Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2]N.[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=O)[CH:12]=[CH:13][N:14](C)C>C(O)C>[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][NH:14][N:2]=1
Reactant: NN
Reactant: CN(C)C=CC(=O)c1ccccc1Cl
Solvent: CCO
Solvent: O
Product: Clc1ccccc1-c1cc[nH]n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.2 %

Procedure:
7 g (0.0540 mol) of hydrazine hydrate are added, slowly and at room temperature, to a solution of 10.5 g (0.050 mol) of 1-(2-chlorophenyl)-3-dimethylamino-2-propen-1-one, prepared in Example 1, in 60 ml of ethanol. The reaction mixture is stirred for 5 hours at room temperature then left standing for 12 hours before being concentrated to dryness. The residue is recrystallised from a heptane/ethyl acetate mixture. 6.9 g (0.0386 mol) of 3-(2'-chlorophenyl)-1H-pyrazole are obtained, which melts at 93° C. (yield 77%) (compound 60).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[I-].[Na+].[CH3:19][O:20][C:21](=[O:27])[CH2:22][O:23][CH2:24][CH2:25]Br>CC(C)=O>[CH3:19][O:20][C:21](=[O:27])[CH2:22][O:23][CH2:24][CH2:25][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COC(=O)COCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COCCOc1ccc([N+](=O)[O-])cc1
Yield: 43.5 %

Procedure:
To a mixture of 4-nitrophenol (5 g, 36 mmol), anhydrous K2CO3 (20 g, 145 mmol) and sodium iodide (2 g, 13.3 mmol) in anhydrous acetone (100 ml) was added (2-bromoethoxy)acetic acid methyl ester (11 g, 56 mmol) and then refluxed for 24 hours. Acetone was distilled off and water (100 ml) was added. Crude 42 was filtered, dried and purified by column chromatography on silica gel using benzene as eluant to give pure 42 (4 g, 43.6%) as a white fluffy powder with an m.p. between 96-97.8° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N=C(N(C)C)N(C)C)(C)(C)C.[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]2[CH2:31][CH2:30][N:29]([C@H:32]3[CH2:36][CH2:35][N:34]([C:37]4[CH:42]=[C:41]([F:43])[C:40]([S:44](Cl)(=[O:46])=[O:45])=[C:39]([F:48])[CH:38]=4)[C:33]3=[O:49])[CH2:28]2)[CH:23]=[C:24]([Cl:26])[CH:25]=1>C(#N)C.CS(C)=O>[Cl:26][C:24]1[CH:23]=[C:22]([CH:27]2[CH2:31][CH2:30][N:29]([C@H:32]3[CH2:36][CH2:35][N:34]([C:37]4[CH:42]=[C:41]([F:43])[C:40]([S:44]([NH:1][C:2]5[S:3][CH:4]=[CH:5][N:6]=5)(=[O:45])=[O:46])=[C:39]([F:48])[CH:38]=4)[C:33]3=[O:49])[CH2:28]2)[CH:21]=[C:20]([Cl:19])[CH:25]=1
Reactant: Nc1nccs1
Reactant: O=C1[C@@H](N2CCC(c3cc(Cl)cc(Cl)c3)C2)CCN1c1cc(F)c(S(=O)(=O)Cl)c(F)c1
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Solvent: CS(C)=O
Product: O=C1[C@@H](N2CCC(c3cc(Cl)cc(Cl)c3)C2)CCN1c1cc(F)c(S(=O)(=O)Nc2nccs2)c(F)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Synthesized according to General Procedure 12, Method B. To a solution of 2-aminothiazole (35 mg, 0.35 mmol) in acetonitrile (0.4 mL) at 0° C. was added 2-tert-butyl-1,1,3,3-tetramethylguanidine (61 mg, 0.35 mmol) dropwise and the reaction mixture stirred at 0° C. for 10 min. 4-[(3′S)-3-(3,5-dichlorophenyl)-2′-oxo-1,3′-bipyrrolidin-1′-yl]-2,6-difluorobenzene-1-sulfonyl chloride (60 mg, 0.12 mmol) was added and the reaction mixture was stirred at RT for 16 hours. The reaction mixture was diluted with DMSO, filtered and purified by reverse phase HPLC using 5%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to afford 4-[(3′S)-3-(3,5-dichlorophenyl)-2′-oxo-1,3′-bipyrrolidin-1′-yl]-2,6-difluoro-N-(thiazol-2-yl)benzenesulfonamide. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=573.3; tR=1.32 min.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-])=O)=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].[H][H]>[Ni].CO>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9]
Reactant: CSc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CSc1ccc(N)c(C(=O)O)c1

