Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[CH3:13][NH2:14]>>[NH2:1][C:2]1[C:3]([C:9]([NH:14][CH3:13])=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: CN
Reactant: COC(=O)c1nc(Br)cnc1N
Product: CNC(=O)c1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
Methyl 3-amino-6-bromo-pyrazine-2-carboxylate (7.5 g, 32.32 mmol) was suspended in 40% aqueous methylamine and the resulting mixture stirred vigorously at RT for 4 hours. The resultant precipitate was collected, washed with water and dried to give the desired product (6.73 g, 90% Yield). 1H NMR (400.0 MHz, DMSO) d 2.76 (s, 3H), 7.75 (br s, 2H), 8.34 (s, 1H), 8.58 (b rs, 1H) ppm; MS (ES+) 232.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:21][CH2:22][CH:23]([OH:26])[CH2:24][OH:25]>>[OH:26][CH:23]([CH2:24][OH:25])[CH2:22][NH:21][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:10](/[CH:9]=[CH:8]/[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:11]=1
Reactant: NCC(O)CO
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(Cl)cc1
Product: COc1ccc(C(=O)NCC(O)CO)cc1/C=C/c1ccc(Cl)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-chlorophenyl)vinyl]benzoic acid obtained in step B of Example 2-2-7 and 3-amino-1,2-propanediol in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: Cc1ccc(C(N)=O)c(Br)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C#N)c(Br)c1
Temperature: 25 °C
Yield: 98.2 %

Procedure:
To a suspension of 2-bromo-4-methylbenzamide (14.8 g, 69.1 mmol) in CHCl3 was added phosphorous pentoxide (24.5 g, 172.8 mmol) and the mixture keep refluxing for 12 h. The reaction was allowed to cool to room temperature, and put into the ice water under the condition of stirring. The organic layer was separated and the aqueous layer was extracted with CHCl3 (150 mL×2). The combined organic phase was washed with brine, and dried over Na2SO4. Evaporation of the solvent afforded the title compound, 2-bromo-4-methylbenzonitrile (13.3 g, 98%). 1H NMR (400 MHz, CDCl3) δ 2.41 (s, 3H), 7.20 (d, J=8.0 Hz, 1H), 7.51-7.54 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].[C:14](=O)([O-])[O-].[K+].[K+].CBr>C(C(C)=O)C(C)C>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][CH3:14])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: CBr
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: COc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 5 h

Procedure:
A 1 liter reactor is charged with 300 ml of methyl isobutyl ketone, 79.17 g of 2,4-dinitrophenol (100%) and 175.9 g of ground potassium carbonate and 63.6 g of methyl bromide. The autoclave is closed and heated for 3 hours to 115°-120° C. (pressure: 3.5 bar). The temperature is then kept for a further 5 hours at 140°-142° C. (pressure: 5-3 bar, falling). After cooling to c. 25° C., the solvent is distilled off at 50° C. under a partial vacuum and the salt-containing residue is taken up in warm water. 2,4-Dinitroanisole is isolated by filtration and washed with 1% ammonia solution and with warm water of c. 50° C. and dried at 50° C. under vacuum, to give 84.6 g (91.2% yield) of 2,4-dinitroanisole with a titre of 91.8%.
Reaction SMILES: BrC1CCCCCC=1C=O.C([O:13][C:14](=[O:38])/[CH:15]=[C:16](\[CH3:37])/[CH:17]=[CH:18][C:19]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]=1[CH:26]=[CH:27][C:28]1[C:33]([CH3:35])([CH3:34])[CH2:32][CH2:31][CH2:30][C:29]=1[CH3:36])C>>[CH3:37]/[C:16](/[CH:17]=[CH:18][C:19]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]=1[CH:26]=[CH:27][C:28]1[C:33]([CH3:35])([CH3:34])[CH2:32][CH2:31][CH2:30][C:29]=1[CH3:36])=[CH:15]\[C:14]([OH:38])=[O:13]
Reactant: CCOC(=O)/C=C(\C)C=CC1=C(C=CC2=C(C)CCCC2(C)C)CCCCC1
Agent: CC1=C(/C=C/C2=C(/C=C/C(C)=C/C(=O)O)CCCCC2)C(C)(C)CCC1
Agent: CCOC(=O)/C=C(C)/C=C/C1=C(/C=C/C2=C(C)CCCC2(C)C)CCCCC1
Agent: O=CC1=C(Br)CCCCC1
Product: CC1=C(C=CC2=C(C=C/C(C)=C/C(=O)O)CCCCC2)C(C)(C)CCC1

