Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH:9]1[CH2:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)=[O:7].[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:35]=1[NH:41][C:42](=[O:50])[CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.[BH4-].[Na+].C(O)C>CC(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].O>[F:31][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([N:47]2[CH2:48][CH2:49][N:44]([CH2:43][C:42]([NH:41][C:35]3[C:36]([CH3:40])=[CH:37][CH:38]=[CH:39][C:34]=3[CH3:33])=[O:50])[CH2:45][CH2:46]2)[CH2:10][C@@H:9]1[CH2:15][C:16]1[CH:17]=[C:18]([F:23])[CH:19]=[C:20]([F:22])[CH:21]=1)=[O:7]
Reactant: O=C1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(Cc2cc(F)cc(F)c2)C1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: O
Solvent: CC(C)O
Solvent: CCO
Product: Cc1cccc(C)c1NC(=O)CN1CCN([C@H]2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](Cc3cc(F)cc(F)c3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.2 %

Procedure:
A mixture of (±)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(3,5-difluorophenyl) methyl]-4-piperidinone (0.0058 mol), N-(2,6-dimethylphenyl)-1-piperazineacetamide (0.0058 mol) and titanium(IV)isopropoxide (0.0064 mol) in 2-propanol (5 ml) was stirred at RT overnight. NaBH4 (0.0116 mol) and ethanol (15 ml) were added. The mixture was stirred for 2 day. Water (5 ml) was added and the mixture was stirred for 10 minutes. CH2C2 (200 ml) was added. The organic layer was separated, dried, filtered and the solvent was evaporated. This fraction was purified by HPLC over silica gel (eluent: CH2Cl2/CH3OH 98/2 to 90/10 over a 30-minute period). Two pure fractions (F1 and F2) were collected and their solvents were evaporated. F1 was purified by column chromatography over RP18 (eluent: NH4OAc (0.5% in H2O)/CH3CN 40/60). The pure fractions were collected and the solvent was evaporated. The residue was dried, yielding 0.33 g (8%) of (±)-cis-4-[1-[3,5-bis (trifluoromethyl)benzoyl]-2-[(3,5-difluorophenyl)methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide (compound 132). F2 was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 100/0 to 98/2 over a 30-minute period). The pure fractions were collected and the solvent was evaporated. The residue was dissolved in CH2Cl2, filtered and the solvent was evaporated. The residue was dried, yielding 0.24 g (6%) of (±)-trans-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(3,5-difluorophenyl) methyl]-4-piperdinyl]-N-( 2,6-dimethylphenyl)-1-piperazineacetamide (compound 133).
Reaction SMILES: CN(OC)[C:3](=[O:20])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[C:9]([O:8][C:6]([NH:5][C@H:4]([CH:3]=[O:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:7])([CH3:11])([CH3:12])[CH3:10]
Reactant: CON(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccccc1
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A solution of N-(tert-butyloxy-carbonyl)-L-phenylalanine N,O-dimethylhydroxylamide (70.05g, 0.229 mol) in 1400 ml of anhydrous ether was cooled in an ice bath while under a nitrogen atmosphere. To this solution was added lithium aluminum hydride (10.88 g) 0.287 mol) as fast as possible while keeping the reaction under control. The ice bath was removed and the mixture was stirred for 30 minutes where upon it was quenched by addition of 1600 mL of aqueous solution containing 62.11 g of potassium bisulfate. The resulting mixture was stirred for 15 minutes and then was filtered through celite. The phases of the filtrate were separated and the aqueous phase was extracted with ether (2×300ml ). The combined ether layers were then extracted with 1N hydrochloric acid (2×1600ml ), saturated aqueous sodium bicarbonate (2×1600ml ) and saturated aqueous sodium chloride (300mL ). Resulting ether solution was then dried over MgSO4 and solvent was removed under vacuum to give a colorless oil 53.1 g which solidified on standing. The NMR shows about 60% aldehyde. This was used without further purification.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:13](OC(C)C)=[O:14])[C:7]=2[CH:6]=[CH:5]1)([CH3:3])[CH3:2].[H-].[Al+3].[H-].[H-]>[O-2].[O-2].[Mn+4]>[CH:1]([N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([CH:13]=[O:14])[C:7]=2[CH:6]=[CH:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1cccc2c1ccn2C(C)C
Agent: [Mn+4]
Agent: [Al+3]
Agent: [H-]
Product: CC(C)n1ccc2c(C=O)cccc21