Procedure:
A mixture of 5-methylthio-2-nitrobenzoic acid (25.4 g; 0.119 mole), methanol (200 ml) and Raney nickel (2 g) is shaken in an atmosphere of hydrogen at 50 lb pressure when theoretical amount of hydrogen is absorbed. The catalyst is filtered off and the filtrate evaporated to dryness. The residue is recrystallized from etheriso-Pr2O. Yield 7.6 g; mp 145°-150°.
Reaction SMILES: [NH2:1][C:2]1[C:28]([Cl:29])=[CH:27][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:11][C@H:10]2[OH:26])=[O:7])=[C:4]([O:30][CH3:31])[CH:3]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40]>O1CCCC1>[C:39]([O:26][C@H:10]1[C@@H:9]([NH:8][C:6](=[O:7])[C:5]2[CH:27]=[C:28]([Cl:29])[C:2]([NH2:1])=[CH:3][C:4]=2[O:30][CH3:31])[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:11]1)(=[O:41])[CH3:40]
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCOc2ccc(F)cc2)C[C@H]1O
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCOc2ccc(F)cc2)C[C@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 7.5 parts of cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-hydroxy-4-piperidinyl]-2-methoxybenzamide in 68 parts of tetrahydrofuran were added dropwise 2.02 parts of N,N-diethylethanamine. After cooling to 0° C., there was added dropwise a solution of 1.4 parts of acetyl chloride in 9 parts of tetrahydrofuran at a temperature below 0° C. Upon completion, stirring was continued for a while while cooling in an ice-bath. The reaction mixture was allowed to reach slowly room temperature and stirring was continued overnight at room temperature. The reaction mixture was evaporated and the residue was taken up in a sodium carbonate solution in water. The product was extracted with methylbenzene. The extract was washed with water, dried, filtered and evaporated The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was further separated by HPLC using a mixture of trichloromethane, hexane and methanol (48:48:4 by volume) as eluent. The second fraction (B-isomer) was collected and the eluent was evaporated. The residue was suspended in petroleum ether. The product was filtered off and dried, yielding 1.7 parts of cis-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-[3-(4-fluorophenoxy)propyl]-3-piperidinol acetate (ester); mp. 58.8° C. (compound 232).
Reaction SMILES: [FH:1].[FH:2].F.C(N(CC)CC)C.[C:11]([CH:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)([O:13][CH2:14][CH3:15])=[O:12]>ClCCl>[C:11]([CH:16]1[CH2:21][CH2:20][C:19]([F:2])([F:1])[CH2:18][CH2:17]1)([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCC(F)(F)CC1
Reaction time: 20 h