Procedure:
As in Examples 4 and 5, 1-bromocycloheptene-2-carboxaldehyde was converted to (2E,4E)-3-Methyl-5-(2-((E)-2(2,6,6-trimethyl-1-cyclohexen-1-yl)ethenyl)-1-cyclohepten-1-yl)-2,4-pentadienoic acid ethyl ester which gave (2E,4E)-3-Methyl-5-(2-((E)-2(2,6,6-trimethyl-1-cyclohexen-1-yl)ethenyl)-1-cyclohepten-1-yl)-2,4-pentadienoic acid after hydrolysis with base.
Reaction SMILES: [F:1][C:2]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[N:11][C:12]([C:14](O)=[O:15])=[CH:13][C:8]=2[N:7]=[CH:6]1.[CH3:22][O:23][NH2:24]>>[F:1][C:2]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[N:11][C:12]([C:14]([NH:24][O:23][CH3:22])=[O:15])=[CH:13][C:8]=2[N:7]=[CH:6]1
Reactant: O=C(O)c1cc2ncn(Cc3cccc(F)c3F)c2cn1
Reactant: CON
Product: CONC(=O)c1cc2ncn(Cc3cccc(F)c3F)c2cn1

Procedure:
The title compound can be prepared by coupling of 3-(2,3-difluorobenzyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid and N-methoxyamine under the same conditions as those in step (c) of example 1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([C:14](=[O:18])[N:15]([CH3:17])[CH3:16])[CH:8]=1)[CH3:2].CN(C)C.[F:24][C:25]([F:42])([F:41])[C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]([C:38](Cl)=[O:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:28][CH:27]=1>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:38]([C:33]2[C:32]([C:29]3[CH:30]=[CH:31][C:26]([C:25]([F:24])([F:41])[F:42])=[CH:27][CH:28]=3)=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:39])=[C:9]([C:14](=[O:18])[N:15]([CH3:16])[CH3:17])[CH:8]=1)[CH3:2]
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)CCc1ccc(N)c(C(=O)N(C)C)c1
Agent: CN(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(C(=O)N(C)C)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-(4-Amino-3-dimethylcarbamoylphenyl)propionic acid ethyl ester (1.52 g) was dissolved in ethyl acetate (10 mL), and trimethylamine (533 mg) was added thereto. After cooling down to 0° C., 4′-trifluoromethylbiphenyl-2-carbonyl chloride (synthesized from the corresponding carboxylic acid 0.529 g) was added thereto, and the mixture was stirred at room temperature overnight. After filtration of the insoluble material, the filtrate was concentrated and purified by column chromatography on silica gel (ethyl acetate:hexane=3:2, v/v) to give the title compound (0.843 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>CN(C=O)C>[CH3:20][N:21]([CH3:23])[CH:22]=[CH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(C)C=Cc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 1 h

