Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:10])([F:9])[CH2:7][NH2:8].C[O:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[C:23]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=3)=[N:24][O:25][C:26]=2[CH2:27][OH:28])=[N:16][CH:15]=1>O1CCOCC1>[F:36][C:31]1[CH:30]=[C:29]([C:23]2[C:22]([CH2:21][O:20][C:17]3[CH:18]=[CH:19][C:14]([C:13]([NH:8][CH2:7][C:6]([F:10])([F:9])[F:5])=[O:12])=[CH:15][N:16]=3)=[C:26]([CH2:27][OH:28])[O:25][N:24]=2)[CH:34]=[CH:33][C:32]=1[F:35]
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Reactant: NCC(F)(F)F
Agent: C[Al](C)C
Solvent: C1COCCO1
Product: O=C(NCC(F)(F)F)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2CO)nc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
Trimethylaluminium solution (2M in toluene, 0.8 mL, 1.60 mmol) was added to a solution of 2,2,2,-trifluoroethylamine (108 mg, 1.06 mmol) in dioxane (5 mL). The mixture was stirred for 1 h at 50° C. Then a solution of 6-[3-(3,4-difluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.27 mmol) in dioxane (5 mL) was added. The reaction mixture was stirred overnight at 85° C. The dioxane was removed by distillation. The remaining material was purified by chromatography (silica, ethyl acetate:heptane=2:3 to 3:2) to afford the title compound (70 mg, 59%) as a white solid. MS: m/e=444.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:7][C:8]=1[Cl:9])#[N:2].[C:14]([N:16]=[C:17]([NH2:19])[NH2:18])#[N:15].[OH-].[K+]>COCCOCCOC.O>[NH2:15][C:14]1[N:16]=[C:17]([NH2:19])[N:18]=[C:1]([C:3]2[C:8]([Cl:9])=[CH:7][CH:6]=[C:5]([C:10]([F:13])([F:11])[F:12])[CH:4]=2)[N:2]=1
Reactant: N#Cc1cc(C(F)(F)F)ccc1Cl
Reactant: N#CN=C(N)N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: COCCOCCOC
Product: Nc1nc(N)nc(-c2cc(C(F)(F)F)ccc2Cl)n1

Procedure:
4.0 g of 3-cyano-4-chlorobenzotrifluoride (90°-102° C./29 mm Hg), 2.0 g of dicyanodiamide and 1.0 g of caustic potash are refluxed in 10 ml of diglyme for 3 hours. After cooling, the mixture is diluted with water and the separated crystals are recrystallized from methanol. Melting point: 210°-212° C.; yield: 3.8 g.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].C1C=CC2N(O)N=NC=2C=1.[C:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][C:28]=1[OH:36])(=[O:26])[CH3:25].C(Cl)CCl>CN(C=O)C>[CH3:2][O:3][C:4]([C:6]1([NH:13][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([C:24](=[O:26])[CH3:25])=[C:28]([OH:36])[CH:29]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)=[O:5]
Reactant: CC(=O)c1ccc(C(=O)O)cc1O
Reactant: COC(=O)C1(N)CCCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)C1(NC(=O)c2ccc(C(C)=O)c(O)c2)CCCCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-Amino-cycloheptanecarboxylic acid methyl ester hydrochloride (968 mg, 4.66 mmol), HOBT (105 mg, 0.78 mmol) and 4-acetyl-3-hydroxy-benzoic acid (700 mg, 3.89 mmol) were dissolved in DMF (5 ml). EDIA (3.01 g, 23.3 mmol) and EDC were added and the mixture was stirred at room temperature for 72 h. Then the mixture was partitioned between EA and saturated sodium chloride solution, the aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by RP HPLC (water/ACN gradient) to yield the title compound.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2.N([O-])=O.[Na+].[BrH:24]>O>[Br:24][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[CH2:16][C@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]1=[O:15])[CH2:5]2
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C1Nc2ncccc2[C@]12Cc1ccc(Br)cc1C2
Temperature: 100 °C

