Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CNC1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7](=[O:15])[N:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5](=[O:22])[C:4]=1[C:23]([NH:25]C(=O)OCC)=[S:24].[CH3:31][N:32]([CH3:35])[CH:33]=[O:34].C(N(CC)CC)C.Cl>O>[SH:24][C:23]1[C:4]2[C:5](=[O:22])[N:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:7](=[O:15])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:31]=2[N:32]([CH3:35])[C:33](=[O:34])[N:25]=1
Reactant: CCOC(=O)NC(=S)c1c(NC)n(-c2ccccc2)c(=O)n(-c2ccccc2)c1=O
Reactant: CN(C)C=O
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1c(=O)nc(S)c2c(=O)n(-c3ccccc3)c(=O)n(-c3ccccc3)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To crude ethyl (6-methylamino-2,4-dioxo-1,3-diphenyl-1,2,3,4-tetrahydro-pyrimidine-5-thiocarbonyl)-carbamate 23 (1.58 g) obtained in Step 4 was added N,N-dimethylformamide (8.4 ml), triethylamine (0.63 ml) was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 30 min. Water (25 ml) was added, the mixture was stirred, 1N hydrochloric acid (5.0 ml) was added, and the mixture was stirred at room temperature for 1 hr. The crystals were collected by filtration, washed with water and dried to give crude 5-mercapto-8-methyl-1,3-diphenyl-1H,8H-pyrimido[4,5-d]pyrimidine-2,4,7-trione 24 (1.53 g, over weight) as yellow crystals, which were used for the next step without purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([CH2:12][CH3:13])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[C:4]([CH2:12][CH3:13])[C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCc1cc(Br)ccc1NC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCc1cc(-c2ccc(Cl)cc2)ccc1NC(C)=O
Temperature: 80 °C
Yield: 91.3 %

Procedure:
To a degassed solution of N-(4-bromo-2-ethylphenyl)acetamide (20 g, 0.082 mol) in toluene (1200 ml) and ethanol (400 ml), 4-chlorobenzene boronic acid (15.5 g, 0.099 mol) is added under an atmosphere of nitrogen, and the reaction mixture is heated to 80° C. Tetrakis(triphenylphosphine)palladium(0) (2.0 g, 0.0017 mol) is added followed by 2M aqueous potassium carbonate solution (160 ml). The reaction mixture is heated at reflux for 4 hours then cooled to room temperature. The reaction mixture is filtered through diatomaceous earth, and the filtrate is evaporated under reduced pressure. The residue is partitioned between ethyl acetate and water. The aqueous phase is extracted with ethyl acetate (3×500 ml) and the organic solutions are combined and concentrated under reduced pressure to give N-(4′-chloro-3-ethylbiphen-4-yl)acetamide (20.5 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][CH2:7][OH:8].[H-].[Na+].I[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:37]=[CH:36][C:19]([O:20][CH2:21][C:22]2[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]3[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=3)[O:25][CH:26]=2)=[CH:18][CH:17]=1.O>CN(C=O)C>[Br:35][C:32]1[CH:31]=[CH:30][C:29](/[CH:28]=[CH:27]/[C:24]2[O:25][CH:26]=[C:22]([CH2:21][O:20][C:19]3[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][CH2:13][CH2:12][N:1]4[CH:5]=[CH:4][N:3]=[C:2]4[CH2:6][CH2:7][OH:8])=[CH:37][CH:36]=3)[N:23]=2)=[CH:34][CH:33]=1
Reactant: OCCc1ncc[nH]1
Reactant: Brc1ccc(/C=C/c2nc(COc3ccc(CCCCI)cc3)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(Br)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
To a solution of 2-(1H-imidazol-2-yl)-ethanol (449 mg) in DMF (10 ml), 60% oily sodium hydride (176 mg) was added under ice cooling. After stirring at room temperature for 30 minutes, 4-[[4-(4-iodobutyl)phenoxy)methyl]-2-[(E)-2-(4-bromophenyl)ethenyl]-1,3-oxazole (2.15 g) was added under ice cooling. After stirring overnight at room temperature, water was added under ice cooling. The reaction mixture was extracted with a mixture of ethyl acetate-THF. The extract was dried over magnesium sulfate, after which it was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to yield the titled compound (2.09 g) as a light-yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:19])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:5]=[CH:6][C:7]=1Cl.[CH3:20][NH:21][NH2:22].O>CO>[Cl:1][C:2]1[C:3](=[O:19])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[N:5]=[CH:6][C:7]=1[N:21]([CH3:20])[NH2:22]
Reactant: O=c1c(Cl)c(Cl)cnn1-c1cccc(C(F)(F)F)c1
Reactant: CNN
Solvent: CO
Solvent: O
Product: CN(N)c1cnn(-c2cccc(C(F)(F)F)c2)c(=O)c1Cl
Temperature: 45 °C

