Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35]#[C:36][C:37]3[CH:50]=[CH:49][C:40]([O:41][CH2:42][CH2:43][NH:44][CH2:45][CH:46]4[CH2:48][CH2:47]4)=[C:39]([CH3:51])[CH:38]=3)=[N:33][CH:34]=2)=[CH:25][CH:24]=1.C([BH3-])#N.[Na+]>CC(O)=O.C1COCC1.C(Cl)Cl>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35]#[C:36][C:37]3[CH:50]=[CH:49][C:40]([O:41][CH2:42][CH2:43][N:44]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:45][CH:46]4[CH2:48][CH2:47]4)=[C:39]([CH3:51])[CH:38]=3)=[N:33][CH:34]=2)=[CH:27][CH:28]=1
Reactant: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCNCC1CC1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN(CC1CC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
30 μL (0.29 mmol) of cyclohexanone, 1 drop of AcOH, and 128 mg (0.68 mmol) of sodium triacetoxyborohydride were added to a solution of 60 mg (0.14 mmol) of (2-{4-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-2-methylphenoxy}ethyl)cyclopropylmethylamine in 10 mL of THF and the mixture was stirred for 24 hours at RT. 5 mL of DCM, 30 μL (0.29 mmol) of cyclohexanone, and 36 mg (0.58 mmol) of sodium cyanoborohydride were added and the mixture was stirred for a further 3 days. The reaction mixture was evaporated down in vacuo and the residue was taken up in EtOAc. The organic phase was washed with semiconcentrated aqueous sodium bicarbonate solution, dried over sodium sulfate, and evaporated down in vacuo. The residue was purified by column chromatography (silica gel, cyc/EtOAc 1:1) and triturated with PE. Yield: 4.5 mg (6% of theoretical); C32H35ClN2O (M=499.086); calc.: molpeak (M+H)+: 499/501 (Cl); found: molpeak (M+H)+: 499/501 (Cl); HPLC-MS: 9.85 minutes (method A).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:18])([CH3:17])[CH2:9][CH:10]([OH:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][C:3]=1[O:19][CH3:20].CS(C)=O.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[CH2:14]([O:13][C:11](=[O:12])[C:10](=[O:16])[CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:19][CH3:20])[CH:4]=1)([CH3:18])[CH3:17])[CH3:15]
Reactant: CCOC(=O)C(O)CC(C)(C)c1ccc(Cl)c(OC)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOC(=O)C(=O)CC(C)(C)c1ccc(Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.15 g (20.45 mmol) of ethyl 4-(4-chloro-3-methoxyphenyl)-2-hydroxy-4-methyl-pentanoate is dissolved in 213 ml of dichloromethane and mixed with 71 ml of dimethyl sulfoxide. After 10.3 g (102.23 mmol) of triethylamine is added, the batch is mixed in portions with 8.1 g (51.12 mmol) of SO3/pyridine complex and then stirred overnight at room temperature. The reaction mixture is mixed while being cooled slightly with 81 ml of saturated ammonium chloride solution and vigorously stirred. After 2× extraction with diethyl ether, the combined organic phases are treated as usual. The residue that remains after the solvent is spun off is chromatographed on silica gel (mobile solvent ethyl acetate/hexane) together with the residue that results from another batch (15.27 g). 15.46 g (72.9%, from the two batches) of the desired compound is isolated.
Reaction SMILES: O[C:2]1[C:10]([CH2:11][CH2:12][OH:13])=[C:9]2[C:5]([CH2:6][CH2:7][C@H:8]2[CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(=O)([O-])O.[Na+].C(N(CC)CC)C.Cl>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:11]1[CH2:12][O:13][C:2]2[CH:3]=[CH:4][C:5]3[CH2:6][CH2:7][C@@H:8]([CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C:9]=3[C:10]1=2
Reactant: CCC(=O)NCC[C@@H]1CCc2ccc(O)c(CCO)c21
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCC(=O)NCC[C@@H]1CCc2ccc3c(c21)CCO3
Temperature: -10 °C
Reaction time: 0.42 h
Yield: 86.5 %

