Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38]([C:40]2([C:43](O)=[O:44])[CH2:42][CH2:41]2)=[O:39])=[CH:33][CH:32]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[F:30][C:31]1[CH:32]=[CH:33][C:34]([NH:37][C:38]([C:40]2([C:43]([NH:1][C:2]3[CH:29]=[CH:28][C:5]([O:6][C:7]4[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]5[CH2:17][CH2:18][CH:19]([CH2:22][N:23]6[CH2:27][CH2:26][CH2:25][CH2:24]6)[CH2:20][CH2:21]5)=[O:15])[CH:8]=4)=[CH:4][CH:3]=3)=[O:44])[CH2:42][CH2:41]2)=[O:39])=[CH:35][CH:36]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(CN4CCCC4)CC3)c2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2)ccn1)N1CCC(CN2CCCC2)CC1
Reaction time: 1 h
Yield: 63.8 %

Procedure:
4-(Pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (125 mg) was dissolved in N,N-dimethylformamide (2 ml), and 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (176 mg), triethylamine (0.11 ml) and (1H-1,2,3-benzotriazol-1-yloxy)[tri(dimethylamino)]phosphonium hexafluorophosphate (349 mg) were added thereto in this order at room temperature, followed by stirring for 1 hr. Liquid-liquid separation was carried out after addition of ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate to the reaction mixture. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:5, then ethyl acetate). The solvent was concentrated under reduced pressure, and the resultant residue was suspended in diethyl ether (4 ml) and hexane (4 ml). The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (121.2 mg, 63.8%).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([C:14](=[O:16])[NH2:15])[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:26]>>[ClH:26].[NH2:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([NH2:15])=[O:16])[CH2:10][CH2:9]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(N)=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NC(=O)[C@H]1CC[C@@H](N)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cis-(4-carbamoyl-cyclohexyl)-carbamic acid tert-butyl ester (62 g, 256 mmol) in CH2Cl2 (250 mL) was added TFA (250 mL) and the mixture was stirred at ambient temperature for 1 hr. The mixture was concentrated and 2 M HCl in Et2O (150 mL) was added to give a white precipitate. The mixture was concentrated to give cis-4-amino-cyclohexanecarboxylic acid amide hydrochloride (45 g, 98%) as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([CH2:18][OH:19])[CH2:14][CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.C1COCC1.[NH3:25]>C(O)(C)C>[NH2:25][C:2]1[C:3]2[N:4]([C:8]([C@H:12]3[CH2:17][CH2:16][C@H:15]([CH2:18][OH:19])[CH2:14][CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: OC[C@H]1CC[C@H](c2nc(I)c3c(Cl)nccn32)CC1
Reactant: N
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Nc1nccn2c1c(I)nc2[C@H]1CC[C@H](CO)CC1
Temperature: -78 °C

