Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].CO.[O:5]=[C:6]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[C:7](OCC)=[O:8]>CO>[CH3:1][NH:2][C:7](=[O:8])[C:6](=[O:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1
Reactant: CN
Reactant: CCOC(=O)C(=O)c1ccccc1COC1CCCCO1
Solvent: CO
Product: CNC(=O)C(=O)c1ccccc1COC1CCCCO1
Yield: 76.8 %

Procedure:
A 40% methylamine-methanol solution (167.4 g, 2.156 mol) was added to a mixed solution of the crude ethyl a-oxo-2-(2-tetrahydropyranyloxymethyl)phenylacetate thus obtained and methanol (100 ml), and the mixture was stirred at room temperature for 40 minutes. After completion of the reaction, the mixture was concentrated under reduced pressure. Benzene (300 ml) was added to the resulting residue to filter off the insoluble materials, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain N-methyl-2-oxo-2-[2-(2-tetrahydropyranyloxymethyl)phenyl]acetamide (114.8 g, Yield: 76.8%) as an oil.
Reaction SMILES: COC[O:4][C:5]1[C:22]([CH3:23])=[CH:21][C:8]([O:9][C:10]2[N:15]=[C:14]([NH:16][CH3:17])[C:13]([N+:18]([O-])=O)=[CH:12][CH:11]=2)=[C:7]([CH3:24])[C:6]=1[CH3:25].CO.[O:28]1CC[CH2:30][CH2:29]1>[Pd]>[OH:28][CH2:29][C:30]1[N:16]([CH3:17])[C:14]2=[N:15][C:10]([O:9][C:8]3[CH:21]=[C:22]([CH3:23])[C:5]([OH:4])=[C:6]([CH3:25])[C:7]=3[CH3:24])=[CH:11][CH:12]=[C:13]2[N:18]=1
Reactant: CNc1nc(Oc2cc(C)c(OCOC)c(C)c2C)ccc1[N+](=O)[O-]
Reactant: C1CCOC1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(Oc2ccc3nc(CO)n(C)c3n2)c(C)c(C)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 288 g of 6-(4-methoxymethoxy-2,3,5-trimethylphenoxy)-2-methylamino-3-nitropyridine, 14 g of 10% palladium on carbon and 1500 ml of methanol was stirred at room temperature for 2 hours under a hydrogen atmosphere. To the reaction mixture, 14 g of 10% palladium on carbon, 500 ml of methanol and 500 ml of tetrahydrofuran were added and the resulting mixture was stirred at 50° C. for 8 hours under a hydrogen atmosphere. The palladium on carbon in the reaction mixture was filtered off and the filtrate was concentrated by evaporation. To the residue, 500 g of glycolic acid were added and the mixture was stirred at 150° C. for 6 hours. To the reaction mixture, 1000 ml of a 4N aqueous hydrochloric acid solution were added and the mixture was stirred at 120° C. for one hour. The reaction mixture was allowed to stand overnight at room temperature. The reaction mixture was poured into iced water, followed by neutralization with an aqueous sodium hydroxide solution and an aqueous sodium carbonate solution. The resulting solid substance was separated by filtration and purified by chromatography through a silica gel column with tetrahydrofuran as an eluting solvent. The resulting solid substance from the eluate was washed with ethanol, whereby 45.5 g of the title compound were obtained.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[NH:4][C:3]=1[C:14]([O:16]C)=O.[NH2:18][C:19]1[S:20][C:21]([CH3:24])=[CH:22][N:23]=1>>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[NH:4][C:3]=1[C:14]([NH:18][C:19]1[S:20][C:21]([CH3:24])=[CH:22][N:23]=1)=[O:16]
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1
Reactant: Cc1cnc(N)s1
Product: Cc1cnc(NC(=O)C2=C(O)c3ccccc3S(=O)(=O)N2)s1
Yield: 31 %