Procedure:
To a solution of (S)-N-[2-(6-hydroxy-7-(2-hydroxyethyl)indan-1-yl)ethyl]propionamide (5 g, 18 mmol.) in pyridine (14.6 mL), was added dropwise, while maintaining the temperature at about −10° C. under cooling with ice, methanesulfonyl chloride (1.4 mL, 18 mmol.). The reaction mixture was stirred for 25 minutes at temperatures ranging from −10 to −5° C. To the reaction mixture was further added dropwise methanesulfonyl chloride (0.7 mL, 9 mmol.). The mixture was stirred for further 25 minutes at temperatures ranging from −10 to −5° C. To the reaction mixture were added gradually ethyl acetate (10 mL) and a saturated aqueous solution of sodium hydrogencarbonate (10 mL). The mixture was warmed to room temperature, followed by stirring for 30 minutes. The organic matter was extracted with ethyl acetate, which was washed with 2N HCl and water, followed by drying over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was dissolved in ethyl acetate (20 mL). To the solution was added triethylamine (4.6 g, 45.1 mmol.), and the mixture was heated under reflux for 40 minutes. To the reaction mixture was added 2N HCl, which was subjected to extraction with ethyl acetate. The extract solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and water, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent. The residue was purified by means of silica gel column chromatography (ethyl acetate) to afford the title compound (yield 4.04 g, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=O)=[C:4]([F:12])[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:22])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[S:22])[NH:8][CH3:9])=[C:4]([F:12])[CH:3]=1
Reactant: CNC(=O)c1ccc(Br)cc1F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CNC(=S)c1ccc(Br)cc1F
Temperature: 100 °C
Reaction time: 4 h
Yield: 104.8 %

Procedure:
A mixture of 4-bromo-2-fluoro-N-methylbenzamide (500 mg, 2 mmol) and Lawesson reagent (872 mg, 2.16 mmol) in toluene (10 mL) was heated to 100° C. and stirred for 4 hours. The reaction was cooled to room temperature, diluted with toluene, and filtered. The filtrate was concentrated and purification of the residue by flash column chromatography (0-20% ethyl acetate/heptanes) gave the title compound (520 mg, 97%) as a yellow solid. +ESI (M+H+1) 250.1; 1H NMR (400 MHz, CDCl3, δ): 8.09 (t, J=8.58 Hz, 1H), 8.03 (br. s., 1H), 7.35 (dd, J=8.19, 2.15 Hz, 1H), 7.27 (dd, J=11.41, 1.85 Hz, 1H), 3.36 (dd, J=4.88, 0.78 Hz, 3H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:37](=[O:44])(=[O:43])[NH:38]C(C)(C)C)=[CH:27][CH:26]=2)[C:7](=[O:23])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[C:19]([F:22])([F:21])[F:20])[N:9]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[CH2:1]([C:5]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:37](=[O:44])(=[O:43])[NH2:38])=[CH:27][CH:26]=2)[C:7](=[O:23])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[C:19]([F:20])([F:22])[F:21])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1