Procedure:
trans-[4-(8-chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methanol (26.50 g, 67.66 mmol) was charged in a 400 mL steel bomb and was dissolved in 2M NH3 in isopropanol (300 mL) and anhydrous THF (10 mL). The reaction mixture was cooled to −78° C. Ammonia gas was bubbled vigorously into the solution for 8 min; then the bomb was tightly sealed and heated to 120° C. for 20 h. The crude reaction mixture was concentrated in vacuo, then the reaction residue was taken up with MeOH/CHCl3, loaded onto silica gel. The mixture was purified by a silica gel glass column chromatography [eluted with 1:1 CH2Cl2/EtOAc to 10%˜7 N NH3 in MeOH/CHCl3] to afford the desired product as a beige cream white solid; MS (ES+): m/z 373.01 (100) [MH+], 373.98 (50) [MH+2]; tR(polar-5 min/openlynx) 1.57 min.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18].C(C(C#N)=C(C#N)C#N)#N>CC(N(C)C)=O>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]2[NH:18][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:19]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: Nc1ccccc1N
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: N#CC(C#N)=C(C#N)C#N
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccc(-c2nc3ccccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
Resin-bound 4-carboxybenzaldehyde (subn. 0.65 mmol/g, 400 mg, 0.26 mmol) was suspended in DMA (3 mL) and treated with 1,2-phenylenediamine (2.6 mmol) and TCNE (2.6 mmol). The suspension was sonicated for 1 h and shaken at 25° C. for an additional 22 h. The resin was filtered, washed with DMA, DCM, and dried under high vacuum. The benzimidazole was cleaved from the solid support with 20% (v/v) TFA in DCM (2×5 mL, 15 min) and the combined filtrates were evaporated to give the title compound. 1H NMR (d6-DMSO) δ 7.35-7.43 (m, 2H), 7.69-7.78 (m, 2H), 8.19 (d, 2H, J=8.3 Hz), 8.26-8.34 (m, 2H), 12.50-14.20 (br s, CO2H). MS (API-ES+) m/z 239 (M+H).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C@H:10]([N:19]([CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[C:20]#[N:21])[CH2:9][C@@H:8]1[CH2:37][CH3:38])=[O:6])([CH3:3])[CH3:2].[N-:39]=[N+:40]=[N-:41].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:1]([O:4][C:5]([N:7]1[C:16]2[C:11](=[N:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C@H:10]([N:19]([CH2:22][C:23]2[CH:24]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=2)[C:20]2[N:39]=[N:40][NH:41][N:21]=2)[CH2:9][C@@H:8]1[CH2:37][CH3:38])=[O:6])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC[C@H]1C[C@@H](N(C#N)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nc(OC)ccc2N1C(=O)OC(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nn[nH]n2)c2nc(OC)ccc2N1C(=O)OC(C)C
Temperature: 120 °C
Yield: 56.4 %

Procedure:
Heat at 120° C. a mixture of (+/−)-cis-4-[(3,5-bis-trifluoromethyl-benzyl)-cyano-amino]-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (100 mg, 0.184 mmol), sodium azide (17 mg, 0.258 mmol) and triethyl amine hydrochloride (35 mg, 0.258 mmol) in dry toluene under an atmosphere of nitrogen for 8 h. Then add more sodium azide (6 mg) and triethyl amine hydrochloride (13 mg) and heat the mixture for 4 h. Cool to room temperature, dilute with ethyl acetate, and wash with 1 N HCl. Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (61 mg, 50%). MS (ES+): 588 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[N:9][C:10]3[N:11]2[N:14]=[C:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:22][CH:21]=2)[C:16]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+].O>CCO.C(Cl)Cl>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][NH:9][C:10]3[N:11]2[N:14]=[C:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:22][CH:21]=2)[C:16]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1ncc1ccc([N+](=O)[O-])cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCc1ccc([N+](=O)[O-])cc1-2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.1 %