Procedure:
Isopropyl 1-isopropylindole-4-carboxylate (2.6 g) was reduced by diusobutyl aluminum hydride, followed by oxidation with manganese dioxide, whereby the title compound was obtained.
Reaction SMILES: [Cl:1][CH2:2][C:3]#[N:4].[Na].Cl.[OH:7][N:8]=[C:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>CO>[ClH:1].[OH:7][N:8]=[C:9]1[CH2:14][CH2:13][N:12]([C:3](=[NH:4])[CH2:2][Cl:1])[CH2:11][CH2:10]1
Reactant: ON=C1CCNCC1
Reactant: N#CCCl
Agent: Cl
Agent: [Na]
Solvent: CO
Product: N=C(CCl)N1CCC(=NO)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.63 ml of chloroacetonitrile was added to a solution of 23 mg of metallic sodium in 4 ml of absolute methanol, and the mixture was stirred for about 30 minutes at room temperature. 1.5 g of 4-hydroxyiminopiperidine hydrochloride were then added and the stirring was continued for 2 hours, during which time a precipitate separated out. 25 ml of anhydrous ether were added to the reaction mixture, and the precipitated crystals were collected by filtration and washed with ether, giving 2.22 g of 2-(4-hydroxyiminopiperidin-1-yl)-2-iminoethylchloride hydrochloride.
Reaction SMILES: [H-].[Na+].[C:3]([SH:6])(=[O:5])[CH3:4].CS(O[C@H:12]1[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[C@H:14]([CH2:30][N:31]2[CH2:36][CH2:35][CH2:34][N:33]3[N:37]=[CH:38][CH:39]=[C:32]23)[CH2:13]1)(=O)=O>CN(C)C=O>[C:3]([S:6][C@@H:12]1[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[C@H:14]([CH2:30][N:31]2[CH2:36][CH2:35][CH2:34][N:33]3[N:37]=[CH:38][CH:39]=[C:32]23)[CH2:13]1)(=[O:5])[CH3:4]
Reactant: CC(=O)S
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](CN2CCCn3nccc32)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](CN2CCCn3nccc32)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C

Procedure:
To a solution of sodium hydride (60% suspension in oil, 0.27 g) in N,N-dimethylformamide (15 ml) was added dropwise thioacetic S-acid (0.51 ml) with stirring under ice-cooling. The mixture was stirred at the same temperature for 30 minutes. A solution of (2S,4R)-4-methanesulfonyloxy -1-(4-nitrobenzyloxycarbonyl)-2-{4,5,6,7-tetrahydropyrazolo [1,5-a]pyrimidin-4-yl)methylpyrrolidine (2.65 g) in N,N-dimethylformamide (15 ml) was added to the mixture obtained above with stirring at the same temperature and the mixture was stirred at 80°~90° C. for 2 hours. The reaction mixture was poured into ice-water (100 ml) and extracted twice with ethyl acetate (100 ml). The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl) -2-{4,5,6,7-tetrahydropyrazolo-[1,5-a]pyrimidin-4-yl}methylpyrrolidine (2.23 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:48][CH3:49])=[C:7]2[CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([N:25](C)[C:26](=O)OC(C)(C)C)[CH3:24])[C@H:17]([CH3:35])[N:16]([C:36]([CH:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[O:37])[C:15]2[CH:44]=[CH:45][CH:46]=[CH:47][C:14]1=2.[ClH:50]>CO.C(OCC)C>[ClH:50].[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([O:48][CH3:49])=[C:7]2[CH2:12][N:13]1[C:19](=[O:20])[C@@H:18]([NH:21][C:22](=[O:34])[C@@H:23]([NH:25][CH3:26])[CH3:24])[C@H:17]([CH3:35])[N:16]([C:36]([CH:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[O:37])[C:15]2[CH:44]=[CH:45][CH:46]=[CH:47][C:14]1=2
Reactant: COc1ccc2c(Br)cccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)C2CCOCC2)c2ccccc21
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(OC)ccc3c(Br)cccc23)c2ccccc2N(C(=O)C2CCOCC2)[C@H]1C
Reaction time: 3.5 h
Yield: 88 %