Procedure:
Procedure for the fluorination of carbonyls (examples 85-96): To a suspension of disubstituted aminodifluorosulfinium salt (2.0 mmol) and triethylamine trihydrofluoride (163 μL, 1.0 mmol) in dichloromethane (2.0 mL), at room temperature and under nitrogen, is added 4-carboethoxy-cyclohexanone (159 μL, 1.0 mmol). The reaction mixture was stirred 20 h, then quenched with a 5% aqueous sodium bicarbonate solution, stirred for 15 min, and the resulting mixture was extracted using dichloromethane. The organic phases were combined, dried over magnesium sulfate and filtered through a pad of silica gel. Solvents were evaporated to provide 4-carbethoxy-1,1-difluorocyclohexane admixed with 4-carboethoxy-1-fluorocyclohex-1-ene as a clear oil (refer to the following table for yields and product distribution).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:15])[C:4]([C:12]([OH:14])=O)=[CH:5][N:6]([CH:9]([CH3:11])[CH3:10])[C:7]=1[CH3:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[C:47]([N:49]=[S:50]([C:53]1[CH:58]=[CH:57][C:56]([CH2:59][NH2:60])=[CH:55][CH:54]=1)([CH3:52])=[O:51])#[N:48]>CN(C=O)C>[C:47]([N:49]=[S:50]([C:53]1[CH:58]=[CH:57][C:56]([CH2:59][NH:60][C:12]([C:4]2[C:3](=[O:15])[C:2]([Br:1])=[C:7]([CH3:8])[N:6]([CH:9]([CH3:10])[CH3:11])[CH:5]=2)=[O:14])=[CH:55][CH:54]=1)([CH3:52])=[O:51])#[N:48]
Reactant: Cc1c(Br)c(=O)c(C(=O)O)cn1C(C)C
Reactant: CS(=O)(=NC#N)c1ccc(CN)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(Br)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=NC#N)cc2)cn1C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-bromo-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 1c, 270 mg, 0.99 mmol), TBTU (316 mg, 0.99 mmol) and DIPEA (513 μL, 2.97 mmol) in DMF (3.00 mL) is stirred for 10 min at room temperature. Then, a solution of (4-(N-cyano-S-methylsulfonimidoyl)phenyl)methanamine (preparation 6, 247 mg, 1.18 mmol) in DMF (1.00 mL) is added and the reaction mixture is stirred for 18 h at room temperature. The reaction mixture is purified by preparative reversed phase HPLC (Sunfire, gradient of acetonitrile in water, 0.1% TFA, 60° C.). Yield: 70 mg (15% of theory); ESI mass spectrum: [M+H]+=465 (bromine isotope pattern); r.t. HPLC: 0.86 min (Z017_S04).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][C:17]3[C:18](Cl)=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=[CH:4][NH:3]1.[H-].[Na+].O.[CH3:27][O:28][CH2:29][CH2:30][OH:31]>>[O:1]=[C:2]1[C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][C:17]3[C:18]([O:31][CH2:30][CH2:29][O:28][CH3:27])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=[CH:4][NH:3]1
Reactant: COCCO
Reactant: O=c1[nH]cccc1CN1CCC(CCc2cccnc2Cl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCCOc1ncccc1CCC1CCN(Cc2ccc[nH]c2=O)CC1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
183 mg of 1-[(2-oxo-1,2-dihydro-3-pyridinyl)methyl]-4-[2-(2-chloro-3-pyridyl)ethyl]piperidine obtained in Example 117 and 226 mg of oil-dispersed 60% sodium hydride were suspended in 3 ml of 2-methoxyethanol, and the mixture was stirred at 150° C. for 2 hours. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by NH form silica gel column chromatography (methanol:ethyl acetate=1:19), to give 135 mg of the title compound as colorless crystals.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.CC1(C)C(C)(C)OB([C:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[N+:11]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc2[nH]nc(Br)c2c1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2n[nH]c3ccc([N+](=O)[O-])cc23)CC1
Temperature: 120 °C
Yield: 89.7 %