Procedure:
To a solution of 8-nitro-2-(4-phenoxyphenyl)pyrazolo[1,5-a]quinazoline-3-carboxamide (240 mg, 0.57 mmol) in 10 mL of EtOH and 10 mL of DCM was added NaBH4 (86 mg, 2.26 mmol) at RT. After stirring at RT for 20 min, 10 mL of water was added. The mixture was concentrated. 5 mL of water was added and filtered. The cake was washed with tert-Butyl methyl ether (30 mL) and dried to afford 200 mg (83%) of 8-nitro-2-(4-phenoxyphenyl)-4,5-dihydropyrazolo[1,5-a]quinazoline-3-carboxamide as a yellow solid. MS (ESI) m/e [M+1]+ 427.9.
Reaction SMILES: CN(C)CC[N:5]1[C:21](=[O:22])[C:20]2[C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([OH:23])[CH:17]=4)[NH:12][C:11]=3[CH:10]=[CH:9][C:8]=2[C:6]1=[O:7].[N:25]1([C:31]([Cl:33])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>N1C=CC=CC=1>[ClH:33].[CH3:30][N:25]([CH3:31])[CH2:26][CH2:27][C:10]1[C:11]2[NH:12][C:13]3[C:18](=[CH:17][C:16]([O:23][C:31]([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[O:32])=[CH:15][CH:14]=3)[C:19]=2[C:20]2[C:21](=[O:22])[NH:5][C:6](=[O:7])[C:8]=2[CH:9]=1
Reactant: O=C(Cl)N1CCCCC1
Reactant: CN(C)CCN1C(=O)c2ccc3[nH]c4ccc(O)cc4c3c2C1=O
Solvent: c1ccncc1
Product: CN(C)CCc1cc2c(c3c1[nH]c1ccc(OC(=O)N4CCCCC4)cc13)C(=O)NC2=O
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
In 8 ml of pyridine was dissolved 200 mg of N-(2-dimethylaminoethyl)-6-hydroxycarbazole-3,4-dicarboximide. There was added 460 mg of 1-piperidylcarbonyl chloride. The mixture was stirred at room temperature overnight. The solvent was removed by distillation under reduced pressure. The residue was mixed with 10 ml of isopropyl alcohol. The mixture was stirred at room temperature for 10 minutes. The resulting crystals were collected by filtration and dried to obtain 180 mg (yield: 62%) of N-(2-dimethylaminoethyl-6-(1-piperidyl-carbonyloxy)carbazole-3,4-dicarboximide hydrochloride as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](SC2C=CC=CC=2C=O)=[CH:4][CH:3]=1.Cl[C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([O:23]O)=O.[S:28](S([O-])=O)([O-:31])(=O)=[O:29].[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:28]([C:19]2[CH:18]=[CH:27][CH:26]=[CH:25][C:20]=2[CH:21]=[O:23])(=[O:31])=[O:29])=[CH:4][CH:3]=1
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=Cc1ccccc1Sc1ccc(Cl)cc1
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1ccccc1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
To a solution of 2-(4-chlorophenylthio)benzaldehyde (2.00 g, 8.00 mmol) in dichloromethane (20 mL) at 0° C. was added meta chloroperoxybenzoic acid (77% max, 5.40 g, 24.17 mmol) in portions over 15 minutes, then warmed to room temperature and stirred for 2 hours. Aqueous sodium metabisulfite solution was added carefully until effervescence ceased. This solution was extracted with dichloromethane and the combined organic extracts were washed with NaOH (1N) then saturated brine, dried over MgSO4 and concentrated in vacuo giving a white solid (1.05 g, 3.74 mmol, 46%). δH (300 MHz, d6-DMSO) 10.69 (1H, s, CHO), 8.25-8.18 (1H, m, Ar), 8.07-8.00 (2H, m, Ar), 8.00-7.90 (3H, m, Ar) and 7.81-7.64 (3H, m, Ar).
Reaction SMILES: [SH:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[CH3:14][N:15]([CH3:24])[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[ClH:19].[CH3:14][N:15]([CH3:24])[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][S:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN(C)c1ccccc1CCl
Reactant: Cc1nc2ccccc2nc1S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1nc2ccccc2nc1SCc1ccccc1N(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 83 %

Procedure:
In a mixture of 50 ml of acetone and 5 ml of water were suspended 2.80 g of 2-mercapto-3-methylquinoxaline, 3.28 g of 2-dimethylaminobenzyl chloride hydrochloride, and 8.0 g of potassium carbonate. The resulting mixture was stirred at room temperature for 40 min., and the solvent was removed under reduced pressure. The residue was extracted with chloroform after addition of chloroform and water. The organic layer was separated and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was placed under reduced pressure to remove the solvent. The residue was diluted with 50 ml of ethanol. To the solution under chilling with ice were successively added 1.33 ml of conc. hydrochloric acid and ether to precipitate crystals. The crystals were collected by filtration to give 4.56 g of 2-(2-dimethylaminobenzylthio)-3-methylquinoxaline hydrochloride as a dark brown crystalline powder.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[S:27][CH:28]=[CH:29][N:30]=4)[CH2:23][CH2:22][C:21]([C:31]([O:33]C)=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[S:27][CH:28]=[CH:29][N:30]=4)[CH2:23][CH2:22][C:21]([C:31]([OH:33])=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2nccs2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2nccs2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.3 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-(thiazol-2-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (212 mg) in a mixture of tetrahydrofuran (18 ml) and methanol (18 ml) was added 1N sodium hydroxide solution (6 ml), and the mixture was stirred at room temperature overnight. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to neutral, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(thiazol-2-ylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (153 mg) as yellow crystals.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[C:5]([O:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][C:14]([O:17]CC)=[CH:13][C:12]1=[O:20])=[O:6]>C(Cl)Cl.C(OCC)C>[CH3:1][NH:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[C:5]([O:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][C:12]1=[O:20])=[O:6]
Reactant: CCOC1=CC(=O)C(CCCOC(=O)c2ccccc2NC)CC1
Solvent: ClCCl
Solvent: CCOCC
Product: CNc1ccccc1C(=O)OCCCC1CCC(=O)CC1=O

