Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][CH2:9][OH:10])[N:3]=1.[N+:11]([C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([N+]([O-])=O)[C:15]=1[C:16]#[N:17])([O-:13])=[O:12]>>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:8][CH2:9][O:10][C:18]2[CH:19]=[CH:20][CH:21]=[C:14]([N+:11]([O-:13])=[O:12])[C:15]=2[C:16]#[N:17])[N:3]=1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: Cc1cc(C)n(CCO)n1
Product: Cc1cc(C)n(CCOc2cccc([N+](=O)[O-])c2C#N)n1
Yield: 90.7 %

Procedure:
Prepared as in Example 197c from 2-(3,5-dimethyl-1H-pyrazol-1-yl)ethanol and 2,6-dinitrobenzonitrile in 90.7% yield. MS 287 (MH+).
Reaction SMILES: [C:1]([NH:4][O:5][CH2:6][C:7]([NH2:9])=[S:8])(=[O:3])[CH3:2].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(=O)(=O)(O)O.C([O-])(=O)C.[Na+]>C(O)(=O)C.C(OC(=O)C)(=O)C>[C:1]([N:4]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:9][C:7](=[S:8])[CH2:6][O:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NOCC(N)=S
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)N1OCC(=S)NC1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.9 %

Procedure:
1.48 g (10 millimoles) of alpha-(acetylaminooxy)-thioacetamide are dissolved in a mixture of 10 ml of acetic acid and 1.3 ml of acetic anhydride, thereafter 1.3 ml (13 millimoles) of freshly distilled benzaldehyde and then 0.5 ml of concentrated sulfuric acid are added. The mixture is stirred for 3 hours at room temperature, then 2.8 g of crystalline sodium acetate are added, stirred for 10 minutes, thereafter the solvent is evaporated under vacuum. The residue is dissolved in 30 ml of ethyl acetate, the solution is extracted with 20 ml of water. The organic layer is dried over anhydrous sodium sulfate then evaporated to dryness. The residue is crystallized from ethanol at a temperature of +5° C. 1.25 g (52.9%) of crystalline title product are obtained. M.p.: 172°-174° C. Rf (A)=0.43.
Reaction SMILES: C1C(CC2C=CC(N=C=O)=CC=2)=CC=C(N=C=O)C=1.[N-]=[C:21]=[O:22].[N-]=[C:24]=[O:25].[O:26]=[C:27]1CC(C)(C)[CH2:30][C:29](C)=[CH:28]1>>[CH2:27]([C:28]([CH2:21][OH:22])([CH2:24][OH:25])[CH2:29][CH3:30])[OH:26]
Reactant: [N-]=C=O
Reactant: CC1=CC(=O)CC(C)(C)C1
Agent: O=C=Nc1ccc(Cc2ccc(N=C=O)cc2)cc1
Product: CCC(CO)(CO)CO
Temperature: 80 °C

Procedure:
8.25 val of 4,4'-diphenylmethane-diisocyanate, which contains its own dimers and trimers (Isonate 143 L), are introduced into a reactor together with 2.5 val of isophorone-diisocyanate and then heated to an internal temperature of 80° C. while stirring and leading in nitrogen to provide an inert atmosphere, the reaction, continuing until a clear solution is present. In the meantime, in a second reactor, a solution of 0.9 val of castor oil and 1.3 val of trimethylolpropane is produced within about 1 hour at 90° C. The trimethylolpropane/castor oil solution after cooling to 70° C. is then added over a one hour period to the isocyanate solution preheated to 80° C. The temperature which increases as a result of the exothermic reaction may reach a maximum of 100° C. However, the reaction temperature should be regulated by cooling so as not to exceed 90° C. The reaction mixture is caused to react for a period of 2 hours, up until the mixture has reached an isocyanate content of 19.3 to 19.7 percent by weight.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.C(O)(=O)CC(O)=[O:15]>CC(C)=O>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:15])[CH2:1]1
Reactant: O=C(O)CC(=O)O
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Solvent: CC(C)=O
Product: CC1(C)CC(=O)CC(C)(C)N1
Yield: 115 %

