Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>>[F:23][C:24]([F:33])([F:34])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]2[C:7]([NH:9][C:10]2([C:13]3[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=3)[CH2:12][CH2:11]2)=[O:8])=[CH:27][CH:26]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CCCCN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1

Procedure:
The title compound (D119) (74 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from (R)-methyl 4-(1-(piperidine-2-carboxamido)cyclopropyl)benzoate (D87) (50 mg) and 4-(trifluoromethyl)benzylbromide (0.039 ml). (Na2CO3: 2.5 eq; reaction time: 6 hrs; 60° C.)
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][CH:10]([OH:13])[CH2:11][OH:12])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:22]([Si:26]([CH3:29])([CH3:28])Cl)([CH3:25])([CH3:24])[CH3:23]>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][CH:10]([OH:13])[CH2:11][O:12][Si:26]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:29])[CH3:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)NCCC(O)CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCC(O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (3,4-dihydroxybutyl)carbamic acid tert-butyl ester (2.60 g, 12.7 mmol), triethylamine (2.03 mL, 14.50 mmol) and 4-(dimethylamino)pyridine (0.05 g, 0.4 mmol) in anhydrous dichloromethane (40 mL) at room temperature was added tert-butyldimethylchlorosilane (2.0 g, 13.17 mmol) in one portion. The resulting mixture was stirred at room temperature for 18 hours, washed with water, brine and dried over anhydrous magnesium sulfate. Filtration and concentration in vacuo gave an oil which was purified by column chromatography on silica using ethyl acetate-petroleum ether mixture as eluent to afford a colourless oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]2[CH:13]=[CH:14][O:15][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=O)=O.[CH3:18][C:19]1([CH3:33])[CH2:23][O:22][C:21]([C:24]2[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=2)=[N:20]1.C(N(CC)CC)C>CN(C)C=O>[O:15]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:26]3[CH:25]=[C:24]([C:21]4[O:22][CH2:23][C:19]([CH3:33])([CH3:18])[N:20]=4)[CH:29]=[CH:28][CH:27]=3)[C:12]=2[CH:13]=[CH:14]1
Reactant: CC1(C)COC(c2cccc(B(O)O)c2)=N1
Reactant: O=S(=O)(Oc1cccc2occc12)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)COC(c2cccc(-c3cccc4occc34)c2)=N1
Temperature: 85 °C
Yield: 69.4 %

Procedure:
A mixture of 4-trifluoromethylsulfonyloxy-benzofuran (2 g), 3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)phenyldihydroxyborane (2.14 g), tetrakis(triphenyl-phosphine)palladium(0) (0.26 g) and triethylamine (2.28 g) in N,N-dimethylformamide (40 ml) was heated at 85° C. for 3 hours under nitrogen atmosphere. After evaporating the solvent, the residue was dissolved in a mixture of ethyl acetate (100 ml) and water (100 ml). The organic layer was successively washed with 10% sodium carbonate aqueous solution, brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with toluene. The fractions containing the desired products were collected and evaporated in vacuo to afford 2-[3-(benzofuran-4-yl)phenyl]-4,4-dimethyl-4,5-dihydrooxazole (1.52 g).
Reaction SMILES: [OH:1][C@H:2]([CH2:25]O)[C@@H:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:11]1=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N:38]1C=CC=C[CH:39]=1>C(OCC)(=O)C>[OH:1][C@H:2]([CH2:25][NH:38][CH3:39])[C@@H:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:11]1=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: c1ccncc1
Reactant: O=C1N([C@@H](c2ccccc2)[C@H](O)CO)c2ccccc2C12CCCCC2
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Product: CNC[C@@H](O)[C@H](c1ccccc1)N1C(=O)C2(CCCCC2)c2ccccc21
Reaction time: 5 h
Yield: 32 %

