Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[C:4]#[N:5].[C:16]([N:24]=[C:25]=[O:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:4]([C:3]1[C:6]([O:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:25]([NH:24][C:16](=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:26])#[N:5]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: CC(C)(C)COc1cccc(N)c1C#N
Product: CC(C)(C)COc1cccc(NC(=O)NC(=O)c2ccccc2)c1C#N
Yield: 96 %

Procedure:
Prepared as in Example 146a from 2-amino-6-(neopentyloxy)-benzonitrile (Example 217b) and benzoyl isocyanate in 96% yield as a white solid. MS 352 (MH+).
Reaction SMILES: [CH3:1][C:2]([O:9][C:10](=[O:12])[CH3:11])([CH2:5][N+:6]([O-])=O)[CH:3]=[CH2:4].P(Cl)(Cl)Cl.Cl>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][C:2]([O:9][C:10](=[O:12])[CH3:11])([C:5]#[N:6])[CH:3]=[CH2:4]
Reactant: C=CC(C)(C[N+](=O)[O-])OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClP(Cl)Cl
Solvent: ClCCl
Product: C=CC(C)(C#N)OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
30 g. (0.17 m) of acetic acid (3-methyl-4-nitro-1-buten-3-yl)ester was diluted with 600 cc of pyridine. To this was added dropwise a solution of 50 g. (0.32 m) PCl3 in 50 cc of CH2Cl2 over a 1/2 hour period. The mixture was stirred overnight at room temperature. Ice, followed by 600 ml. concentrated HCl, was subsequently added to the reaction mixture. Extraction with ether and chromatographic separation of the crude product yielded acetic acid (3-methyl-3-cyano-1-propen-3-yl)ester as a colorless oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1COCC1.[Br:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[C:33]([F:40])[CH:32]=1.Cl.[CH3:42][O:43][C:44](=[O:48])[CH2:45][CH2:46][NH2:47]>CCOC(C)=O.Cl>[Br:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:47][CH2:46][CH2:45][C:44]([O:43][CH3:42])=[O:48])=[O:37])=[C:33]([F:40])[CH:32]=1
Reactant: COC(=O)CCN
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCNC(=O)c1ccc(Br)cc1F
Temperature: 25 °C

Procedure:
Solid HATU (1.6 g, 4.2 mmol) was added to a THF solution (7 mL) of 4-bromo-2-fluorobenzoic acid (750 mg, 3.2 mmol), i-Pr2Net (1.1 mL, 6.4 mmol), and β-alanine methyl ester hydrochloride (584 mg, 4.2 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture was diluted with EtOAc and 1N aqueous HCl. The organic layer was separated, washed with brine, dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH:33]([C:36]([OH:38])=[O:37])[CH2:32][CH2:31]1)=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:52]1[C:57](=[O:58])[CH2:56][CH2:55][C:53]1=[O:54])=[N+](C)C)C>C1COCC1.C(#N)C>[O:54]=[C:53]1[CH2:55][CH2:56][C:57](=[O:58])[N:52]1[O:37][C:36]([CH:33]1[CH2:34][CH2:35][CH:30]([CH2:29][NH:28][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:31][CH2:32]1)=[O:38]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NCC1CCC(C(=O)O)CC1
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NCC1CCC(C(=O)ON2C(=O)CCC2=O)CC1
Yield: 87.8 %

Procedure:
To a solution of 4-[(19-tert-butoxycarbonylnonadecanoylamino)methyl]cyclohexanecarboxylic acid (5.56 g) in THF (100 ml) was added a solution of TSTU (3.42 g) in acetonitrile (25 ml). The mixture was concentrated in vacuo after stirring over night. The solid residue was recrystallized from acetonitrile to give 4-[(19-tert-butoxycarbonylnonadecanoylamino)methyl]cyclohexanecarboxylic acid 2,5-dioxopyrrolidin-1-yl ester (5.76 g, 88%).
Reaction SMILES: ClC[N:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][CH2:4]1.[NH2:10][C:11]1[S:12][CH:13]=[N:14][N:15]=1.[I-].[Na+].[CH3:18]C(C)=O>>[Cl:9][C:8]1[N:3]=[CH:4][C:5]([CH2:18][N:10]=[C:11]2[NH:15][N:14]=[CH:13][S:12]2)=[CH:6][CH:7]=1
Reactant: ClCN1CC=CC=C1Cl
Reactant: Nc1nncs1
Reactant: CC(C)=O
Agent: [I-]
Agent: [Na+]
Product: Clc1ccc(CN=c2[nH]ncs2)cn1
Temperature: 25 °C
Yield: 28 %