Procedure:
Prepared from methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide and 2-amino-5-methyl-thiazole analogous to Example 1. The crude product (65% of theory) was purified by column chromatography (Merck-silica gel 60, particle size: 0.2-0.5 mm), using chloroform/ethanol (97:3) as eluant. 4-Hydroxy-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide was obtained with a yield of 31% of theory.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[O:25]1[CH2:29][CH2:28][CH:27]([CH2:30][NH2:31])[CH2:26]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:31][CH2:30][CH:27]2[CH2:28][CH2:29][O:25][CH2:26]2)=[O:21])=[CH:17][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NCC1CCOC1
Agent: Cl
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCC2CCOC2)cn1
Yield: 81 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using (tetrahydrofuran-3-yl)methanamine hydrochloride instead of methylamine, to the title compound (103 mg, 81%) which was obtained as a white solid. MS: m/e=394.3 [M+H]+.
Reaction SMILES: FC(F)OC1C=C(C(O)=O)N(C)N=1.[CH3:14][N:15]1[C:19]([C:20]([O:22]C)=[O:21])=[C:18]([C:24]([F:27])([F:26])[F:25])[C:17]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:16]1>>[CH3:14][N:15]1[C:19]([C:20]([OH:22])=[O:21])=[C:18]([C:24]([F:25])([F:26])[F:27])[C:17]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:30][CH:29]=2)=[N:16]1
Reactant: COC(=O)c1c(C(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)nn1C
Agent: Cn1nc(OC(F)F)cc1C(=O)O
Product: Cn1nc(-c2ccc(C(F)(F)F)cc2)c(C(F)(F)F)c1C(=O)O

Procedure:
This compound is prepared analogously to the preparation of 3-(difluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylic acid from methyl 1-methyl-4-(trifluoromethyl)-3-[4-(trifluoromethyl)phenyl]-1H-pyrazole-5-carboxylate.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:30]=[CH:31][CH:32]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=2)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].O1CCCC1>CO.[C].[Pd]>[NH2:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:30]=[CH:31][CH:32]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=3)[CH:17]=[CH:16][C:15]=2[O:18][CH3:19])=[CH:26][CH:25]=1
Reactant: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.7 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)-N-[4-methoxy-3-(4-nitrophenoxy)phenyl]benzamide (1.80 g, 4.17 mmol) in methanol (5 mL)/tetrahydrofuran (5 mL) was added 10%-palladium carbon (1 g), and the mixture was vigorously stirred under a hydrogen atmosphere at room temperature for 18 hr. The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure to give the title compound (1.10 g, 66%) as a colorless amorphous substance.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[C:11](Cl)=[N:12][C:13]([Cl:16])=[N:14][CH:15]=2)=O)[CH:5]=[CH:4][CH:3]=1.[NH2:18][NH2:19]>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[C:10]3[C:11](=[N:12][C:13]([Cl:16])=[N:14][CH:15]=3)[NH:19][N:18]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1cccc(Br)n1)c1cnc(Cl)nc1Cl
Solvent: C1CCOC1
Product: Clc1ncc2c(-c3cccc(Br)n3)n[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (6-bromo-pyridin-2-yl)-(2,4-dichloro-pyrimidin-5-yl)-methanone (from Example 29 supra) (2.42 g, 7.54 mmol) in THF (30 mL) was added hydrazine (454 mg, 9.08 mmol) and the mixture was stirred for 30 minutes at room temperature and then at 50° C. for 1 hour. The solvent was then removed and the solid was washed with water and dried to give crude 3-(6-bromo-pyridin-2-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidine as a yellow solid. (Yield 1.7 g, crude).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[N+:27](C1C=CC=CC=1C1CCC2C(=CC=C(O)C=2)O1)([O-:29])=[O:28]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=2[N+:27]([O-:29])=[O:28])[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: O=[N+]([O-])c1ccccc1C1CCc2cc(O)ccc2O1
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2[N+](=O)[O-])O3)nc1

Procedure:
5-Nitro-2-[2-(2-nitrophenyl)chroman-6-yloxy]pyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 2-(2-nitrophenyl)chroman-6-ol. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.1, 2.9 Hz), 8.03 (d, 1H, J 7.9 Hz), 7.80-7.85 (m, 2H), 7.62-7.66 (m, 1H), 7.22 (d, 1H, J 9.1 Hz), 7.04 (d, 1H, J 2.8 Hz), 6.98 (dd, 1H, J 8.8, 2.8 Hz), 6.88 (d, 1H, J 8.8 Hz), 5.52 (dd, 1H, J 10.3, 2.0 Hz), 2.99-3.31 (m, 1H), 2.80-2.85 (m, 1H), 2.35-2.40 (m, 1H), 1.99-2.04 (m, 1H).
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:14][CH2:13][O:12][C:11]2=[O:15])[CH:5]=1.[Li+].[OH-]>O1CCOCC1>[O:15]=[C:11]1[N:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:16])=[O:2])[CH2:14][CH2:13][O:12]1
Reactant: COC(=O)c1cccc(N2CCOC2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1cccc(N2CCOC2=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.9 %

