Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:20]=[CH:19][C:11]([C:12]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](=O)([O-])[O-].[Li+].[Li+].CI.C(OCC)C>CN(C)C=O>[O:1]([C:8]1[CH:20]=[CH:19][C:11]([C:12]([CH:14]=[CH:15][C:16]([O:18][CH3:21])=[O:17])=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C=CC(=O)c1ccc(Oc2ccccc2)cc1
Reactant: O=C([O-])[O-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C=CC(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
5.36 g of 3-(4-phenoxybenzoyl)acrylic acid were dissolved in 30 ml of dimethylformamide, then 1.48 g of lithium carbonate and 5.68 g of methyl iodide were added. The mixture was stirred at room temperature for 3 hours and then allowed to stand overnight. Diethyl ether was added to the reaction mixture, which was then washed, in turn, with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over magnesium sulfate. The diethyl ether was removed by evaporation under reduced pressure, and the residue was recrystallized from a mixture of benzene and hexane to give 5.24 g of methyl 3-(4-phenoxybenzoyl)acrylate.
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][NH:10][C:11](=[O:25])[CH:12]([O:22][CH2:23][CH3:24])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[F:21])=[C:7]([O:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][N:30]=2)[CH:6]=1)(=[NH:4])[NH2:3]>CCO.C1COCC1.[Pd]>[ClH:1].[NH2:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][C:7]2[CH:6]=[C:5]([C:2](=[NH:3])[NH2:4])[CH:27]=[CH:26][C:8]=2[CH2:9][NH:10][C:11](=[O:25])[CH:12]([O:22][CH2:23][CH3:24])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[F:21])=[N:30][CH:31]=1
Reactant: CCOC(C(=O)NCc1ccc(C(=N)N)cc1Oc1ccc([N+](=O)[O-])cn1)c1ccc(OC)cc1F
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(C(=O)NCc1ccc(C(=N)N)cc1Oc1ccc(N)cn1)c1ccc(OC)cc1F

Procedure:
(RS)-N-[4-Carbamimidoyl-2-(5-nitro-pyridin-2-yloxy)-benzyl]-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide hydrochloride was hydrogenated at rt and normal pressure in EtOH/THF using Pd (10% on charcoal) as a catalyst to give (RS)-N-[2-(5-amino-pyridin-2-yloxy)-4-carbamimidoyl-benzyl]-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide hydrochloride. Light yellow solid. MS 468.1 ([M+H]+)
Reaction SMILES: [O:1]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[OH:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>>[NH2:6][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:27](=[O:28])[C:26]3[CH:25]=[CH:24][C:23]([N:20]4[CH2:21][CH2:22][CH:17]([OH:16])[CH2:18][CH2:19]4)=[CH:31][CH:30]=3)=[CH:11][CH:10]=2)=[CH:8][CH:7]=1
Reactant: Nc1ccc(Oc2ccc(N)cc2)cc1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Product: Nc1ccc(Oc2ccc(NC(=O)c3ccc(N4CCC(O)CC4)cc3)cc2)cc1

Procedure:
Compound 919 was prepared according to the procedure described in Scheme IV from 4,4′-oxydianiline and 4-(4-hydroxypiperidin-1-yl)benzoic acid. [M+H]+ calcd for C24H25N3O3: 404.19; found 404.05.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:19])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[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.N1CCC[C@H]1C(O)=O>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:11]2[O:10][C:9]([NH:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([OH:1])[CH2:3][CH2:4]3)=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]2=[O:19])=[CH:21]1
Reactant: CCOC(=O)C1=C(N[C@H]2CC[C@H](O)CC2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C1=C(N[C@H]2CC[C@H](O)CC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C

Procedure:
To a solution of ethyl 2-[(trans-4-hydroxycyclohexyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.30 g, 1.1 mmol) which similarly prepared according to the procedure described in the Example 4, First step and 7-azaindole-3-carboxaldehyde (0.16 g, 1.1 mmol) in ethanol (20 mL), L-proline (0.013 g, 0.11 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.14 g, y. 40%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C:15]4([C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:67][C:68]1([CH2:71]O)[CH2:70][CH2:69]1>O1CCCC1>[CH3:67][C:68]1([CH2:71][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]([N:13]4[CH2:17][CH2:16][C:15]5([C:25]6[CH:24]=[CH:23][N:22]=[CH:21][C:20]=6[C:19](=[O:26])[O:18]5)[CH2:14]4)=[O:12])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:70][CH2:69]1
Reactant: CC1(CO)CC1
Reactant: O=C1OC2(CCN(C(=O)C3(c4ccc(O)cc4)CC3)C2)c2ccncc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(COc2ccc(C3(C(=O)N4CCC5(C4)OC(=O)c4cnccc45)CC3)cc2)CC1