Procedure:
N-Chloromethyl-6-chloropyridine (717 mg (4.43 mM)) (prepared according to the method of J. Het. Chem., 1979, 16, 333-336), 537 mg (5.31 mM) of 2-amino-1,3,4-thiadiazole and 1.99 g (13.29 mM) of sodium iodide were mixed together in 60 mL of acetone and refluxed for 18 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated. The residue was dissolved in a 1:1 mixture of 50 mL of 10% NaOH and 50 mL of methylene chloride. The organic layer was dried (Na2SO4) and the solvent was evaporated. The residue was chromatographed on silica using 2% methanol in methylene chloride as the eluant. Appropriate fractions were combined to yield 282 mg (28%) of the title product as an oil. 1H-NMR (CDCl3) δ 8.45, (d, 1H, J=2.8 Hz), 7.70 (dd, 1H, J=2.8, 10.7 Hz), 7.60 (s, 1H, J=10.7 Hz), 7.28 (d, 1H, J=10.7 Hz), 5.10 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:9]=[C:8]([OH:16])[C:3]=1[C:4](OC)=[O:5].[Li+].[BH4-].CCOC(C)=O>C1COCC1>[F:1][C:2]1[C:3]([CH2:4][OH:5])=[C:8]([OH:16])[CH:9]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:11]=1
Reactant: COC(=O)c1c(O)cc(S(C)(=O)=O)cc1F
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc(O)c(CO)c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95.6 %

Procedure:
Methyl 2-fluoro-6-hydroxy-4-(methylsulfonyl)benzoate (0.14 g, 0.57 mmol) was dissolved in THF (dry) (5 ml). LiBH4 (2M in THF) (0.57 ml, 1.14 mmol) was added dropwise under nitrogen at 0° C. The mixture was allowed to warm to RT and stirred under nitrogen for 45 min. EtOAc was added and the mixture was further quenched with MeOH, then water. The mixture was acidified with 1N HCl and extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO4) and concentrated to give the crude title compound (0.12 g) 1H-NMR (400 MHz, CD3OD): δ 7.20 (1H, s), 7.16 (1H, dd, J 8.4, 2), δ 4.73 (2H, d, J 1.6), δ 3.10 (3H, s) ppm (J-values are in Hz and shifts relative to solvent-peak at 3.31 ppm).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=3[F:26])=[O:17])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:35]2[NH:39][CH:38]=[C:37]([C:40]([O-:42])=[O:41])[CH:36]=2)O1.[CH2:44](Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:26][C:20]1[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=1[NH:18][C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([S:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:35]3[NH:39][CH:38]=[C:37]([C:40]([O:42][CH3:44])=[O:41])[CH:36]=3)[CH:7]=2)=[CH:10][CH:11]=1)=[O:17]
Reactant: CC1(C)OB(c2cc(C(=O)[O-])c[nH]2)OC1(C)C
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Sc3ccnc(Cl)c3)cc2)c1
Reactant: ClCCl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: COC(=O)c1c[nH]c(-c2cc(Sc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)ccn2)c1
Temperature: 95 °C
Reaction time: 16 h
Yield: 20 %