Procedure:
3-(2-Oxooxazolidin-3-yl)benzoic acid methyl ester (D118) (110 mg, 0.5 mmol) in dioxane (2.5 ml) was treated with 1M LiOH solution (0.75 ml) and the mixture was stirred at room temperature for 1.5 h. Amberlyst 15 was then added and stirring continued for 15 mins. The resin was filtered and the filtrate evaporated to dryness. Th residue was tritutated with diethyl ether to afford the title compound (62 mg, 60%).
Reaction SMILES: [C:1](#[N:4])[CH2:2]O.[CH2:5]([O:7][CH:8]([O:11][CH2:12][CH3:13])[CH2:9][NH2:10])[CH3:6]>>[CH2:5]([O:7][CH:8]([O:11][CH2:12][CH3:13])[CH2:9][NH:10][CH2:2][C:1]#[N:4])[CH3:6]
Reactant: N#CCO
Reactant: CCOC(CN)OCC
Product: CCOC(CNCC#N)OCC

Procedure:
A mixture of glycolonitrile (8.33 g, 70% solution in water, 0.1 mol) and aminoacetaldehyde diethyl acetal (14.5 mL, 0.1 mol) was heated to reflux for 3 h. After cooling, the mixture was filtered to remove traces of solid and the filtrate then concentrated in vacuo to give the desired product 4.
Reaction SMILES: CC(C)([O-])C.[K+].[Si:7]([O:24][CH2:25][C:26]1[C:27](=[O:32])[NH:28][CH:29]=[CH:30][CH:31]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:33][C:34]1[CH:39]=[C:38]([N+:40]([O-:42])=[O:41])[CH:37]=[CH:36][C:35]=1F.O>CN(C=O)C>[Si:7]([O:24][CH2:25][C:26]1[C:27](=[O:32])[N:28]([C:35]2[CH:36]=[CH:37][C:38]([N+:40]([O-:42])=[O:41])=[CH:39][C:34]=2[Cl:33])[CH:29]=[CH:30][CH:31]=1)([C:20]([CH3:23])([CH3:21])[CH3:22])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)[Si](OCc1ccc[nH]c1=O)(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1cccn(-c2ccc([N+](=O)[O-])cc2Cl)c1=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 0.500 g (4.46 mmol) of potassium tert-butoxide is added to 1.08 g (2.97 mmol) of the compound from Example 3A in 21 ml of DMF, and the mixture is stirred at room temperature for 30 min. 0.571 g (3.27 mmol) of 2-chloro-1-fluoro-4-nitrobenzene is added, and the mixture is stirred at RT. After 4.5 h, 200 ml of water are added, and the mixture is then extracted three times with ethyl acetate. The combined organic phases are washed with water and then dried over sodium sulphate. After filtration, the solvents are removed under reduced pressure. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 9:1). This gives 872 mg (56% of theory) of the desired compound.
Reaction SMILES: [C:1]1([OH:14])[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[OH-].[K+].[CH2:17](Br)[CH:18]=[CH2:19]>C(O)C>[CH2:19]([O:14][C:1]1[CH:2]=[CH:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:5][CH:6]=1)[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CCOc1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C

Procedure:
In a 1 L, three-necked, round bottom flask 4,4'-biphenol (40 g, 215 mmol) and potassium hydroxide (24 g, 430 mmol) were dissolved in 600 mL of absolute ethanol. The solution was warmed and allyl bromide (26 g, 215 mmol) was added. The reaction mixture was heated to reflux overnight, after which additional allyl bromide (13 g, 157 mmol) was added. The reaction mixture was refluxed for an additional 24 hours. The reaction mixture was cooled to room temperature and the solids were filtered. The filtrate was poured into distilled water (4 L) and then acidified with concentrated aqueous HCl. The solid product was filtered off and washed with a large amount of water and then dried. The product was purified by repeated recrystallization from ethanol. Product characterization included: m.p. 168°-170° C., 1H (200 MHz, CDCl3): 7.05 (m, 4H), 6.8 (m, 4H), 6.1 (m, 1H), 4.4 (m, 2H).
Reaction SMILES: [CH2:1]([C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])[CH2:2][CH3:3].[C:12]([O-])([O-])=O.[K+].[K+].IC.Cl>CN(C=O)C>[CH3:12][O:11][C:10]1[C:4]([CH2:1][CH2:2][CH3:3])=[C:5]([OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: CCCc1c(O)cccc1O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCCc1c(O)cccc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 4 %