Procedure:
A mixture of 4-methyl-5-nitro-2-phenoxy-pyridine (0.2 g, 0.86 mmol) and N,N-dimethylformamide dimethyl acetal (0.13 g, 1.1 mmol) in DMF (1 mL) was stirred at 130° C. for 1 hr, then cooled and concentrated to yield crude dimethyl-[2-(5-nitro-2-phenoxy-pyridin-4-yl)-vinyl]-amine as a syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:11][C:10](OC)([O:12]C)[CH2:9]2)=[CH:4][C:3]=1[N:22]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>C1COCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:9][C:10](=[O:12])[CH2:11]2)=[CH:4][C:3]=1[N:22]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)CC1(c2ccc(Cl)c(N(Cc3ccccc3)Cc3ccccc3)c2)CC(OC)(OC)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(c2ccc(Cl)c(N(Cc3ccccc3)Cc3ccccc3)c2)CC(=O)C1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
770 mg (1.52 mmol) of ethyl {1-[4-chloro-3-(dibenzylamino)phenyl]-3,3-dimethoxycyclobutyl}-acetate were dissolved in 10 ml of THF, 2 ml of 1 M hydrochloric acid were added and the mixture was stirred at 50° C. for 1 h. The reaction solution was then diluted with 10 ml of water and 10 ml of ethyl acetate. The phases were separated, and the organic phase was then dried over magnesium sulphate, filtered and concentrated to dryness using a rotary evaporator. This gave 607 mg of the title compound (87% of theory).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13](/[C:19](/[CH3:31])=[CH:20]\[C:21]4[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH-].[Na+]>CO>[C:1]12([C:11]3[CH:12]=[C:13](/[C:19](/[CH3:31])=[CH:20]/[C:21]4[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COC(=O)c1ccc(/C=C(/C)c2ccc(OC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C(C)=C/c2ccc(C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
3 g (7.2 mol) of methyl 4-[(Z)-2-(3-(1-adamantyl)-4-methoxyphenyl)propenyl]benzoate are treated with 4 g of sodium hydroxide in 50 ml of methanol and refluxed for 2 h 30min. After evaporation, the reaction medium is treated under the conditions described in Example 1(b). After recrystallization from absolute ethanol, 2.4 g (84%) of 4-[(Z)-2-(3-(1-adamantyl)-4-methoxyphenyl)propenyl]benzoic acid are isolated, which acid melts at 267° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:6]([CH2:12]Cl)=[N:7]2.O.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[C:6]([CH2:12][S:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)=[N:7]2
Reactant: Sc1ncnc2nc[nH]c12
Reactant: O=c1c2c(Cl)cccc2nc(CCl)n1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cl)cccc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 84.8 %

Procedure:
Prepared according to Procedure C using Intermediate 2f (300 mg, 0.883 mmol), 6-mercaptopurine monohydrate (165 mg, 0.972 mmol), K2CO3 (134 mg, 0.972 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 341 mg of a pale orange crystalline solid (85%), mp 233.7-234.4° C. (decomposes). 1H NMR (DMSO-d6) δ: 13.58 (br s, 1H); 8.50 (s, 1H); 8.47 (s, 1H); 7.77-7.85 (m, 2H); 7.68 (d, J=8.1 Hz, 2H); 7.65 (d, J=7.7 Hz, 1H); 7.41-7.56 (m, 2H); 4.45 (d, J=1.2 Hz, 2H). 13C NMR (DMSO-d6) ppm: 158.7, 156.8, 153.8, 151.5, 149.6, 149.5, 143.5, 135.4, 134.1, 133.3, 132.2, 131.6, 131.6, 130.5, 130.2, 128.8, 127.1, 117.6, 32.0. MS (ES): m/z 455.0 (M+). Anal. calcd. for C20H12Cl2N6OS.C2H6O.0.3H2: C, 52.14; H, 3.70; Cl, 13.99; N, 16.58; S, 6.33. Found: C, 52.07; H, 3.37; Cl, 13.40; N, 16.65; S, 6.42.
Reaction SMILES: Br[C:2]1[C:19]2[C:10](=[CH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2OC2C=CC=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:59][O:60][C:61]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=1B(O)O)=[O:62].C(=O)([O-])[O-].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C(O)C.C1(C)C=CC=CC=1>[CH3:59][O:60][C:61](=[O:62])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=1[C:9]1[C:10]2[C:19](=[CH:18][C:17]3[C:12]([CH:11]=2)=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:2]=[C:3]2[C:8]=1[CH:7]=[CH:6][CH:5]=[CH:4]2
Reactant: Brc1c2ccccc2cc2cc3ccccc3cc12
Reactant: COC(=O)c1ccccc1B(O)O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1ccccc1-c1c2ccccc2cc2cc3ccccc3cc12
Yield: 73 %

