Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.O[CH2:14][CH2:15][C@@H:16]1[CH2:18][C@@H:17]1[CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]2([CH3:31])[CH2:30][CH2:29]2)=[O:26])[CH2:21][CH2:20]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1.C(OCC)(=O)C.O>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:14][CH2:15][C@@H:16]2[CH2:18][C@@H:17]2[CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]3([CH3:31])[CH2:30][CH2:29]3)=[O:26])[CH2:21][CH2:20]2)=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: CC1(OC(=O)N2CCC([C@H]3C[C@H]3CCO)CC2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OC3(C)CC3)CC2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Methyl (4-hydroxyphenyl)acetate (37 mg, 0.22 mmol), 1-methylcyclopropyl 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl)piperidine-1-carboxylate (60 mg, 0.22 mmol), and triphenylphosphine (88 mg, 0.34 mmol) were dissolved in tetrahydrofuran (1 mL) under an atmosphere of nitrogen and cooled at 0° C. DIAD (68 mg, 0.34 mmol) was added and the resulting mixture was warmed to RT and stirred overnight. The mixture was diluted with ethyl acetate (10 mL) and water (5 mL), and the layers were separated. The organic layer was washed with brine (2×10 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (24 g of silica gel, ISCO, eluted with a gradient 0-100% ethyl acetate in Hexane) to afford the title compound. HPLC/MS; 1.27 min, 438 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5](=O)[C:6](=[O:8])[N:7]=1.[N+]([O-])(O)=[O:11].O.NC(N)=C([N+]([O-])=O)[N+]([O-])=O>S(=O)(=O)(O)O>[CH3:1][C:2]1[NH:7][C:6](=[O:8])[CH2:5][C:4](=[O:11])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: CC1=NC(=O)C(=O)C=N1
Agent: NC(N)=C([N+](=O)[O-])[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1=NC(=O)CC(=O)N1
Reaction time: 3 h
Yield: 35 %

Procedure:
Finely ground 2-methyl-4,5pyrimidindione (5.1 g, 0.05 mole) was dissolved in concentrated sulphuric acid (40 ml, 1.84 g/cm3) at 15-20° C. during vigorous stirring. At the same temperature nitric acid (8.0 ml, 1.52 g/cm3) was added over a 30-min period. After 3 h, the reaction mixture was poured into water. Within a few seconds, bright yellow crystals settled out (1,1-diamino-2,2-dinitroethylene). The precipitate were washed with water and dried at 50° C. 2.6 g 1,1-diamino-2,2-dinitroethylene was recovered (35% yield).
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([NH2:27])[N:18]=1>ClCCl>[N:27]([C:19]1[N:18]=[CH:17][C:26]2[C:21]([CH:20]=1)=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:1]=[S:2]
Reactant: Nc1cc2ccccc2cn1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: S=C=Nc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.805 g, 3.47 mmol) in dichloromethane at room temperature was added isoquinolin-3-amine (0.5 g, 3.47 mmol). The reaction was stirred at room temperature for 18 hours. The LC/MS showed the desired product peak a major peak. The deep orange solution was concentrated and filtered. The filtrate was purified by silica gel chromatography (0-40% ethyl acetate-hexanes) to afford 4-isothiocyanato-6-(3-methoxyphenyl)pyrimidine (0.55 g, 2.96 mmol, 85% yield) a white solid. LCMS R.T.=2.47; [M+H]+=187.23.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([OH:18])=O)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[C:19]1([C:25]2([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+]>ClCCl.O1CCCC1.CN(C)C=O>[C:19]1([C:25]2([NH:31][C:16]([C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[NH:7][N:8]=[CH:9]4)=[O:18])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Reactant: NC1(c2ccccc2)CCCCC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(NC1(c2ccccc2)CCCCC1)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
Oxalyl dichloride (38.7 μl, 0.444 mmol) and N,N-dimethylformamide (about 1 μl) were added to a solution of the 1H-indazole-5-carboxylic acid (40.0 mg, 0.247 mmol) obtained in Reference Example 1 in dichloromethane (2.5 ml), and the resulting mixture was stirred at room temperature for 0.5 hour and then was stirred with heating under reflux for 2 hours while maintaining the temperature. The reaction solution was concentrated to dryness and a solution of the resulting residue in tetrahydrofuran (1.5 ml) was added dropwise to a solution of 1-phenylcyclohexylamine (130 mg, 0.742 mmol) in tetrahydrofuran (2.0 ml). The resulting mixture was stirred for 18 hours while being maintained at room temperature. A 5% aqueous sodium bicarbonate solution was added to the reaction solution and stirred, followed by extraction with ethyl acetate. The organic phase was washed with a 5% aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The organic phase dried was concentrated under reduced pressure, and the resulting crude product was purified by a silica gel column chromatography (eluent: chloroform/methanol=50/1 to 30/1) to obtain N-(1-phenylcyclohexyl)-1H-indazole-5-carboxamide (62 mg, 78%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]3[N:21]=[C:22]([NH:24][C:25]([NH:27][C@H:28]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=4)[CH3:29])=[O:26])[N:23]=[C:19]3[N:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]3[N:21]=[C:22]([NH:24][C:25]([NH:27][C@H:28]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=4)[CH3:29])=[O:26])[N:23]=[C:19]3[N:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: COc1cccc([C@H](C)NC(=O)Nc2nc3nccc(-c4ccc(OCc5ccccc5)cc4)n3n2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cccc([C@H](C)NC(=O)Nc2nc3nccc(-c4ccc(O)cc4)n3n2)c1