Procedure:
The mixture of 3-bromo-5-nitro-1H-indazole (484.1 mg, 2.0 mmol, 1.0 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (927.7 mg, 1.0 eq), (PPh3)4Pd (0) (462 mg, 0.2 eq), Na2CO3 (2M, 3.0 mL, 3.0 eq) in dioxane (12 mL) was degassed and heated at 120° C. in a microwave-oven synthesizer for 2 h. The mixture was cooled to room temperature and filtered through a celite pad to remove Na2CO3 and catalyst. The celite pad was washed with EtOAc. The solvent was removed and the crude was purified by silica gel chromatography (0%˜20% MeOH/DCM) to obtain the desired product tert-butyl 4-(5-nitro-1H-indazol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (618 mg, isolated yield 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]([NH:15][C:16]2[C:21]([C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:28])=O)=[CH:11][C:10]([C:29]([F:32])([F:31])[F:30])=[N:9]1.S(Cl)(Cl)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[O:23][C:22](=[N:24][CH:25]([CH3:26])[CH3:27])[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:28])[C:16]=3[N:15]=2)=[CH:11][C:10]([C:29]([F:32])([F:31])[F:30])=[N:9]1
Reactant: Cc1cccc(C(=O)NC(C)C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ccccc1Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Cc1cccc2c(=NC(C)C)oc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)nc12
Yield: 58 %

Procedure:
To the title compound of Step D (1.2 g, 2.7 mmol) dissolved in 8 mL of dichloromethane, 5 mL of thionyl chloride was added and the solution heated at reflux for 8 hours. The solvent was removed in vacuo aid remaining residue partitioned between 70 mL of ethyl acetate and water. The organic layer was separated, washed with water, saturated aqueous sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo to give a crude oily solid residue. Purification by flash chromatography on silica gel (2:1 hexane/ethyl acetate) and filtering from hexane afforded 700 mg of the title compound, a compound of the invention, isolated as a white solid melting at 133–135° C.
Reaction SMILES: [OH-].[Na+].C(OC([N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]1[CH2:23][OH:24])=O)(C)(C)C>C(O)C>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][NH:10][CH:11]([CH2:23][OH:24])[CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(CO)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCNC(CO)C1
Yield: 113.9 %

Procedure:
Sodium hydroxide (5.42 g) was added to a solution of 2-hydroxymethylpiperazine-1,4-dicarboxylic acid di-tert-butyl ester (10.87 g) in ethanol (300 ml), and the reaction mixture was heated to reflux for 16 hours. The solvent was removed by distillation at reduced pressure, and the residue was dissolved in ethyl acetate (400 ml) and water (50 ml). After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed by distillation at reduced pressure to give 8.46 g of the title compound.
Reaction SMILES: [NH2:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:11]([O:13][CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])=[C:6]([CH2:9][Cl:10])[CH2:7][S:8][C@H:3]12.[CH2:29]([O:32]/[N:33]=[C:34](/[C:38]1[N:39]=[C:40]([NH:43][C:44]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[S:41][CH:42]=1)\[C:35](O)=[O:36])[CH:30]=[CH2:31].P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl.C(OCC)(=O)C>[CH2:29]([O:32]/[N:33]=[C:34](/[C:38]1[N:39]=[C:40]([NH:43][C:44]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[S:41][CH:42]=1)\[C:35]([NH:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:11]([O:13][CH:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:12])=[C:6]([CH2:9][Cl:10])[CH2:7][S:8][C@H:3]12)=[O:36])[CH:30]=[CH2:31]
Reactant: C=CCO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of Compound V (1.35 g, 3 mmoles) in methylene chloride (20 mL) was added BSA (1.1 mL, 4.5 mmoles), and the mixture was stirred for 30 minutes at room temperature to become a clear solution. A mixture of (Z)-2-allyloxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (IV-3) (1.40 g, 3.0 mmoles) and phosphorus pentachloride (690 mg, 3.3 mmoles) in methylene chloride (20 mL) was stirred for 15 minutes at room temperature and poured in one portion into the solution of the trimethylsilylated Compound V. The mixture was stirred for 20 minutes at room temperature and diluted with ethyl acetate (200 mL), washed with aqueous sodium bicarbonate and water, dried and evaporated under reduced pressure. The oily residue was purified by silica gel column chromatography (Wako-gel, C-200, 30 g). The column was eluted with chloroform and the fractions containing the desired product were combined. Evaporation under reduced pressure afforded the title compound (VI-3) as an amorphous powder, yield 2.32 g (89%). Mp. 100°-115° C. (dec.).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:10])[CH3:7].Cl.[CH2:19]([O:26][C:27]1[CH:32]=[C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:30]=[CH:29][C:28]=1Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.CCCCCC>[CH2:6]([O:8][C:9]([N:11]1[CH2:12][CH2:13][C:14]([C:30]2[CH:29]=[CH:28][C:27]([O:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:32][C:31]=2[O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)([OH:17])[CH2:15][CH2:16]1)=[O:10])[CH3:7]
Reactant: Brc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(O)(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
In a 500 ml three-necked flask, 20 g of 2,4-bis(benzyloxy)-1-bromobenzene are dissolved in 240 ml of tetrahydrofuran. The mixture is cooled to −70° C. and then 26 ml of 2.5M n-butyllithium in hexane are added. The reaction medium is stirred at −70° C. for 1 hour, and then 11.1 g of 4-oxo-piperidine-1-carboxylic acid ethyl ester are added dropwise. The reaction medium is stirred at −70° C. for 2 hours and then left at ambient temperature overnight. The reaction medium is poured into 100 ml of a 2M solution of hydrochloric acid and then extracted with 400 ml of ethyl acetate. The organic phases are combined, washed with 150 ml of water and then dried over magnesium sulphate and evaporated.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([C:14](OCC)=O)=[C:7]([CH3:13])[C:8]=1[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:2][CH3:3].C=O>>[CH2:1]([C:4]1[NH:5][C:6]([CH3:14])=[C:7]([CH3:13])[C:8]=1[CH2:9][CH:10]([CH3:11])[CH3:12])[CH2:2][CH3:3]
Reactant: CCCc1[nH]c(C(=O)OCC)c(C)c1CC(C)C
Agent: C=O
Product: CCCc1[nH]c(C)c(C)c1CC(C)C