Procedure:
To a cooled 0° C. solution of (R)-5-Amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (0.5 g, 2 mmol, Intermediate 1), in 48% HBr (4 mL) was added slowly over 10 minutes a solution of sodium nitrite (137 mg, 2 mmol) in water (0.6 mL with a 0.2 mL wash). After 5 minutes CuBr (285 mg, 2 mmole) was added and a condenser with nitrogen flow was attached. The reaction mixture was placed into a 100° C. bath and heated to 100° C. for 20 minutes. The reaction was diluted with water to obtain a large amount of precipitate. The reaction was quenched with concentrated aqueous NH4OH (about 2.5 mL) and the subsequently formed solid was collected by filtration and washed with water. The solid was air dried to obtain 740 mg of a free flowing solid, to which was added about 2 g of silica gel. The mixture was dry-loaded onto a silica gel column and the product was eluted using a tertiary solvent mixture/gradient (10-70%/80%-20%/10% EtOAc/Hex/DCM). The product containing fractions were combined and concentrated at reduced pressure to give the title compound. MS: m/z=315 (M+1).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[OH:7][OH:8].[C:9]1(=[O:19])[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.OS(O)(=O)=O>O>[CH:17]1[CH:18]=[C:10]([C:9]([OH:14])=[O:19])[C:11]([C:12]([O:7][OH:8])=[O:13])=[CH:15][CH:16]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: OO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccccc1C(=O)OO
Reaction time: 0.08 h
Yield: 76.9 %

Procedure:
Deionized water (125 ml), Na2CO3 (31.0 g, 0.25 mol) and 35% H2O2 (29.15 g, 0.3 mol) are successively charged in a 500 ml four-neck flask, and the mixture was stirred in a dry ice-methanol bath at −5° C.–0° C. Thereto was added phthalic anhydride (37.0 g, 0.25 mol) and the mixture was stirred for 30 min. The bath was removed, ethyl acetate (100 ml) was added to the mixture, and the reaction system was neutralized in a solution obtained by diluting 98% H2SO4 (15 ml) with deionized water (50 ml). After partitioning, the aqueous layer was extracted with ethyl acetate (60 ml). The obtained organic layer (0.64 g) was taken up and saturated NaI-IPA (isopropyl alcohol) solution (5 ml) and 10% acetic acid-IPA solution (20 ml) were added thereto. The mixture was boiled for 5 min. It was titrated with 0.1N aqueous sodium thiosulfate solution. As a result, mono-perphthalic acid was present in 33.5 g and the yield was 76.9%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11](/[C:14](=[N:19]\[S@@:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])/[CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al]([C:31]#[N:32])(CC)CC.CC(O)C>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C@@:14]([NH:19][S@@:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])([C:31]#[N:32])[CH2:15][CH2:16][CH:17]=[CH2:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCC/C(=N/[S@](=O)C(C)(C)C)C1CCN(Cc2ccccc2)CC1
Reactant: CC[Al](C#N)CC
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C=CCC[C@@](C#N)(N[S@](=O)C(C)(C)C)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
A solution of (R,Z)—N-(1-(1-benzylpiperidin-4-yl)pent-4-enylidene)-2-methylpropane-2-sulfinamide (2.74 g, 7.6 mmol) in THF (130 mL, 0.06 M) was cooled to −78° C. Separately, a 1 M solution of Et2AlCN (11.4 mmol, 11.4 mL) was dissolved in THF (20 mL) and cooled to −78° C. iPrOH (0.64 mL, 8.26 mmol) was added dropwise and the solution was warmed to RT over 20 min, then added dropwise to the sulfinamide solution. The reaction was allowed to warm gradually to RT and stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride (50 mL) and filtered through Celite. The Celite pad was washed with ethyl acetate (3×) and the combined organics were washed saturated aqueous sodium chloride, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel (1-9% methanol in dichloromethane and again with 2-5% methanol in ethyl acetate) to afford the desired product (1.99 g, 67%) along with its undesired diastereoisomer (0.46 g, 15%). Rf 0.26 (10% MeOH/CH2Cl2). 1H NMR (CDCl3, 300 MHz) δ 7.31-7.25 (m, 5H), 5.83-5.78 (m, 1H), 5.13-5.03 (m, 2H), 3.51 (d, J=1.5 Hz, 2H), 3.41 (s, 1H), 3.00 (d, J=11.0 Hz, 2H), 2.34-2.29 (m, 2H), 2.05-1.83 (m, 6H), 1.60-1.44 (m, 3H), 1.25 (s, 9H). ESI MS found for C22H33N3OS m/z [388.4 (M+1)].
Reaction SMILES: [CH:1]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH2:3][CH2:2]1.[Li+].[CH3:11]C([N-]C(C)C)C.IC>C1COCC1>[CH3:11][C:1]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CCC1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of ethyl cyclobutanecarboxylate (20.0 g, 156.0 mmol) in THF (160 mL) was added dropwise to a cold (−78° C.) solution of LDA (164 mmol of 2M solution) in THF (40 mL). The solution was warmed to 0° C. and then cooled again to −40° C. before the addition of iodomethane (10.2 mL, 163.8 mmol). The solution was slowly warmed to room temperature and stirred overnight. The reaction was quenched with an aqueous saturated solution of ammonium chloride and ether was added. The layers were separated and the aqueous layer was washed with ether. The combined organic layers were washed with 1N HCl then dried over MgSO4. The product was purified by distillation: 1H NMR (400 MHz, MeOD) δ 4.20-4.05 (m, 2H), 2.57-2.33 (m, 2H), 2.08-1.94 (m, 1H), 1.94-1.77 (m, 3H), 1.40 (s, 3H), 1.27 (tt, J=7.1, 1.5 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([CH:11]([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].[CH:21]([NH2:25])([CH2:23][CH3:24])[CH3:22]>>[CH:21]([NH:25][C:2]1[C:10]2[NH:9][C:8]([CH:11]([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18])([CH2:23][CH3:24])[CH3:22]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c2[nH]c(C(F)F)nc12
Reactant: CCC(C)N
Product: CCC(C)Nc1c(C(F)(F)F)cc([N+](=O)[O-])c2nc(C(F)F)[nH]c12