Procedure:
A solution of tert-butyl(S)-1-((3S,4S)-1-((5-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (45 mg, 61 μmol) in methanol (500 μl) at room temperature was treated with a 2 M hydrochloric acid in diethyl ether solution (1.3 ml) and stirred for 3.5 h. The reaction was then concentrated in vacuo, dissolved in water and placed on a lyophilizer over night to afford (S)-N-((3S,4S)-1-((5-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (36 mg, 88%) as a light yellow powder: LC-MS m/z 637 [M+H]+.
Reaction SMILES: [OH-].[CH2:2]([N+:9]([CH3:12])([CH3:11])[CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:13]1([NH:19][C:20](=[O:26])/[CH:21]=[CH:22]\[C:23]([OH:25])=[O:24])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(O)(=O)C>CO>[CH2:2]([N+:9]([CH3:12])([CH3:11])[CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:13]1([NH:19][C:20](=[O:26])/[CH:21]=[CH:22]\[C:23]([O-:25])=[O:24])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)/C=C\C(=O)Nc1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: O=C([O-])/C=C\C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 108.1 %

Procedure:
48.2 g (0.1 mole) of benzyltrimethylammonium hydroxide solution (34.7% in methanol) is added to 19.1 g (0.1 mole) of N-phenylmaleamic acid in 100 ml of methanol, and the reaction mixture is stirred for one hour at room temperature. The pH-value is adjusted to about 7.0 with acetic acid, and the solvent is removed in vacuo in a rotary evaporator to leave 36.8 g of N-phenylmaleamic acid benzyltrimethyl-ammonium salt in the form of yellow oil, which crystallises after prolonged standing.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:19][CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1)O)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CS(Cl)(=O)=O.O>C(Cl)Cl>[Si:1]([O:8][C@H:9]1[CH2:10][N:11]([C:12]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:18])[CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH2:19]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC[C@@H](CC(O)c1cccc(F)c1)O[Si](C)(C)C(C)(C)C
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)CC1c1cccc(F)c1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (2R)-2-(tert-butyldimethylsilyloxy)-4-(3-fluorophenyl)-4-hydroxybutylcarbamate (I-2) (15.8 g, 38.2 mmol) in DCM (120 mL) at −60° C. under N2 was added TEA (16 mL, 114.6 mmol) and MsCl (3.3 mL, 42.0 mmol). The resulting mixture was stirred at −60° C. for 1 hour. The reaction was poured into water, washed with brine, dried over sodium sulfate, filtered and concentrated to yield (4R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-(3-fluorophenyl)pyrrolidine-1-carboxylate (I-3). MS m/z 418.1 (M+23)+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([C:13]3[C:14]([O:19]C)=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[CH:21]=[CH:22][CH:23]=[CH:24][C:4]=2[N:3]=1.[ClH:25]>>[ClH:25].[NH2:1][C:2]1[N:6]([C:7]2[C:12]([C:13]3[C:14]([OH:19])=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[CH:21]=[CH:22][CH:23]=[CH:24][C:4]=2[N:3]=1
Reactant: COc1ncccc1-c1ccccc1-n1c(N)nc2ccccc21
Agent: Cl
Product: Nc1nc2ccccc2n1-c1ccccc1-c1cccnc1O

Procedure:
2-Amino-1-[6-(2-hydroxypyridyl)phenyl]benzimidazole hydrochloride was prepared from 2-amino-1-[6-(2-methoxypyridyl)phenyl]benzimidazole by refluxing in 25% aqueous hydrochloric acid. mp 215°-217° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O-:12])(=[O:11])=[O:10].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([S+:22]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:35][CH:34]=2)[C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)CCN(C)C.[CH:57]([O:59][CH2:60][CH2:61]Cl)=[CH2:58]>CS(C)=O>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O-:12])(=[O:11])=[O:10].[CH:57]([O:59][CH2:60][CH2:61][O:15][C:16]1[CH:21]=[CH:20][C:19]([S+:22]([C:33]2[CH:34]=[CH:35][C:36]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:37][CH:38]=2)[C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[CH2:58]
Reactant: CC(C)(C)c1ccc([S+](c2ccc(O)cc2)c2ccc(C(C)(C)C)cc2)cc1
Reactant: C=COCCCl
Agent: CN(C)CCN(C)C
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])c1ccccc1C(F)(F)F
Solvent: CS(C)=O
Product: C=COCCOc1ccc([S+](c2ccc(C(C)(C)C)cc2)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
4-Hydroxyphenyldi(4-t-butylphenyl)sulfonium 2-trifluoromethylbenzenesulfonate (4.51 g), potassium carbonate (5.30 g), and N,N,N′,N′-tetramethylethylenediamine (0.53 g) were dissolved in dimethyl sulfoxide (30 g). Subsequently, chloroethyl vinyl ether (10.03 g) was added to the resultant solution, followed by heating to 80° C. and stirring for 15 hours. The resultant reaction mixture was cooled to 30° C. or lower. After removal of solid matter through filtration, water (150 g) and dichloromethane (93 g) were added to the filtrate for extraction of a target substance into the dichloromethane layer. The organic layer was repeatedly washed with distilled water until the pH of the separated aqueous layer became 7. The solvent was removed by means of a rotary evaporator, to thereby yield 8.57 g of a red powdery substance. Through 1H-NMR analysis and ion chromatography, this substance was identified to be 4-vinyloxyethoxyphenyldi(4-t-butylphenyl)sulfonium 2-trifluoromethylbenzenesulfonate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][CH:18]=1.[O:26]=[S:27]1(=[O:41])[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[O:41]=[S:27]1(=[O:26])[CH2:28][CH2:29][N:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:23]([C:20]3[CH:21]=[CH:22][C:17]([C:3]4[C:2]([CH3:1])=[CH:7][CH:6]=[C:5]([NH:8][C:9]([N:11]5[CH2:12][CH2:13][O:14][CH2:15][CH2:16]5)=[O:10])[CH:4]=4)=[CH:18][CH:19]=3)=[O:25])=[CH:36][CH:35]=2)[CH2:31][CH2:32]1
Reactant: Cc1ccc(NC(=O)N2CCOCC2)cc1-c1ccc(C(=O)O)cc1
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)N2CCOCC2)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1
Reaction time: 18 h
Yield: 48.8 %