Procedure:
2-Propyl resorcinol (1.50 g, 9.86 mmol) was dissolved in DMF (anhydrous, 20 mL) and K2CO3 (681 mg, 4.93 mmol) was added. After stirring for 10 min at rt, iodomethane (0.92 mL, 14.8 mmol) was added and the reaction mixture was stirred for 6 h at 60° C. After cooling to rt, the reaction mixture was acidified with HCl (1 N aqueous solution) and concentrated under reduced pressure. Water was added and the aqueous phase was extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/hexane (v/v) 1:15) gave 33 mg (24%) of the title compound as an oil. 1H NMR (400 MHz, CDCl3): δ 0.97 (t, 3H), 1.54 (m, 2H), 2.61 (t, 2H), 3.81 (s, 3H), 4.68 (br, 1H), 6.47 (m, 2H), 7.03 (t, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]2.Br[C:20]1[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=[C:24]([Br:26])[N:25]=1.C(N(CC)CC)C>CC(O)C>[Br:26][C:24]1[N:25]=[C:20]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]3)[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cn1cc(Br)nc(Nc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)C3)c1=O
Temperature: 70 °C
Yield: 65 %

Procedure:
A mixture of tert-butyl 6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (3 g, 12 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (2.68 g, 10 mmol), and triethylamine (1.5 g, 15 mmol) in IPA (50 mL) was heated at 70° C. for 15 h. The mixture was cooled to room temperature. The resulting yellow solids were collected by filtration and dried in vacuum to afford 120a as a yellow solid (2.83 g, 65%).MS: [M+H]+ 435.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([OH:16])=[O:15])[N:10]([CH2:17][CH:18]([CH3:20])[CH3:19])[N:9]=[CH:8]2.CCN=C=NCCCN(C)C.O[N:38]1[C:42](=[O:43])[CH2:41][CH2:40][C:39]1=[O:44]>ClCCl>[O:44]=[C:39]1[CH2:40][CH2:41][C:42](=[O:43])[N:38]1[O:15][C:14]([C:13]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:6][C:5]=1[O:4][C:3]1[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:2]=1[F:1])=[O:16]
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)O)cc21
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)ON3C(=O)CCC3=O)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(2,4-Difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (17d; prepared according to Example 110) (25.0 g, 72.2 mmol), EDCI (18.0 g, 93.8 mmol), and 1-hydroxypyrrolidine-2,5-dione (9.97 g, 86.6 mmol) were suspended in dichloromethane and stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane (500 mL) and washed with saturated NH4Cl (2×200 mL), saturated NaHCO3 (2×200 mL) and brine (200 mL). The organics were dried over MgSO4 and concentrated under reduced pressure to afford the crude product as yellow foam.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].F[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16]>CN(C=O)C.OS([O-])(=O)=O.[K+]>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[CH2:4][CH2:3]1
Reactant: N#Cc1cccc(F)c1
Reactant: CN1CCC(O)CC1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCC(Oc2cccc(C#N)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-Methyl-piperidin-4-ol (7.17 g, 62.25 mmol) was dissolved in DMF (40 ml) and cooled to 0° C. NaH (4.48 g, 93.4 mmol) was added in small portions and the reaction stirred for 30 min. 3-Fluoro-benzonitrile (8.0 ml, 74.7 mmol) was added and the reaction allowed to reach r.t. over 1 h and stirred for a further 16 h. The resulting brown solution was cooled to 0° C. and quenched by addition of water. The reaction mixture was separated between DCM (500×2 ml) and water (750 ml). The combined organics were washed with water (500 ml), dried through a phase separator and evaporated in vacuo. Flash silica gel chromatography using a 100 g Biotage column with a gradient of 20-100% EtOAc/MeOH/TEA 100:10:1 in heptane failed to give a pure product. The oil was dissolved in 0.1 M KHSO4 (aq) and washed with ether (×4), the aqueous layer basified (2 M NaOH (aq)) and extracted twice with ether. The organic phase was dried over a phase separator and evaporated in vacuo. To the red brown oil was added 4M HCl in dioxane and the resulting precipitate was filtered. To the salt was added 10% NaHCO3 (aq), extracted with DCM, dried through a phase separator and evaporated in vacuo to give a light orange oil. Yield: 4.73 g (29%). 1H NMR (400 MHz, CDCl3) δ 7.35 (t, 1H, JHH=7.84 Hz), 7.21 (dt, 1H, J=7.39 Hz, J=1.06 Hz), 7.15-7.10 (m, 2H), 4.32 (m, 1H, J=3.74 Hz), 2.68 (m, 2H), 2.33-2.24 (m, 5H), 2.04-1.95 (m, 2H), 1.88-1.78 (m, 2H). MS (ESI+) 217.07 (M+1H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].[Cl:13][C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].CCN=C=NCCCN(C)C>N1C=CC=CC=1>[Cl:13][C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[OH:12])=[O:17]
Reactant: O=C(O)c1ccncc1Cl
Reactant: Nc1cc(C(F)(F)F)ccc1O
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(F)F)ccc1O)c1ccncc1Cl
Temperature: 60 °C
Yield: 56.9 %