Procedure:
1′-[(1S,2S)-2,3-dihydroxy-1-phenyl-propyl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one (250 mg, 0.71 mmol) was dissolved in pyridine (2.5 mL) and para-toluenesulfonyl chloride (169 mg, 0.89 mmol) was added. The reaction was stirred for 5 hours, then the reaction mixture was diluted with ethyl acetate and washed with water, a saturated aqueous solution of copper sulfate, a 2N aqueous solution of hydrochloric acid, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was immediately dissolved in methylamine (8M solution in ethanol, 15 mL) and stirred for 16 hours. The mixture was concentrated in vacuo and purified via flash column chromatography (silica, 5% methanol saturated with ammonia in chloroform) to give 85 mg (32%) 1′-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]spiro[cyclo-hexane-1,3′-indol]-2′(1′H)-one as a colorless oil. The freebase was dissolved in diethyl ether (5 mL) and treated with a 1 N ethereal solution of hydrochloric acid (0.23 mL, 0.23 mmol, 1 equivalent). The white precipitate was collected and dried under vacuum to give 193 mg (60%) of 1′-[(1S,2R)-2-hydroxy-3-(methylamino)-1-phenylpropyl]spiro[cyclo-hexane-1,3′-indol]-2′(1′H)-one hydrochloride. HRMS: calcd for C23H28N2O2+H+, 365.22235; found ([M+H]+), 365.2226;
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=O.[C:24](OCC)(=[O:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C1CCN2C(=NCCC2)CC1.C(O)C>[CH3:23][O:22][C:17]1[CH:16]=[C:3]2[C:2](=[CH:19][C:18]=1[O:20][CH3:21])[NH:1][C:24](=[O:31])[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:4]2[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc2[nH]c1=O
Temperature: 180 °C
Reaction time: 0.17 h
Yield: 92.1 %

Procedure:
A mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone (10.0 g), diethyl malonate (6.0 g) and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU)(0.396 g) was stirred at 180° C. for 10 minutes. After cooling, ethanol was added to the reaction mixture, and the crystals were collected by filtration to give ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2(1H)-quinolone-3-carboxylate (12.0 g, 91%) which was then recrystallized from chloroform-acetone. mp. 273°-276° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[NH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][CH2:17][CH:18]=O.[BH3-]C#N.[Na+].C(O)(=O)C>CO>[Cl:16][CH2:17][CH2:18][NH:10][C:9]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1
Reactant: O=CCCl
Reactant: COc1ccc(N)cc1OC1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(NCCCl)cc1OC1CCCC1
Temperature: 15 °C
Yield: 63.4 %

Procedure:
To a solution of 2.15 g (10.4 mmol) 3-cyclopentyloxy-4-methoxyaniline (J. Org. Chem. 2005,70, 1050) in 100 ml methanol were added 2.0 g (14.1 mmol) chloroacetaldehyde solution (55% in water), 3.9 g (62.6 mmol) NaBH3CN and 0.5 ml acetic acid. The reaction was stirred over night at 15° C. and the solvent was subsequently evaporated. The residue was taken up in 120 ml dichloromethane and the organic phase was washed with brine, dried over Na2SO4 and evaporated in vacuo. The crude product was purified by chromatography on silica gel (hexane:ethyl acetate 100:1 then 15:1) to give 1.78 g (63.5%) of the desired product as a yellow oil. 1H-NMR (DMSO): 6.70 (d, 1H), 6.28 (s, 1H), 6.06 (d, 1H), 5.43 (m, 1H), 4.69 (m, 1H), 3.68 (m, 2H), 3.60 (m, 3H), 3.32 (m, 2H), 1.83 (m, 2H), 1.69 (m, 4H), 1.55 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[C:12]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:12][O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH2:1]
Reactant: O=C([O-])[O-]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To acetone (60 mL) charged with 2-amino-3-nitrophenol (32 mmol, 4.9 g) and K2CO3 (48 mmol, 6.62 g) was added MeI (32 mmol, 1.98 mL). The reaction mixture was stirred rapidly at ambient temperature for 16 h. Acetone was removed under reduced pressure and the residue was partitioned between CH2Cl2 and brine. The organic phase was dried over MgSO4 and concentrated under reduced pressure to provide the product as a brown solid. LC-MS (ESI, Method C) 2.56 min, m/z 169.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[CH:23]1([NH:26][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:21])[CH2:25][CH2:24]1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NC4CC4)cc3)c2)o1
Temperature: 25 °C
Reaction time: 20 h
Yield: 39 %