Procedure:
(S)-1-[7-(4-benzyloxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]-3-[1-(3-methoxyphenyl)ethyl]urea (the compound obtained in Example 222; 7.83 g) was dissolved in acetic acid (600 ml). Thereafter, 10% palladium carbon (50% water content; 2.0 g) was added to the solution, and the obtained mixture was stirred at 40° C. overnight in a hydrogen atmosphere. The reaction solution was filtrated with a filter medium (Celite), and the resultant was then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (eluted with 4% methanol-containing methylene chloride) to obtain the captioned compound (5.37 g).
Reaction SMILES: [B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C(N(C(C)C)C(C)C)C.[C@H:32]1([CH2:42][O:43][C:44]2[CH:49]=[CH:48][C:47]([NH2:50])=[CH:46][CH:45]=2)[C@@H:41]2[N:36]([CH2:37][CH2:38][CH2:39][CH2:40]2)[CH2:35][CH2:34][CH2:33]1.[CH2:51]([O:55][C:56]1[CH:64]=[CH:63][C:59]([C:60](O)=[O:61])=[CH:58][CH:57]=1)[CH2:52][CH2:53][CH3:54]>CN(C=O)C.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[CH2:51]([O:55][C:56]1[CH:57]=[CH:58][C:59]([C:60]([NH:50][C:47]2[CH:48]=[CH:49][C:44]([O:43][CH2:42][C@H:32]3[C@@H:41]4[N:36]([CH2:37][CH2:38][CH2:39][CH2:40]4)[CH2:35][CH2:34][CH2:33]3)=[CH:45][CH:46]=2)=[O:61])=[CH:63][CH:64]=1)[CH2:52][CH2:53][CH3:54]
Reactant: Nc1ccc(OC[C@@H]2CCCN3CCCC[C@H]23)cc1
Reactant: CCCCOc1ccc(C(=O)O)cc1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOc1ccc(C(=O)Nc2ccc(OC[C@@H]3CCCN4CCCC[C@H]34)cc2)cc1