Procedure:
To a solution consisting of 15.5 grams of 4,5-dichloro-2-(3-trifluoromethylphenyl)-pyridazine-3(2H)-one in 120 grams of methanol is added 9.2 grams methylhydrazine. The reaction mixture is heated to 45° C for three hours, cooled and poured onto 250 grams of water. The resulting precipitate is separated by filtration, washed with water and dried. The solid is crystallized from benzene to yield 4-chloro-2-(3-trifluoromethylphenyl)-5-(1-methylhydrazino)-pyridazin-3(2H)-one (m.p. 140° to 141° C, with decomposition).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][C:10]([C:12]2C(C3C=CC=C([N+]([O-])=O)C=3)C(C(OC)=O)=C(C)[NH:16][C:17]=2[CH3:18])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C>[C:1]1([CH2:7][CH2:8][O:9][C:10](=[O:11])/[CH:12]=[C:17](\[NH2:16])/[CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: C/C(N)=C/C(=O)OCCc1ccccc1
Yield: 74 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 3'-nitrobenzylideneacetoacetic acid methyl ester and 75 mmols of β-aminocrotonic acid 2-phenylethyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-methoxycarbonyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 2-phenylethyl ester of melting point 122° C (from ethanol).
Reaction SMILES: O=[C:2]([NH:9][C:10](=[O:15])[C:11](OC)=[O:12])[CH2:3][C:4]([F:8])=[C:5]([F:7])[F:6].[NH3:16]>CO>[F:8][C:4](=[C:5]([F:7])[F:6])[CH2:3][CH2:2][NH:9][C:10](=[O:15])[C:11]([NH2:16])=[O:12]
Reactant: N
Reactant: COC(=O)C(=O)NC(=O)CC(F)=C(F)F
Solvent: CO
Product: NC(=O)C(=O)NCCC(F)=C(F)F
Yield: 68 %

Procedure:
A solution of Compound 142 (5.0 g, 0.0237 mole) in methanol (50 mL) is saturated with dry gaseous ammonia at room temperature. The precipitate is filtered, washed with methanol and dried to give 3.16 g of the title compound as a white solid, a 68% yield. m.p. 190°-220° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:34]1[CH2:39][CH2:38][O:37][CH:36]([C:40]([OH:42])=[O:41])[CH2:35]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:34]4[CH2:39][CH2:38][O:37][CH:36]([C:40]([OH:42])=[O:41])[CH2:35]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: O=C(O)C1CNCCO1
Product: O=C1N=C(N2CCOC(C(=O)O)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
4-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]morpholine-2-carboxylic acid was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]2-methylsulfanyl-thiazol-4-one and morpholine-2-carboxylic acid following General Procedure C.
Reaction SMILES: [CH:1]1([CH2:5][NH:6][C:7]([C:9]2[C:10]([C:16]([F:19])([F:18])[F:17])=[N:11][C:12](Cl)=[N:13][CH:14]=2)=[O:8])[CH2:4][CH2:3][CH2:2]1.[CH3:20][C:21]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:22]=1[NH2:23]>O1CCOCC1.CS(C)=O>[CH:1]1([CH2:5][NH:6][C:7]([C:9]2[C:10]([C:16]([F:19])([F:18])[F:17])=[N:11][C:12]([NH:23][C:22]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:21]=3[CH3:20])=[N:13][CH:14]=2)=[O:8])[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(Cl)ccc1N
Reactant: O=C(NCC1CCC1)c1cnc(Cl)nc1C(F)(F)F
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: Cc1cc(Cl)ccc1Nc1ncc(C(=O)NCC2CCC2)c(C(F)(F)F)n1
Temperature: 180 °C
Yield: 53 %

