Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([O:13]CC)=O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]#[N:25])=[CH:19][CH:18]=1.Cl>C(O)C.O>[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([OH:13])=[C:23]([C:24]#[N:25])[C:20]1[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: CCOC(=O)c1ccccn1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CC(=C(O)c1ccccn1)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a solution of 40.8 g (0.60 mol) of sodium ethoxide in 200 ml absolute ethanol was added a mixture of 60.5 g (0.40 mol) of ethyl picolinate and 54.1 g (0.40 mol) of 4-fluorophenylacetonitrile. The solution was refluxed 10 minutes, then cooled to ambient temperature. The solids were dissolved by the addition of 330 ml of water. Then, 50 ml 12N hydrochloric acid was added dropwise. The solid was collected by filtration, washed with water, and dried overnight (30° C. in vacuo) to give 1-(2-pyridinyl)-2-cyano-2-(4-fluorophenyl)-ethen-1-ol. This compound was dissolved in 250 ml 48% hydrobormic acid and refluxed for 17 hours. Upon cooling, aqueous ammonium hydroxide was added until the reaction mixture was basic. The aqueous solution was extracted three times with chloroform. The combined organic extracts were washed with water, dried (MgSO4), and concentrated. The resulting solid was chromatographed on silica gel with ether-petroleum ether (1:3) as eluant, and recrystallized from 2-propanol-hexane to give the title Formula (X) compound, m.p. 56.58° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([NH:8][C:9](=[S:15])[NH:10][CH2:11][C:12](N)=[O:13])[CH:7]=1.[CH2:17](I)[CH3:18]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([N:8]2[C:12](=[O:13])[CH2:11][N:10]=[C:9]2[S:15][CH2:17][CH3:18])[CH:7]=1
Reactant: CCI
Reactant: Cc1ccc(Cl)cc1NC(=S)NCC(N)=O
Solvent: CCO
Product: CCSC1=NCC(=O)N1c1cc(Cl)ccc1C
Yield: 63.2 %

Procedure:
A mixture of 2-[3-(5-chloro-2-methylphenyl)-thioureido]-acetamide (25.8 g) and ethyl iodide (32.0 g) was heated at reflux in ethanol (500 mL) for 5 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (500 mL) and water (300 mL). The organic phase was washed with water, dried over anhydrous MgSO4, then evaporated to dryness. The residue was triturated with diethyl ether and the solid was collected by filtration and dried to give the title compound (17.0 g) as a yellow solid, m.p. 137°-139° C. Anal. Calcd. for. C12H13Cl N2O S: C, 53.63; H, 4.88; N, 10.42. Found: C, 53.58; H, 4.74; N, 10.32. Mass spectrum (EI, M.+) m/z 268/270. 1H-NMR (DMSO-d6 ; 400 MHz) δ7.45-7.49 (m, 1H), 7.40-7.43 (m, 2H), 4.35 (dd, 2H), 3.07 (m, 2H), 2.1 (s, 3H), and 1.28 ppm (t, 3H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6]([C:8]1[C@H:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:10]([C:16]([OH:18])=[O:17])=[C:11]([CH3:15])[NH:12][C:13]=1[CH3:14])=[O:7])#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH3:34][O:35][CH2:36]Cl>CN(C)C=O.C(OCC)(=O)C>[C:1]([CH2:3][CH2:4][O:5][C:6]([C:8]1[C@H:9]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:10]([C:16]([O:18][CH2:34][O:35][CH3:36])=[O:17])=[C:11]([CH3:15])[NH:12][C:13]=1[CH3:14])=[O:7])#[N:2]
Reactant: CC1=C(C(=O)O)[C@@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OCCC#N)=C(C)N1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCC#N)[C@@H]1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 10 mg of (4R)-5-(2-cyanoethoxycarbonyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid in 0.5 ml of N,N-dimethylformamide were added 4.3 mg of potassium carbonate, and then 8 μl of chloromethyl methyl ether. The mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with 5 ml of ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and with water, and dried over anhydrous Glauber's salt (sodium sulfate), followed by distilling off the solvent under reduced pressure the residue was purified using preparative TLC to obtain 3.6 mg of the objective compound.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[S:13])[C:4]2=[CH:14][S:15][CH:16]=[C:3]12.O1CCOC[CH2:18]1.[OH-].[K+].S([O-])(OC)(=O)=O>CO>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]([S:13][CH3:18])[C:4]2=[CH:14][S:15][CH:16]=[C:3]12