Procedure:
A mixture of 2′-methyl-5′-[(morpholine-4-carbonyl)-amino]-biphenyl-4-carboxylic acid (40 mg), 4-(1,1-Dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-phenylamine (28 mg), triethylamine (0.033 ml) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (67 mg) in dry DMF (3 ml) was stirred at 20 C for 18 h. The mixture was then partitioned between water and dichloromethane. The dried extracts were evaporated and the residue purified on silica gel. Elution with dichloromethane:ethanol:0.880 ammonia; 200:8:1 gave an off-white solid (32 mg).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:6]=1[CH:7]=O)([CH3:3])[CH3:2].C1(P(=[CH:36][C:37]([O:39][CH3:40])=[O:38])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:40][O:39][C:37](=[O:38])[CH:36]=[CH:7][C:6]1[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc(C(F)(F)F)ccc1C=O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1ccc(C(F)(F)F)cc1OC(C)C
Temperature: 80 °C
Yield: 72 %

Procedure:
To a suspension of 2-isopropoxy-N-methoxy-N-methyl-4-trifluoromethyl-benzamide (28 mg, 0.096 mmol) in THF (1.5 mL) was added dropwise 1.0M LiAlH4 (0.048 ml, 0.5 eq) at −60° C. The mixture was slowly warmed up to −20° C. until the reaction was completed. The reaction was slowly quenched with sat'd KHSO4 (1 mL) and then diluted with water (1 mL). The reaction mixture was extracted with ether and the combined organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulting compound was vacuum dried to yield the 2-isopropoxy-4-trifluoromethyl-benzaldehyde. To the aldehyde prepared above was added toluene (1 mL) followed by portionwise addition of methyl (triphenylphosphoranylidene)acetate (32 mg, 0.105 mmol) (exothermic). Toluene (1 mL) was added to the reaction mixture, and the resulting mixture was heated at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, and then was directly loaded to a short silica-gel column and eluted with the solvent (Hex/EtOAc=20/1) to give the title compound (20 mg, 72%).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=2)=[N:4][CH:3]=1.[CH2:21]([C:23]1[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[O:26])[CH3:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.O.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>[CH2:21]([C:23]1[C:30]([C:2]2[S:6][C:5]([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=3)=[N:4][CH:3]=2)=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[O:26])[CH3:22]
Reactant: CC(C)Oc1ccc(-c2ncc(Br)s2)cc1C(F)(F)F
Reactant: CCc1c(C=O)cccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCc1c(C=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Temperature: 130 °C
Yield: 48.3 %