Procedure:
1′-{[1-(4-Hydroxyphenyl)cyclopropyl]-carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (8.2 mg, 0.023 mmol), triethylamine (3.6 ul, 0.026 mmol), triphenylphosphine (15 mg, 0.056 mmol), and diisopropyl azodicarboxylate (11 ul, 0.056 mmol) were mixed in tetrahydrofuran (0.2 ml) at room temperature for 10 minutes. To the mixture, with stirring, was added (1-methylcyclopropyl)methanol (4.8 mg, 0.056 mmol). The resulting mixture then was stirred at room temperature overnight. The desired product was obtained from the mixture by prep-HPLC (5.8 mg, 59%). LCMS: m/z 419.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([OH:14])=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:34][NH:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=1>ClCCl>[CH3:44][O:43][C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=1)[CH2:36][N:35]([CH3:34])[C:12](=[O:14])[CH:11]([C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(OC)cc(C(Sc2ccccc2)C(=O)O)c1
Reactant: CNCc1cccc(OC)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COc1cccc(CN(C)C(=O)C(Sc2ccccc2)c2cc(OC)cc(OC)c2)c1
Reaction time: 1 h
Yield: 105.5 %

Procedure:
A solution of 2-(3,5-dimethoxyphenyl)-2-(phenyl-sulfanyl)acetic acid (6.0 g) in dichloromethane (50 ml) was treated with 1,1′-carbonyldiimidazole (3.24 g) at room temperature for 2 hours. A solution of N-methyl-3-methoxy-benzylamine (3.4 g) in dichloromethane (15 ml) was added and the stirring was continued for one hour. The reaction mixture was washed with aqueous hydrochloric acid (1M, 50 ml) and aqueous sodium hydroxide (1M, 50 ml). The organic phase was dried and concentrated to dryness leaving crude N-(3-methoxy-benzyl)-N-methyl-2-(3,5-dimetoxyphenyl)-2-(phenylsulfanyl)-acetamide (9.1 g) as a viscous oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[O:10][CH3:11].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:4]([O:10][CH3:11])[CH:5]=1
Reactant: C1COCCN1
Reactant: COc1cc(Cl)ccc1CBr
Solvent: Cc1ccccc1
Product: COc1cc(Cl)ccc1CN1CCOCC1
Temperature: 110 °C
Yield: 93.3 %

Procedure:
A mixture of 1-bromomethyl-4-chloro-2-methoxy-benzene (705 mg), morpholine (0.52 mL, 6 mmol) in toluene (15 mL) was heated to 110° C. for 2 hours. The solution was then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum to provide 675 mg (93%) of the title compound. MS (ESI) m/e 242 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Br)=[C:9]([NH2:12])[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][CH3:21])[C:14]=2[F:22])[N:6]=1)=[O:4].[CH:23](/B(O)O)=[CH:24]\[CH3:25].[F-].[Cs+].O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10](/[CH:23]=[CH:24]/[CH3:25])=[C:9]([NH2:12])[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][CH3:21])[C:14]=2[F:22])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1Br
Reactant: C/C=C/B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: C/C=C/c1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OC

Procedure:
6-Amino-5-bromo-2-(4-chloro-2-fluoro-3-methoxyphenyl)-pyrimidine-4-carboxylic acid methyl ester (400 mg, 1.02 mmol), trans-propenyl boronic acid (2132 mg, 1.54 mmol), bis(triphenylphosphine)palladium(II) dichloride (72 mg, 0.1 mmol), and cesium fluoride (311 mg, 2.05 mmol) were combined in 1,2-dimethoxyethane (2 mL) and water (2 mL) and heated at 100° C. for 15 min in a CEM microwave reactor. The cooled reaction mixture was partitioned between ethyl acetate and water; and the organic phase was dried and concentrated. The product was purified by flash chromatography on silica gel (hexane/ethyl acetate gradient) then purified again by reverse phase HPLC to yield the title compound: mp 133-135° C.: 1H NMR (CDCl3) δ 7.63 (m, 1H), 7.22 (m, 1H), 6.43 (m, 1H), 6.12 (m, 1H), 5.35 (br s, 2H), 3.99 (d, 3H), 3.94 (s, 3H), 1.94 (dd, 3H).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH2:11]([O:13][C:14]([N:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][C:20]([O:31][CH3:32])=[C:21]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:22]=2)[CH:17]1[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=1)=[O:15])[CH3:12].C([O-])(=O)C.[K+]>ClCCl.O>[CH2:11]([O:13][C:14]([N:16]1[CH:25]=[C:24]([CH:3]=[O:4])[C:23]2[C:18](=[CH:19][C:20]([O:31][CH3:32])=[C:21]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:22]=2)[CH:17]1[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=1)=[O:15])[CH3:12]
Reactant: CN(C)C=O
Reactant: CCCCOc1cc2c(cc1OC)C(Cc1cccc(OC)c1)N(C(=O)OCC)C=C2
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCCCOc1cc2c(cc1OC)C(Cc1cccc(OC)c1)N(C(=O)OCC)C=C2C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.1 %