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (59 mg, 0.2 mmol), cyclopropylamine (11 mg, 0.2 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.2 mmol) were suspended in dry DCM (7 ml) and stirred at room temperature under nitrogen for 20 h. Cyclopropylamine (33 mg, 0.6 mmol) was added and the reaction stirred at room temperature for 21 h. 1-Hydroxybenzotriazole (27 mg, 0.2 mmol) was added and the reaction heated at 35° C. for 70 h. Water (10 ml) was added to the cooled reaction, and the organic fraction separated. The organic phase was absorbed onto a silica flash column and eluted with DCI/ethanol/ammonia (300:8:1). Solvent was evaporated from the product fractions under vacuum to give N-(cyclopropyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide (26 mg, 39%).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH2:16][CH2:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C1C=C2N=NN(O)C2=CC=1.O.[C:32]([O:36][C:37](=[O:51])[CH2:38][CH:39]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:40](O)=[O:41])([CH3:35])([CH3:34])[CH3:33].Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CCOCC>[C:32]([O:36][C:37](=[O:51])[CH2:38][CH:39]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:40]([N:17]1[C:18]2[C:14](=[CH:13][C:12]([O:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:6][CH2:7]3)=[CH:20][CH:19]=2)[CH2:15][CH2:16]1)=[O:41])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)C1CCC(Oc2ccc3c(c2)CCN3)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CC(NC(=O)OC(C)(C)C)C(=O)N1CCc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc21
Temperature: 50 °C

Procedure:
To a solution of 5-(4-tert-butyl-cyclohexyloxy)-2,3-dihydro-1H-indole (110 mg, 0.4 mmol) in dimethylformamide (2 mL) was added HOBT monohydrate (10 mg, 0.1 mmol), 2-tert-butoxycarbonylamino-succinic acid 4-tert-butyl ester (230 mg, 0.8 mmol) and finally N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (92 mg, 0.48 mmol). The reaction was heated at 50° C. overnight. The solution was diluted with ether and washed twice with water. The organic phase was dried over MgSO4, filtered and concentrated to give crude product (220 mg, yield: 100%). The crude was used directly in Example 53. ESI-MS: 545.4 (M+H)+.
Reaction SMILES: Br[CH2:2][CH:3]([F:5])[F:4].[NH:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([C:15]([O:17][CH3:18])=[O:16])=[CH:7]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:4][CH:3]([F:5])[CH2:2][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([C:15]([O:17][CH3:18])=[O:16])=[CH:7]1
Reactant: COC(=O)c1c[nH]c2ncccc12
Reactant: FC(F)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(CC(F)F)c2ncccc12
Temperature: 70 °C

Procedure:
2-Bromo-1,1-difluoroethane (677 μl, 8.51 mmol) was added to a suspension of methyl 1H-pyrrolo[2,3-b]pyridine-3-carboxylate (500 mg, 2.84 mmol) and K2CO3 (1177 mg, 8.51 mmol) in DMF (2838 μl) at RT. The mixture was heated at 70° C. for 14 h and purified by column chromatography (SiO2; DCM/MeOH) to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:8]([CH3:21])[C:9](=O)/[CH:10]=[C:11]1\[CH2:12][CH2:13][CH2:14][C:15]2[S:16][CH:17]=[CH:18][C:19]\1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1>[CH2:1]([N:8]([CH3:21])[CH2:9]/[CH:10]=[C:11]1\[CH2:12][CH2:13][CH2:14][C:15]2[S:16][CH:17]=[CH:18][C:19]\1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)C(=O)/C=C1\CCCc2sccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C/C=C1\CCCc2sccc21)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
(E)-N-benzyl-2-(6,7-dihydrobenzo[b]thiophen-4(5H)-ylidene)-N-methylacetamide (0.32 g, 1.01 mmol) in THF anh. (5 mL) is added slowly to a suspension of AlLiH4 (0.1 g, 2.63 mmol) in THF anh. (20 mL) cooled in an ice bath and is stirred at room temperature for 1 hour and refluxed for 2 hours. The solution is cooled in an ice bath and some drops of NaOH 10% is added. The mixture is filtered and washed with ethyl acetate. The filtrate is evaporated to dryness and the residue is dissolved in ethyl acetate and washed with water. The organic phase is removed and the resulting crude is purified by column chromatography, giving (E)-N-benzyl-2-(6,7-dihydrobenzo[b]thien-4(5H)-ylidene)-N-methylethanamine (0.25 g, 0.88 mmol, 87%, oil). 1H NMR (300 MHz, CDCl3): δ 1.90 (m, 2H), 2.29 (s, 3H), 2.44 (m, 2H), 2.84 (t, J=6.1 Hz, 2H), 3.26 (d, J=7.0 Hz, 2H), 3.62 (s, 2H), 5.94 (t, J=7.0 Hz, 1H), 7.04 (d, J=5.3 Hz, 1H), 7.20 (d, J=5.3 Hz, 1H), 7.25-7.40 (m, 5H).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:15][C:14]=3[O:25][CH:26]([CH3:28])[CH3:27])[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH3:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1>>[CH:26]([O:25][C:14]1[CH:15]=[C:16]([C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)[CH:17]=[CH:18][C:13]=1[NH:12][C:9]1[N:10]=[CH:11][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:33]3[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=3)[C:7]=2[N:8]=1)([CH3:28])[CH3:27]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)Oc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(Cl)c2n1
Product: CC(C)Oc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(-c3cnn(C)c3)c2n1