Procedure:
To a solution of 5-bromo-2-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3-thiazole (D67) (120 mg), 2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (D5) (77 mg) and tripotassium phosphate (157 mg) in 1,2-dimethoxyethane (DME) (3 mL) and water (0.750 mL) stirred under nitrogen at room temperature was added Pd(Ph3P)4 (34.1 mg) in one charge. The reaction vessel was sealed and heated under microwave at 130° C. for 15 min. After cooling the reaction, the reaction mixture was filtered and the filtrate was partitioned between ethyl acetate (250 mL) and saturated brine (50 mL). The organic phase was dried over sodium sulphate and evaporated in vacuo. The crude product was purified by column chromatography to give 2-ethyl-3-{2-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}benzaldehyde (D72) (60 mg). MS (ES): C22H20F3NO2S requires 419. found 420.0 (M+H+).
Reaction SMILES: OS(O)(=O)=O.[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1.[N+:14]([O-])([OH:16])=[O:15].[OH-].[Na+]>>[NH2:6][C:7]1[C:12]([N+:14]([O-:16])=[O:15])=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1
Reactant: O=[N+]([O-])O
Reactant: Nc1ccc(Cl)cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Nc1ncc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 56 %

Procedure:
To 150 mL of conc. H2SO4 was added 42.96 g (334 mmol) of 2-amino-5-chloropyridine in portions with stirring and cooling (ice-water bath). To the resulting solution was added dropwise 22.5 mL of 69-71% HNO3 (355 mmol) at 50° C. (at such a rate that maintain the temperature within 50°-55° C.) over 1 h. The resulting mixture was stirred at 60° C. for 3 h, poured into ice-water (about 1,500 mL) with stirring, then basified to pH 9 by the addition of 40% aq NaOH with stirring and cooling. The precipitate was filtered, washed with water (6×50 mL), and dried to give 32.47 g (56%) of 2 as a yellow powder, mp 190°-191° C. (lit. 191°-2° C. (Israel, M. & Day, A. R., J. Org. Chem. 24:1455-1460 (1959))). 1H NMR (DMSO-d6), 8.044-8.055 (m, 3H), 8.054 (d, 1H, J=3.9).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([Cu])#[N:25].C(N)CN>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:24]#[N:25])=[CH:11][C:10]=1[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(OCc2ccccc2)c(CCc2ccccc2)c1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: NCCN
Product: N#Cc1ccc(OCc2ccccc2)c(CCc2ccccc2)c1
Temperature: 25 °C
Yield: 42.5 %

Procedure:
To a stirred solution of the 4-benzyloxy-3-(phenethyl)phenylbromide, (5.5 g, 15 mmol) in DMF (200 ml, dried) was added CuCN (3.32 g, 37 mmol). The reaction was heated to reflux and held at reflux for 20 hours, under argon. The reaction mixture was allowed to cool to ambient temperature, poured into ice water, treated with ethylene diamine (200 ml) and extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with brine (2×60 ml), dried (MgSO4) and evaporated. The crude material was purified by chromatography to give 4-benzyloxy-3-phenethylbenzonitrile as a white solid (2.0 g, 43%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]1[C:20]2[C:15](=[CH:16][C:17]([NH:21][C:22](=[O:36])[C@@H:23]3[CH2:27][C@H:26]([OH:28])[CH2:25][N:24]3[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:12]1[C:20]2[C:15](=[CH:16][C:17]([NH:21][C:22](=[O:36])[C@@H:23]3[CH2:27][C@H:26]([O:28][S:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=4)(=[O:9])=[O:8])[CH2:25][N:24]3[C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)Nc1ccc2c(c1)CCC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@H](C(=O)Nc3ccc4c(c3)CCC4)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.3 %

Procedure:
4-Dimethylaminopyridine (4.1 g) and p-toluenesulphonyl chloride (4.8 g) were added to a solution of cis-4-hydroxy-N-tert-butoxycarbonyl-L-proline 5-indanylamide (B, 5.8 g) in dichloromethane (85 mL) at 0° C. After stirring at room temperature for 6 hr, additional 4-dimethylaminopyridine (1.0 g) and p-toluenesulphonyl chloride (1.6 g) were added. The resulting solution was stirred at room temperature for 19 hr, and the solvent was evaporated in vacuo. The residue was diluted with ethyl acetate, and washed with 0.5 M citric acid, saturated sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to afford the title compound (7.4 g) as a pale brown sticky oil: 1H NMR (400 MHz, CD3OD) δ 1.3-1.6 (m, 9H), 2.10 (m, 2H), 2.2 (m, 1H), 2.39 (s, 3H), 2.5 (m, 1H), 2.88 (m, 4H), 3.68 (m, 2H), 4.3-4.4 (m, 1H), 5.17 (m, 1H), 7.15 (m, 2H), 7.31-7.35 (m, 3H), and 7.73 (d, J=7.8 Hz, 2H).