Procedure:
TOTU (78 mg) and ethyldiisopropylamine (31 mg), followed by 4-[(1R,9aR)-1-(octahydroquinolizin-1-yl)methoxy]phenylamine (62 mg), were added to a solution of 4-butoxybenzoic acid (46.4 mg) in DMF (2 ml) at 0° C. After a reaction time of three hours at room temperature, the mixture was diluted with sodium bicarbonate solution and ethyl acetate. After separation of the phases, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 436.60 (C27H36N2O3); MS (ESI): 437 (M+H+) was obtained in this way.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]3=[CH:11][NH:12][C:13](=[O:17])[C:14]([C:15]#[N:16])=[C:8]3[NH:7][C:6]=2[CH:18]=1.C(OO)(=[O:21])C>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10](=[O:21])[C:9]3=[CH:11][NH:12][C:13](=[O:17])[C:14]([C:15]#[N:16])=[C:8]3[NH:7][C:6]=2[CH:18]=1
Reactant: CC(=O)OO
Reactant: N#Cc1c2c(c[nH]c1=O)Sc1ccc(Cl)cc1N2
Solvent: CC(=O)O
Product: N#Cc1c2c(c[nH]c1=O)S(=O)c1ccc(Cl)cc1N2
Temperature: 25 °C
Reaction time: 27 h

Procedure:
A mixture of 1 part of 7-chloro-2,3-dihydro-3-oxo-5H-pyrido[3,4-b][1,4]benzothiazine-4-carbonitrile, 14 parts of ethaneperoxoic acid, and 58 parts of acetic acid is stirred at room temperature for 27 hours, whereupon insoluble solids are filtered out, dried in air, and recrystallized from aqueous N,N-dimethylformamide to give 7-chloro-2,3-dihydro-3-oxo-5H-pyrido[3,4-b][1,4]benzothiazine-4-carbonitrile 10-oxide as a colorless solid melting above 300°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=2[OH:16])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:24]1([SH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>>[C:24]1([S:30][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=3[OH:16])=[CH:4][CH:3]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(O)cc1O
Reactant: Sc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(c1ccc(Sc2ccccc2)cc1)c1ccc(O)cc1O
Temperature: 200 °C
Reaction time: 2.5 h
Yield: 108 %

Procedure:
To 50 grams of 4′-chloro-2,4-dihydroxybenzophenone and 27.8 grams of potassium carbonate in 50 mL of 1-methyl-2-pyrrolidinone (NMP)is added 22.2 grams of thiophenol. The resulting suspension is heated at 200° C. with strrring for 2.5 hours. The reaction mixture is then allowed to cool to room temperature, made acidic with 10% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water and brine, dried over anhydrous magnesium sulfate and concentrated to leave 70 grams of a deep red syrup. The crude material is dissolved in an ethyl acetate/heptane mixture (1:1) and partially purified by filtration through a bed of silica gel to yield after concentration 66.6 grams of a light orange solid; 1H NMR and IR data are consistent with the tide compound; Mass. Spec m/z 322 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([NH:11][CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:10])[O:4][N:3]=1.[OH-].[Na+].[C:22](Cl)(=[O:33])[O:23][CH2:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=1>C(Cl)Cl>[OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([NH:11][CH2:12][CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([C:22]([O:23][CH2:24][C:25]3[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=3)=[O:33])[CH2:18][CH2:19]2)=[O:10])[O:4][N:3]=1
Reactant: O=C(CCc1cc(O)no1)NCCC1CCNCC1
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(CCc1cc(O)no1)NCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1

Procedure:
3-(3-Hydroxyisoxazol-5-yl)-N-(2-(piperidin-4-yl)ethyl)propanamide (step 2) (201 mg, 0.662 mmol) was suspended in DCM (2 ml). 2M NaOH (1 ml, 2.00 mmol) was added and the reaction mixture stirred. To the mixture was added a solution of 3,5-dichlorobenzyl carbonochloridate (158 mg, 0.662 mmol) in DCM (1 ml) and the reaction mixture was stirred vigorously overnight. The resulting mixture was diluted with DCM and washed with citric acid. The organics were separated and evaporated under reduced pressure. The crude residue was dissolved in DMSO and purified by preparative HPLC. The product fractions were concentrated under reduced pressure and partitioned between EtOAc and water. The organics were separated, dried over MgSO4 (anh) filtered and evaporated under reduced pressure and dried in a high vacuum oven to afford the title compound;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)(=[O:16])=[O:15])[CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[NH2:27][CH:28]1[CH2:37][CH2:36][CH2:35][C:34]2[N:33]=[C:32]([CH2:38][CH2:39][OH:40])[N:31]=[CH:30][C:29]1=2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)(=[O:16])=[O:15])[CH2:9][C:10]([NH:27][CH:28]2[CH2:37][CH2:36][CH2:35][C:34]3[N:33]=[C:32]([CH2:38][CH2:39][OH:40])[N:31]=[CH:30][C:29]2=3)=[O:12])=[CH:4][CH:3]=1
Reactant: NC1CCCc2nc(CCO)ncc21
Reactant: O=C(O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1)NC1CCCc2nc(CCO)ncc21