Procedure:
The title compound was prepared from 5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)-biphenyl-4-yl]methyl]-2,4-dihydro-2-[5-nitro-2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Step C) by reaction with trifluoroacetic acid in the presence of anisole according to the method of Example 28, Step G. Flash chromatography on silica gel (elution with 0.3% MeOH in CH2Cl2) yielded 60 mg (79%) of the product, homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 576 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:12])[N:3]=1.C(=O)([O-])O.[Na+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>[Cu]I.CN(C)C=O>[Cl:12][C:4]1[N:3]=[C:2]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Reactant: COc1ccc(CN)cc1
Agent: [Cu]I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)nc1NCc1ccc(OC)cc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of methyl 2,6-dichloropyridine-3-carboxylate (2.06 g), sodium hydrogen carbonate (1.26 g), 4-methoxybenzylamine (1.50 ml), copper(I) iodide (190 mg) and N,N-dimethylformamide (20 ml) was heated to 80° C., and the mixture was stirred for 1 hr and 30 min. The reaction mixture was concentrated under reduced pressure, the obtained residue was diluted with ethyl acetate (150 ml), and the insoluble solid was removed by filtration. To the filtrate was 28% aqueous ammonia (5 ml), and the mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained yellow oil residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.58 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([C@@H:13]3[C@@H:18]([CH3:19])[CH2:17][CH2:16][CH2:15][C:14]3([CH3:21])[CH3:20])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[OH-].[Na+]>C(O)(=O)C.ClCCl.[Pt](=O)=O>[CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([C@@H:13]3[C@@H:18]([CH3:19])[CH2:17][CH2:16][CH2:15][C:14]3([CH3:20])[CH3:21])=[O:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: C[C@H]1CCCC(C)(C)[C@@H]1C(=O)c1ccc2cnccc2c1
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@H]1CCCC(C)(C)[C@@H]1C(=O)c1ccc2c(c1)CCNC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.3 %

Procedure:
To a solution of the product of Example 13a (178 mg, 0.63 mmol) in acetic acid (2 mL) was added platinum dioxide (25 mg) and the reaction was stirred at room temperature under an atmosphere of hydrogen for 4 hours. The mixture was diluted with dichloromethane (40 mL) and basified with 1 N NaOH (35 mL) and the organic phase was separated. The aqueous layer was extracted with dichloromethane (30 mL). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=50/1->10/1) to afford the title compound as a dark brown oil (130 mg, Yield: 72%). 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J=8.4 Hz, 1H), 7.73 (s, 1H), 7.13 (d, J=8.4 Hz, 1H), 4.18 (s, 2H), 3.28 (t, J=6.2 Hz, 2H), 3.01 (t, J=6.2 Hz, 2H), 2.11-2.02 (m, 1H), 1.81-1.77 (m, 1H), 1.61-1.54 (m, 2H), 1.44-1.41 (m, 1H), 1.34-1.24 (m, 3H), 1.10-0.98 (m, 4H), 0.77 (s, 3H), 0.74 (d, J=6.4 Hz, 3H) ppm; Mass spectrum (ESI +ve) m/z 286 (M+H+).
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.C([O:19][C:20](=O)[CH:21]=[C:22]([C:30]1[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=1)C.Cl>C1COCC1>[Br:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([C:30]2[CH:31]=[CH:32][C:33]([Br:36])=[CH:34][CH:35]=2)=[CH:21][CH2:20][OH:19])=[CH:24][CH:25]=1
Reactant: CCOC(=O)C=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCC=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.9 %

