Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2](S(C1C=CC=CC=1)(=O)=O)([F:4])[F:3].[CH3:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1.C(O[K])(C)(C)C>CN(C=O)C>[CH3:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:2]([F:4])([F:3])[F:1])[OH:20])=[CH:17][CH:16]=1
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Reactant: O=S(=O)(c1ccccc1)C(F)(F)F
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Product: Cc1ccc(C(O)(c2ccccc2)C(F)(F)F)cc1
Temperature: -50 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
Into a dry Schlenk flask under an argon atmosphere, was added 7 mL DMF solution of phenyl trifluoromethyl sulfone (1a, 420 mg, 2 mmol) and 4-methylbenzophenone (196 mg, 1 mmol) at −50° C., was added 3 mL DMF solution of tBuOK (280 mg, 2.5 mmol). The reaction flask was then sealed and the reaction mixture was then stirred from −50° C. for 1 h, followed by stirring at −50° C. to room temperature overnight. The reaction mixture was quenched with 10 mL of ice water, and extracted with ether (20 ml×3). The combined ether phase was washed with saturated NH4Cl aqueous solution, followed by washing with water. After drying over MgSO4, the ether solvent was removed under vacuum. The crude product was further purified by column chromatography (hexanes/ether=9/1) to give 225 mg of product, 4-methyl-α-phenyl-α-(trifluoromethyl)benzenemethanol as a colorless oily liquid, yield 85%. 1H NMR (CDCl3): δ 2.36 (s, 3H); 2.89 (s, 1H); 7.17–7.51 (m, 9H). 19F NMR (CDCl3): δ −74.4. MS: 266 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[C:13]([F:21])=[C:14]([F:20])[C:15]4[N:16]=[CH:17][O:18][C:19]=4[C:11]=3[NH:10][C:9]2=[O:22])=[C:4]([F:23])[CH:3]=1.[CH3:24][N:25]([CH3:30])[S:26](Cl)(=[O:28])=[O:27].[H-].[Na+]>>[CH3:24][N:25]([CH3:30])[S:26]([N:10]1[C:11]2[C:19]3[O:18][CH:17]=[N:16][C:15]=3[C:14]([F:20])=[C:13]([F:21])[C:12]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:23])[C:9]1=[O:22])(=[O:28])=[O:27]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: O=c1[nH]c2c3ocnc3c(F)c(F)c2n1-c1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Product: CN(C)S(=O)(=O)n1c(=O)n(-c2ccc(Br)cc2F)c2c(F)c(F)c3ncoc3c21
Yield: 14.5 %

Procedure:
Intermediate I-24a was prepared from 6-(4-bromo-2-fluoro-phenyl)-4,5-difluoro-6,8-dihydro-imidazo[4′,5′:3,4]benzo[1,2-d]oxazol-7-one (I-16a: 350 mg, 0911 mmol), N,N-dimethylaminosulfonyl chloride (196.32 mg, 1.36 mmol) and NaH (54.4 mg, 1.36 mmol) using procedures analogous to those described above for Intermediate I-19a to afford 65 mg of the product (14.5% yield). H1NMR (DMSO-d6, 300 MHz): δ 8.96 (s, 1H), 7.95 (dd, 1H), 7.79 (t, 1H), 7.69 (dd, 1H), 3.08 (s, 6H). HPLC: 95.7%
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1.[Cl:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([Cl:41])[C:27]=1[OH:42].Cl>ClCCl.CO>[ClH:25].[Cl:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]2)[CH:29]=[C:28]([Cl:41])[C:27]=1[OH:42]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](N(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](N(C)C)CC1