Procedure:
To a mixture of 1.77 g of 2-amino-4-(trifluoromethyl)phenol, 1.58 g of 3-chloroisonicotinic acid and 15 ml of pyridine, 2.70 g of WSC was added and stirred while heating at 60° C. for four hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was washed with a mixture solvent of tert-butyl methyl ether and hexane to give 1.80 g of 3-chloro-N-[2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide.
Reaction SMILES: C([O:5][C:6]([C:8]1([C:18](=[O:31])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:22][CH:21]=2)[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])(C)(C)C>Cl.O1CCOCC1>[CH2:29]([N:26]([CH2:27][CH3:28])[C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:18]([C:8]2([C:6]([OH:7])=[O:5])[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9]2)=[O:31])=[CH:25][CH:24]=1)[CH3:30]
Reactant: CCN(CC)c1ccc(NC(=O)C2(C(=O)OC(C)(C)C)CCc3ccccc3C2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCN(CC)c1ccc(NC(=O)C2(C(=O)O)CCc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The t-butyl ester from Example 16A was dissolved in 4 N HCl in dioxane (1.0 mL) and the resulting mixture was stirred at ambient temperature for 4 hours. The mixture was concentrated under reduced pressure to provide the titled compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:30]=[CH:29][C:10]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][C:20]=3[CH3:28])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1.[NH3:32]>>[O:1]=[S:2]1(=[O:31])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([C:11]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH2:32])=[O:24])=[CH:21][C:20]=3[CH3:28])[CH2:17][CH2:18]2)=[O:12])=[CH:29][CH:30]=1
Reactant: Cc1cc(C(=O)O)ccc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2)CC1
Reactant: N
Product: Cc1cc(C(N)=O)ccc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2)CC1

Procedure:
Using 4-{4-[4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoyl]piperazin-1-yl}-3-methylbenzoic acid (200 mg) described in Example 218 and 28% aqueous ammonia (5 mL) and by the reaction and treatment in the same manner as in Example 220, the title compound (68 mg) was obtained.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([O:16][CH3:17])[CH2:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:3])C.[CH2:18]([N:36]=C=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>N1C=CC=CC=1>[CH2:9]([O:8][CH2:7][CH:6]([O:16][CH3:17])[CH2:5][S:4][C:1](=[O:3])[NH:36][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: COC(COCc1ccccc1)CSC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCNC(=O)SCC(COCc1ccccc1)OC
Yield: 117.5 %

Procedure:
A solution of 7.258 g (34.2 mM) of 3-benzyloxy-2-methoxypropylthioalcohol VII 6 and 11.65 g (39.4 mM) of octadecylisocyanate in 100 ml of pyridine is heated under reflux for 1 hour. The reaction mixture is concentrated and the residue is purified by column chromatography on silica gel using a toluene-ethyl acetate (9:1 to 4:1) mixture as an eluent to give 17.027 g (33.6 mM) of the titled compound, 3-benzyloxy-2-methoxy-1-octadecylcarbamoylthiopropane VI 6 as a solid in 98% yield.
Reaction SMILES: C(=[N:8][C:9]1([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:14][CH2:13][C:12](=[O:15])[NH:11][C:10]1=[O:16])C1C=CC=CC=1.[ClH:32]>C1COCC1>[ClH:32].[NH2:8][C:9]1([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:14][CH2:13][C:12](=[O:15])[NH:11][C:10]1=[O:16]
Reactant: O=C1CCC(CCCCNC(=O)OCc2ccccc2)(N=Cc2ccccc2)C(=O)N1
Agent: Cl
Solvent: C1CCOC1
Product: NC1(CCCCNC(=O)OCc2ccccc2)CCC(=O)NC1=O
Reaction time: 5 h

Procedure:
To a solution of 3 (3.6 g, 8.54 mmol) in THF (21 mL) was added portionwise aqueous 4 M HCl at 0° C. The mixture was allowed to reach room temperature and stirred over 5 h. A white precipitated that formed during the reaction was filtered and washed with THF. Two recrystallizations affored 4 (2.88 g, 91.2%) as a white solid. 1H NMR (400 MHz, DMSO) ä 11.30 (s, 1H), 8.62 (br s, 3H), 7.46-7.15 (m, 5H), 4.97 (m, 2H), 3.59 (m, 2H), 2.98 (m, 2H), 2.76 (m, 1H), 2.58 (m, 1H), 2.24-1.97 (m, 2H), 1.85 (m, 2H), 1.74 (m, 1H), 1.21 (m, 1H).