Procedure:
A solution of 6.3 g. of acetonine in 40 g. of acetone was added with 0.5 g. of malonic acid and the mixture was heated at 60°C. for 10 hours in a sealed equipment to effect the reaction. After completion of the reaction, the reaction mixture was purified in the same manner as in Example 1 to obtain triacetonamine in a yield of 115%.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:6]=2[N:7]=1.Cl.[OH-:23].[Na+]>>[NH2:1][C:2]1[NH:3][C:4](=[O:23])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@@:12]3([CH3:20])[OH:13])[C:6]=2[N:7]=1
Reactant: [OH-]
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(Cl)nc(N)nc21
Agent: Cl
Agent: [Na+]
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(=O)[nH]c(N)nc21

Procedure:
A mixture of product from Step B (90 mg, 0.3 mmol) in aqueous NaOH (2N, 9 mL) was heated at reflux temperature for 5 h, then neutralized at 0° C. with 2 N aqueous HCl and evaporated to dryness. Purification on a silica gel column with CH2Cl2/MeOH, 5/1 as eluent afforded the title compound as a white solid (70 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:32][C@H:33]([NH2:36])[CH2:34][CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(#N)C>[C@@H:33]([NH:36][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[CH:19]=1)=[O:22])([CH2:34][CH3:35])[CH3:32]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: CC[C@H](C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (50 mg, 0.11 mmol), (S)-butan-2-amine (9 mg, 0.12 mmol), and HATU (45 mg, 0.12 mmol). Then added acetonitrile (1 mL) followed by N,N-diisopropylethylamine (0.09 mL, 0.55 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water. The mixture was extracted with ethyl acetate (3×). The organic layers were combined, dried over Na2SO4, and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/heptanes (gradient: 0-50% EtOAc) to afford 40 mg (71%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-sec-butyl)-amide as a white solid. [M+Na]+=519.
Reaction SMILES: [SH2:1].[Cl:2][C:3]1[C:8]2[C:9](=[O:20])[N:10]([CH3:19])[CH2:11][C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17]#[N:18])[C:7]=2[CH:6]=[CH:5][C:4]=1[F:21]>N1C=CC=CC=1.C(N(CC)CC)C>[Cl:2][C:3]1[C:8]2[C:9](=[O:20])[N:10]([CH3:19])[CH2:11][C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17](=[S:1])[NH2:18])[C:7]=2[CH:6]=[CH:5][C:4]=1[F:21]
Reactant: CN1Cc2c(C#N)ncn2-c2ccc(F)c(Cl)c2C1=O
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CN1Cc2c(C(N)=S)ncn2-c2ccc(F)c(Cl)c2C1=O
Reaction time: 64 h
Yield: 73 %

Procedure:
A stream of hydrogen sulphide was conducted for 1/2 hr. through a solution of 3.0 g (0.0103 mol) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile in 10 ml of pyridine and 1.0 ml of triethylamine. The green solution was left to stand for 64 hrs., then degassed with a stream of nitrogen and subsequently completely freed from the solvents. The residue was partitioned between dichloromethane and water and the suspension obtained was suction filtered. There were obtained 2.45 g (73%) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-thiocarboxamide.
Reaction SMILES: [C:1]1([C:7]([CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[CH:8][CH2:9][CH2:10]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25].[OH-].[Na+]>C(OCC)C>[C:1]1([C:7]([CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)=[CH:8][CH2:9][CH2:10][N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCNCC
Reactant: ClCCC=C(c1ccccc1)C1Cc2ccccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CCN(CC)CCC=C(c1ccccc1)C1Cc2ccccc2C1
Temperature: 100 °C

