Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]([CH:7]1[CH2:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:4]([OH:6])=[O:5].S(Cl)([Cl:17])=O.[CH3:19]O>>[ClH:17].[NH2:2][CH:3]([CH:7]1[CH2:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:4]([O:6][CH3:19])=[O:5]
Reactant: NC(C(=O)O)C1Cc2ccccc21
Reactant: O=S(Cl)Cl
Reactant: CO
Agent: Cl
Product: COC(=O)C(N)C1Cc2ccccc21

Procedure:
To a mixture of #101 (195 mg, <0.913 mmol, 1 eq.) in methanol (20 mL, 0.04 M) was added thionyl chloride (0.666 mL, 9.13 mmol, 10 eq.). After two hours at reflux, the reaction mixture was concentrated in vacuo to give the single enantiomer #102 (175 mg, 84% over two steps) as a light-colored solid. LC-MS: m/z 192.3 [M+H+], retention time=0.80 minutes; GC-MS: m/z 192 [M+H+], retention time=3.206 minutes; 1H NMR (400 MHz, CD3OD) δ 7.24-7.33 (m, 2H), 7.11-7.18 (m, 2H), 4.40 (d, J=6.9 Hz, 1H), 3.99-4.05 (m, 1H), 3.78 (s, 3H), 3.46 (dd, J=14.8, 5.4 Hz, 1H), 3.23 (dd, J=14.8, 2.5 Hz, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[NH2:15][C:16]1[C:17]([O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=2)=[N:18][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)=[CH:20][CH:21]=1>>[C:38]([C:35]1[CH:36]=[CH:37][C:32]([O:31][C:17]2[C:16]([NH:15][S:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)(=[O:13])=[O:12])=[CH:21][CH:20]=[C:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[N:18]=2)=[CH:33][CH:34]=1)#[N:39]
Reactant: N#Cc1ccc(Oc2ccc(N)c(Oc3ccc(C#N)cc3)n2)cc1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Product: N#Cc1ccc(Oc2ccc(NS(=O)(=O)c3ccc4ccccc4c3)c(Oc3ccc(C#N)cc3)n2)cc1
Yield: 68.5 %

Procedure:
2-Naphthyl sulfonyl chloride (0.17 g, 0.76 mmol) was added to a stirred solution of 3-amino-2,6-bis(4-cyano phenoxy)pyridine (0.25 g, 0.76 mmol) along with other reagents as mentioned in Example 1(c) to afford 0.27 g of the required product. 1H NMR (DMSO-d6): δ 5.38 (1H, brs), 6.82 (1H, d), 7.12 (1H, d), 7.22 (2H, d), 7.35 (2H, dd), 7.44 (1H, d), 7.80 (7H, m), 7.95 (2H, m), 8.15 (2H, d), 8.56 (1H, s).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])=[CH:5][CH:4]=1.CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([NH:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][O:1][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:18][CH:17]=1)=[O:10]
Reactant: O=C(NCc1ccc(CO)cc1)c1ccccn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(CNC(=O)c2ccccn2)cc1
Yield: 80.5 %

Procedure:
Using General Procedure G: Reaction of pyridine-2-carboxylic acid 4-hydroxymethyl-benzylamide (200 mg, 0.83 mmol), Et3N (144 uL, 0.99 mmol), and MsCl (71 uL, 0.91 mmol) for 10 minutes at 0° C. gave the title compound (214 mg, 81%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.92 (s, 3H), 4.69 (d, 2H, J=3.3 Hz), 5.23 (s, 2H), 7.41-7.47 (m, 5H), 7.85-7.87 (m, 1H), 8.24 (d, 1H, J=7.8 Hz), 8.50 (br s, 1H), 5.84 (d, 1H, J=3.9 Hz).
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[OH-].[K+].C(#N)C.[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH2:29][N:30]1[C:34]([Cl:35])=[C:33]([Cl:36])[N:32]=[CH:31]1>O>[Cl-:2].[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][N+:32]1[C:33]([Cl:36])=[C:34]([Cl:35])[N:30]([CH2:29][C:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:19]=2)[CH:31]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Clc1ncn(Cc2ccc3ccccc3n2)c1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Clc1c(Cl)[n+](Cc2ccc3ccccc3n2)cn1Cc1ccc2ccccc2n1
Product: [Cl-]