Procedure:
To anhydrous N,N-dimethylformamide (0.102 mL, 1.32 mmol) at 0° C. was added phosphorus oxychloride (0.053 mL, 0.58 mmol) dropwise. The mixture was warmed to room temperature and stirred for 30 minutes. The mixture was cooled in an ice-bath, 6-butoxy-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (230 mg, 0.53 mmol) in dichloromethane (3 mL) was added dropwise. After addition was complete, the mixture was heated on an oil bath for 4 hrs at 80° C. The mixture was cooled to 0° C. and a solution of potassium acetate (154 mg, 1.56 mmol) in water (2 mL) was added slowly. The mixture was then heated at 80° C. for 20 minutes. The mixture was cooled, poured into water and diluted with dichloromethane (60 mL). The organic layer was washed water (2×20 mL), saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 6-butoxy-4-formyl-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (243 mg, 99% yield) as a yellow oil. The crude product was used without further purification.
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5](Br)[N:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:3]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>CN(C)C=O>[Br:1][C:2]1[N:6]=[C:5]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:3]=1
Reactant: C1CCNC1
Reactant: COc1ccc(Cn2nc(Br)nc2Br)cc1
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(Br)nc2N2CCCC2)cc1
Yield: 49.4 %

Procedure:
A mixture of 3,5-dibromo-1-(4-methoxybenzyl)-1H-1,2,4-triazole (1.268 g, 3.65 mmol, Eq: 1.00) and pyrrolidine (273 mg, 317 μl, 3.84 mmol, Eq: 1.05) in dimethyl formamide (12 ml) was heated for 18 hours to 110° C. under argon atmosphere. The crude material was applied on silicagel and purified by flash chromatography over a 50 g silicagel column using heptane/ethyl acetate 30-50% as eluent affording 3-bromo-1-(4-methoxy-benzyl)-5-pyrrolidin-1-yl-1H-[1,2,4]triazole (608 mg/49.3%) as a colorless oil. MS: m/e=338339 (M+H+)
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=1[C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[O:23]C>ClCCl>[F:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=1[C:16]1[C:17]([OH:23])=[CH:18][CH:19]=[C:20]([CH3:22])[CH:21]=1
Reactant: COc1ccc(C)cc1-c1c(F)c(F)c(F)c(F)c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc(O)c(-c2c(F)c(F)c(F)c(F)c2F)c1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A 1.0 M boron tribromide solution in dichloromethane (67.3 mL, 67.3 mmol, 2 equiv) was added drop wise, at −78° C., over 30 minutes to a solution of compound 11 (9.7 g, 33.65 mmol, 1 equiv) in anhydrous dichloro-methane (300 mL). The reaction was warmed to room temperature, when LCMS indicated that the reaction was complete. The reaction was quenched with ice-water (200 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on an AnaLogix 65-200 g column, eluting with a gradient of 0 to 20% ethyl acetate in heptanes to give 2′,3′,4′,5′,6′-pentafluoro-5-methyl-[1,1′-biphenyl]-2-ol (12) (8.15 g, 88% yield) as a light-brown oil.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:40](=[O:39])[CH2:41][OH:42])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)CO)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f46) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:28])[CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:4][CH:3]=1.[C:29]([O:33]C)(=[O:32])[CH:30]=[CH2:31]>CO.C(COC)OC>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH:14]=[CH:13][CH2:12][C:11]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:10](=[O:28])[CH:9]=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:31][CH2:30][C:29]([OH:33])=[O:32]
Reactant: Cc1ccccc1C=CCC(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Reactant: C=CC(=O)OC
Solvent: CO
Solvent: COCCOC
Product: Cc1ccccc1C=CCC(CCC(=O)O)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Reaction time: 24 h