Procedure:
To a solution of 29.5 g. of 1-phenyl-1-(2-indanyl)-4-chloro-1-butene in 125 cc. of 95 percent (v/v) ethanolbenzene (commercial 2B ethanol) was added 100 cc. of diethylamine in one portion. The reaction mixture was shaken and heated in a sealed bomb to about 100° C for 16 hours. The reaction mixture was cooled to about 25° C. and the solvent was removed under reduced pressure to afford the product as an oily residue. The oil was dissolved in 400 cc. of diethyl ether and shaken with 5N sodium hydroxide and washed with water. The ethereal solution was dried and the solvent was removed under reduced pressure, affording 1-phenyl-1-(2-indanyl)-4-diethylamino-1-butene.
Reaction SMILES: [C:1]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:7]2=[C:6]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]=1[C:23](OCC)=[O:24])(=O)[CH3:2].[F:28][C:29]1[CH:37]=[CH:36][C:32]([CH2:33][NH:34][NH2:35])=[CH:31][CH:30]=1>C(O)(=O)C.C1(C)C=CC=CC=1>[CH2:16]([O:15][C:6]1[C:5]2[C:23](=[O:24])[N:34]([CH2:33][C:32]3[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=3)[N:35]=[C:1]([CH3:2])[C:4]=2[N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:7]=12)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NNCc1ccc(F)cc1
Reactant: CCOC(=O)c1c(OCc2ccccc2)c2n(c1C(C)=O)CCN(C)C2=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1nn(Cc2ccc(F)cc2)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Temperature: 120 °C

Procedure:
A mixture of ethyl 6-acetyl-8-(benzyloxy)-2-methyl-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]-pyrazine-7-carboxylate (65 mg, 0.18 mmol) and 4-fluorobenzyl hydrazine (0.12 g, 0.88 mmol), and acetic acid (3 drops) in toluene (40 mL) was heated in a sealed tube at 120° C. overnight. The reaction mixture was concentrated under vacuum, and the residue was subjected to column chromatography on silica gel eluted with 1-5% methanol in ethyl acetate gradient to provide titled product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][S:8][C:9]2[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH2:16])[CH:10]=2)=[CH:5][CH:4]=1.[C:19]([N:27]=[C:28]=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCOC(C)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[C:14]([Br:15])=[CH:13][N:12]=[C:11]([NH:16][C:28]([NH:27][C:19](=[O:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[S:29])[CH:10]=2)=[CH:17][CH:18]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1ccc(CSc2cc(N)ncc2Br)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CSc2cc(NC(=S)NC(=O)c3ccccc3)ncc2Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
4-(4-methoxybenzylthio)-5-bromopyridin-2-amine (7.45 g, 22.9 mmol) was dissolved in THF (80 mL). Benzoyl isothiocyanate (3.4 ml, 25 mmol) was added, and the reaction was stirred overnight at ambient temperature. The solution was diluted in 9:1 hexanes:EtOAc and stirred for 5 minutes, then filtered and dried to provide the desired product (8.5 g, 76% yield) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([O:15][CH:16]2[CH2:33][CH:32]3[CH:18]([C:19](=[O:39])[N:20]([CH3:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH:27]4[C:29]([C:35]([OH:37])=O)([NH:30][C:31]3=[O:34])[CH2:28]4)[CH2:17]2)[CH:4]=1.CCN=C=NCCCN(C)C.[C:51]1([S:57]([NH2:60])(=[O:59])=[O:58])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([O:15][CH:16]2[CH2:33][CH:32]3[CH:18]([C:19](=[O:39])[N:20]([CH3:38])[CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH:27]4[C:29]([C:35]([NH:60][S:57]([C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)(=[O:59])=[O:58])=[O:37])([NH:30][C:31]3=[O:34])[CH2:28]4)[CH2:17]2)[CH:4]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: COc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)nc(-c2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)c5ccccc5)CC4C=CCCCCN(C)C(=O)C3C2)nc(-c2ccccc2)n1
Temperature: 25 °C