Procedure:
4-Chloro-7-nitro-5-trifluoromethyl-2-difluoromethylbenzimidazole is reacted with sec-butylamine to obtain 4-secbutylamino-7-nitro-5-trifluoromethyl-2-difluoromethylbenzimidazole, m.w., 352.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[CH2:23]([O:25][C:26](=[O:36])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]=[C:34]=[O:35])[CH:28]=1)[CH3:24].O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([C:34]([NH:33][C:29]5[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=5)[C:26]([O:25][CH2:23][CH3:24])=[O:36])=[O:35])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:21][CH:22]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CNCC4)cc1
Reactant: CCOC(=O)c1cccc(N=C=O)c1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cccc(NC(=O)N2CCc3c(cnc4c3cnn4Cc3ccc(OC)cc3)C2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
To a solution of 3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (0.208 g, 0.707 mmol) in anhydrous dichloromethane (10 mL) was added 3-isocyanato-benzoic acid ethyl ester (0.135 g, 0.707 mmol). The reaction was then shaken at room temperature for 30 minutes. On completion of the reaction water (10 mL) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane (20 mL). The organic extracts were combined, washed with brine (2×20 mL), dried using sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified using flash column chromatography (SiO2, gradient from 50% EtOAc in hexanes to 66% EtOAc in hexane) to give the pure desired product, ethyl 3-(3-(4-methoxybenzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7-carboxamido)benzoate (0.265 g, 77%) as a white solid. M.p.=>80° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.97 (s, 1H), 8.41 (s, 1H), 8.2 (s, 1H), 8.14-8.1 (m, 1H), 7.85-7.8 (m, 1H), 7.57-7.53 (m, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.21-7.16 (m, 2H), 6.88-6.82 (m, 2H), 5.59 (s, 2H), 4.81 (s, 2H), 4.31 (q, J=7.2 Hz, 2H), 3.84 (t, J=6 Hz, 2H), 3.69 (s, 3H), 3.15 (t, J=6 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H); LCMS [M+H]: 486.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([Cl:9])[C:7]=1F.[NH2:12]C1C(F)=C(F)N=C(F)C=1Cl>>[NH2:12][C:7]1[C:2]([Cl:1])=[C:3]([F:11])[N:4]=[C:5]([F:10])[C:6]=1[Cl:9]
Reactant: Nc1c(F)c(F)nc(F)c1Cl
Reactant: Fc1nc(F)c(Cl)c(F)c1Cl
Product: Nc1c(Cl)c(F)nc(F)c1Cl

Procedure:
This compound was prepared from 3,5-dichloro-2,4,6-trifluoropyridine (24.5 g) by a procedure similar to that described for compound 2: yield, 23.7 g (98%); mp 110° C. (Lit., Chambers et al., J. Chem. Soc. 1964, 5634-5640 mp 112-113° C.).
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:7][CH2:6][N:5]([C:8]2[O:9][CH2:10][C:11](=[O:18])[C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:4][CH2:3]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>C(O)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22]([CH:29]=[C:10]2[O:9][C:8]([N:5]3[CH2:6][CH2:7][S:2](=[O:1])(=[O:19])[CH2:3][CH2:4]3)=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]2=[O:18])=[CH:21]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(N2CCS(=O)(=O)CC2)OCC1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(N2CCS(=O)(=O)CC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Yield: 96.3 %