Procedure:
A 1M solution of DIBAL-H in toluene (150 ml, 150 mmol) was added dropwise, at −70° C. over 30 min, to a stirred solution of 3,3-bis-(4-bromophenyl)-acrylic acid ethyl ester (24.5 g, 59.7 mmol) in dry THF (400 ml) and stirred for 30 min. The mixture was warmed to room temperature, and stirred for 1.5 h. The mixture was poured into 1N HCl (700 ml) with vigorous stirring and the product extracted with ethyl acetate (3×200 ml). The combined organic extracts were washed with brine, dried (MgSO4), and evaporated to give the crude product as an off-white solid, which was purified by column chromatography on silica gel (15% ethyl acetate in n-heptane eluent). The purified product was diluted in boiling heptane, filtered and the filtrate cooled, giving 15.8 g (72%) 3,3-bis-(4-bromophenyl)prop-2-en-1-ol as an crystalline solid.
Reaction SMILES: C([Mg]Br)C.[CH3:5][C:6]1[CH:21]=[CH:20][C:9]([S:10][CH2:11][C:12]#[C:13][CH2:14][C:15]#[C:16][CH2:17][C:18]#[CH:19])=[CH:8][CH:7]=1.[CH2:22]([O:24][C:25](=[O:33])[CH2:26][CH2:27][CH2:28][C:29]#[C:30][CH2:31]I)[CH3:23].S(=O)(=O)(O)O>CCOCC.O1CCCC1>[CH2:22]([O:24][C:25](=[O:33])[CH2:26][CH2:27][CH2:28][C:29]#[C:30][CH2:31][C:19]#[C:18][CH2:17][C:16]#[C:15][CH2:14][C:13]#[C:12][CH2:11][S:10][C:9]1[CH:20]=[CH:21][C:6]([CH3:5])=[CH:7][CH:8]=1)[CH3:23]
Reactant: C#CCC#CCC#CCSc1ccc(C)cc1
Reactant: CCOC(=O)CCCC#CCI
Agent: CC[Mg]Br
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CCCC#CCC#CCC#CCC#CCSc1ccc(C)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
12.03 ml (6.077 g, 0.0455 mol) of 3.8N ethylmagnesium bromide in ether was added dropwise to a solution of 9.65 g (0.0379 mol) of 9-(p-methylthiophenoxy)-1,4,7-nonatriyne in 80 ml of anhydrous tetrahydrofuran. The temperature was maintained at -10° C. The reaction mixture was stirred for 1 hour further at 0° C., allowed to warm to room temperature, and then 374 mg of cuprous cyanide were added. The mixture was stirred for 20 additional minutes, heated to 40° C. and then treated with 13.83 g (49.38 mmol) of 7-iodo-5-heptynoic acid ethyl ester in 30 ml of anhydrous tetrahydrofuran.The resulting mixture was stirred for 3 additional hours at 40° C., then poured on to 300 ml of 1N sulfuric acid and ice. After extraction with ether (3×150 ml), the combined extract was concentrated to a small volume and washed several times with Versene solution and water, dried and evaporated in vacuo. The crude material was purified by column chromatography on 125 g of silica gel, using hexane:ethyl acetate (95:5) as eluant, to obtain 16-(p-methylthiophenoxy)-hexadeca-5,8,11,14-tetraynoic acid ethyl ester, as an oil. The product was stored in dry ice.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[CH:24]=[C:23]([CH3:37])[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:37][C:23]1[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=3)[N:20]=2)[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:29][CH:28]=2)[CH:24]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(N)(=O)=O)c3)n2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 58.3 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{4-[6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-pyrimidin-2-yl}-benzenesulfonamide (example 262) (0.480 g, 0.912 mmol) in dichloromethane (10 mL) was added TFA (10 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane/diethyl ether and dried to yield the title compound as a white solid (0.25 g, 46%). MS (ISP) 469.3 [(M+H)+]; mp>250° C.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:13]([CH3:19])[CH2:14][O:15][C:16](=[O:18])[CH3:17])[C:7]2=[O:12].N([O-])=O.[Na+].CS(C)=O.[IH:28].C([O-])([O-])=O.[Na+].[Na+]>>[I:28][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:13]([CH3:19])[CH2:14][O:15][C:16](=[O:18])[CH3:17])[C:7]2=[O:12]
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(N)cccc2c1=O
Reactant: I
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)OC[C@@H](C)n1ccc2c(I)cccc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetic acid (R)-2-(5-amino-1-oxo-1H-isoquinolin-2-yl)-propyl ester (790 mg, 0.0030 mol) was added to a solution of sodium nitrite (800 mg, 0.01 mol) in dimethyl sulfoxide (10 mL, 0.1 mol) at room temperature. Aqueous hydrogen iodide (4 mL, 0.03 mol) in dimethyl sulfoxide (10 mL, 0.1 mol) was added. The reaction mixture was stirred at room temperature for 1 hour. The cooled reaction mixture was neutralized with saturated aq. Na2CO3 and extracted with methylene chloride (3×100 mL). The combined methylene chloride extracts were washed with brine and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was chromatographed on 40 of silica gel column (0-50% EtOAc/Hexane) to give the desired product as a brown oil. MS m/z (M+H) 371.9
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@:4]([N:9]=[C:10]=[O:11])([CH:6]([CH3:8])[CH3:7])N.[OH:13][CH2:14][C:15]1[S:16][CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH:9][C:10]([O:13][CH2:14][C:15]1[S:16][CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=1)=[O:11]
Reactant: CC(C)c1csc(CO)n1
Reactant: COC(=O)[C@](N)(N=C=O)C(C)C
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H](NC(=O)OCc1nc(C(C)C)cs1)C(C)C
Yield: 52.3 %