Procedure:
A mixture of 1-[4-(2-Chloro-pyridin-4-ylsulfanyl)-phenyl]-3-(2-fluoro-5-methyl-phenyl)-urea (410 mg, 1.06 mmol), methyl-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-3-carboxylate (532 mg, 2.12 mmol) and PdCl2(dppf).CH2Cl2 (10 mg, 0.012 mmol) was added to a thick-walled reaction vessel and purged with N2. A solution of 2M Na2CO3 (1.0 mL) was added, followed by DMSO (10 mL). The reaction vessel was sealed and the mixture stirred at 95° C. for 16 h. The reaction vessel was cooled to room temperature and the mixture was poured into 100 ml of water. The precipitates were filtered, washed with water and dried to give the crude, which was purified via silica gel chromatography eluting with 2-5% MeOH/CHCl3 to afford methyl 5-(4-{[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenyl]thio}pyridin-2-yl)-1H-pyrrole-3-carboxylate as off-white solid. Yield: 100 mg, 20% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC.Cl.[CH3:30][O:31][NH:32][CH3:33]>C(Cl)Cl>[CH3:30][O:31][N:32]([CH3:33])[C:13]([C@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:15]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
To a solution of (R)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (11.93 g, 55.42 mmol) and DCM (70 mL) cooled to −15° C. was added a solution of NMM (5.79 g, 57.3 mmol), ethyl carbonochloridate (12.03 g, 110.8 mmol) and DCM (50 mL) and the mixture was stirred for 15 min. Additional NMM (11.59 g, 114.5 mmol) was added followed by portion wise addition of O,N-dimethylhydroxylamine hydrochloride (10.81 g, 110.8 mmol). The reaction was stirred at RT for 18 h. The reaction was poured onto water and extracted with DCM. The organic layer was dried, filtered, and concentrated and the crude residue was purified by SiO2 chromatography eluting with EtOAc/hexane (1:1) to afford 9.74 g (68.03%) of (R)-tert-butyl 2-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (74).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][C:16]([NH:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[O:26]CC=C)=O)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30]1(OC2C=CC=CC=2)[CH:35]=CC=C[CH:31]=1>>[CH2:35]([C:21]1[C:20]2[O:26][C:16]([CH2:15][C:9]3[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:8]=3)=[N:18][C:19]=2[CH:24]=[C:23]([Cl:25])[CH:22]=1)[CH:30]=[CH2:31]
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: C=CCOc1ccc(Cl)cc1NC(=O)Cc1ccc(OC)c(OC2CCCC2)c1
Product: C=CCc1cc(Cl)cc2nc(Cc3ccc(OC)c(OC4CCCC4)c3)oc12
Yield: 52 %