Procedure:
To a solution of ethyl 2-(1,1-dioxidothiomorpholino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.027 g, 0.092 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step and 7-azaindole-3-carboxaldehyde (0.014 g, 0.092 mmol) in ethanol (0.5 mL), piperidine (0.00092 mL, 0.0093 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed with hexane then dried to afford the titled compound as solid (0.037 g, y. 47%).
Reaction SMILES: [CH3:1][C:2]([CH:7]=[CH:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([OH:6])=O.[CH2:23]([NH2:25])[CH3:24]>>[CH2:23]([NH:25][C:4](=[O:6])[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[CH3:24]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CC=CC(C)=CC(=O)O
Reactant: CCN
Product: CCNC(=O)C=C(C)C=CC=C(C)CCC=C(C)CCC=C(C)C

Procedure:
3,7,11,15-Tetramethyl-2,4,6,10,14-hexadecapentaenoic acid and ethylamine were reacted in the same manner as in Preparation Example 9 to obtain the desired product as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[OH:12].[H][H]>[Pd].C(O)C>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([F:11])[C:3]=1[OH:12]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(F)c(O)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(F)c(O)c(F)c1
Yield: 90.3 %

Procedure:
2,6-Difluoro-4-nitrophenol (1.75 g, 10 mmol) and 10% palladium on carbon catalyst (0.3 g) in ethanol (100 ml) were shaken in a closed vessel under an initial hydrogen pressure of 3.5 bar. When hydrogen uptake was complete, the catalyst was filtered off, and the filtrate evaporated to a solid, triturated with petroleum ether, filtered, washed and dried to give the title compound (1.31 g), m.p. indeterminate.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11].Br[C:20]1[S:21][C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:23]([CH3:25])[N:24]=1.C(=O)(O)[O-].[Na+].O>CN(C=O)C>[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:20]2[S:21][C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:23]([CH3:25])[N:24]=2)[CH2:15][CH2:14]1)=[O:11]
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Reactant: CCOC(=O)c1sc(Br)nc1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc1C
Temperature: 50 °C
Yield: 30.6 %

Procedure:
3,4-Dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 1; 0.500 g, 2.00 mmol), ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (0.625 g, 2.00 mmol) and sodium bicarbonate (0.336 g, 2.00 mmol) were stirred in DMF (5 ml). The reaction was heated to 50° C. overnight. The solution was diluted by the addition of water and the resulting layers were separated. The aqueous layer was extracted with EtOAc (3×), and the organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated. Hexanes were added to the crude material, and the precipitate was filtered and rinsed with EtOAc to give the title compound as a beige solid (0.273 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][C:15](=[O:19])[CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:20](Br)[C:21]#[CH:22]>C1COCC1.CN(C=O)C>[CH2:3]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:22][C:21]#[CH:20])[C:15](=[O:19])[CH2:14]1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C#CCN1CCN(C(=O)OCc2ccccc2)CC1=O
Reaction time: 0.08 h
Yield: 100 %

Procedure:
Sodium hydride (0.82 g, 23.0 mmol, 60% mineral oil dispersion) is added to a solution of 4-benzyloxycarbonylpiperazin-2-one (5.13 g, 21.9 mmol) in THF/DMF (75 mL, 3/1 v/v) at 0° C. The mixture is stirred for 5 minutes, then propargyl bromide (3.7 mL, 41.5 mmol) is added dropwise. The resulting solution is stirred for 1 hour then brought to room temperature and stirred for 2 hours. The reaction is quenched with saturated ammonium chloride solution then diluted with ethyl acetate and washed with water (4×) and brine. The organic layer is dried over MgSO4, filtered and concentrated to dryness. The residue is purified by column chromatography eluting with 5% MeOH/CH2Cl2 to give the product (5.96 g, 21.9 mmol) as a white solid. 1H NMR (CDCl3, 300 MHz) δ7.3 (m, 5H), 5.12 (s, 2H), 4.25 (s,2H), 4.16 (s, 2H), 3.75 (m, 2H), 3.47 (m, 2H), 2.22 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](OCC)(=[O:14])[CH2:10][C:11]([CH3:13])=O.[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[OH:8][C:7]1[C:2]2=[N:1][C:11]([CH3:13])=[CH:10][C:9](=[O:14])[N:3]2[CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(=O)n2cccc(O)c2n1
Temperature: 100 °C
Yield: 60.4 %