Procedure:
4,5-Dichloroimidazole (2.00 g, 14.6 mmol) was dissolved in 15 mL acetonitrile in a round bottom flask. Potassium hydroxide (0.90 g, 16.0 mmol) was added and the mixture was refluxed for 15 min. Concurrently, 2-chloromethylquinoline hydrochloride (3.13 g, 14.6 mmol) and potassium hydroxide (0.82 g, 14.6 mmol) were added to a second round bottom flask and stirred in 60 mL acetonitrile at reflux for 10 min. The contents of the second flask were added to the first, and the combined mixture was refluxed overnight, during which time a white precipitate formed. The reaction mixture was filtered hot, yielding a clear, tan filtrate. Slow evaporation and cooling of the filtrate yielded tan crystals of 1-(quinolin-2-ylmethyl)-4,5-dichloroimidazole, which were collected by a second filtration. 2-Chloromethylquinoline hydrochloride (0.19 g, 0.88 mmol) and potassium hydroxide (0.05 g, 0.90 mmol) were added to 5 mL acetonitrile and refluxed for 30 min. Crystals of 1-(quinolin-2-ylmethyl)-4,5-dichloroimidazole (0.1087 g, 0.39 mmol) were added, and the mixture was refluxed overnight, during which time it became red in color and viscous. The residue was extracted with dichloromethane (2×10 mL) and the combined organic layers were dried with Mg2SO4. The volatile components were removed under reduced pressure yielding an oil. The oil was dissolved in water, and the solution was extracted with toluene (2×). The combined aqueous layer was collected and the solvent allowed to evaporate in air. A sticky brown solid was collected in low yield. 1H NMR (300 MHz, DMSO-d6) 10.03 (1H, s, NCHN), 8.55 (2H, d, Ar), 8.07 (2H, d, Ar), 7.89 (2H, d, Ar), 7.79 (2H, t, Ar), 7.74 (2H, d, Ar), 7.67 (2H, t, Ar), 6.07 (4H, s, CH2).
Reaction SMILES: [C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].[CH3:12][N:13]1[N:17]=[N:16][C:15]([C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)=[N:14]1.C(N(CC)CC)C.CN(C)C=O>ClCCl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:12][N:13]1[N:17]=[N:16][C:15]([C:18]2[CH:19]=[CH:20][C:21]([C:2]#[C:1][C:3]3([OH:11])[CH:8]4[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]4)[CH2:4]3)=[CH:22][CH:23]=2)=[N:14]1
Reactant: Cn1nnc(-c2ccc(Br)cc2)n1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccc(C#CC3(O)CN4CCC3CC4)cc2)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 42.4 %

Procedure:
A mixture of 3-ethynyl-3-hydroxyquinuclidine (0.3 g), 2-methyl-5-(4-bromophenyl)tetrazole (0.48 g), bis(triphenylphosphine)-palladium (II) chloride (70 mg), copper (I) iodide (35 mg), triethylamine (1 ml) and dimethylformamide (2 ml) was stirred at 70° C. for 2 hours. The mixture was diluted with dichloromethane (4 ml) and filtered down a short column of silica (Varian Bond-sluts S1 silica) eluting with a gradient of 0:100 (v/v) to 100:0 (v/v) methanol/dichloromethane. The appropriate organic fractions were combined, washed with saturated aqueous sodium carbonate (3×30 ml), dried (Na2CO3) and evaporated to give 3-[2-(4-[2-methyl-tetrazol-5-yl]phenyl)ethynyl]-3-hydroxyquinuclidine (260 mg) as a solid, m.p. 228°-230° C.; microanalysis, found: C, 65.9; H, 6.1; N, 22.2%; C17H19N5O requires: C, 66.0; H, 6.2; N, 22.6%; NMR: 1.2-1.4(1H,m), 1.5-1.7(1H,m), 1.8-2.0(3H,m), 2.7(4H,m), 2.8-3.2(2H,m), 4.4(3H,s), 5.6(1H,s), 7.6(2H,m), 8.05(2H,m); m/z 310(M+H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][NH:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:12]=1.[O:13](C(OC(C)(C)C)=O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=O.C(N(CC)CC)C>C(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:13])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Ic1ccc2c(c1)CCCNC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCc2cc(I)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.7 %