Procedure:
Following general procedure F, 1-(6-bromo-4-(trans-4-(dimethylamino)cyclohexylamino)quinolin-3-yl)ethanone (4.48 g, 11.0 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (3.65 g, 13.0 mmol) to obtain the free base. The purified product was suspended in dichloromethane/methanol (2:1, 325 mL) after which HCl (115 mL, 1.25 M in methanol) was added to from a solution. The solution was concentrated to ˜100 mL and the resultant solid was filtered, washed with dichloromethane, and dried to obtain desired product (4.2 g, 70% over two steps) as a yellow solid: 1H NMR (500 MHz, MeOD) δ 9.13 (s, 1H), 8.48 (br s, 1H), 8.30 (dd, J=8.8, 1.8 Hz, 1H), 8.01 (d, J=8.7 Hz, 1H), 7.77 (s, 2H), 4.62 (br s, 1H), 3.50-3.46 (m, 1H), 2.91 (s, 6H), 2.75 (s, 3H), 2.58-2.54 (m, 2H), 2.35-2.29 (m, 2H), 1.92-1.82 (m, 4H); ESI MS m/z 472 [C25H27Cl2N3O2+H]+; HPLC>99% (AUC), tR=6.41 min.
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:13][C@H:12]([CH3:14])[C@H:11]3[O:15][C:16](=[O:18])[NH:17][C@@H:10]3[CH2:9]2)=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:14][C@H:12]1[CH2:13][NH:8][CH2:9][C@H:10]2[NH:17][C:16](=[O:18])[O:15][C@H:11]12
Reactant: COc1ccc(CN2C[C@H](C)[C@H]3OC(=O)N[C@@H]3C2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@H]1CNC[C@H]2NC(=O)O[C@H]12
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of (3aR,7S,7aR)-5-(4-methoxybenzyl)-7-methylhexahydrooxazolo[4,5-c]pyridin-2(3H)-one (1.0 equiv.) in methanol, at a concentration of 0.1 M, was added 20% palladium hydroxide on carbon (0.3 eq.). The resultant heterogeneous solution was put under an atmosphere of hydrogen and was stirred for 2 hours. At this time the mixture was filtered through a pad of celite eluting with methanol. The volatiles were removed in vacuo yielding (3aR,7S,7aR)-7-methylhexahydrooxazolo[4,5-c]pyridin-2(3H)-one (99%). LCMS (m/z): 157.1 (MH+) at 0.17 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11](Cl)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:14]1(C(OC(C)(C)C)=O)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)Cc1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Cc1cccc([N+](=O)[O-])c1)N1CCNCC1
Reaction time: 1 h

Procedure:
2-(3-nitrophenyl)acetyl chloride (0.20 ml, 1.0 mmol.) was added to a vigorously stirred mixture of tert-butyl piperazine-1-carboxylate (0.19 g, 1.0 mmol.) in CH2Cl2 (2 ml) and sat. aq. NaHCO3 (1 ml). The reaction was stirred for 1 hour; then the organic layer was separated, filtered through a plug of MgSO4, and concentrated under vacuum. The residue was treated with TFA in CH2Cl2 to remove the Boc group to give 2-(3-nitrophenyl)-1-(piperazin-1-yl)ethanone, which was carried on crude.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]([CH2:15]/[CH:16]=[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])\[CH3:18])[C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1.[CH2:29]([N:36]=[C:37]=[O:38])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>ClCCl>[CH3:13][N:12]([CH3:14])[C:9]1[CH:8]=[CH:7][C:6]([N:5]([CH2:4][C:3]2[CH:25]=[CH:26][CH:27]=[CH:28][C:2]=2[NH:1][C:37]([NH:36][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:38])[CH2:15]/[CH:16]=[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:23])[CH3:24])\[CH3:18])=[CH:11][CH:10]=1
Reactant: CCCCCCCN=C=O
Reactant: CC(C)=CCC/C(C)=C/CN(Cc1ccccc1N)c1ccc(N(C)C)cc1
Solvent: ClCCl
Product: CCCCCCCNC(=O)Nc1ccccc1CN(C/C=C(\C)CCC=C(C)C)c1ccc(N(C)C)cc1
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of N-(2-aminobenzyl)-N-geranyl-N',N'-dimethyl-1,4-phenylenediamine (0.54 g) in dichloromethane (10 ml) was added under ice-cooling heptyl isocyanate (0.3 g) and the mixture was stirred overnight while returning slowly to room temperature. After distilling off the solvent, the residue was purified by a silica gel column chromatography (hexane:ethyl acetate=3:1) to give 1-[2-[N-(4-dimethylaminophenyl)-N-geranylaminomethyl]phenyl]-3-heptylurea (0.62 g, 85%) as an oily product.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[O:28])[CH:22]=3)[CH:18]=[CH:19][CH:20]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:37](O)(=[O:46])/[CH:38]=[CH:39]/[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>ClCCl.CN(C=O)C>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][N:13]([CH2:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[O:28])[CH:22]=3)[CH:18]=[CH:19][CH:20]=2)[C:37](=[O:46])/[CH:38]=[CH:39]/[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: NS(=O)(=O)c1ccc(CCNCc2cccc(-c3cccc(C(=O)NCCN4CCCC4)c3)c2)cc1
Reactant: O=C(O)/C=C/c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(CCN(Cc2cccc(-c3cccc(C(=O)NCCN4CCCC4)c3)c2)C(=O)/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3′-[{2-[4-(Aminosulfonyl)phenyl]ethyl}aminomethyl]-N-[2-(1-pyrrolidinyl)ethyl]-[1,1′-biphenyl]-3-carboxamide (506 mg), trans-cinnamic acid (163 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl; 211 mg) and 1-hydroxybenzotriazole (HOBT; 149 mg) were dissolved in a mixed solvent of dichloromethane (15 ml) and DMF (7 ml), and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure, and water was added to the residues which were then extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residues were purified by silica gel column chromatography (dichloromethane/methanol=98/2), whereby the title compound (284 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:27])[C:10]([NH:24][CH2:25][CH3:26])=[C:11]([C:13]3[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]4[C:14]=3[CH:15]=[CH:16][CH:17]=[N:18]4)[CH:12]=2)=[C:5]([CH3:28])[O:4][N:3]=1.[C:29](N1C=CN=C1)(N1C=CN=C1)=[O:30].O1CCCC1>CCOC(C)=O>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([C:13]3[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]4[C:14]=3[CH:15]=[CH:16][CH:17]=[N:18]4)[C:10]3[N:24]([CH2:25][CH3:26])[C:29](=[O:30])[NH:27][C:9]=3[CH:8]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: CCNc1c(N)cc(-c2c(C)noc2C)cc1-c1c(C)ccc2ncccc12
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCn1c(=O)[nH]c2cc(-c3c(C)noc3C)cc(-c3c(C)ccc4ncccc34)c21
Temperature: 105 °C