Procedure:
Compound 4 was stirred in a mixture of THF/3N HCl (1/1) at rt for 3 h and the mixture was concentrated. The crude product was washed with EtOAc/hexane/MeOH (1/2/0.5) to afford 6 as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.83 (1H, m), 7.34 (1H, m), 6.55 (2H, m), 4.22 (2H, t, J=6.3 Hz), 3.60 (2H, m), 2.84 (3H, s), 2.52-1.50 (9H, m); 13C NMR (75 MHz, CDCl3) δ 204.3, 203.8, 168.6, 151.6, 134.9, 131.7, 131.5, 115.2, 111.6, 110.5, 64.1, 58.4, 49.1, 39.9, 30.1, 26.4, 26.0, 24.7; ESI MS m/z 326 (M++Na+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.[F:51][C:52]1[CH:60]=[CH:59][CH:58]=[CH:57][C:53]=1[CH:54]([OH:56])[CH3:55]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:40](=[O:42])[O:56][CH:54]([C:53]2[CH:57]=[CH:58][CH:59]=[CH:60][C:52]=2[F:51])[CH3:55])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(O)c1ccccc1F
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC(C)c4ccccc4F)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 78.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (74 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (103 mg) in methylene chloride was then added- to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-fluoro-α-methylbenzyl alcohol (55 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (88 mg, yield 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>ClCCl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 176.8 %

Procedure:
To a solution of tert-butyl 4-{[(3,4-dichlorophenyl)amino]carbonyl}piperidine-1-carboxylate (3.0 g) in dichloromethane (15 mL) was added 4M HCl in dioxane (15 mL). The mixture was stirred at room temperature for 1 hour and then filtered to give the title compound as a white solid (2.2 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.Cl[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[CH:27][N:26]=1.C(N(CC)CC)C.O1CCOCC1>C(OCC)(=O)C>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:25]4[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][CH:28]=[CH:27][N:26]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(Nc4ncccc4[N+](=O)[O-])cc23)CC1
Temperature: 101 °C
Yield: 70 %