Procedure:
To a solution of 2-chloro-4-trifluoromethyl-pyrimidin-5-carboxylic acid cyclobutylmethyl-amide (50 mg) in 1,4-dioxan (1.0 ml) was added 2-methyl-4-chloroaniline (120 mg) and the solution heated at 180° C. under microwave irrdiation for 30×2 minutes. The residue was dissolved in 1:1 DMSO:methanol (11.0 ml) and purified by Mass Directed Auto-Purification to afford the title compound (36 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28].[CH2:29](Br)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2O)c1
Reactant: CCCCCCCCBr
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(CCC(=O)OCC)cc1-c1cc(CCC(=O)OCC)ccc1O
Yield: 121 %

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl and 913.3 μl (5.181 mmol) of octyl bromide, there were added 85.5 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated overnight at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 20 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 100/1 and 50/1) to obtain 230.4 mg (0.627 mmol, 89%) of 2-octyloxy-2'-hydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl as an oily product.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]2[NH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[C:12]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25]OS(C)(=O)=O)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:12]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][N:11]1[C:4]2[C:3]([S:2][CH3:1])=[N:8][CH:7]=[N:6][C:5]=2[CH:9]=[N:10]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CSc1ncnc2cn[nH]c12
Reactant: CS(=O)(=O)OCCOCCOC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ncnc2cnn(CCOCCOC(=O)c3ccccc3)c12
Temperature: 60 °C
Reaction time: 4 h
Yield: 33.1 %