Procedure:
A solution of N-(3-cyclopentyloxy-4-methoxyphenylacetyl)-2-allyloxy-5-chloroaniline (38.1 g, 0.092 mol) in 200 ml of diphenyl ether was heated under nitrogen at 180° for 8 hours. Protracted heating resulted in reduced yields. The reaction mixture was diluted with 500 ml of petroleum ether, applied to a column packed with 500 g of flash chromatography silica gel and eluted with petroleum ether followed by methylene chloride. Fractions of 800 ml were collected. The material from fractions 9-14 weighed 30 g (80% of theoretical). This material was recrystallized from hexane to give 19 g (52%) of the title compound, mp 43-44° C., which was greater than 98.3% pure by HPLC.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([OH:15])=O)[CH2:11][Si:10]([CH3:17])([CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[F:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C@H:44]([NH:46][CH2:47][C:48]1[CH:57]=[CH:56][C:51]([C:52]([O:54][CH3:55])=[O:53])=[CH:50][CH:49]=1)[CH3:45].CCN(C(C)C)C(C)C>C(Cl)Cl.[Cl-].[Na+].O>[F:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[C@H:44]([N:46]([CH2:47][C:48]1[CH:49]=[CH:50][C:51]([C:52]([O:54][CH3:55])=[O:53])=[CH:56][CH:57]=1)[C:13]([C@H:12]1[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][Si:10]([CH3:17])([CH3:16])[CH2:11]1)=[O:15])[CH3:45]
Reactant: CC(C)(C)OC(=O)N1C[Si](C)(C)C[C@H]1C(=O)O
Reactant: COC(=O)c1ccc(CN[C@H](C)c2ccccc2F)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(CN(C(=O)[C@@H]2C[Si](C)(C)CN2C(=O)OC(C)(C)C)[C@H](C)c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
To a solution of (R)-1-(tert-butoxycarbonyl)-3,3-dimethyl-1,3-azasilolidine-5-carboxylic acid (0.25 g, 0.96 mmol) in DCM (5 mL) were added 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (0.60 g, 2.2 mmol) and a solution of (R)-methyl 4-(((1-(2-fluorophenyl)ethyl)amino)methyl)benzoate (250 mg, 0.87 mmol) in DCM (2 mL) followed by DIEA (0.30 mL, 1.74 mmol). The resulting suspension was stirred at rt overnight and diluted with DCM and brine. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 20% EtOAc/DCM) to afford the title compound as a white solid (87 mg, 19%). MS(ESI+) m/z 529.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[H-].[Na+].[N+:9]([C:12]1[CH:13]=[C:14](F)[CH:15]=[CH:16][CH:17]=1)([O-:11])=[O:10]>CN(C=O)C>[Br:1][C:2]1[N:3]=[CH:4][N:5]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:9]([O-:11])=[O:10])[CH:17]=2)[CH:6]=1
Reactant: Brc1c[nH]cn1
Reactant: O=[N+]([O-])c1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(-n2cnc(Br)c2)c1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-imidazole (32 g; 217.7 mmol) in DMF (300 mL) was carefully added NaH (60% dispension; 10.8 g; 270 mmol) such that the temperature did not exceed 30° C. The slurry was stirred for 20 min after which 3-nitro-fluorobenzene 35 mL; 329 mmol) was added. The reaction mixture was stirred for another 30 min, heated to 150° C. and left with stirring overnight. The reaction mixture was poured onto 750 mL of ice-water under stirring. The precipitate was isolated by filtration, washed with H2O, air-dried and trituated with a diethyl ether-petrol ether (bp=80-100° C.) mixture (100 mL+100 mL) to give after filtration and drying of the solid 70 g crude product.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.O=C1CCC(=O)N1[O:17][C:18](=O)[C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:35])[N:27]([CH3:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:21][CH:20]=1>>[CH3:1][N:2]([CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)[C:18]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:35])[N:27]([CH3:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:21][CH:20]=1)=[O:17]
Reactant: CN(C(=O)Oc1ccc(C(=O)ON2C(=O)CCC2=O)cc1)c1ccccc1
Reactant: CNCc1cccnc1
Product: CN(Cc1cccnc1)C(=O)c1ccc(OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title product was prepared from methyl-pyridin-3-ylmethyl-amine and 4-(methyl-phenyl-carbamoyloxy)-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester. The crude product was subjected to preparative HPLC (method C) (48%, clear colourless oil). HPLC-MS m/z=376.2 (M+1), Rt: 2.37 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a stirred solution of the title compound of Example 1 (44.3 g, 220 mmol) and Et3N (61.4 mL, 440 mmol, 2 eq) in THF (250 mL) was added dropwise at rt (maintained by cooling from an ice bath), methanesulfonyl chloride (27.77 g, 242 mmol, 1.1 eq). The reaction mixture was stirred for 1 h at rt when TLC (solvent system C) indicated completion. The precipitated Et3NHCl was removed by filtration and the filter cake was washed with 50 mL of THF. The combined filtrate and washings were evaporated in vacuo to give the crude product as a yellow oil. This was dissolved in EtOAc/hexanes (1:2) and passed through a pad of silica gel eluting with ethyl acetate/hexanes (1:3). Evaporation of the filtrate afforded the product as a pale yellow oil (59.1 g, 96%) which crystallized on standing. Recrystallization from EtOAc/hexane (1:10) afforded an analytically pure sample of the title compound: mp 69°-70° C.; 1H-NMR (CDCl3) ∂ 4.72 (m,1H), 3.63 (m, 2H), 3.46 (m, 1H), 3.32 (m, 1H), 3.05 (s, 3H), 1.75-2.06 (complex m, 4H), 1.46 (s, 9H); CIMS (MH+ calcd for C11H21NO5S): 280. Found (MH+): 280; Anal. (calcd for C11H21NO5S): C, H, N.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([C:17]2[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.CCN(C(C)C)C(C)C.Cl[C:37](Cl)([O:39]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)(Cl)Cl>[N:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([C:17]2[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)=[C:37]=[O:39]
Reactant: COC(=O)c1cccc(-c2cccc(OCCCCCCN)c2)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(-c2cccc(OCCCCCCN=C=O)c2)n1
Reaction time: 0.5 h