Procedure:
Compound 7e (60 mg, 0.112 mmol) was dissolved in DCM (5 ml). EDAC (26 mg, 0.135 mmol) was added and the reaction mixture was stirred at RT over night. benzensulfonamide (19 mg, 0.123 mmol) and DBU (35 μl, 0.235 mmol) were added and the reaction mixture was stirred at RT for 2 h. Citric acid (5%) was added, the organic layer was separated, washed with brine, dried, filtered and evaporated. The residue was purified by preparative HPLC which gave the pure title compound. (36 mg, 48%), MS (M+H)+674.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:29]=[CH:28][C:22]4[CH:23]=[CH:24][C:25](=[O:27])[O:26][C:21]=4[CH:20]=3)[O:9][C:8]=2[CH:30]=1.CI.[CH:33](N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([CH2:13][N:14]([CH3:33])[CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:29]=[CH:28][C:22]4[CH:23]=[CH:24][C:25](=[O:27])[O:26][C:21]=4[CH:20]=3)[O:9][C:8]=2[CH:30]=1
Reactant: COc1ccc2c(c1)OC(CNCCCOc1ccc3ccc(=O)oc3c1)CO2
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc2c(c1)OC(CN(C)CCCOc1ccc3ccc(=O)oc3c1)CO2
Temperature: 80 °C
Yield: 9.7 %

Procedure:
7-[3-[[(2,3-Dihydro-7-methoxy-1,4-benzodioxin-2-yl)methyl]amino]propoxy]-2H-1-benzopyran-2-one hydrochloride (2.2 g, 5.0 mmole) was dissolved in 100 ml of DMF and 700 mg (5.0 mmole) of methyl iodide added, followed by 2.6 g (20 mmole) of diisopropylethylamine. The mixture was heated at 80° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed in vacuum and replaced with 300 ml of dichloromethane. The mixture was washed with 300 ml portions of saturated aqueous sodium bicarbonate, saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography on 100 g of silica gel using chloroform as eluant and crystallized from isopropanol with addition of 2.5 ml of 4N isopropanolic HCl to give 0.20 g of the title compound as a monohydrochloride, m.p. 176°-178° C.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([O:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([NH:7][C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[C:15]([O:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:16])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=NC1CCCCC1
Reactant: O=C(OCCCc1cccnc1)[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCCCc1cccnc1)[C@@H]1CCCN1C(=O)NC1CCCCC1
Reaction time: 1 h
Yield: 37.1 %