Procedure:
A solution of 3-(4-fluorophenyl)-3-(3-trifluoromethyl-benzenesulfonylamino)-propionic acid (172 mg, 0.44 mmol), crude 2-(5-amino-5,6,7,8-tetrahydro-quinazolin-2-yl)-ethanol (Step G, 85 mg, 0.44 mmol), HOBt (65.5 mg, 0.484 mmol) and EDC (93 mg, 0.484 mmol) in 1.5 mL of DMF was stirred overnight at RT. After quenching with Sat. NaHCO3 solution, the mixture was extracted with EtOAc. The combined organic phase was washed brine, dried over Na2SO4, and evaporated in vacuo. Flash chromatography (SiO2, EtOAc/MeOH=100:5 to 100:10 to 100:12) gave the title compound as a white solid. MS: 567.0 (M+1).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([CH:28]([CH3:30])[CH3:29])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@H:23]([OH:25])[CH2:24][C:19]4=[CH:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH3:7].[C:31]([OH:36])(=[O:35])[CH:32]([CH3:34])[OH:33].C1(C)C=CC=CC=1>O>[CH3:1][CH2:2][C@@H:3]([CH:28]([CH3:29])[CH3:30])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@H:23]([OH:25])[CH2:24][C:19]4=[CH:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH3:7].[C:31]([O-:36])(=[O:35])[CH:32]([CH3:34])[OH:33]
Reactant: CC(O)C(=O)O
Agent: CC[C@H](CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CC(O)C(=O)[O-]
Reaction time: 11.5 h

Procedure:
200 g β-sitosterol, 250 g lactic acid, and 500 ml toluene were dissolved in a 5 l flask. The mixture was refluxed at 110-115° C. at the same time as water (free water+reaction water) was collected using water separation apparatus, in order to monitor the progress of the reaction. Reaction time was 11.5 h. At this point, 68 ml of water had been collected (free water: 33.8 ml+reaction water 34.2 ml), representing a 77.5% conversion in relation to the starting material. The toluene was evaporated from the reaction mixture using a rotavapor, and the product was dried in a vacuum oven at 40-60° C. The esterification experiment was repeated 5 times.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=O)=O.[I-:17].[Na+]>CC(C)=O>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][I:17])=[CH:10][CH:11]=1
Reactant: [I-]
Reactant: COc1ccc(CCCOS(C)(=O)=O)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(CCCI)cc1
Yield: 93 %

Procedure:
A solution of 6.30 g of 3-(4-methoxyphenyl)propyl methanesulfonate and 11.1 g of sodium iodide in 100 ml of acetone was refluxed for 15 hours. The reaction mixture was concentrated under reduced pressure and, after addition of water, the residue was extracted with ether. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6.62 g of 3-(4-methoxyphenyl)propyl iodide.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][C:7](=O)[NH:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[NH:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C1COCC1>[CH3:1][C:2]1([CH3:14])[CH2:8][C:7](=[S:24])[NH:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[NH:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)CC(=O)Nc2ccccc2N1
Solvent: C1CCOC1
Product: CC1(C)CC(=S)Nc2ccccc2N1
Temperature: 80 °C
Reaction time: 3 h
Yield: 144.4 %