Procedure:
Triton B (1 ml., 40% in MeOH) is added to a stirred soluton of 1-(p-chlorophenyl)-4-phenyl-7-(o-methylphenyl)-1,6-heptadien-3-one (15.47 g., 0.04 mole) in glyme (150 ml.), followed by addition of methyl acrylate (4.13 g., 0.048 mole) in glyme (25 ml.). After stirring for 24 hours, the solvent is removed in vacuo, and water (600 ml.) and dilute hydrochloric acid (25 ml.) are added to the residue. The organic material is extracted into ether and these extracts are washed with water, saturated brine and dried (Na2SO4). After removal of the solvent, the residue is heated on a steam bath with a solution of 20% sodium hydroxide (25 ml.) in methanol (300 ml.) for 20 hours. The methanol is removed in vacuo and the residue is dissolved in water (1200 ml.). Extraction with ether removes unreacted ketone. Ether is expelled from the aqueous phase by warming. The solution is cooled in an ice bath, acidified with dilute hydrochloric acid (30 ml.), and the yellowish solid that precipitates is filtered and air-dried; yield 12.85 g., m.p. 60°-80°C. (glass). Several recrystallizations from n-butyl chloride, followed by a final recrystallization and ethanol gives material with m.p. 163.5°-165°C. Anal. Calcd. for C29H27ClO3 : C, 75.89; H, 5.93; Found: C, 75.67; H, 5.76.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH2:25][CH3:26])C(=O)OCC3C=CC=CC=3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:27])[N:3]=1>CO.[OH-].[OH-].[Pd+2]>[CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH2:25][CH3:26])[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:27])[N:3]=1
Reactant: CCN(C(=O)OCc1ccccc1)C1CCN(c2cc(C)nc(C)n2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCNC1CCN(c2cc(C)nc(C)n2)CC1
Reaction time: 1 h
Yield: 66 %

Procedure:
A solution of benzyl 1-(2,6-dimethylpyrimidin-4-yl)piperidin-4-yl(ethyl)carbamate (960 mg, 2.6 mmol, 1.0 eq) in MeOH (40 ml) was degassed for 15 minutes with nitrogen; Pd(OH)2 (480 mg) was added and hydrogenation was carried out for 1 hour at RT. After monitoring by TLC, the reaction mixture was filtered off over Celite and washed with MeOH (100 ml) and the filtrate was concentrated under reduced pressure and dried. Yield: 66% (400 mg, 1.709 mmol) C. Single Substance Syntheses General Method for the Synthesis of the Illustrative Compounds (H)
Reaction SMILES: CS(O)(=O)=O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[CH:13]([CH2:19][C:20]([OH:22])=[O:21])[CH2:12][CH2:11]2.[CH2:23](O)[CH3:24]>>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[CH:13]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:11]2
Reactant: CCO
Reactant: COc1ccc2c(c1)CCC(CC(=O)O)C2=O
Agent: CS(=O)(=O)O
Product: CCOC(=O)CC1CCc2cc(OC)ccc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
Methane sulfonic acid (450 mL) was added to a solution of 1B (250 g, 1067 mmol) in ethanol (1.5 L), and the mixture was stirred at room temperature for 16 h. Ethanol was removed from the reaction mixture under reduced pressure, and residue was diluted with ethyl acetate and extracted with brine solution. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under vacuum to afford the title compound (241 g, 81%) as a solid. 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J=8.8 Hz, 1H), 6.82 (dd, J1=2.4 Hz, J2=8.8 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 4.18 (q, J=8.1 Hz, 2H), 3.8 (s, 3H), 3.12-2.85 (m, 4H), 2.39 (q, J=9.0 Hz, 1H), 2.23 (m, 1H), 1.94 (dq, J1=4.5 Hz, J2=12.6 Hz, 1H), 1.28 (t, J=7.5 Hz, 3H). ESI-MS m/z: 263 (M+H)+.
Reaction SMILES: [C:1]1([CH2:11][C:12]([NH:14][C:15]2[N:16]=[CH:17][N:18]([C@H:20]3[CH2:23][C@H:22](OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:21]3)[CH:19]=2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N-:35]=[N+:36]=[N-:37].[Na+].C(Cl)(Cl)Cl>C(O)C.O>[N:35]([C@@H:22]1[CH2:23][C@H:20]([N:18]2[CH:19]=[C:15]([NH:14][C:12](=[O:13])[CH2:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[N:16]=[CH:17]2)[CH2:21]1)=[N+:36]=[N-:37]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2C[C@H](n3cnc(NC(=O)Cc4cccc5ccccc45)c3)C2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=N[C@H]1C[C@@H](n2cnc(NC(=O)Cc3cccc4ccccc34)c2)C1
Reaction time: 96 h