Procedure:
A mixture of cyclohexylisocyanate (100 mg; 0.9 mmol), 3-(3-pyridyl)-1-propyl (2S)-pyrrolidine-2-carboxylate (200 mg; 0.9 mmol) and triethylamine (90 mg; 0.9 mmol) in 20 mL of methylene chloride was stirred for 1 hour and then partitioned between water and a 1:1 mixture of ethyl acetate and hexane. The organic phase was dried, concentrated and purified by column chromatography (50w ethyl acetate/hexane) to obtain 120 mg (36%) of the compound of Example 4 (Compound 4, Table I). 1H NMR (CDCl3, 300 MHz):δ 1.10-1.27 (m, 6H); 1.69-1.75 (m, 4H); 1.94-2.03 (m, 4H); 2.67-2.73 (t, 2H); 3.31-3.44 (m, 3H); 4.12-4.16 (m, 2H); 4.39-4.42 (m, 1H); 7.25-7.34 (m, 1H); 7.25-7.55 (dd, 1H); 8.45 (s, 2H). Analysis calculated for C20H29N3O3—0.6 H2O: C, 64.88; H, 8.22; N, 11.35. Found: C, 64.60; H, 8.18; N, 11.21.
Reaction SMILES: [CH:1]1([NH:6][C:7]([NH:9][C@:10]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([OH:36])[CH:30]=2)([C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([F:28])[CH:19]=2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[CH3:43][C:44]1([CH3:47])[CH2:46][O:45]1>CN(C=O)C>[CH:1]1([NH:6][C:7]([NH:9][C@:10]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([O:36][CH2:43][C:44]([OH:45])([CH3:47])[CH3:46])[CH:30]=2)([C:18]2[CH:23]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:21]=[C:20]([F:28])[CH:19]=2)[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(NC1CCCC1)N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)c(O)c1
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(O)COc1cc([C@@](Cc2ccccc2)(NC(=O)NC2CCCC2)c2cc(F)cc(C(F)(F)F)c2)ccc1F
Temperature: 60 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
To a solution of (R)-1-cyclopentyl-3-(1-(4-fluoro-3-hydroxyphenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)urea, prepared as described in Procedure 59, (20 mg, 0.039 mmol) in DMF (0.1 mL) was added K2CO3 (12 mg, 0.086 mmol), followed by 2,2-dimethyloxirane (28 mg, 0.39 mmol). The resulting mixture was stirred at 60° C. for 16 h. The reaction mixture was filtered and the solid was washed with EtOAc. The filtrate was washed with H2O, sat. NaCl and dried over Na2SO4 and filtered. The organic solvent was evaporated under reduced pressure and the residue was purified by Prep HPLC (phenomenex AXIA Luna 75×30 mm, 5 column eluting with 10-90% ACN/H2O over 10 minutes containing 0.1% TFA; 40 mL/min, monitoring at 220 nm) to afford (R)-1-cyclopentyl-3-(1-(4-fluoro-3-(2-hydroxy-2-methylpropoxy)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)urea (Example 304) as white lyophillate (11 mg, 56% yield). LCMS: RT=4.066 min [M+H] 577.3 (4 min Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm (retention time, column type, size, solvent, flow rate, gradient) NMR: 400 MHz 1H (CD3OD) ppm 1.27 (d, J=2.20 Hz, 6H), 1.32-1.49 (m, 2H), 1.54-1.76 (m, 4H), 1.81-1.98 (m, 2H), 3.53 (d, J=9.23 Hz, 1H), 3.69 (d, J=9.23 Hz, 1H), 3.78 (d, J=12.74 Hz, 1H), 3.91 (t, J=6.15 Hz, 1H), 4.02 (d, J=12.74 Hz, 1H), 6.63-6.70 (m, 1H), 6.72-6.79 (m, 3H), 7.01 (dd, J=10.99, 8.79 Hz, 1H), 7.09-7.20 (m, 3H), 7.27-7.42 (m, 3H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[CH:7][C:8]2[C:12]([OH:13])=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:10][C:9]=2[N:20]=1)([CH3:4])[CH3:3].[C:21]([O-])(=[O:23])[CH3:22].[Na+]>C(OC(=O)C)(=O)C>[C:21]([O:13][C:12]1[C:8]2[CH:7]=[CH:6][C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])=[N:20][C:9]=2[S:10][C:11]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:23])[CH3:22]
Reactant: CC(C)(C)c1ccc2c(O)c(-c3ccccc3)sc2n1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1c(-c2ccccc2)sc2nc(C(C)(C)C)ccc12
Yield: 91.6 %

Procedure:
A solution of 1.42 g (5 mmol) of 6-(1,1-dimethylethyl)-3-hydroxy-2-phenyl-7-azabenzo[b]-thiophene and 1.42 g sodium acetate in 20 mL of acetic anhydride was heated at reflux for 1 hour. The solution was concentrated and the residue was partitioned between ether and water. The ether layer was washed with sodium bicarbonate solution and brine, dried and concentrated. The residue was crystallized from ether-hexane to afford 1.49 g (91%) of fine white needles, m.p. 128°-9° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.C1C=CC(P([N:34]=[N+:35]=[N-:36])(C2C=CC=CC=2)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:34]=[N+:35]=[N-:36])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(O)/C=C/c1ccc(F)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)/C=C/c1ccc(F)cc1
Reaction time: 18 h
Yield: 90.7 %

Procedure:
To a solution of (E)-3-(4-fluorophenyl)acrylic acid (25 g, 150 mmol) in benzene (120 mL) was added triethylamine (30.5 g, 301 mmol) followed by DPPA (41.4 g, 150 mmol) at room temperature. The reaction mass was stirred at the same temperature for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to get crude compound. The crude compound was purified by conventional column chromatography (Silica gel, 60-120 mesh) using 10% ethyl acetate in pet ether as mobile phase to get the desired compound as a white solid (26 g, 90%). 1H NMR (400 MHz, CDCl3): δ ppm 7.73-7.69 (d, J=16 Hz, 1H), 7.55-7.51 (m, 2H), 7.11-7.07 (m, 2H), 6.36-6.32 (d, J=16 Hz, 1H).
Reaction SMILES: [F:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])=O.[C:12]([S@:16]([NH2:18])=[O:17])([CH3:15])([CH3:14])[CH3:13]>>[F:1][CH2:2]/[C:3](=[N:18]/[S@@:16]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:17])/[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=C(CF)c1ccccc1F
Product: CC(C)(C)[S@@](=O)/N=C(/CF)c1ccccc1F
Yield: 62 %