Procedure:
5-Amino-3-(N-t-butoxycarbonylpiperid-4-yl)-1H-indole and 2-chloro-3-nitropyridine were used. Triethylamine was the base, dioxane was the reaction solvent, the reaction was heated at reflux (101° C.) for 5 hours, and the chromatographic solvent system was ethyl acetate [30-40%] in hexanes to afford the title compound (70%) as a dark red foam: 1H NMR (CDCl3) δ155.8, 155.0, 151.6, 135.5, 134.6, 129.4, 126.9, 121.3, 120.8, 119.8, 114.8, 113.1, 111.5, 79.4, 44.5, 33.6, 32.8, 28.5. Anal. calcd. for C23H27N5O4.1/4 C4H8O2 [ethyl acetate]: C, 62.73; H, 6.36; N, 15.24. Found: C, 62.51; H, 6.08; N, 15.21.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[N:10]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:19]([CH2:22][C:23](=[O:25])[CH3:24])(=[O:21])[CH3:20]>C(O)(=O)C.Cl.O>[F:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][N:10]=[C:22]([C:23](=[O:25])[CH3:24])[C:19](=[O:21])[CH3:20]
Reactant: CC(=O)CC(C)=O
Reactant: O=N[O-]
Reactant: Nc1cccc(F)c1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)C(=NNc1cccc(F)c1F)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
To a solution of 2,3-difluoroaniline (1.0 g, 7.75 mmol) in 11.1 mL of acetic acid and 1.69 mL of concentrated hydrochloride solution, sodium nitrite (600 mg, 9.3 mmol) in 2.7 mL of water was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 h. Then to the reaction mixture was added dropwise a mixture of sodium acetate (1.78 g, 21.7 mmol, 3.0 equiv.) and acetylacetone (1 g, 10 mmol, 1.3 equiv.). The mixture was stirred at room temperature for 2 h, filtered, washed with water, EtOH/H2O (1/1) and hexane, and dried to give the title compound (900 mg, 48% yield): 1H NMR (400 MHz, CDCl3): δ ppm 2.49 (s, 3H), 2.61 (s, 3H), 6.93-7.00 (m, 1H), 7.11-7.17 (m, 1H), 7.50-7.56 (m, 1H), 14.64 (s, 1H).
Reaction SMILES: CO[C:3](=[O:22])[C:4](=[C:9]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]=[C:10]1[CH3:21])[C:5]([F:8])([F:7])[F:6].[CH3:23][C:24]1([CH3:38])[CH2:29][C:28](=[O:30])[CH:27]=[C:26]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:25]1>C(Cl)(Cl)Cl>[CH3:21][C:10]1[NH:11][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13](=[O:14])[C:9]=1[C:4]1([C:5]([F:8])([F:7])[F:6])[C:27]2[C:28](=[O:30])[CH2:29][C:24]([CH3:38])([CH3:23])[CH2:25][C:26]=2[N:31]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:3]1=[O:22]
Reactant: CC1(C)CC(=O)C=C(Nc2ccccc2)C1
Reactant: COC(=O)C(=C1C(=O)N(c2ccccc2)N=C1C)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1[nH]n(-c2ccccc2)c(=O)c1C1(C(F)(F)F)C(=O)N(c2ccccc2)C2=C1C(=O)CC(C)(C)C2
Reaction time: 14 h

Procedure:
To a chloroform solution (5 ml) of 2-(1,5-dihydro-3-methyl-5-oxo-1-phenyl-4H-pyrazol-4-ylidene)-3,3,3-trifluoro-propanoic acid methyl ester (565 mg, 1.81 mmol), 5,5-dimethyl-3-phenylamino-2-cyclohexen-1-one (390 mg, 1.81 mmol) was added and the mixture was stirred for 14 hours. After concentrating the liquid reaction mixture under reduced pressure, the residue was purified by silica gel flash column chromatography. Thus, the title compound was obtained as a colorless solid (780 mg).
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(F)=CC=1)C.C=O.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][CH:24]=1.[F:32][C:33]1[CH:51]=[CH:50][C:36]([CH2:37][N:38]([CH3:49])[C:39]([C:41]2[CH2:42]N(C)[C:44](=[O:47])[C:45]=2[OH:46])=[O:40])=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:51]=[CH:50][C:36]([CH2:37][N:38]([CH3:49])[C:39]([C:41]2[CH2:42][N:31]([CH2:30][CH2:29][C:26]3[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=3)[C:44](=[O:47])[C:45]=2[OH:46])=[O:40])=[CH:35][CH:34]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(F)cc2)=C(O)C1=O
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(F)cc1
Product: CN(Cc1ccc(F)cc1)C(=O)C1=C(O)C(=O)N(CCc2ccc(Cl)cc2)C1

Procedure:
3-[(4-Fluoro-benzyl)-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 1-D) was treated with paraformaldehyde and 2-(4-chlorophenyl)-ethylamine as described in the preparation of Compound 1. HRMS (M−H) calcd for C21H19ClFN2O3; 401.1068. found: 401.1080. 1H NMR (500 MHz, CDCl3)δ: 2.90 (t, 2, j=7), 2.95 (s, 3), 3.72 (t, 2, J=7), 3.95 (s, 2), 4.57 (s, 2), 7.03–7.26 (overlapping m, 8). 13C NMR (125 MHz, CDCl3) δ: 33.92, 34.45, 44.42, 49.37, 51.46, 108.49, 118.91, 128.87, 129.22, 129.98, 131.99, 132.67, 136.60, 154.21, 161.42, 163.37, 164.51, 166.31.