Procedure:
trans-Toluene-4-sulfonic acid 3-[4-(2-naphthalen-i -yl-acetylamino)-imidazol-1-yl]-cyclobutyl ester (Preparation 4, Step 3; 593 mg, 1.25 mmol) was mixed with sodium azide (813 mg, 12.5 mmol) in ethanol (15 mL), water (5 mL), and chloroform (5 mL). The mixture was then heated at reflux with stirring for 96 h. The solvent was removed in vacuo and the residue was diluted with water and was extracted with methylene chloride. The organic layer was dried (MgSO4), filtered, and was concentrated in vacuo. Purification by silica gel chromatography (50:1 chloroform-methanol) afforded 340 mg (79% yield) of N-[1-(cis-3-azido-cyclobutyl)-1H-imidazol-4-yl]-2-naphthalen-1-yl-acetamide; 1H NMR (400 MHz, CDCl3) δ8.41 (s, 1H), 7.98 (d, J=6.4 Hz, 1H), 7.87 (m, 1H), 7.82 (m, 1H), 7.5 (m, 2H), 7.45 (m, 3H), 7.08 (d, J=1.7 Hz, 1H), 4.2 (m, 3H), 3.75 (m, 1H), 2.85 (m, 2H), 2.35 (m, 2H); MS (AP/Cl): 347.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([O:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([CH3:42])[CH3:41])=[CH:36][CH:35]=4)[C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([O:33][C:34]4[CH:35]=[CH:36][C:37]([CH:40]([CH3:42])[CH3:41])=[CH:38][CH:39]=4)[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=3)=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccc(F)cc3)cc2)cc1)Oc1ccc(C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1ccc(OC(Cc2ccc(OCCNC(=O)c3ccc(-c4ccc(F)cc4)cc3)cc2)C(=O)O)cc1
Yield: 88.8 %

Procedure:
In a similar manner to that described in Example 2, ethyl 3-[4-[2-(4′-fluorobiphenyl-4-carbonylamino)ethoxy]phenyl]-2-(4-isopropylphenoxy)propionate (450 mg), which is the product of Example 90, was reacted with aqueous sodium hydroxide solution (1N, 2.00 ml) and the reaction mixture was treated to give the title compound (380 mg) as a white powder.
Reaction SMILES: Cl.[CH2:2]([NH2:6])[CH2:3][C:4]#[CH:5].C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>ClCCl.Cl>[CH2:2]([NH:6][S:15]([CH3:14])(=[O:17])=[O:16])[CH2:3][C:4]#[CH:5]
Reactant: CS(=O)(=O)Cl
Reactant: C#CCCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCCNS(C)(=O)=O
Reaction time: 3 h

Procedure:
To a 5-10° C. solution of tert-butyl but-3-yn-1-ylcarbamate (115 g, 0.675 mol) in dichloromethane (500 mL) was added 4N hydrochloric acid in dioxane (650 mL, 2.60 mol). After 3 hours at ambient temperature, the reaction mixture was concentrated in vacuo. The residue was washed with dichloromethane, then with diethyl ether, and then dried in vacuo to afford but-3-yn-1-amine hydrochloride as an intermediate. To a −5 to −10° C. solution of but-3-yn-1-amine hydrochloride and triethylamine (206 mL, 1.47 mol) in dichloromethane (500 mL) was added methanesulfonyl chloride (68.4 mL, 0.88 mol). After 3 hours at ambient temperature, the reaction mixture was diluted with 1N hydrochloric acid (150 mL). The organics were separated, washed with saturated aqueous sodium bicarbonate (150 mL) and with brine, then dried over magnesium sulfate, filtered, and concentrated in vacuo to afford N-but-3-yn-1-ylmethanesulfonamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:13].[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:13])=[O:16]
Reactant: COC(=O)C(=O)C(Cl)c1c(F)cccc1Cl
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1c(F)cccc1Cl

Procedure:
prepared by reaction of 3-chloro-3-(2-chloro-6-fluoro-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.92 min; [M+H]+=286.2.