Procedure:
4-(3,5-Dimethylisoxazol-4-yl)-N1-ethyl-6-(6-methylquinolin-5-yl)benzene-1,2-diamine (90 mg, 0.24 mmol) and 1,1′-carbonyldiimidazole (86.2 mg, 0.53 mmol) were added to tetrahydrofuran (10 ml) in a sealed vessel and heated to 105° C. overnight. The reaction mixture was the diluted in EtOAc and aqueous ammonium chloride and extracted with EtOAc (3 times). Organics were washed with ammonium chloride, water and brine and dried over sodium sulfate. Solvent was evaporated to dryness Crude material was purified by silica gel chromatography (DCM/MeOH as eluent) then by preparative HPLC to afford 5-(3,5-dimethylisoxazol-4-yl)-1-ethyl-7-(6-methylquinolin-5-yl)-1H-benzo[d]imidazol-2(3H)-one.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)(=[O:24])=[O:23])=[C:6]1[CH3:30].O1CCCC1.[OH-].[Li+]>O>[F:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([CH2:4][C:3]([OH:31])=[O:2])[C:6]([CH3:30])=[C:7]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:23])=[O:24]
Reactant: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)c2cccs2)c2cc(F)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cc2ccccc2S(=O)(=O)c2cccs2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
A mixture of {5-fluoro-2-methyl-3-[2-(thiophene-2-sulfonyl)benzyl]indol-1-yl}acetic acid methyl ester (0.21 g) and tetrahydrofuran (5.0 mL) was treated with 1.0 M aqueous lithium hydroxide solution (1.2 mL), and the resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with water (25 mL), concentrated to low bulk under reduced pressure and the pH adjusted to 4 by the addition of 0.1 M aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate and the combined organic extract was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and ethyl acetate containing 0.1% formic acid (1:0 to 0:1 by volume), followed by preparative reverse-phase HPLC, eluting with a mixture of acetonitrile and water (3:7 to 9:1 by volume) to afford the title compound as a white solid (0.14 g).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([C:25]([CH3:29])([CH3:28])[CH:26]=[O:27])=[CH:6][CH:5]=1>O1CCCC1>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])=[CH:6][CH:5]=1
Reactant: CC(C)(C=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
Sodium borohydride (11.4 mg, 0.300 mmol) was added to a stirred solution of 2-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2-methylpropanal (127 mg, 0.300 mmol) in tetrahydrofuran (3.0 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction was quenched by aqueous saturated ammonium chloride at 0° C. and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was recrystallized from ethanol/ethyl acetate to give the title compound as a colorless crystal (108 mg, 0.254 mmol, 85%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=O.[Na]>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:3])[CH:4]=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CC=O
Reactant: CNC
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCOC(=O)C=CN(C)C
Temperature: 20 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
13.1 g (0.29 mol) of dimethylamine were introduced into a suspension of 40 g (0.29 mol) of sodium ethyl formylacetate in 50 ml of toluene and 50 ml of ethanol. HCl gas was then introduced until the point of neutrality was reached and the mixture was stirred at 20° C. for 2 h. After filtering off the precipitate with suction, the mixture was worked up in a customary manner. Ethyl β-dimethylaminoacrylate was obtained in a yield of 91.6%.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C@@H:11]([CH3:25])[CH2:10][C@H:9]2[N:26]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:27](=[O:30])[CH2:28][CH3:29].[NH3:39]>CO>[C:3]([CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16](=[O:24])[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[C@@H:11]([CH3:25])[CH2:10][C@H:9]2[N:26]([C:31]1[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=1)[C:27](=[O:30])[CH2:28][CH3:29])(=[O:2])[NH2:39]
Reactant: N
Reactant: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(OCC(=O)OC)cc21
Solvent: CO
Product: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(F)cc2)c2ccc(OCC(N)=O)cc21
Temperature: 25 °C