Procedure:
7-Iodo-2,3,4,5-tetrahydro-1H-2-benzazepine (Preparation 2) (450 mg, 1.648 mmol) was dissolved in DCM (30 ml) and treated with BOC2O (0.459 ml, 1.977 mmol) followed by triethylamine (0.459 ml, 3.30 mmol). The reaction mixture was stirred at RT for 30 minutes. LC/MS showed one major product. The reaction was washed with 0.5M HCl (20 ml), sat NaHCO3 (20 ml), dried over anhydrous MgSO4 and evaporated to yield the title compound (650 mg) as a colourless oil. MS (ES) C15H20INO2 requires 373; found 318 (M+H−56)+.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=1>>[F:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:14][CH:13]=2)=[CH:9][CH:8]=1
Reactant: Fc1ccc(Oc2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(Cl)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Chlorosulfonic acid (26 mL, 0.392 mole) was added dropwise to ice-cooled 4-fluorophenoxybenzene (36.9 grams, 0.196 mole) with mechanical stirring. When addition was complete, the mixture was stirred at room temperature for 4 hours. The mixture was then poured into ice water. The product, 4-(4-fluorophenoxy)benzene-sulfonylchloride (18.6 grams, 33%) was collected by filtration and dried in the air.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:7][CH:8]([O:10][C@H:11]([CH3:19])[C:12](OCC(C)C)=[O:13])[CH3:9])[CH:4]([CH3:6])[CH3:5].CO.O>C1(C)C=CC=CC=1>[CH2:3]([O:7][CH:8]([O:10][C@H:11]([CH3:19])[CH2:12][OH:13])[CH3:9])[CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)COC(=O)[C@@H](C)OC(C)OCC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)COC(C)O[C@H](C)CO
Yield: 85.1 %

Procedure:
1.0 g (0.024 mole) of sodium borohydride was suspended at room temperature in a solution of 5.0 g (0.02 mole) of isobutyl (R)-(+)-2-(1-isobutoxyethoxy)propionate dissolved in 20 ml of toluene. Thereto was dropwise added slowly 7.0 ml (0.12 mole) of methanol with stirring, so that the internal temperature of the reaction system could be kept at 40° C. After the completion of the dropwise addition, the resulting mixture was stirred at 40° C. for 7 hours, at room temperature overnight and at 60° C. for 2 hours to give rise to a reaction. To the reaction mixture was added 20 ml of water, followed by stirring for 0.5 hour. The organic layer was separated. The water layer was subjected to extraction with 20 ml of toluene. The two organic layers were combined and washed with 20 ml of water and 20 ml of a saturated aqueous sodium chloride solution in this order. The washed solution was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove the solvent, whereby was obtained 3.0 g (yield: 84.4%) of an oily title compound (diastereomixture).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:16]([O:26][CH3:27])([O:24][CH3:25])[CH2:15][CH2:14]1)(=[O:12])=[O:11].[CH3:28][C:29]1([CH3:46])[O:33][C@H:32](CO[Si](C)(C)C)[C@@H:31](CO[Si](C)(C)C)[O:30]1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[CH2:14][CH2:15][C:16]2([O:24][C@@H:25]([C@H:31]3[CH2:32][O:33][C:29]([CH3:46])([CH3:28])[O:30]3)[CH2:27][O:26]2)[CH:17]=[C:18]1[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:11])=[O:12]
Reactant: CC1(C)O[C@H](CO[Si](C)(C)C)[C@@H](CO[Si](C)(C)C)O1
Reactant: CCOC(=O)C1=CC(OC)(OC)CCC1S(=O)(=O)Nc1ccc(F)cc1Cl
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1=CC2(CCC1S(=O)(=O)Nc1ccc(F)cc1Cl)OC[C@H]([C@H]1COC(C)(C)O1)O2
Yield: 24.4 %