Procedure:
In a manner analogous to that described for the preparation of sulfinyl imine E2.1 the reaction of 2-fluoro-1-(2-fluoro-phenyl)-ethanone with (R)-tert-butylsulfinamide yielded the (R)-2-methyl-propane-2-sulfinic acid [2-fluoro-1-(2-fluoro-phenyl)-eth-(E)-ylidene]-amide (62% yield) as an orange oil. MS (ISP): m/z=260.2 [M+H]+.
Reaction SMILES: [CH2:1]([C@H:4]([C@H:8]([OH:10])[CH3:9])[C:5]([OH:7])=O)[C:2]#[CH:3].[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][NH2:18].C(Cl)CCl>ClCCl>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][NH:18][C:5](=[O:7])[C@H:4]([CH2:1][C:2]#[CH:3])[C@H:8]([OH:10])[CH3:9]
Reactant: NOC1CCCCO1
Reactant: C#CC[C@@H](C(=O)O)[C@@H](C)O
Solvent: ClCCl
Solvent: ClCCCl
Product: C#CC[C@@H](C(=O)NOC1CCCCO1)[C@@H](C)O
Temperature: 23 °C
Reaction time: 4 h
Yield: 37.3 %

Procedure:
To a solution of (2R,3R)-2-(2-propyne-1-yl)-3-hydroxybutanoic acid (3.0 g, 21.13 mmol) in dichloromethane (50 mL) is added 2-tetrahydropyranyloxyamine (3.0 g, 25.35 mmol) and EDC (4.5 g, 23.24 mmol). The resulting solution is stirred at 23° C. for 4 h, then diluted with dichloromethane (100 mL) and washed with 1 M hydrochloric acid. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2R,3R)-2-(2-propyne-1-yl)-3-hydroxybutanoic acid 2-tetrahydropyranyloxyamide as a foam (1.9 g, 37% yield). 1H NMR (400 MHz, CDCl3) δ 8.82 (bs, 1H), 4.96 (m, 1H), 3.94 (m, 2H), 3.62 (m, 1H), 2.64 (m, 1H), 2.56 (m, 1H), 2.23 (m, 1H), 2.04 (m, 1H), 1.82 (m, 2H), 1.61 (m, 4H), 1.23 (d, 3H) ppm. ESI-MS m/z 240.4 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[SH:10])[C:5]#[N:6].[CH2:11]([OH:13])[CH3:12]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[NH:6])[O:13][CH2:11][CH3:12])[CH:7]=[CH:8][C:9]=1[SH:10]
Reactant: CCO
Reactant: N#Cc1ccc(S)c(Br)c1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=N)c1ccc(S)c(Br)c1
Reaction time: 0.5 h

Procedure:
3-Bromo-4-mercaptobenzonitrile (10 g) was dissolved in toluene (50 ml) and chloroform (80 ml), followed by adding thereto ethanol (3.0 ml), and the resulting mixture was cooled to −10° C. Hydrochloric acid gas was bubbled into the mixture through a bubbler for 10 minutes and the resulting mixture was stirred at the same temperature for 30 minutes. The reaction mixture was allowed to stand in a refrigerator for 60 hours and then the completion of the reaction was confirmed by HPLC(ODS-A212). Dry nitrogen was bubbled into the reaction solution through a bubbler for 20 minutes and the hydrochloric acid gas was distilled off. The precipitate was collected by filtration, washed with toluene/chloroform and then dried to obtain ethyl 3-bromo-4-mercaptobenzene-carboximidate (13.6 g) as a light-yellow solid.