Procedure:
2-n-propyl-3-isobutyl-4-methyl-5-carbethoxy-pyrrole was reductively alkylated with paraformaldehyde to yield 2-n-propyl-3-isobutyl-4,5-di-methyl-pyrrole. ##STR109##
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[F:22][C:23]([F:40])([F:39])[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:31][C:32]([CH3:38])=[C:33]([CH2:35][CH2:36]O)[N:34]=2)=[CH:26][CH:25]=1>>[NH2:5][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:36][CH2:35][C:33]2[N:34]=[C:30]([C:27]3[CH:28]=[CH:29][C:24]([C:23]([F:40])([F:22])[F:39])=[CH:25][CH:26]=3)[O:31][C:32]=2[CH3:38])=[CH:18][CH:19]=1)[C:3]([OH:2])=[O:21]
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCO
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1

Procedure:
Intermediate 50 was prepared from 185 mg of N-(Boc)-L-Tyrosine methyl ester and 170 mg of Intermediate 13 to yield 130 mg (48% overall yield) of the title compound as a solid: 1H NMR (DMSO-d6, 400 MHz) δ8.16 (d, 2H, J=8.2), 7.92 (d, 2H, J=8.4), 7.21 (d, 2H, J=8.5), 6.93 (d, 2H, J=8.5), 4.25 (t, 2H, J=6.5), 3.1 (dd, 1H, J=14.4, 4.8), 3.0 (t, 2H, J=6.5), 2.76 (dd, 1H, J=14.4, 7.9), 2.46 (s, 3H); low resolution MS (ES+)m/e 434.9 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:11]([C:13]1[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=1)#[CH:12].CCN(CC)CC>C1COCC1>[C:11]([C:13]1[CH:14]=[C:15]([NH:19][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])[CH:16]=[CH:17][CH:18]=1)#[CH:12]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: C#Cc1cccc(N)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#Cc1cccc(NC(=O)c2ccccc2C)c1
Temperature: 25 °C
Yield: 88 %