Procedure:
300 mg (0.71 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-1-carboxylate obtained in Example (16a) and 436 mg (1.42 mmol) of (4R,5R)-2,2-dimethyl-4,5-bis[(trimethylsilyl)oxy]methyl[1.3]dioxolane were dissolved in 12 ml of dichloromethane and 26 μl (0.142 mmol) of trimethylsilyl trifluoromethanesulfonate was added thereto with stirring under ice-cooling, followed by stirring for 90 hours at room temperature. Saturated aqueous sodium hydrogencarbonate was added to the reaction solution and the mixture was extracted with dichloromethane. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=4:1) to give 90 mg of ethyl (2R)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2-((4R)-2,2-dimethyl[1.3]dioxolan-4-yl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate as an amorphous substance (yield: 24%).
Reaction SMILES: [O:1]=[C:2]([C:4]1[N:11]2[C:7](=[N:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=32)[S:6][N:5]=1)[CH3:3].[BH4-].[Na+].O>CO>[OH:1][CH:2]([C:4]1[N:11]2[C:7](=[N:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=32)[S:6][N:5]=1)[CH3:3]
Reactant: CC(=O)c1nsc2nc3ccccc3n12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(O)c1nsc2nc3ccccc3n12
Reaction time: 0.5 h

Procedure:
To a suspension of 3-(1-oxoethyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole (729 mg, 3.36 mmol) in 200 mL methanol, was added sodium borohydride (140 mg, 3.69 mmol). The mixture was stirred for 30 min and 0.1 mL of water was added. The methanol was evaporated and the residue was partitioned between ethyl acetate and 0.1 M hydrochloric acid. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed twice with brine, dried and evaporated. The crude residue was purified by chromatography using chloroform/methanol to give 3-(1-hydroxyethyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole. mp 174-175° C.; 1H NMR (CDCl3) δ 8.05 (d, 1H), 7.80 (d, 1H), 7.47 (td, 1H), 7.36 (td, 1H), 5.39 (q, 1H), 2.76 (d, 1H), 1.84 (d, 3H) ppm; IR (KBr) ν 3136, 1544, 1494, 1478, 1451, 1374, 1250, 1200, 1123, 1103, 1093, 752, 729, 711 cm-1 ; MS m/z 219 (M+), 148 (M+ -CH3CH(OH)CN)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:14][C:15](=[O:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:17]=[C:15]([CH3:16])[CH2:14][O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: CC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(OCC(C)=O)c1

Procedure:
Following a procedure similar to that described in Preparation 3, but using 2.8 g of methyl 3-hydroxyphenylacetate, 3.5 g of bromoacetone, 4 g of potassium carbonate and 30 ml of dimethylformamide, the title compound was obtained having an Rf=0.41 (thin layer chromatography over silica gel, using a 2:5 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[N:11]=[CH:10][NH:9][C:8]=2[C:7](=O)[NH:6][C:5]1=[O:14])[CH2:2][CH3:3].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:16]>N1C=CC=CC=1>[CH2:1]([N:4]1[C:12]2[N:11]=[CH:10][NH:9][C:8]=2[C:7](=[S:16])[NH:6][C:5]1=[O:14])[CH2:2][CH3:3]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCn1c(=O)[nH]c(=O)c2[nH]cnc21
Solvent: c1ccncc1
Product: CCCn1c(=O)[nH]c(=S)c2[nH]cnc21