Reactant: CN1c2ccccc2NC(=S)c2cscc21
Reactant: C1COCCO1
Agent: COS(=O)(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSC1=Nc2ccccc2N(C)c2cscc21
Reaction time: 3 h

Procedure:
To a stirred suspension of 0.7 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b] [1,5] benzodiazepin-10-thione in 10 ml. of dioxane is added dropwise and simultaneously at 30°-40°C., a solution of 0.95 g. of potassium hydroxide in 10 ml. of methanol and 0.8 ml. of methyl sulfate. After addition is complete, the mixture is stirred for 3 hours, diluted with methanol and filtered. The filtrate is concentrated to about 20 ml., diluted with water and extracted with chloroform. The chloroform solution is concentrated to give a solid, which is recrystallized from methanol-water to give orgnae crystals, m.p. 113°-115°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:16](=[O:18])[CH3:17])[CH:5]=[CH:6][C:7]=1[C:8]1[CH2:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][CH:9]=1.[K+].[C:20]([C:22]1[N:23]=[C:24]([C:35]([O-])=[O:36])[N:25]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:26]=1)#[N:21]>CCOC(C)=O.CCCCCC>[C:16]([C:4]1[CH:5]=[CH:6][C:7]([C:8]2[CH2:13][CH2:12][C:11]([CH3:14])([CH3:15])[CH2:10][CH:9]=2)=[C:2]([NH:1][C:35]([C:24]2[N:25]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:26]=[C:22]([C:20]#[N:21])[N:23]=2)=[O:36])[CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)c1ccc(C2=CCC(C)(C)CC2)c(N)c1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)c1ccc(C2=CCC(C)(C)CC2)c(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c1
Yield: 84 %

Procedure:
The title compound was prepared by the procedure of Example 11, step (f) using 1-[3-amino-4-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-ethanone (as prepared in the previous step, 243 mg, 1.00 mmol) and potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 11, step (d), 321 mg, 1.05 mmol). Silica gel chromatography (5-15% EtOAc/hexane) afforded the title compound (415 mg, 84%) as a white solid. Mass spectrum (ESI, m/z): Calcd. for C27H36N4O3Si, 493.3 (M+H), found 493.0.
Reaction SMILES: I[C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:7])=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:35]=[CH:34][C:23]([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:25])=[CH:22][CH:21]=1)#[CH:19]>C(N(CC)CC)C.O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[CH:16]=[CH:17][C:2]([C:19]#[C:18][C:20]2[CH:35]=[CH:34][C:23]([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:25])=[CH:22][CH:21]=2)=[CH:3][CH:4]=1)=[O:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(C(=O)OCCCCCCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCOC(=O)c1ccc(C#Cc2ccc(C(=O)OCCCCCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
Under a nitrogen atmosphere, heptyl 4-iodobenzoate (2a) (3.64 g, 10.5 mmol) was dissolved in anhydrous triethylamine (8.6 mL), and anhydrous tetrahydrofuran (4.0 mL), triphenylphosphine (39.3 mg, 0.150 mmol), copper (I) iodide (43.8 mg, 0.230 mmol), and Pd(PPh3)2Cl2 (27.9 mg, 0.0397 mmol) were added. Thereafter, a solution of heptyl 4-ethynylbenzoate (4a) (2.64 g, 10.8 mmol) in anhydrous tetrahydrofuran (2.0 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 3 hr. The reaction solution was filtered through celite and, after removal under reduced pressure, diluted with ethyl acetate, washed with water and saturated brine, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (ethyl acetate:hexane=1:10). Subsequent recrystallization from methanol/ethanol (5:1, v/v) gave bis[4-(heptyloxycarbonyl)phenyl]acetylene (5a) (4.64 g, yield 95%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]([CH3:20])([CH3:19])[CH2:7][CH:8]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.Cl[C:24]1[N:29]=[C:28]([NH:30][C:31]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:32]=2[C:33]([NH:35][CH3:36])=[O:34])[C:27]([Cl:42])=[CH:26][N:25]=1>>[Cl:42][C:27]1[C:28]([NH:30][C:31]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:32]=2[C:33]([NH:35][CH3:36])=[O:34])=[N:29][C:24]([NH:1][C:2]2[CH:22]=[CH:21][C:5]3[C:6]([CH3:19])([CH3:20])[CH2:7][CH:8]([NH:12][C:13](=[O:18])[C:14]([F:17])([F:15])[F:16])[C:9](=[O:11])[NH:10][C:4]=3[CH:3]=2)=[N:25][CH:26]=1