Procedure:
5-Bromotetracene (3.0 g, 9.77 mmol), tris(dibenzylideneacetone)dipalladium (448 mg, 0.489 mmol), (bis(2-diphenylphosphinophenyl)ether (1.05 g, 1.95 mmol), (2-(methoxycarbonyl)phenyl)boronic acid (3.52 g, 19.5 mmol) and potassium carbonate (5.40 g, 39.1 mmol) were added to a solvent mixture containing 200 mL of toluene, 12 mL of ethanol and 24 mL of water. The mixture was reacted under reflux at the boiling point for 24 hours in a nitrogen atmosphere to obtain methyl-2-(tetracen-5-yl)benzoate at a yield of 73%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH2:7][CH2:8][N:9]2[C:12]([C:14]2[CH:18]=[CH:17][S:16][C:15]=2[CH3:19])=[O:13])=[CH:4][CH:3]=1.C(O)C.Cl.[OH:25][NH2:26].N1C=CC=CC=1>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[N:26][OH:25])[CH2:7][CH2:8][N:9]2[C:12]([C:14]2[CH:18]=[CH:17][S:16][C:15]=2[CH3:19])=[O:13])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1sccc1C(=O)N1CCC(=O)c2ccc(Cl)cc21
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCO
Product: Cc1sccc1C(=O)N1CCC(=NO)c2ccc(Cl)cc21
Yield: 87.1 %

Procedure:
To a mixture of 7-chloro-2,3-dihydro-l-(2-methyl-3-thienylcarbonyl)-4(lH)-quinolinone (17.5 g), obtained in example 5, and ethanol (250 ml) were added hydroxyl amine hydrochloride (8 g) and pyridine (8.8 g), and the mixture was heated under reflux for 1.5 hours. After cooling, the reaction mixture was poured into 1000 ml of water, and precipitated crystals were separated by filtration, washed, dried and recrystallized with ethanol to obtain 7-chloro-2,3-dihydro-1-(2-methyl-3-thienylcarbonyl)-4(lH)-quinolinone-4-oxime (yield 16 g) as white crystal.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[NH4+:22].[OH-]>>[N+:1]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([NH2:22])=[O:7])([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Product: NC(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 89 %

Procedure:
2,4-Dinitrobenzoic acid (8.17 g, 38.5 mmol) was treated with oxalyl chloride (3.90 mL, 44.7 mmol). The resulting acid chloride was treated with saturated NH4OH solution (200 mL) to yield the title compound (7.25 g, 89%). m.p. 202°-204° C. 1H NMR (300 MHz, DMSO) δ8.75 (d, 1H), 8.58 (dd, 1H), 8.48 (br s, 1H), 7.99 (br s, 1H), 7.91 (d, 1H), 5.50-6.20 (br s, 2H). MS (DCI/NH3) m/e 229 (M+NH4)+.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][CH:7]2[NH:12][C:13](=[O:36])[CH2:14][CH:15]([NH:22][S:23]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1)(=[O:25])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[S:23]([NH:22][CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:14][C:13]([NH:12][CH:7]1[C:8]2[C:4](=[C:3]([CH2:1][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)=[O:36])(=[O:24])=[O:25]
Reactant: C1CCNCC1
Reactant: O=Cc1cccc2c1CCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Product: O=C(CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1)NC1CCc2c(CN3CCCCC3)cccc21