Procedure:
The title compound was prepared according to the method described for Example 95 using 8-chloro-N-(2-isopropoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine (Preparation 115) and 1-methylpyrazole-4-boronic acid pinacol ester.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[N:8]([CH3:17])[C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[N:8]([CH3:17])[C:9]2[C:14]([C:15]=1[N:23]1[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1c(Cl)c2ccccc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(N2CCN(C)CC2)c2ccccc2n(C)c1=O

Procedure:
A stirred mixture of 9.5 g. of 4-chloro-1,2-dihydro-1-methyl-2-oxo-3-quinolinecarboxylic acid ethyl ester, 3.6 g. of N-methylpiperazine and 3.8 g. of sodium carbonate in 50 ml. of ethanol was heated under reflux for 3 hours and filtered. The filtrate was taken to dryness on a rotary evaporator leaving a thick, tarry oily residue. On triturating the oil with diethyl ether, there was obtained 9.4 g. of impure title compound, m.p. 144°-148° C. Recrystallization from ethanol gave 5.5 g. of the title compound, m.p. 154°-156° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][C:8]3=[C:11]([C:16]([O:18]CC)=[O:17])[S:12][C:13]([S:14][CH3:15])=[C:7]3[C:5]=2[N:6]=1.C(O)C.O1CCCC1.[OH-].[Na+]>O>[CH3:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][C:8]3=[C:11]([C:16]([OH:18])=[O:17])[S:12][C:13]([S:14][CH3:15])=[C:7]3[C:5]=2[N:6]=1
Reactant: CCOC(=O)c1sc(SC)c2c1CCc1sc(C)nc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CSc1sc(C(=O)O)c2c1-c1nc(C)sc1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
Ethyl 4,5-dihydro-2-methyl-8-methylthiothieno[3,4-e]benzothiazole-6-carboxylate (0.76 g) was suspended in a mixed solvent of ethanol (10 ml) and tetrahydrofuran (25 ml); a 2 N aqueous solution of sodium hydroxide (2.3 ml) was added at room temperature. After the reaction mixture was stirred at room temperature for 1 hour, the solution obtained was diluted with water (30 ml) and washed with diethyl ether. The water layer was acidified with 1 N hydrochloric acid (5 ml) and extracted with a mixed solvent of ethyl acetate and tetrahydrofuran. The ethyl acetate-tetrahydrofuran layer was washed with water and dried (MgSO4), after which the solvent was distilled off to yield 4,5-dihydro-2-methyl-8-methylthiothieno[3,4-e]benzothiazole-6-carboxylic acid (0.35 g, 50%), which was then recrystallized from ethyl acetate-hexane. Brown prisms. Melting point 273-274° C.
Reaction SMILES: C[N:2](/[CH:4]=[C:5]1/[C:6](=[O:15])[NH:7][CH2:8][C:9]2[C:14]/1=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:3].[N:16]1([CH2:22][C:23]2[CH:28]=[CH:27]C(N)=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C)C=O>[N:16]1([CH2:22][C:23]2[CH:28]=[CH:27][C:3]([NH:2][CH:4]=[C:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:8][NH:7][C:6]3=[O:15])=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Reactant: CN(C)/C=C1/C(=O)NCc2ccccc21
Solvent: CN(C)C=O
Product: O=C1NCc2ccccc2C1=CNc1ccc(CN2CCCCC2)cc1
Yield: 15.8 %