Reactant: CC1(C)CC(NC(=O)C(F)(F)F)C(=O)Nc2cc(N)ccc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)C(NC(=O)C(F)(F)F)CC3(C)C)ncc1Cl

Procedure:
2-{5-Chloro-2-[5,5-dimethyl-2-oxo-3-(2,2,2-trifluoro-acetylamino)-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-methyl-benzamide was prepared from N-(8-Amino-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-2,2,2-trifluoro-acetamide and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 12211d. The title compound was isolated as a white solid (73 mg, 25%). HPLC purity 99%, LCMS 594.24 (M+H), HNMR (DMSO) 9.73 (s, 1H), 9.60 (d, J=7.8 Hz, 1H), 9.43 (s, 1H), 9.37 (s, 1H), 8.50 (d, J=4.5 Hz, 1H), 8.19 (s, 1H), 7.48-7.44 (m, 2H), 7.35-7.30 (m, 2H), 7.18 (s, 1H), 7.10 (d, J=8.9 Hz, 1H), 4.27-4.20 (m, 1H), 2.73 (d, J=4.2 Hz, 3H), 2.18-2.12 (m, 2H), 1.35 (s, 3H), 1.26 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([CH:25]=O)[CH:24]=1)[O:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:18][CH:19]([CH3:21])[CH3:20])C(=O)OC(C)(C)C)=O.[NH2:27][CH2:28][CH2:29][CH2:30][NH:31][CH2:32][CH2:33][CH2:34][NH:35]C(=O)OC(C)(C)C.[BH4-].[Na+].[OH-].[Na+]>CCOC(C)=O.CO>[CH2:18]([NH:10][CH2:9][CH2:8][CH2:7][O:6][C:5]1[CH:4]=[C:3]([CH2:1][NH:35][CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29][CH2:28][NH2:27])[CH:24]=[C:23]([CH2:25][NH:27][CH2:28][CH2:29][CH2:30][NH:31][CH2:32][CH2:33][CH2:34][NH2:35])[CH:22]=1)[CH:19]([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCCNCCCN
Reactant: CC(C)CN(CCCOc1cc(C=O)cc(C=O)c1)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)CNCCCOc1cc(CNCCCNCCCN)cc(CNCCCNCCCN)c1
Reaction time: 24 h

Procedure:
tert-Butyl (3-(3,5-diformylphenoxy)propyl)-(isobutyl)carbamate (0.15 g, 0.42 mmol) and MeOH (10 mL) were added to a round-bottom flask. To the solution was added tert-butyl (3-((3-aminopropyl)amino)propyl)carbamate (0.20 g, 0.84 mmol) and the reaction mixture was stirred for 24 h. Sodium borohydride (0.06 g, 1.69 mmol) was added and the reaction mixture stirred for 1 h. The reaction mixture was concentrated under reduced pressure to afford a white solid. Aqueous NaOH (10%, 50 mL) and EtOAc (50 mL) were added, the layers separated and the aqueous layer was extracted with EtOAc (50 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product as clear oil which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[C:11]([CH2:13][C:14]1([N:25]2[CH:29]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:27]=[N:26]2)[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1)#[N:12].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[C:11]([CH2:13][C:14]1([N:25]2[CH:29]=[C:28]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[NH:8][CH:9]=[CH:10][C:3]=34)[CH:27]=[N:26]2)[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1)#[N:12]
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)C1
Reactant: Brc1ccnc2[nH]ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ccnc4[nH]ccc34)cn2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine (1.1 g, 5.7 mmol), tert-butyl 3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (2.00 g, 5.15 mmol) (Example 40, Step 1), tetrakis(triphenylphosphine)palladium(0) (0.30 g, 0.26 mmol) and sodium carbonate (1.64 g, 15.4 mmol) in 1,4-dioxane (100 mL) and water (50 mL) under N2 (g) was stirred at 100° C. overnight. The reaction mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure until 5 mL of solvent was left. The resulting precipitate (0.90 g) was collected by filtration and washed with ether. The filtrate was further concentrated under reduced pressure to a volume of about 3 mL. The precipitate formed was filtered, and washed with ether to afford additional product (0.50 g). The filtrate was concentrated under reduced pressure again. The residue was purified by flash chromatography on a silica gel column with methanol in dichloromethane (0-5%) to afford additional desired product (0.55 g). Total amount of product was 1.95 g (yield: 92.3%). LCMS (M+H)+: m/z=379.1.