Procedure:
(±)-Cis-N-[6-carbamoylmethoxy-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-(4-chloro-phenyl)-propionamide was prepared from (±)-cis-4-[(4-chloro-phenyl)-propionyl-amino]-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-6-yloxy]-acetic acid ester. To solid (±)-cis-[4-[(4-chloro-phenyl)-propionyl-amino]-1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-6-yloxy]-acetic acid methyl ester (76 mg, 0.14 mmol) was added a solution of ammonia in methanol (2 M, 10 mL). The resulting solution was stirred over night at room temperature and concentrated. The resulting crude amide was purified by silica gel chromatography (100% hexanes-100% ethyl acetate gradient) to afford pure product (59 mg, 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10].[H-].[Na+].CCCCCC.[CH3:33][C:34]1[CH:35]=[N:36][NH:37][CH:38]=1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:36]2[CH:35]=[C:34]([CH3:33])[CH:38]=[N:37]2)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][N:14]2[CH:22]=[CH:23][CH:24]=[C:13]2[CH2:12]1)=[O:10]
Reactant: Cc1cn[nH]c1
Reactant: O=C(c1ccc(F)cc1Cl)N1Cc2cccn2Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1cnn(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)c(Cl)c2)c1
Yield: 62.6 %

Procedure:
In the manner of Example 9's Method 1, employing (2-chloro-4-fluorophenyl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (1.0 g), 60% sodium hydride in oil (0.3 g, degreased with hexane), 4-methylpyrazole (0.48 g) and dimethylformamide (25 ml), the title compound (0.74 g) was obtained as an amorphous solid, MS, m/z: 403.2 (M+H)+, 425.2 (M+Na)+, 805.3 (2M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[S:5][C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:16])[C:7]=2[N:17]=1)[CH2:2][CH3:3].C(O)(=O)C.[Br:22]Br>O>[Br:22][C:13]1[CH:12]=[CH:11][C:10]2[N:9]=[C:8]([NH2:16])[C:7]3[N:17]=[C:4]([CH2:1][CH2:2][CH3:3])[S:5][C:6]=3[C:15]=2[CH:14]=1
Reactant: BrBr
Reactant: CCCc1nc2c(N)nc3ccccc3c2s1
Solvent: O
Solvent: CC(=O)O
Product: CCCc1nc2c(N)nc3ccc(Br)cc3c2s1
Temperature: 60 °C
Reaction time: 18 h
Yield: 189.2 %

Procedure:
2-Propylthiazolo[4,5-c]quinolin-4-amine (1.0 g, 0.41 mmol) was combined with acetic acid (15 mL) and heated to 60° C. Bromine (0.10 mL, 1.94 mmol) was added dropwise and the reaction mixture was stirred at 60° C. for 18 hours. The reaction mixture was diluted with water and the resulting precipitate was isolated by filtration to provide 0.25 g of 8-bromo-2-propylthiazolo[4,5-c]quinolin-4-amine as a yellow solid, m.p. 177-180° C. Analysis: Calculated for C13H12BrN3S: % C, 48.46; % H, 3.75; % N, 13.04; Found: % C, 47.98; % H, 3.95; % N, 12.70.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:7]=[C:6]1[CH3:22].[OH:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:31]([O:30][C:28](=[O:29])[C:27]1[CH:33]=[CH:34][C:24]([O:23][CH2:2][CH2:3][CH2:4][N:5]2[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:7]=[C:6]2[CH3:22])=[CH:25][CH:26]=1)[CH3:32]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: Cc1nc(-c2ccccc2)c(-c2ccccc2)n1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCCn2c(C)nc(-c3ccccc3)c2-c2ccccc2)cc1
Temperature: 55 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
(Scheme 2 (H)) To a solution of 1-(3-Bromo-propyl)-2-methyl-4,5-diphenyl-1H-imidazole (0.80 g, 2.2 mmol) and ethyl 4-hydroxybenzoate (1.20 g, 7.2 mmol) in DMF (30 mL) was added K2CO3 (0.40 g, 2.9 mmol). The resulting mixture was stirred at 55° C. for 1 hour, quenched by addition of water, extracted by EtOAc, washed by water, and then was dried over MgSO4. After filtration and concentration in vacuo, the residue was purified by flash chromatography (SiO2: EtOAc/Hexanes). This compound was obtained as a pale yellow gum (0.92 g, 2.0 mmol, 94% yield): 1H NMR (DMSO): δ1.32 (t, 3H), 1.85 (m, 2H), 2.402 (s, 3H), 3.87 (m, 4H), 4.28 (q, 2H), 6.89 (d, J=8.82 Hz, 2H), 7.143 (m, 3H), 7.36 (m, 4H), 7.46 (m, 3H), 7.82 (d, J=8.85 mHz, 2H). Mass spec: 441.28 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH3:21]>CN(C=O)C>[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[CH3:21])=[CH:8][N:9]=1
Reactant: Cc1ccc(O)cn1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cc2C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.9 %