Procedure:
3-(Naphthalen-2-yl-sulfonylamino)-3-phenyl-N-(4-piperidin-1-ylmethyl-indan-1-yl)-propionamide was prepared from N-(4-formyl-indan-1-yl)-3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionamide Example 4, Step G and piperidine, using essentially the same procedure described in Example 1, Step H, yielding a white solid. MS (ESI) m/z 568 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[OH:11])=[CH:6][CH:5]=1)([O-])=O>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[OH:11])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(C(O)c2ccccn2)cc1
Solvent: CCO
Product: Nc1ccc(C(O)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 95 %

Procedure:
In ethanol (50 ml) was dissolved (4-nitrophenyl)-(2-pyridyl)methanol (2.30 g), and to the mixture was added dried 10% palladium on carbon (0.12 g). Under hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 19 hours. The palladium was filtered off, and the filtrate was concentrated. The residue was recrystallized f rom ethyl acetate-hexane to give (4-aminophenyl) (2-pyridyl)methanol (1.90 g) as pale yellow crystals.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][C:4]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=1)=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[N:13]2)=[CH:8][CH:7]=1.[OH-].[Na+]>CO.O1CCCC1>[CH3:1][CH:2]([CH3:31])[CH2:3][C:4]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=1)=[CH:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[N:13]2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(C(=Cc2ccc(-n3cc(C(F)(F)F)cn3)cc2)CC(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CC(=Cc1ccc(-n2cc(C(F)(F)F)cn2)cc1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 96 %

Procedure:
Methyl 4-(4-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pent-1-en-2-yl)benzoate (19.8 mg, 0.0460 mmol) was dissolved in methanol (0.5 mL) and tetrahydrofuran (0.5 mL). 1 N Sodium hydroxide (0.092 mL) was added and the reaction was stirred at room temperature for 60 hours. The reaction was concentrated. The crude residue was taken up in water and acidified to pH=2 with 1N HCl. This solution was extracted four times with ethyl acetate, dried over magnesium sulfate, filtered, and concentrated to provide 4-(4-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pent-1-en-2-yl)benzoic acid (18.3 mg, 96%) as an approximate 1:1 mixture of E/Z isomers. 1H NMR (400 MHz, CD3OD, δ): 8.76 (s, 1H), 8.62 (s, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.98 (s, 1H), 7.97-7.93 (m, 2H), 7.90 (s, 1H), 7.85-7.79 (m, 2H), 7.58 (d, J=8.4 Hz, 2H), 7.54-7.47 (m, 4H), 7.30-7.24 (m, 2H), 7.06-7.00 (m, 2H), 6.84 (s, 1H), 6.56 (s, 1H), 2.70 (d, J=7.2 Hz, 2H), 2.46 (dd, J=7.2, 1.0 Hz, 2H), 1.63 (dt, J=13.5, 6.7 Hz, 1H), 1.57-1.46 (m, 1H), 0.92 (d, J=6.6 Hz, 6H), 0.80 (d, J=6.6 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:27]C1CCC(B(O)O)=CC1>>[C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:21]1[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23][CH:22]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2ccccc2c(C2=CCCCC2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: CC1CC=C(B(O)O)CC1
Product: Cc1cc2ccccc2c(C2=CCC(C)CC2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(2S)-2-tert-Butoxy-2-(3-methyl-1-(4-methylcyclohex-1-enyl)naphthalen-2-yl)acetic acid was prepared following the procedure to make (S)-2-tert-butoxy-2-(1-cyclohexenyl-3-methylnaphthalen-2-yl)acetic acid of Example 6, except that 4-methylcyclohex-1-enylboronic acid was used instead of cyclohexenylboronic acid. 1H-NMR: 400 MHz, (CD3OD) δ: 7.92-7.78 (m, 1H), 7.70 (m,1H), 7.52 (s, 1H), 7.39 (m, 2H), 6.10-5.58 (m, 2H), 2.56 (s,3H), 2.65-1.84 (m, 6H), 1.50 (m, 1H), 1.22 (s, 9H), 1.14 (t, 3H). LCMS-ESF (m/z): [M−H]− calcd for C24H29O3: 365.49. found: 365.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=1)[OH:9].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8](=[O:9])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=1
Reactant: CCc1ccc(C(O)c2cnccc2Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClC(Cl)Cl
Product: CCc1ccc(C(=O)c2cnccc2Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 107.3 %