Procedure:
A mixture of 7-(methylthio)-1H-pyrazolo[4,3-d]pyrimidine (747 mg), 2-{2-[(methylsulfonyl)oxy]ethoxy}ethyl benzoate (1.43 g), potassium carbonate (931 mg) and N,N-dimethylformamide (12 mL) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water (30 mL), and the mixture was extracted with ethyl acetate (50 mL×2). The organic layers were combined, washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→20:80), and further purified by basic silica gel column chromatography (eluent, hexane:ethyl acetate=90:10→40:60) to give the title compound (533 mg).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[O:30]1C[CH:31]1[CH2:33][N:34]1[C:42]2[CH2:41][CH2:40][N:39]([C:43](=[O:45])[CH3:44])[CH2:38][C:37]=2[C:36]([C:46]2[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=2)=[N:35]1>>[O:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:14]([N:11]2[CH2:10][CH2:9][N:8]([CH2:6][CH:31]([OH:30])[CH2:33][N:34]3[C:42]4[CH2:41][CH2:40][N:39]([C:43](=[O:45])[CH3:44])[CH2:38][C:37]=4[C:36]([C:46]4[CH:51]=[CH:50][C:49]([C:52]([F:55])([F:54])[F:53])=[CH:48][CH:47]=4)=[N:35]3)[CH2:13][CH2:12]2)=[N:15]1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Reactant: CC(C)(C)OC(=O)N1CCN(c2noc3ccccc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCN(c3noc4ccccc34)CC2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
A solution of 82 mg (0.27 mmol) of 4-benzo[d]isoxazol-3-yl-piperazine-1-carboxylic acid tert-butyl ester in 2 mL of CH2Cl2was treated with trifluoroacetic acid (0.5 mL) at room temperature overnight. The solvent was then removed and the crude product dissolved in EtOH and stirred over 100 mg of sodium bicarbonate for 1 h, the solid was then filtered off and the filtrate concentrated. The crude piperazine was then dissolved in 4 mL EtOH and treated with 100 mg (0.27 mmol) of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone. The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH/EtOAc) to afford 105 mg (68%) of a white solid. MS (electrospray), exact mass calculated for C29H31F3N6O3, 568.24; m/z found, 569.2 [M+H]+. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 7.77 (d, J=8.41 Hz, 1H), 7.69 (m, 2H), 7.67-7.62 (m, 2H), 7.50-7.44 (m, 1H), 7.45-7.42 (m, 1H), 7.23-7.18 (m, 1H), 4.93 (br m, 1H), 4.87 and 4.75 (A and B of AB quartet, J=15.65 Hz, 1H), 4.65 (br s, 1H), 4.27-4.15 (m, 2.3H), 4.09-3.95 (m, 1.7H), 3.91-3.82 (m, 0.7H), 3.81-3.66 (m, 1.3H), 3.62-3.49 (m, 4H), 3.01-2.85 (m, 1.5H), 2.85-2.74 (m, 2.5H), 2.71-2.60 (m, 2H), 2.58-2.45 (m, 2H), 2.20 (s, 1.5H), 2.15 (s, 1.5H).
Reaction SMILES: FC(F)(F)[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[CH:11][CH:12]=2)[N:7]([CH:17]([CH3:19])[CH3:18])[CH:6]=1)=[O:4].[OH-:22].[Na+]>>[CH:17]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[C:5]([C:3]([OH:4])=[O:22])=[CH:6]1)([CH3:19])[CH3:18]
Reactant: CC(C)n1cc(C(=O)C(F)(F)F)c2ccc([N+](=O)[O-])cc21
Reactant: [OH-]
Agent: [Na+]
Product: CC(C)n1cc(C(=O)O)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 2,2,2-trifluoro-1-(1-isopropyl-6-nitro-1H-indol-3-yl)-ethanone (525 mg, 1.75 mmol) in a 20% aqueous sodium hydroxide solution (10 mL) was heated at 1110° C. for 2 h. At this time, the reaction was cooled to 25° C., partitioned between water (75 mL) and ethyl acetate (75 mL), and treated with a 1N aqueous hydrochloric acid solution (25 mL). The organic layer was washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 1-isopropyl-6-nitro-1H-indole-3-carboxylic acid (436 mg, 99%) as a yellow solid: mp 242-243° C.; EI-HRMS m/e calcd for C12H12N2O4 (M+) 248.0797, found 248.0796.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:41])[C:7]=1[CH:8]([OH:40])[CH2:9][N:10]([CH2:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[CH:33]=1)[C:11]([C:13]1[CH:14]=[N:15][N:16]([C@H:22]2[CH2:27][CH2:26][C@H:25]([C:28]([OH:30])=O)[CH2:24][CH2:23]2)[C:17]=1[C:18]([F:21])([F:20])[F:19])=[O:12].Cl.[CH3:43][O:44][NH2:45].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:41])[C:7]=1[CH:8]([OH:40])[CH2:9][N:10]([CH2:31][C:32]1[CH:33]=[C:34]([F:39])[CH:35]=[C:36]([F:38])[CH:37]=1)[C:11]([C:13]1[CH:14]=[N:15][N:16]([C@H:22]2[CH2:23][CH2:24][C@H:25]([C:28](=[O:30])[NH:45][O:44][CH3:43])[CH2:26][CH2:27]2)[C:17]=1[C:18]([F:21])([F:20])[F:19])=[O:12]
Reactant: O=C(c1cnn([C@H]2CC[C@H](C(=O)O)CC2)c1C(F)(F)F)N(Cc1cc(F)cc(F)c1)CC(O)c1c(Cl)cncc1Cl
Reactant: CON
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CONC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(Cc3cc(F)cc(F)c3)CC(O)c3c(Cl)cncc3Cl)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of compound 5-3 (75 mg, 0.12 mmol) and O-methylhydroxylamine hydrochloride (10 mg, 0.12 mmol) in DMF (3 mL) were added HATU (55 mg, 0.14 mmol) and DIPEA (0.05 mL, 0.30 mmol) and mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure to afford crude compound 6-1 (65 mg, 82%) as a white foam. LCMS: 650 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])=O.[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])[CH3:13].[OH-].[Na+].Cl>C(O)C.O>[O:14]=[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:13]=[CH:1][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: CC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccc(C=CC(=O)c2ccccc2)c1
Yield: 84.5 %

Procedure:
A mixture of 3-formylbenzoic acid (2 g, 13.32 mmol), acetophenone (1.6 g, 13.32 mmol), and sodium hydroxide (1.06 g, 26.64 mmol) is stirred 18 hours in ethanol-water (175 mL, 1:1) and then acidified with concentrated hydrochloric acid. The resulting solid is collected by filtration and dried to provide 2.84 g of the title compound; mp 198°-201° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][C@H:27]([C:34]([NH:36]N)=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(N[C@@H:46]([CH2:52][CH:53]([CH3:55])[CH3:54])[C@@H:47]([OH:51])[CH2:48][CH2:49][OH:50])=O)(C)(C)C>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([NH:26][C@H:27]([C:34]([NH:36][C@@H:46]([CH2:52][CH:53]([CH3:55])[CH3:54])[C@@H:47]([OH:51])[CH2:48][CH2:49][OH:50])=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CCO
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1)[C@@H](O)CCO