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:4]([F:7])([F:6])[F:5].[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C1C=CN=CC=1.CCN(CC)CC>[C:24]1([S:30]([O:14][C:11]2[CH:10]=[CH:9][C:8]([C:3]([C:15]3[CH:20]=[CH:19][C:18]([O:21][S:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)(=[O:32])=[O:31])=[CH:17][CH:16]=3)([C:4]([F:6])([F:5])[F:7])[C:2]([F:22])([F:23])[F:1])=[CH:13][CH:12]=2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Oc1ccc(C(c2ccc(O)cc2)(C(F)(F)F)C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1ccc(C(c2ccc(OS(=O)(=O)c3ccccc3)cc2)(C(F)(F)F)C(F)(F)F)cc1)c1ccccc1
Yield: 89.2 %

Procedure:
An oven-dried 100 ml 3-necked flask is equipped with a magnetic stirring bar, a reflux condenser carrying a CaCl2 -Drierite drying tube, and a heating mantle, and is charged with 4,4'-(hexafluoroisopropylidene)diphenol (Aldrich) (5.45 grams, 16.2 mmol), 4-dimethylaminopyridine (0.4 gram, 3.3 mmol), and anhydrous Et3N (40 ml). The solution is stirred and treated slowly with benzenesulfonyl chloride (4.7 ml, 36.8 mmol) via syringe. The resulting mixture is heated at reflux for 9 hours. Workup consists of partitioning the reaction mixture between CH2Cl2 (100 ml) and a mixture of H2O (150 ml) and concentrated HCl (40 ml), washing the organic phase successively with 100 ml portions of H2O, 5 percent NaOH, H2O, and saturated brine, drying (MgSO4), filtration and concentration. This gives 10.6 grams of a reddish oily residue. TLC analysis on silica gel shows one main component (Rf =0.54; CH2Cl2). Chromatography on a column packed with flash-grade silica gel (3"×1" i.d.), eluting with CH2Cl2, gives 9.32 grams of a faintly yellowish oil. which solidifies on standing. Recrystallization from EtOAc-MeOH-H2O (20 ml:100 ml:10 ml)affords 8.91 grams crystalline solid. m.p. 133° C. to 134° C.
Reaction SMILES: [CH3:1][C:2]([CH3:46])([CH2:42][CH2:43][CH2:44][CH3:45])[C:3]([NH:5][CH2:6][C@@H:7]1[O:11][C:10]([CH3:13])([CH3:12])[N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:8]1[CH2:21][C@H:22]([CH:26]([OH:41])[C:27]1[CH:35]=[C:34]2[C:30]([CH:31]=[N:32][N:33]2[CH2:36][CH2:37][CH2:38][O:39][CH3:40])=[CH:29][CH:28]=1)[CH:23]([CH3:25])[CH3:24])=[O:4].N1C=CC=CC=1.[NH4+].[Cl-].[CH3:55][C:56](OC(C)=O)=[O:57]>>[C:56]([O:41][CH:26]([C:27]1[CH:35]=[C:34]2[C:30]([CH:31]=[N:32][N:33]2[CH2:36][CH2:37][CH2:38][O:39][CH3:40])=[CH:29][CH:28]=1)[C@H:22]([CH:23]([CH3:25])[CH3:24])[CH2:21][C@H:8]1[C@H:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([CH3:1])([CH3:46])[CH2:42][CH2:43][CH2:44][CH3:45])[O:11][C:10]([CH3:12])([CH3:13])[N:9]1[C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])(=[O:57])[CH3:55]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCC(C)(C)C(=O)NC[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](C(C)C)C(O)c1ccc2cnn(CCCOC)c2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Product: CCCCC(C)(C)C(=O)NC[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](C(C)C)C(OC(C)=O)c1ccc2cnn(CCCOC)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a solution of (4S,5S)-tert-butyl 5-((2,2-dimethylhexanamido)methyl)-4-((S)-2-(hydroxy(1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-3-methylbutyl)-2,2-dimethyloxazolidine-3-carboxylate (32 mg, 0.05 mmol) in Ac2O (6 mL) was added pyridine (0.5 mL) dropwise. The reaction mixture was stirred at rt overnight. Satd aq NH4Cl (10 mL) was added and the mixture was extracted with EtOAc (3×15 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel to give (4S,5S)-tert-butyl 4-((S)-2-(acetoxy(1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-3-methylbutyl)-5-((2,2-dimethylhexanamido)methyl)-2,2-dimethyloxazolidine-3-carboxylate (25 mg, 73%). MS: 687 (M+1)