Procedure:
To a 500 mL flask equipped with addition funnel at 0° C. was added NaH (8.26 g, 95%, 327 mmol), followed by slow addition of DMF (100 mL). The mixture was stirred for 10 minutes. The addition funnel was then charged with 6-methyl-pyridin-3-ol (30.2 g, 277 mmol) and DMF (100 mL), and the solution in addition funnel was added to the flask dropwise over 45 minutes. The reaction mixture was stirred at 0oC. for another 30 minutes once the addition was finished. To the addition funnel was then added 4-fluoro-3-methyl-nitrobenzene (39.1 g, 252 mmol) and DMF (100 mL) and the resulting solution was added to the flask dropwise over 45 minutes. The cold bath was removed at the end of the addition and the reaction mixture was allowed to stir at room temperature for 15 hours. The red dark solution was cooled to 0° C. and water (100 mL) was added cautiously to the reaction mixture. The resulting solution was stirred for 30 minutes and solid product was purified by filtration and washed with cold water (500 mL). The wet solid was dried in vacuo to give product (49.8 g, 81%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([CH:1]=[CH:17][N:18]([CH3:20])[CH3:19])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1ccc(C)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C=CN(C)C)c([N+](=O)[O-])c1
Temperature: 140 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
Methyl 4-methyl-3-nitrobenzoate (5 g, 25.6 mmol) was dissolved in DMF (25 mL, 5 vol) and to this was added N,N-dimethylformamide dimethylacetal (4.4 mL, 33.3 mmol). The mixture was allowed to stir at 140° C. for 3 h. The resulting deep red solution was allowed to cool and concentrated under vacuum. The residue was triturated with methanol and filtered. The filtrate was washed with methanol and dried on the sinter to yield 4-(2-dimethylamino-vinyl)-3-nitrobenzoic acid methyl ester (5.2 g, 80%). 1H NMR (300 MHz, DMSO), δ: 2.98 (6H, s, 2×CH3), 3.87 (3H, s, CH3), 5.58 (1H, m, CH), 7.72-7.83 (3H, m, ArH), 8.32 (1H, m, CH).
Reaction SMILES: [Br:1]Br.[OH-].[Na+].[C:5]([C:7]([C:17]1[CH:22]=[CH:21][C:20]([C:23]#[CH:24])=[CH:19][CH:18]=1)([CH2:14][CH:15]=[CH2:16])[CH2:8][N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)#[N:6].O>O1CCOCC1>[C:5]([C:7]([C:17]1[CH:18]=[CH:19][C:20]([C:23]#[C:24][Br:1])=[CH:21][CH:22]=1)([CH2:14][CH:15]=[CH2:16])[CH2:8][N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)#[N:6]
Reactant: BrBr
Reactant: C#Cc1ccc(C(C#N)(CC=C)Cn2cncn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=CCC(C#N)(Cn1cncn1)c1ccc(C#CBr)cc1

Procedure:
0.8 g of bromine are added, at 0°, to 5 ml of 10% NaOH while stirring vigorously. After the solution has become colourless a solution of 1 g 2-cyano-2-(4-ethinylphenyl)-1-(1H-1,2,4-triazol-1-yl)-4-pentene in 3 ml of dioxane are added dropwise, at 0°, within a few minutes. The reaction mixture is then stirred for 3 hours at room temperature, poured into 100 ml of water, extracted with diethylether, the ether extract washed with water (3 times), dried and the ether evaporated. The residue is heated for 3 hours at high vacuum and a temperature of 50°-60° C. The thus obtained title compound has a Rf value of 0.75, employing CH2Cl2 /CH3OH 9:1 as eluant (Compound 4).