Procedure:
A solution of 1.4 mmol of α-isocyanato-valine methyl ester and 0.22 g (1.4 mmol) of 2-(hydroxymethyl)-4-isopropylthiazole in 10 ml of chloroform was heated at reflux for 3 h. After being allowed to cool, the solvent was removed in vacuo, and the residue was purified by silica gel chromatography using 2% methanol in chloroform to provide 0.23 g (52%) of the desired compound (Rf 0.54, 5% methanol in dichloromethane). NMR 1H NMR (DMSO-d6) δ 0.87 (d, J=7 Hz, 3 H), 0.88 (d, J=7 Hz, 3 H), 1.23 (d, J=7 Hz, 6 H), 2.04 (octet, J=7 Hz, 1 H), 3.01 (heptet, J'7 Hz, 1 H), 3.73 (s, 3 H), 3.94 (dd, J=8, 6 Hz, 1 H), 5.26 (AA', 2 H), 7.28 (s, 1 H), 7.92 (d, J=8 Hz, 1 H). Mass spectrum: (M+H)+ =315.
Reaction SMILES: [CH2:1]([C:8]1([CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:12](=[O:13])[NH:11][NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O:30][CH3:31])(=[O:29])[CH:25]=[CH:26][CH:27]=[CH2:28]>>[CH2:1]([C:8]1([CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:12](=[O:13])[N:11]2[CH2:28][CH:27]=[CH:26][CH:25]([C:24]([O:30][CH3:31])=[O:29])[N:10]2[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC=CC(=O)OC
Reactant: O=C1NNC(=O)C1(CCOC1CCCCO1)Cc1ccccc1
Product: COC(=O)C1C=CCN2C(=O)C(CCOC3CCCCO3)(Cc3ccccc3)C(=O)N12
Yield: 33 %

Procedure:
In a manner analogous to that described in Example 7(B) (b), from 2.7 g of 4-benzyl-4-[2-(tetrahydro-2-pyranyloxy)ethyl]pyrazolidine-3,5-dione and 1.05 g of methyl penta-2,4-dienoate there were obtained 1.2 g (34%) of methyl 2-benzyl-2,3,5,8-tetrahydro-1,3-dioxo-2-[2-(tetrahydro-2-pyranyloxy)ethyl]-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate in the form of a white solid having a melting point of 113°-114° C. (from diethyl ether).
Reaction SMILES: [OH:1][CH:2]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])[C:3]1[N:4]=[C:5]2[C:11]([C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>>[CH3:14][C:13]([CH3:16])([CH3:15])[C:12]([C:11]1[C:5]2[C:6](=[N:7][CH:8]=[C:3]([C:2](=[O:1])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[N:4]=2)[NH:9][CH:10]=1)=[O:17]
Reactant: Cc1ccccc1C(O)c1cnc2[nH]cc(C(=O)C(C)(C)C)c2n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: Cc1ccccc1C(=O)c1cnc2[nH]cc(C(=O)C(C)(C)C)c2n1

