated to 40° C. for 2 h and evaporated. The residue was dissolved in methanol and heated to reflux for 1 h. After cooling to room temperature the precipitate was collected by filtration to yield 320 mg (41%). (M.p. 224° C.; M+ : 201 and 203; Compound 17).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=2[N:16]=1)[CH3:14].C[Si]([N:29]=[C:30]=[S:31])(C)C>C1C=CC=CC=1>[CH2:13]([C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][CH2:20][CH2:19][CH:18]([C:30](=[S:31])[NH2:29])[C:17]=2[N:16]=1)[CH3:14]
Reactant: CCc1ccc2c(n1)CCCC2
Reactant: C[Si](C)(C)N=C=S
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: c1ccccc1
Product: CCc1ccc2c(n1)C(C(N)=S)CCC2
Yield: 19.5 %

Procedure:
By the method described in Example 11 using di-isopropylamine (2 ml 0.014 mol) in benzene (20 ml), n-butyl lithium solution (9% w/v, 10 ml, 0.014 mol), 2-ethyl-5,6,7,8-tetrahydroquinoline (2.3 g, 0.014 mol) and trimethylsilyl isothiocyanate (2 ml 0.015 mol) was obtained 2-ethyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide (600 mg, 20%) m.p. 73-5° C (Found: C, 65.25; H, 7.6; N, 12.75. C12H16N2S requires C, 65.4; H, 7.3; N, 12.7%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.[CH2:21]1[C:24]2([CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH2:23][C:22]1=[CH:30][C:31]#[N:32]>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:22]4([CH2:30][C:31]#[N:32])[CH2:23][C:24]5([CH2:25][CH2:26][O:27][CH2:28][CH2:29]5)[CH2:21]4)[CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1
Reactant: N#CC=C1CC2(CCOCC2)C1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cn[nH]c3)n2)cn1
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CC5(CCOCC5)C4)c3)n2)cn1
Yield: 60.3 %

Procedure:
This was prepared from 7-(1-methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (40 mg; 0.151 mmol) and 2-(7-oxaspiro[3.5]nonan-2-ylidene)acetonitrile (37 mg; 0.226 mmol) in analogous fashion to Example 148, Step D to give the desired product (39 mg). MS (apci) m/z=429.2 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH:17]([CH3:19])[CH3:18])=[O:5])[CH3:2].[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[CH:13][CH:12]=[CH:11][C:10]=2[CH:17]([CH3:19])[CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(C(C)C)cccc2c1Cl
Reactant: NC1CCCC1
Product: CCOC(=O)c1cnc2c(C(C)C)cccc2c1NC1CCCC1

Procedure:
4-Chloro-8-isopropyl-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.9 mmol) was treated with cyclopentylamine following general procedure B to afford 4-cyclopentylamino-8-isopropyl-quinoline-3-carboxylic acid ethyl ester (240 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (165 mg) following general procedure E.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=[CH:12]3)O1.Br[C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][N:29]=[CH:30]2.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CCO>[CH:30]1[C:31]2[C:26](=[C:25]([C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=[CH:12]4)[CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:28][N:29]=1
Reactant: Brc1cccc2cnccc12
Reactant: COC(=O)c1cccc2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2cc(-c3cccc4cnccc34)ccc12
Yield: 70.9 %

Procedure:
Methyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthoate (2.2 g, 7.0 mmol), 5-Bromoisoquinoline (1.33 g, 6.3 mmol), a 2M solution of sodium carbonate (9.6 mL) and palladium tetrakistriphenylphospine (0.37 g, 0.32 mmol) were heated in Toluene-EtOH (105 mL-21 mL) at 80° C. overnight. Solvent was evaporated and mixture was extracted with ethyl acetate. Organic phase was washed with brine, dried, filtered and evaporated. Residue was purified by chromatography (ethyl acetate-hexane 10:90->20:80->30:70->40:60->60-40. to give 1.4 g of the title compound as an off-white solid
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[CH2:6]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][NH2:12])[CH3:7].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:22][CH:23]1[C:29]2[CH:30]=[C:31]([O:36][CH3:37])[C:32]([O:34][CH3:35])=[CH:33][C:28]=2[O:27][CH2:26][CH2:25][NH:24]1>>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[CH2:22][CH:23]1[C:29]2[CH:30]=[C:31]([O:36][CH3:37])[C:32]([O:34][CH3:35])=[CH:33][C:28]=2[O:27][CH2:26][CH2:25][N:24]1[CH2:2][C:3]([NH:12][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[O:8][CH2:6][CH3:7])=[O:4]
Reactant: CCOc1ccccc1CN
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCOc3cc(OC)c(OC)cc32)cc1OC
Product: CCOc1ccccc1CNC(=O)CN1CCOc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-bromoacetyl bromide with 2-ethoxy-benzylamine and 5-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10](C)[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[C:13]([Cl:20])[CH:12]=3)[CH:6]=[N:7][CH:8]=1.[CH3:22][CH2:23][CH2:24][O:25][C:26](Cl)=[O:27]>>[CH2:24]([O:25][C:26](=[O:27])[NH:1][CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[C:5]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[C:13]([Cl:20])[CH:12]=3)[CH:4]=1)[CH2:23][CH3:22]
Reactant: CCCOC(=O)Cl
Reactant: Cn1c(-c2cncc(CN)c2)c(C#N)c2ccc(Cl)cc21
Product: CCCOC(=O)NCc1cncc(-c2[nH]c3cc(Cl)ccc3c2C#N)c1

Procedure:
2-(5-aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile (Example 186e) and N-propyl chloroformate are processed according to the method described in Example 190 to give [5-(6-chloro-3-cyano-1H-indol-2-yl)-pyridin-3-ylmethyl]-carbamic acid propyl ester as a solid. 1H NMR (400 MHz, MeOD) δ ppm 0.98 (t, J=7.3 Hz, 3H), 1.58-1.74 (m, 2H), 3.83 (s, 3H), 4.06 (t, J=6.6 Hz, 2H), 4.49 (s, 2H), 7.38 (dd, J=8.6, 1.77 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 8.09 (t, J=2.0 Hz, 1H), 8.74 (d, J=2.0 Hz, 1H), 8.78 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 383.1260 [(M+H)+ Calcd for C20H20ClN4O2: 383.1275].