Procedure:
A suspension of 9.32 g. (48 mM) of 3-propylxanthine in 80 ml. of pyridine, was treated with 17.33 g. (78 mM.) of phosphorus pentasulfide in 80 ml. of pyridine, and worked up analogously to Example I. 8.9 g. of 3-propyl-6-thioxanthine was obtained. Recyrstallization from methanol-acetone gave 7.4 g. (59% yield) of needles with a melting point of 249°-250° C.
Reaction SMILES: [Cl:1][C:2]([Cl:13])([Cl:12])[CH:3]1[N:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[C:5](=[O:11])[O:4]1.[Li+].[CH3:15]C([N-]C(C)C)C.C1COCC1.CCCCCCC.ICI>C1COCC1>[CH3:15][C:6]12[CH2:10][CH2:9][CH2:8][N:7]1[CH:3]([C:2]([Cl:1])([Cl:12])[Cl:13])[O:4][C:5]2=[O:11]
Reactant: CC(C)[N-]C(C)C
Reactant: O=C1OC(C(Cl)(Cl)Cl)N2CCC[C@H]12
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ICI
Solvent: CCCCCCC
Product: CC12CCCN1C(C(Cl)(Cl)Cl)OC2=O
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of (7aR)-3-(trichloromethyl)tetrahydropyrrolo[1,2-c]oxazol-1(3H)-one (D48) (0.2 g, 0.82 mol) in THF (10 ml) cooled at −78° C. LDA 2M sol in THF/heptane (0.58 ml, 1.17 mol) was added and the mixture stirred 30 min. Diiodomethane (0.185 ml, 2.97 mol) was added and the temperature was allowed to warm to −40° C. over a period of 2 hrs then left at this temperature for an additional hour. The resulting mixture was partitioned between DCM and H2O. The aqueous phase was extracted with DCM (2×10 ml); the organic phases were collected, dried over Na2SO4 and evaporated in vacuo. The residue was purified by SPE-Si cartridge (25 g) eluting with DCM. Collected fractions after solvent evaporation afforded title compound (D49) in mixture (4:1) with starting material (110 mg).
Reaction SMILES: COC1C=C[C:6]([C:9]([CH3:15])([CH3:14])[C:10]([F:13])([F:12])[F:11])=CC=1.I([O-])(=O)(=O)=[O:17].[Na+].C(Cl)(Cl)(Cl)Cl.CC#N.[OH2:30]>O.[Ru](Cl)(Cl)Cl>[F:13][C:10]([F:11])([F:12])[C:9]([CH3:15])([CH3:14])[C:6]([OH:17])=[O:30]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COc1ccc(C(C)(C)C(F)(F)F)cc1
Reactant: O
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(C)(C(=O)O)C(F)(F)F
Reaction time: 0.08 h

Procedure:
To a biphasic mixture of 1-methoxy-4-(1,1,1-trifluoro-2-methylpropan-2-yl)benzene (10.0 g, 45.8 mmol) and sodium periodate (137 g, 642 mmol) in a mixture solvent of CCl4:CH3CN:H2O (2:2:3, 550 ml) was added slowly ruthenium(III) chloride hydrate (0.517 g, 2.29 mmol) (black powder) while the reaction flask was kept in an ice-water bath. The mixture turned yellow rapidly then red after 5 minutes, ans was stirred for 0.5 h. The ice-water bath was removed and the reaction mixture was stirred vigorously, via a mechanical stirrer, overnight. The solids were filtered off, washed with 100 ml of DCM, 100 ml of H2O. The filtrate (pH ˜1) was basified with 10 N NaOH to pH>11, and the layers were separated, and the aq. layer was extracted with 130 ml of DCM. The aq. layer was then acidified carefully with conc. HCl to pH ˜1, extracted with 3×150 ml of DCM. The org layers were combined, dried (Na2SO4), and concentrated to give the title compound as an oil, which became a semi-solid upon drying on the vac line.
Reaction SMILES: [CH3:1][C:2]([C:6]1[N:10]([CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[CH:18]=[CH:19][C:20]([S:22]([N:25]3[CH:29]=[CH:28][C:27]([C:30]([OH:32])=O)=[CH:26]3)(=[O:24])=[O:23])=[CH:21][C:8]=2[N:7]=1)([CH3:5])CC.CN(C(O[N:41]1N=N[C:43]2C=CC=N[C:42]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:58](N)C>CN(C=O)C>[C:2]([C:6]1[N:10]([CH2:11][CH:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[C:9]2[CH:18]=[CH:19][C:20]([S:22]([N:25]3[CH:29]=[CH:28][C:27]([C:30]([NH:41][CH2:42][CH3:43])=[O:32])=[CH:26]3)(=[O:23])=[O:24])=[CH:21][C:8]=2[N:7]=1)([CH3:1])([CH3:58])[CH3:5]
Reactant: CCN
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)O)c3)ccc2n1CC1CCOCC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)c1
Yield: 79.7 %