Procedure:
To a mixture of 1.1 g of 2-amino-3-hydroxypyridine VIII and 1.1 g of etyl acetoacetate is added 4 ml of polyphosphoric acid and the resultant mixture is stirred under heating at 100° C. for 4 hours. The reaction mixture is poured into ice water, and the resulting solution is adjusted to PH 4 with 2N aqueous sodium hydroxide, then to PH 7 with aqueous sodium carbonate and shaken with CHCl3. The organic layer is washed with water and dried over anhydrous sodium sulfate. The solvent is evaporated to give 0.9 g of the titled compound XV-1.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]=O>C(O)=O>[CH2:1]([O:8][N:9]=[C:10]([CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: c1ccc(CON=C(c2ccccc2)C2CCCN2)cc1
Solvent: O=CO
Product: CN1CCCC1C(=NOCc1ccccc1)c1ccccc1

Procedure:
1.2 g (4.28 mmol) of phenyl(2-pyrrolidinyl)methanone O-benzyloxime in 4 ml of a mixture (1/1) of formic acid and aqueous 37% formaldehyde are introduced into a 50 ml round-bottomed flask equipped with a magnetic stirrer, and the mixture is refluxed for 16 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:12][CH:13]1[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:12][CH:13]2[CH2:15][CH2:14]2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: BrCC1CC1
Reactant: O=Cc1ccc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCC2CC2)cc1Cl
Temperature: 50 °C
Yield: 80.2 %

Procedure:
A solution of 2-chloro-4-hydroxybenzaldehyde (1.00 g, 6.39 mmol), bromomethylcyclopropane (0.93 mL, 9.58 mmol) and potassium carbonate (1.77 g, 12.8 mmol) in DMF (8 mL) was stirred under heating at 50° C. for 1 day. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 3:1) to give the title compound (1.08 g, yield 80%) as an oil.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])(O)=[O:2].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[OH:8][CH2:7][C:6]1[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:5]=1[CH2:4][CH2:1][OH:2]
Reactant: O=C(O)Cc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1ccc(CO)c(CCO)c1
Yield: 92.4 %

Procedure:
A mixture of 2-carboxymethyl-4-nitrobenzoic acid (13 g, 57.7 mmol), acetic anhydride (5.45 mL, 57.7 mmol) and toluene (130 mL) were heated to reflux for 5 hrs. The solvent was removed under vacuum to yield 6-nitro-isochroman-1,3-dione (compound (10) in Scheme 2) as a yellow solid (10.51 g, 88%). Borane tetrahydrofuran complex (35.6 mL, 1M in THF) was added dropwise over 40 min to a solution of 6-nitro-isochroman-1,3-dione (2 g, 9.66 mmol) in THF (40 mL) at 0° C. The contents were then stirred for 18 hrs at 25° C., cooled to 0° C., quenched with methanol (30 mL), and stirred for 1 hr. The solvents were removed under vacuum, ethyl acetate (30 mL) was added and the organic phase was washed with 10% aqueous hydrochloric acid. The aqueous acidic layer was backwashed with ethyl acetate (30 mL), the combined organic layers were dried with magnesium sulfate, and evaporated under vacuum until approximately 2 mL of ethyl acetate remained. This solution was filtered through silica gel washing with methylene chloride (30 mL) to remove impurities. The silica gel was flushed with ethyl acetate, the solvent was removed under vacuum to give a solid which was slurried in methylene chloride and filtered to afford the title diol as a white solid, 1.38 g , 73%.
Reaction SMILES: C(O[C:4]([C:6]1[N:10]=[CH:9][N:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:20]=2[C:21]([F:24])([F:23])[F:22])[NH:17][C:16](=[O:25])[N:15]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:14]3=[O:31])[N:7]=1)=[O:5])C.[CH3:32][NH2:33]>CO.C(O)C>[CH3:32][NH:33][C:4]([C:6]1[N:10]=[CH:9][N:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:20]=2[C:21]([F:22])([F:24])[F:23])[NH:17][C:16](=[O:25])[N:15]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[C:14]3=[O:31])[N:7]=1)=[O:5]
Reactant: CCOC(=O)c1ncn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)n1
Reactant: CN
Solvent: CCO
Solvent: CO
Product: CNC(=O)c1ncn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 22 h
Yield: 86 %

Procedure:
A solution of 150 mg (0.324 mmol) of 1-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H-[1,2,4]triazole-3-carboxylic acid ethyl ester in 0.8 ml of methanol is treated with 0.40 ml (3.24 mmol) of a ˜8M methylamine solution in ethanol. The mixture is stirred for 22 hours at room temperature and then concentrated in vacuo. The crude product is taken up in water and the pH of the solution is adjusted to 3 with 1 M aqueous HCl solution and the mixture is stirred for 3 hours at 0° C. The crystals are filtered, washed with cold water and dried in vacuo to give 124 mg (86%) of 1-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H-[1,2,4]triazole-3-carboxylic acid methylamide as white crystals, m.p. 257-260° C.