Procedure:
Methyl 6-(3-(6-aminohexyloxy)phenyl)picolinate dihydrochloride (19) (40 mg, 0.10 mmol) and DIEA (34 μL, 26 mg, 0.20 mmol) were dissolved in CHCl3 (0.7 mL). Triphosgene (14 mg, 0.047 mmol) was dissolved in CHCl3 (0.3 mL). The solutions were combined and a second portion of DIEA (34 μL, 26 mg, 0.20 mmol) was immediately added. The mixture was left to stand 30 min at RT and evaporated. The residue was dissolved in ethyl acetate and the precipitated DIEA hydrochloride was filtered off. The solvent was evaporated and the crude isocyanate (20) was used directly for the next step.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[S:3]([CH2:6][CH2:7][NH:8][C:9]1[C:10]([C:15]([O:17]C)=O)=[N:11][CH:12]=[CH:13][CH:14]=1)(=[O:5])=[O:4].[H-].[Na+].Cl[C:23](=[O:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26]>C1COCC1.CO>[CH3:19][N:2]([CH3:1])[S:3]([CH2:6][CH2:7][N:8]1[C:9]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[C:15]([OH:17])=[C:24]([C:25]([O:27][CH3:28])=[O:26])[C:23]1=[O:29])(=[O:4])=[O:5]
Reactant: COC(=O)c1ncccc1NCCS(=O)(=O)N(C)C
Reactant: COC(=O)CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(O)c2ncccc2n(CCS(=O)(=O)N(C)C)c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Methyl 3-({2-[(dimethylamino)sulfonyl]ethyl}amino)pyridine-2-carboxylate (0.877 g, 3.05 mmol) was dissolved in dry THF (10 mL) and cooled to 0° C. NaH (338 mg, 60% suspension in oil, 8.45 mmol) was added and a precipitate formed. The slurry was treated with methyl 3-chloro-3-oxopropionate (0.410 mL, 3.82 mmol) and 3 drops of MeOH and allowed to warm and stir overnight. The reaction was concentrated somewhat in vacuo, then poured into water. The mixture was extracted once with CHCL3, then acidified and extracted repeatedly with CHCl3 until only a trace of UV active material is removed. The acidic organic extracts were dried over Na2SO4, filtered and evaporated to give the product as a pink foam.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:13]([F:16])([F:15])[F:14])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][C:18]=2[O:25]C)=[N:5]1)[CH:2]=[CH2:3].C1CCCCC=1.B(Br)(Br)Br.O>C(Cl)Cl>[CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:13]([F:16])([F:15])[F:14])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=2[OH:25])=[N:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1nc(-c2ccc(OC)cc2OC)c2cccc(C(F)(F)F)c21
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Solvent: O
Product: C=CCn1nc(-c2ccc(O)cc2O)c2cccc(C(F)(F)F)c21
Temperature: 25 °C

Procedure:
1-allyl-3-(2,4-dimethoxyphenyl)-7-(trifluoromethyl)-1H-indazole (0.065 g, 0.18 mmol) in CH2Cl2 containing 1.0 mL of cyclohexene at −78° C. was treated with boron tribromide (0.136 mL, 1.4 mmol) and slowly allowed to warm to ambient temperature. The reaction was quenched by dropwise edition of CH3OH to the cooled reaction. The solvent was removed in vacuo and the residue partitioned with EtOAc and 1 N HCl. The organic phase was washed with brine and dried (Na2SO4). Removal of the solvent in vacuo afforded the crude product. Pure product was obtained by crystallization or flash chromatography through water deactivated silica gel. A sample of 0.066 g was obtained as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][S:5][C:6]([CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[CH:7][CH:8]=1.[F:18][C:19]([F:28])([F:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C(OCC)(=O)C.CCCCCC>[Si:11]([O:10][CH2:9][C:6]1[S:5][S:4][C:3]([CH2:2][O:1][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([F:28])([F:27])[F:18])=[CH:8][CH:7]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OCC1=CC=C(CO)SS1
Reactant: Oc1ccccc1C(F)(F)F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCC1=CC=C(COc2ccccc2C(F)(F)F)SS1
Temperature: 0 °C
Yield: 37 %