Procedure:
Following the same procedure in Example 24, Step A, using DIPLA (105 uL, 78 mg, 0.60 mmol), 1-{[2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrrole-3-carboxylic acid (0.85 mmol) (see following Steps B and C for preparation) in DMF (15 mL), HATU (582 mg, 10.53 mmol) and ethylamine hydrochloride (154 mg, 1.87 mmol). The crude product was purified by MPLC on silica gel using EtOAc to give 0.32 g (81%) of a white solid as the title compounds 1H NMR (400 MHz, CHLOROFORM-D) δ 1.19 (t, J=7.23 Hz, 3 H), 1.45-1.54 (m, 4 H), 1.56 (s, 9 H), 2.15-2.33 (m, 1 H), 3.26-3.35 (m, 2 H), 3.36-3.44 (m, 2 H), 3.93-4.03 (m, 2 H), 4.22 (d, J=7.42 Hz, 2H), 5.79 (t, J=5.66 Hz, 1 H), 6.47 (dd, J=3.22, 1.66 Hz, 1 H), 7.17 (dd, J=3.32, 2.15 Hz, 1 H), 7.41 (d, J=8.59 Hz, 1 H) 7.62 (dd, J=2.34, 1.76 Hz, 1 H), 7.76 (dd, J=8.69, 1.86 Hz, 1 H), 8.32 (d, J=1.76 Hz, 1 H); MS (ESI) (M+H)+=473.3.
Reaction SMILES: O=[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[N+:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])#[C-:19]>>[C:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]3[CH:19]=[N:18][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:2]3[CH:11]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: O=c1cc(-c2ccccc2)c2ccccc2[nH]1
Product: CCOC(=O)c1ncn2c1cc(-c1ccccc1)c1ccccc12

Procedure:
Ethyl 5-phenyl-imidazo(1,5-a)quinoline-3-carboxylate was prepared from 1,2-dihydro-2-oxo-4-phenyl-quinoline and ethyl isocyanoacetate. M.p. 176°-185° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]=1[CH2:25][S:26][C:27]1[CH2:31][C:30]([CH3:33])([CH3:32])[O:29][N:28]=1.O>C(Cl)(Cl)Cl>[Cl:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:14]=1[CH2:25][S:26]([C:27]1[CH2:31][C:30]([CH3:33])([CH3:32])[O:29][N:28]=1)=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1nc(-c2ccccc2)c(CSC2=NOC(C)(C)C2)c1Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cn1nc(-c2ccccc2)c(CS(=O)C2=NOC(C)(C)C2)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
0.87 g of m-chloroperbenzoic acid (purity: 70%, 3.54 mmoles) was added, with ice-cooling, to a solution of 0.85 g (2.53 mmoles) of 3-(5-chloro-1-methyl-3-phenyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline dissolved in 30 ml of chloroform. The mixture was stirred at room temperature for 1 hour to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.48 g (yield: 53.9%) of 3-(5-chloro-1-methyl-3-phenyl-1H-pyrazol-4-ylmethylsulfinyl)-5,5-dimethyl-2-isoxazoline as a transparent viscous substance.
Reaction SMILES: [CH2:1]([N:8]([CH2:23][CH2:24]Cl)[C:9](=[O:22])[C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:11]([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([N:8]1[CH2:23][CH2:24][N:14]([C:15]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:21])[C@H:10]([CH:11]([CH3:13])[CH3:12])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N(CCCl)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[C@@H]1C(=O)N(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.9 %

Procedure:
To a solution of (R)-tert-butyl (1-(benzyl(2-chloroethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (2.0 g, 5.40 mmol) in DMF (30 mL) was added NaH (1.0 g, 27.0 mmol, 60% in oil mineral) at 0° C. under N2. The mixture was stirred at rt for 2 h. The mixture was quenched with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography to afford (R)-tert-butyl 4-benzyl-2-isopropyl-3-oxopiperazine-1-carboxylate (1.13 g, 63% yield) as a white solid. LC-MS m/z 277.1 [M-56+H]+. 1H NMR (CDCl3 400 MHz): δ 7.38-7.29 (m, 3H), 7.29-7.22 (m, 2H), 5.02-4.86 (m, 1H), 4.49-4.39 (m, 1H), 4.31-4.06 (m, 2H), 3.41-3.18 (m, 3H), 2.42-2.31 (m, 1H), 1.46 (s, 9H), 1.12 (d, J=6.8 Hz, 3H), 1.00 (d, J=6.8 Hz, 3H).