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:34]=[CH:33][C:16]([CH:17]([C:19]3[N:23]([CH3:24])[N:22]=[C:21]([C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:32])[N:20]=3)O)=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(N(S(F)(F)[F:41])CC)C.O>C1C=CC=CC=1>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:34]=[CH:33][C:16]([CH:17]([C:19]3[N:23]([CH3:24])[N:22]=[C:21]([C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[Cl:32])[N:20]=3)[F:41])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1C(O)c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: c1ccccc1
Product: Cn1nc(-c2c(F)cccc2Cl)nc1C(F)c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
To a solution of 0.9 g of 5-{4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-α-hydroxybenzyl}-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole in 10 ml of benzene at room temperature, were added 0.85 g of diethylaminosulfur trifluoride (DAST). After stirring at room temperature for 1 hour, the reaction mixture was poured into iced water and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium hydrogen carbonate and then with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to afford 0.8 g of 5-{4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-α-fluorobenzyl}-3-(2-chloro-6-fluorophenyl)-1 methyl-1H-1,2,4-triazole.
Reaction SMILES: C1C=C(O[C:8](OC2N=CC=CC=2)=[S:9])N=CC=1.[C:17]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:26]=[C:8]=[S:9])=[CH:27][CH:28]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(CN=C=S)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
Di-2-pyridyl thionocarbonate (45 mg) was dissolved in methylenechloride (2 ml) and to the solution were added 4-t-butylbenzylamine (29 mg) and triethylamine (20 μl), followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and the obtained residue was chromatographed on a silica gel column eluting with ethyl acetate/hexane (1/10) to yield 4-t-butylbenzylisothiocyanate (26 mg, 71%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].Cl[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23]>CN(C=O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([O:3][C:4]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=2[CH:6]=[O:7])=[C:16]([N+:22]([O-:24])=[O:23])[CH:17]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: COc1ccc(C=O)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)c(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 16 h
Yield: 53.9 %

Procedure:
Sodium hydride (0.66 q) Was added in portions to a stirred solution of 3.90 g of 2-hydroxy-4-methoxybenzaldehyde in N,N'-dimethylformamide (70 mL) under nitrogen. To the resulting milky, green mixture was added 1,4-dichloro-2-nitrobenzene (4.47 g). The reaction was placed in an oil bath and stirred at 90° C. for 16 hours. The reaction was then evaporated and the residue partitioned between chloroform (75 mL) and 1 N NaOH (50 mL). The layers were separated and the aqueous layer was extracted with chloroform (75 mL). The chloroform extracts were combined and washed with water (75 mL) and brine (75 mL), dried over magnesium sulfate, and evaporated in vacuo. The orange solid was recrystallized from ethyl acetate/iso-propyl ether to yield 3.86 g (53.9%) of product as light yellow, shiny crystals. Melting Point: 130°-131° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@:10]1([N:38]2[CH:46]=[C:44]([CH3:45])[C:42](=[O:43])[NH:41][C:39]2=[O:40])[O:37][C@H:17]([CH2:18][O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:12]([O:13][CH2:14][CH2:15]O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:67]>CN(C=O)C>[CH2:1]([O:8][CH2:9][C@@:10]1([N:38]2[CH:46]=[C:44]([CH3:45])[C:42](=[O:43])[NH:41][C:39]2=[O:40])[O:37][C@H:17]([CH2:18][O:19][Si:20]([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:12]([O:13][CH2:14][CH2:15][Cl:67])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](OCCO)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](OCCCl)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O

Procedure:
Compound 10 is converted to the chloroethyl derivative with triphenylphosphine and carbon tetrachloride in DMF via the procedure of Verheydan, J. P. H. and Moffatt, J. G. J. Org. Chem. 1972 37, 2289 to give the title compound, 89.