Procedure:
A dry 25 mL flask was charged with 2-methylbenzoyl chloride (0.155 g, 1.00 mmol) was cooled to room temperature, and THF (10 mL) was added. 3-Ethynyl-phenylamine (0.117 g, 1.00 mmol) was added to the THF solution of the acid chloride followed by NEt3 (0.272 mL, 2.00 mmol), and the mixture was allowed to stir at 55° C. The reaction mixture was then allowed to cool to room temperature and partitioned between EtOAc (10 mL) and H2O (15 mL). The organic layer was washed with then washed once with 1M HCl (˜20 mL) followed by of saturated aqueous NaHCO3 (˜20 mL) and of brine (˜20 mL). The organic extracts were concentrated and the crude residue was purified by chromatography (silica gel, gradient elution EtOAc/hexanes 10 to 70%). The product containing fractions were concentrated to give the title compound as a tan solid (434 mg, 0.88 mmol, 88%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[CH:6]=O)[CH3:2].C1(P(=[CH:35][C:36]([O:38][CH3:39])=[O:37])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:39][O:38][C:36](=[O:37])[CH:35]=[CH:6][C:5]1[CH:8]=[CH:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:4]=1[NH:3][CH2:1][CH3:2]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCNc1cc(C(F)(F)F)ccc1C=O
Product: CCNc1cc(C(F)(F)F)ccc1C=CC(=O)OC

Procedure:
2-Ethylamino-4-trifluoromethyl-benzaldehyde (22 mg) was reacted with methyl (triphenylphosphoranylidene)acetate (49 mg, 0.14 mmol) at 110° C. overnight as described above to yield 3-(2-ethylamino-4-trifluoromethyl-phenyl)-acrylic acid methyl ester. 3-(2-Ethylamino-4-trifluoromethyl-phenyl)-acrylic acid methyl ester was reacted with 1N LiOH (5 ml) as described above to yield the title compound (20.2 mg)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:28])[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]=[C:11]([C:13]23[CH2:20][CH2:19][C:16]([CH2:21][CH2:22][CH2:23][CH:24]([OH:26])[CH3:25])([CH2:17][CH2:18]2)[CH2:15][CH2:14]3)[N:10](C)[N:9]=1.[CH3:29][N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:1][C:2]1[CH:3]=[C:4]([OH:28])[CH:5]=[CH:6][C:7]=1[C:8]1[N:12]([CH3:29])[C:11]([C:13]23[CH2:18][CH2:17][C:16]([CH2:21][CH2:22][CH2:23][C:24](=[O:26])[CH3:25])([CH2:15][CH2:14]2)[CH2:19][CH2:20]3)=[N:10][N:9]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(O)CCCC12CCC(c3nc(-c4ccc(O)cc4Cl)nn3C)(CC1)CC2
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Product: CC(=O)CCCC12CCC(c3nnc(-c4ccc(O)cc4Cl)n3C)(CC1)CC2
Reaction time: 0.25 h

Procedure:
3-Chloro-4-{5-[4-(4-hydroxypentyl)bicyclo[2.2.2]oct-1-yl]-4-methyl-4H-1,2,4-triazol-3-yl}phenol (5-K) (0.0035 g, 0.00869 mmol) was stirred in 0.5 mL of dry methylene chloride over activated 4 Å sieves. N-methylmorpholine N-oxide (0.0015 g, 0.013 mmol) was added. The mixture was allowed to stir under N2 for 15 min. Tetrapropylammonium perruthenate (0.00112 g, 0.00956 mmol) was added and the reaction was allowed to stir for 2 h. The mixture was filtered through celite filtering agent. The product, 5-{4-[5-(2-chloro-4-hydroxyphenyl)-4-methyl4H-1,2,4-triazol-3-yl]bicyclo[2.2.2]oct-1-yl}pentan-2-one (6-L), was purified by preparative reverse phase HPLC on a C-18 silica gel column using a gradient of acetonitrile-water buffered with 0.1% trifluoroacetic acid. The effluent containing the pure triazole was basified with 10% NaHCO3, evaporated in vacuo to remove most of the acetonitrile, and extracted with methylene chloride. The organic extract was dried (MgSO4) and evaporated, and the residue dried under vacuum to provide the desired compound. MS (ESI+)=402.3 (M+1).