Procedure:
The procedure described in Example 12(c) was repeated, but using 125 mg. (0.25 mmole) of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidine hydrazide and 65 mg. (0.25 mmole) of the alcohol prepared as described in (a) above. There were obtained 42 mg. of the desired compound as a white powdery solid, melting at 196°-198° C.; [α]24 -57.8° (C=0.5, methanol).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH2:22]1[C@@H:26]2[CH2:27][NH:28][CH2:29][C@@H:25]2[CH2:24][O:23]1>>[CH2:22]1[C@@H:26]2[CH2:27][N:28]([C:12]([C:10]3[CH:9]=[CH:8][C:7]([N:15]4[CH2:18][C:17]([F:20])([F:19])[CH2:16]4)=[C:6]([O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[N:11]=3)=[O:14])[CH2:29][C@@H:25]2[CH2:24][O:23]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: C1NC[C@H]2COC[C@@H]12
Agent: Cl
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1C[C@H]2COC[C@H]2C1
Yield: 54.7 %

Procedure:
In analogy to the procedure described in Example 127 e), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b, 30 mg, 106 μmol) was reacted with (3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole hydrochloride (CAN 57710-36-8, 15.8 mg, 106 μmol) to obtain the title compound (22 mg, 55%) as white solid, MS (EI): m/e=380.3 [MH+].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:8][C:5]2[C:4]([O:9][CH3:10])=[N:3][C:2]([Cl:1])=[CH:7][N:6]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COc1nc(Cl)cnc1N
Product: COc1nc(Cl)cnc1NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-chloro-3-methoxy-2-pyrazinamine (0.1 g) and 4-chlorobenzenesulphonyl chloride (0.13 g).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH2:18][O:19]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C@H:14]1[CH2:13][S:12][C:11]([NH:39][C:40](=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[N:10]2.O.Cl>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH2:18][OH:19])[C@H:14]1[CH2:13][S:12][C:11]([NH:39][C:40](=[O:47])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[N:10]2
Reactant: O=C(NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2CS1)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C(NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](CO)[C@H]2CS1)c1ccccc1
Reaction time: 8 h

Procedure:
N-((4aS,5S,7aS)-7a-(2,3-difluorophenyl)-5-((trityloxy)methyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide, obtained in preparation example 1-(5), (8.42 g) was suspended in methanol (100 mL) and water (3 mL) and conc. hydrochloric acid (5 mL) were added. The reaction mixture was stirred vigorously overnight, and then concentrated under reduced pressure to a volume of about 30 mL. The mixture was then carefully neutralised with NaHCO3 (sat., aq., 100 mL) and extracted with EtOAc (3×100 mL). The combined organic portions were dried over MgSO4, evaporated, and the residue purified by silica gel column chromatography (0% to 50% EtOAc in hexanes) to afford the title compound (4.20 g). 1H NMR (400 MHz, CDCl3) δ ppm 1.94 (br. s., 1H), 2.83 (d, J=10.6 Hz, 1H), 3.14-3.49 (m, 2H), 3.77 (d, J=8.8 Hz, 1H), 3.97 (dd, J=11.7, 2.7 Hz, 1H), 4.08 (d, J=6.3 Hz, 1H), 4.46-4.63 (m, 2H), 7.07-7.25 (m, 3H), 7.37-7.60 (m, 3H), 8.00-8.26 (m, 2H)
Reaction SMILES: [OH-].[Na+].[O:3]=[CH:4][C:5]1[CH:13]=[CH:12][C:10]([OH:11])=[C:7]([O:8][CH3:9])[CH:6]=1.Cl[CH2:15][C:16]([OH:18])=[O:17].Cl>O>[CH3:9][O:8][C:7]1[CH:6]=[C:5]([CH:4]=[O:3])[CH:13]=[CH:12][C:10]=1[O:11][CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=C(O)CCl
Reactant: COc1cc(C=O)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(C=O)ccc1OCC(=O)O
Temperature: 25 °C
Yield: 57 %

Procedure:
A solution of 80 g sodium hydroxide in 200 ml water was added to a mixture of 152 g of vanillin, 95 g chloroacetic acid, and 800 ml water with stirring. The mixture was heated to reflux 65 hours, cooled to room temperature, acidified with 70 ml conc. HCl, and the product collected by filtration. The solid was washed with 2 l of distilled water and dried to give 120 g, 57% yield.