Procedure:
A solution of 0.400 g (1.98 mmol) of (4E)-4-[(Dimethylamino)methylene]-1,4-dihydro-3(2H)-isoquinolinone and 0.300 g (1.58 mmol) of 4-piperidin-1-ylmethyl-phenylamine in 4 mL of N,N-dimethylformamide (DMF) is heated at 125° C. for 3 h. The solvent is removed and the residue is slurried with Et2O and filtered. The Et2O soluble material is evaporated, redissolved in a small volume of PhCH3 and chilled. A precipitate is collected, boiled with MeOH (ca 20 mL) and filtered. The filtrate is evaporated and the residue is recrystallized from a minimum volume of MeOH. The resulting solid is collected, washed with cold MeOH and Et2O and dried in vacuo to yield 0.087 g (13%) of yellow crystals: mp 188-189° C. (dec); 1H NMR (DMSO-d6) δ 11.5 (d, 1H, J=11.8 Hz), 8.04 (d, 1H, J=11.8 Hz), 7.66 (m, 2H), 7.20 (s, 5H), 7.08 (m, 2H), 4.41 (s, 2H), 3.34 (s, 2H), 2.29 (s(br), 4H), 1.46 (m, 6H); HRMS (ESI) m/e calcd for C22H25N3O 348.20704. found 348.20704 (M+H)+1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:11]([CH3:13])[CH:12]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[NH2:24][C:25]1[C:30]([CH:31]=[O:32])=[C:29](Cl)[N:28]=[CH:27][N:26]=1.CCN(C(C)C)C(C)C.O>C(#N)C>[NH2:24][C:25]1[C:30]([CH:31]=[O:32])=[C:29]([N:17]2[CH2:18][CH2:19][CH:14]([C:10]3[N:11]([CH3:13])[CH:12]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:20]([F:21])([F:22])[F:23])[CH:4]=4)[N:9]=3)[CH2:15][CH2:16]2)[N:28]=[CH:27][N:26]=1
Reactant: Nc1ncnc(Cl)c1C=O
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C=O)CC1
Temperature: 40 °C
Yield: 85 %

Procedure:
A mixture of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine (600.00 mg; 1.83 mmol; 1.0 eq.), 4-amino-6-chloropyrimidine-5-carbaldehyde (303.25 mg; 1.92 mmol; 1.05 eq.), DIEA (0.95 ml; 5.5 mmol; 3.0 eq.) in acetonitrile (10.0 ml) was heated at 40° C. for 1 h. The reaction mixture was poured into water. The precipitate was filtered, washed with water and dried under vacuum to afford the title compound in 85% yield. LC-MS: (M+1=449, obsd.=449).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[CH2:23][NH2:24].CCOC(C)=O>CS(C)=O>[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=1[CH2:23][NH:24][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[N:3]=1
Reactant: Cc1ccc2nc(Cl)cnc2c1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2cnc3cc(C)ccc3n2)c(OC)c1
Yield: 95.8 %

Procedure:
2-Chloro-6-methylquinoxaline (0.51 g, 2.86 mmol), prepared according to J. Chem. Soc. 1948, 1310-1313, and (2,4-dimethoxyphenyl)methanamine (1.29 mL, 8.57 mmol) were microwaved in DMSO (2.5 mL) for 30 min at 150° C. This was diluted into 150 mL EtOAc and extracted three times with 100 mL brine. The crude product was purified by flash chromatography on a 90 g silica gel cartridge with 20 to 60% EtOAc in hexane, 50 min, at 40 mL/min to afford N-(2,4-dimethoxybenzyl)-6-methylquinoxalin-2-amine (848 mg, 2.74 mmol, 96% yield).
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[C:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([N+:20]([O-])=O)[CH:7]=1.O>[Fe].CCCCCC.C(OCC)(=O)C>[NH2:20][C:8]1[CH:7]=[C:6]([Cl:5])[CH:11]=[CH:10][C:9]=1[CH:12]=[C:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(C)=Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)=Cc1ccc(Cl)cc1N
Reaction time: 2 h
Yield: 73.6 %

Procedure:
Into 170 ml of acetic acid, 11.0 g of ethyl 3-(4-chloro-2-nitrophenyl)-2-methyl-2-propenate were C) dissolved; and, while the mixture was stirred, 10.9 g (195.2 mmol) of iron powder (Koso Chem. Co.) and 13 ml of distilled water were added thereto at room temperature. The temperature of the mixture was raised, so that the reaction was carried out at 97° C. for 2 hours. After the end point of the reaction was verified by TLC, the reaction liquid was cooled, and acetic acid was evaporated under a reduced pressure. To the residue, 300 ml of water and 400 ml of ethyl acetate were added. Then, insoluble matters were filtered out. The filtrate was successively washed with water, an aqueous sodium hydrogencarbon ate solution, and a saturated aqueous sodium chloride solution; and then was dried for one night with sodium sulfate being added thereto. After sodium sulfate was filtered out, the filtrate was concentrated under a reduced pressure, whereby 9.8 g of a crude crystal were obtained. This crystal was refined by a silica gel column chromatography (aminopropyl-modified silica gel (Fuji Silysia Chem. Co., NH-DM1020); developing solvent: hexane/ethyl acetate=2/1), whereby 7.2 g of the aimed compound were obtained (yield: 73.3%).