Procedure:
1-[2-(Hydroxy-o-tolyl-methyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one was treated with Dess-Martin periodinane, following general procedures described in these Examples. MP=152-154 C, (M+H)+=322.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C@:10]([CH3:17])([CH:12]([O:15][CH3:16])[O:13][CH3:14])[C@@H:9]([OH:18])[C@H:8]([NH2:19])[C:7]=2[CH:20]=1)#[N:2].[Na].[C:22]([NH:24][C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)=S)#[N:23].Cl.CN(C)CCCCCN=C=N.C(OCC)(=O)C>CN(C=O)C>[C:22]([N:24]=[C:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[NH:19][C@@H:8]1[C:7]2[CH:20]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11][C@:10]([CH3:17])([CH:12]([O:15][CH3:16])[O:13][CH3:14])[C@H:9]1[OH:18])#[N:23]
Reactant: COC(OC)[C@@]1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: N#CNC(=S)Nc1ccc(Cl)cc1
Agent: CN(C)CCCCCN=C=N
Agent: Cl
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(OC)[C@@]1(C)Oc2ccc(C#N)cc2[C@@H](NC(=NC#N)Nc2ccc(Cl)cc2)[C@@H]1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 42.7 %

Procedure:
To a solution of 100 mg of (2S,3S,4R)-6-cyano-2-methyl-2-dimethoxymethyl-3-hydroxy-4-amino-3,4-dihydro-2H-1-benzopyran prepared in the preparation example 6 is dissolved in 3 ml of DMF, were added 92 mg of N-cyano-N′-(4-chlorophenyl)thiourea sodium salt and 89 mg of 1-[3-(dimethylamino)propyl]-2-ethylcarbodiimide hydrochloride. The reaction mixture was stirred for 6 hours at room temperature, and extracted with 30 ml of ethyl acetate after acidifying the mixture by adding 5 ml of 1N HCl. The organic Layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by siLica gel chromatography (n-hexane:ethyl acetate=1:1 to afford 70 mg (yield: 43%) of the desired compound Of (2S,3R,4S) stereochemistry.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.CC(O)=O.[Rh]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C@@H:15]1[CH2:24][CH2:23][C@H:18]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [Rh]
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)[C@H]1CC[C@@H](OC[C@@H]2CCCN2C(=O)OC(C)(C)C)CC1
Reaction time: 36 h

Procedure:
A mixture of methyl 4-(1-tert-butoxycarbonyl-(2S)-pyrrolidinyl)methoxybenzoate (1.0 g, 2.9 mmol) and 5% Rh on alumina (500 mg) in EtOH (10.0 ml) and AcOH (1.0 ml) was hydrogenated at room temperature at 5 atm for 36 hr. The catalyst was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (6:1, v/v) as eluent to give methyl cis-4-[(1-tert-butoxycarbonyl-(2S)-pyrrolidinyl) methoxy]cyclohexanecarboxylate (900 mg, 89%) as a pale yellow oil. 1H-NMR (CDCl3) δ 1.46 (s, 9H), 1.46–2.00 (m, 12H), 2.34 (m, 1H), 3.20–3.55 (m, 5H), 3.67 (s, 3H), 3.84–3.92 (m, 1H).
Reaction SMILES: [CH2:1]([S:5]([NH:8][C:9](=[O:29])[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[CH:11]=1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].S(S([O-])=O)([O-])=O.[Na+].[Na+].C(O)C.O1CCCC1>O>[CH2:1]([S:5]([NH:8][C:9](=[O:29])[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[CH:11]=1)(=[O:6])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)NC(=O)c1ccc([N+](=O)[O-])c(NCc2ccc(Cl)cc2Cl)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCCCS(=O)(=O)NC(=O)c1ccc(N)c(NCc2ccc(Cl)cc2Cl)c1
Yield: 46.6 %

Procedure:
N-1-butanesulfonyl-3-(2,4-dichlorobenzylamino)-4-nitrobenzamide (0.505 g) was added to a mixture of 1.32 g of sodium hydrosulfite, 1 ml of ethanol, 1 ml of tetrahydrofuran and 1 ml of water at room temperature. The mixture was heat-refluxed for 40 minutes. The solvent was distilled off under reduced pressure, and water was added to the residue. The solid material precipitated was collected, and was dried. Further, the resulting material was washed with a mixed solution of 10 ml of methanol and 3 ml of water, and was dried to give 0.220 g of N-1-butanesulfonyl-4-amino-3-(2,4-dichlorobenzylamino)benzamide.