Procedure:
A disposable tube was charged with 4,4-dimethyl-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (697 mg, 3.66 mmol) in THF (20 mL). Lawesson's Reagent (815 mg, 2.015 mmol) was added, and the solution was stirred at 80° C. for 3 h. The solution was concentrated, partitioned between water and ethyl acetate, separated, dried with sodium sulfate, concentrated with celite, and purified by silica gel chromatography to yield 4,4-dimethyl-4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-thione as a yellow oily solid (0.60 g, 2.91 mmol, 79%).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH3:18])[CH:11]=1)([CH3:9])[C:5]([F:8])([F:7])[F:6].Cl.O.C(OCC)(=O)C>C1COCC1>[F:6][C:5]([F:7])([F:8])[C:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH3:18])[CH:11]=1)([OH:3])[CH3:9]
Reactant: COc1ccc(C(C)(O[Si](C)(C)C)C(F)(F)F)cc1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(C)(O)C(F)(F)F)cc1C
Temperature: 25 °C
Reaction time: 144 h
Yield: 81.3 %

Procedure:
Trimethyl-[2,2,2-trifluoro-1-(4-methoxy-3-methylphenyl)-1-methylethoxy]silane (711 mg) was dissolved in THF (20 ml) and 1N HCl solution (20 ml) was added. After stirring at room temperature for 6 days, water and ethyl acetate were added to the reaction mixture and the organic layer was separated. The obtained organic layer was washed with brine and dried over anhydrous magnesium sulfate. After removing the drying agent, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane→heptane:ethyl acetate 7:3) to obtain the title compound (442 mg). The property values of the obtained compound are as follows; 1H-NMR (CDCl3) δ (ppm): 1.76 (s, 3H), 2.24 (s, 3H), 3.84 (s, 3H), 6.83 (d, J=8.4 Hz, 1H), 7.34-7.37 (m, 2H).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si](C(C)(C)C)(C)C)[CH2:9][C@H:8]1[CH2:20][CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)=[O:6])[CH:2]=[CH2:3].Cl.C[O-].[Na+].CO.C(Cl)(Cl)Cl>CO>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:20][CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCn1ccnc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1CCn1ccnc1
Yield: 118.3 %

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-2-[2-(imidazol-1-yl)ethyl]-4-(t-butyldimethylsilyloxy)pyrrolidine (11.11 g) in methanol (110 ml) was added conc. hydrochloric acid (7.32 ml) at ambient temperature with stirring and the solution was stirred at the same temperature for 2 hours. To a reaction solution was added 28% sodium methoxide-methanol solution (16.89 ml) under ice-cooling with stirring and the resulting insoluble material was filtered off. The filtrate was evaporated in vacuo to give a residue. To the residue was added chloroform. The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo to give crude (2R,4R)-1-allyloxycarbonyl-2-[2-(imidazol-1-yl)ethyl]-4-hydroxypyrrolidine (9.19 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][CH:5]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.[F-].[Cs+]>O1CCOCC1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=2)=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 100 °C
Yield: 90.4 %

Procedure:
To an ambient temperature solution of 6-chloro-nicotinic acid methyl ester (12.4 g, 72 mmol) and 4-(trifluoromethyl)phenylboronic acid (15 g, 79 mmol) in dioxane (270 mL) is added CsF (38.3 g, 252 mmol) and the reaction mixture is degassed with nitrogen. PdCl2(dppf) (1.5 g) is added and the reaction mixture is heated to 100° C. over weekend. The reaction mixture was diluted with ethyl acetate, filtered through celite. The filtrate is concentrated. Purification of the crude product by column on silica gel (hexanes/ethyl acetate) gives 6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (18.3 g, 82.3% yield).
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=O)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[F:32][C:33]([F:44])([F:43])[O:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41]N)=[CH:37][CH:36]=1>>[CH3:1][CH:2]([CH3:30])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:39]4[C:38](=[CH:37][CH:36]=[C:35]([O:34][C:33]([F:44])([F:43])[F:32])[CH:40]=4)[NH:41][C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:16][CH2:17]2)[CH:7]=1)=[O:4]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3)CC2)c1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(5-oxo-5-phenylpentyl)-4-piperidinyl]phenyl}propanamide and 1-[4-(trifluoromethoxy)phenyl]hydrazine hydrochloride: ESMS m/e: 564.2 (M+H)+.