Procedure:
To a stirred solution of 3-(hydroxymethyl)-6-[(tert-butyldimethylsilyloxy)methyl]-1,2-dithiin (U.S. Ser. No. 08/212,096) (200 mg, 0.69 mmol) in 5 mL dry THF was added a solution of 2-(trifluoromethyl)phenol (223 mg, 1.37 mmol) in 5 mL THF, followed by addition of triphenylphosphine (234 mg, 0.89 mmol) The resulting solution was cooled to 0° C., then 140 μL (156 mg, 0.89 mmol) of diethylazodicarboxylate was added, and the reaction mixture was kept at 0°-5° C. until TLC analysis showed the reaction to be complete. For isolation of the products, the reaction mixture poured directly onto a silica gel column using ethyl acetate-hexane, 1:3, to provide 110 mg (37%) of 3-[(tert-butyldimethylsilyloxy)methyl]-6-[(2-trifluoromethylphenyloxy)methyl]-1,2-dithiin; 1H NMR (CDCl3):δ7.56 (d, J=8.0, 1 H), 7.45 (t, J=8.0, 1 H), 7.01 (m, 2 H), 6.49 S (d, J=6.0 Hz, 1 H), 6.37 (d, J=6.0 Hz, 1 H), 4.71 (s, 2 H), 4.26 (s, 2 H), 0.88 (s, 9 H), 0.07 (s, 6 H); 13C NMR (CDCl3):δquaternary carbons missing, 136.19, 133.24, 127.23, 123.57, 120.81, 113.15, 69.58, 64.85, 25.79, 18.34, -5.38; MS (LSIMS) (M+) 434.1.
Reaction SMILES: O.C([C@@](C(O)=O)(O)[C@@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.[O:28]=[C:29]([N:43]1[CH2:48][CH2:47][N:46]2[C:49]([C:52]([F:55])([F:54])[F:53])=[N:50][N:51]=[C:45]2[CH2:44]1)[CH2:30][CH:31]([NH2:42])[CH2:32][C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41].C([C@@](C(O)=O)(O)[C@@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.O=C(N1CCN2C(C(F)(F)F)=NN=C2C1)C[C@H](N)CC1C=C(F)C(F)=CC=1F>CO.CC(O)C>[O:28]=[C:29]([N:43]1[CH2:48][CH2:47][N:46]2[C:49]([C:52]([F:55])([F:54])[F:53])=[N:50][N:51]=[C:45]2[CH2:44]1)[CH2:30][C@@H:31]([NH2:42])[CH2:32][C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41]
Reactant: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: O=C(O)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)O)C(=O)c1ccccc1
Solvent: CC(C)O
Solvent: CO
Solvent: O
Product: N[C@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 62.5 °C
Reaction time: 0.33 h

Procedure:
In a 50 mL three neck flask IPA (5 mL) and Dibenzoyl-L-tartaric acid monohydrate (1.84 g) were taken. It was heated to 60-65° C. 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (2.0 g, % purity-70%) dissolved in methanol (6 mL) was added into reaction mixture at 60-65° C. After 20 min. Dibenzoyl-L-tartaric acid salt of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (20 mg, % Chiral purity by HPLC of R-isomer 99.6%) was added as a seeding. It was stirred for 60 min. at 60-65° C. Solid salt was precipitated. It was gradually cooled to room temperature over a period of 2-3 h. The salt was filtered and washed with a mixture of IPA: MeOH (2:1). An enantiomerically enriched desired Dibenzoyl-L-tartaric acid salt of a mixture of (2R) and (2S)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine was obtained (Wt.-0.742 g, % Y-19.2%, Purity by HPLC-99.0%, % Chiral purity by HPLC of R-isomer 78.3%).