Procedure:
Next, to a solution of (4-chloropyridin-3-yl)-(4-ethylphenyl)methanol (3.2 g, 0.0129 mol) in chloroform (45 mL), Dess-Martin periodine (6.5 g, 0.0154 mol) was added under ice cooling and the reaction mixture was stirred at room temperature for 5 hours. After filtration to remove the precipitated insoluble materials, the filtrate was washed with 1M NaOH (40 mL) and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by NH silica gel chromatography (ethyl acetate) to give 4-chloro-3-(4-ethylbenzoyl)pyridine (3.4 g) as a yellow oil. A mixture of 4-chloro-3-(4-ethylbenzoyl)pyridine (3.4 g), 3M HCl (35 mL) and 30% H2O2 (2 drops) was heated under reflux for 6.5 hours. After cooling to room temperature, the reaction mixture was neutralized with Na2CO3. The resulting precipitate was filtered and washed with ethyl acetate to give 3-(4-ethylbenzoyl)-4-hydroxypyridine (2.9 g, 92% for 2 steps) as a light-yellow crystal.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].[CH2:7]([NH:11][C:12]#[N:13])[CH2:8][CH2:9][CH3:10].C(N(CC)CC)C>CCOCC>[C:12]([N:11]([CH2:7][CH2:8][CH2:9][CH3:10])[C:3](=[O:4])[CH:2]([Br:1])[CH3:6])#[N:13]
Reactant: CC(Br)C(=O)Br
Reactant: CCCCNC#N
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCCCN(C#N)C(=O)C(C)Br
Reaction time: 3 h
Yield: 70.8 %

Procedure:
29.5 g (0.137 mole) of 2-bromopropionyl bromide are added dropwise at 15° C. to 13.4 g (0.137 mole) of butyl cyanamide and 13.8 g (0.137 mole) of triethylamine in 150 ml of ether. The mixture is stirred for 3 hours at 20° to 25° C., then filtered to remove the precipitated salt. The filtrate is extracted with dilute hydrochloric acid and the extract is dried over sodium sulfate and concentrated by evaporation. The oily residue is distilled under high vacuum, affording 22.6 g (70.8% of theory) of 2-bromopropionic acid N-cyano-N-butylamide with a boiling point of 53°-54° C. at 0.0052 mbar.
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[NH4+:10]>>[OH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([NH2:10])=[O:8]
Reactant: O=C1CCCCCO1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)CCCCCO

Procedure:
ε-Caprolactone was charged to a flask equipped with a mechanical stirrer and thermometer and cooled in an ice bath to below 5°C. A pre-cooled 30% solution of ammonium hydroxide was added and the reaction temperature was maintained below 5° C. until all ε-caprolactone was consumed as indicated by gas chromatography. The water and excess ammonia were vacuum stripped at 50° C. at the completion of which the acid value was measured to be 2300. The acid by-product was removed via flocculation by addition of lithium hydroxide hydrate in methanol solution and ethyl acetate followed by isopropanol until clarified. A second portion of ethyl acetate was added and the flocculated acid was filtered. All solvents were stripped under reduced pressure at 50° C. to yield 6-hydroxycaproamide (2750 g) as a pale yellow oil which crystallized upon standing at room temperature. Gas chromatographic and NMR spectral data indicated greater than 95% purity.