Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[F:2][C:3]([F:22])([S:18]([OH:21])(=[O:20])=[O:19])[C:4]([O:6][C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([C:10]3=[O:17])[CH2:8]1)[CH2:14]2)=[O:5].[Br-].[O:24]=[C:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:26][S+:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>O.C(#N)C>[O:17]=[C:10]1[CH:11]2[CH2:16][C:7]3([O:6][C:4]([C:3]([F:22])([F:2])[S:18]([O-:21])(=[O:19])=[O:20])=[O:5])[CH2:14][CH:13]([CH2:15][CH:9]1[CH2:8]3)[CH2:12]2.[O:24]=[C:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:26][S+:27]1[CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: O=C1C2CC3CC1CC(OC(=O)C(F)(F)S(=O)(=O)O)(C3)C2
Agent: O=C(C[S+]1CCCC1)c1ccccc1
Agent: [Br-]
Agent: [Na]
Solvent: CC#N
Solvent: O
Product: O=C1C2CC3CC1CC(OC(=O)C(F)(F)S(=O)(=O)[O-])(C3)C2
Reaction time: 15 h

Procedure:
10 Parts of sodium slat of 4-oxo-1-adamantyl difluorosulfoacetate (purity: 55.2%) was charged in a vessel, and a mixed solvent of 30 parts of acetonitrile and 20 parts of ion-exchanged water was added thereto to give a mixture. A solution prepared by mixing 5.0 parts of 1-(2-oxo-2-phenylethyl)tetrahydrothiophenium bromide, 10 parts of acetonitrile and 20 parts of ion exchanged water was added to the mixture. After stirred for 15 hours, the stirred mixture was concentrated and extracted with 98 parts of chloroform. The organic layer was washed with ion-exchanged water. The obtained organic layer was concentrated. The concentrate was washed with 70 parts of ethyl acetate and the solvent was decanted and the crystals was dried to obtain 5.2 parts of 1-(2-oxo-2-phenylethyl)tetrahydrothiophenium 4-oxo-1-adamantyloxycarbonyldifluoromethanesulfonate in the form of white solid, which is called as acid generator B3.
Reaction SMILES: C([BH3-])#N.[Na+].O=[C:6]1[CH2:9][C:8]([CH2:32][C:33]#[N:34])([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7]1.[Si:35]([O:52][CH2:53][C:54]1[CH:59]=[C:58]([C:60]([F:63])([F:62])[F:61])[N:57]=[C:56]([O:64][CH:65]2[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]2)[CH:55]=1)([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CO.CCOC(C)=O.[Cl-].[Cl-].[Zn+2].[BH3-]C#N.[Na+].[Cl-].[Cl-].[Zn+2]>[Si:35]([O:52][CH2:53][C:54]1[CH:59]=[C:58]([C:60]([F:63])([F:62])[F:61])[N:57]=[C:56]([O:64][CH:65]2[CH2:66][CH2:67][N:68]([CH:6]3[CH2:7][C:8]([CH2:32][C:33]#[N:34])([N:10]4[CH:14]=[C:13]([C:15]5[C:16]6[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:17]=6[N:18]=[CH:19][N:20]=5)[CH:12]=[N:11]4)[CH2:9]3)[CH2:69][CH2:70]2)[CH:55]=1)([C:48]([CH3:50])([CH3:49])[CH3:51])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(=O)C4)c3)ncnc21
Reactant: CC(C)(C)[Si](OCc1cc(OC2CCNCC2)nc(C(F)(F)F)c1)(c1ccccc1)c1ccccc1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OCc1cc(OC2CCN(C3CC(CC#N)(n4cc(-c5ncnc6c5ccn6COCC[Si](C)(C)C)cn4)C3)CC2)nc(C(F)(F)F)c1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
Sodium cyanoborohydride (8.8 mg, 0.14 mmol) and zinc dichloride (9.5 mg, 0.070 mmol) were combined in methanol (0.56 mL, 14 mmol) and stirred for 2 hours to generate the reducing solution referenced in JOC 1985, 50, 1927-1932. Subsequently, {3-oxo-1-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile (66 mg, 0.14 mmol, from Step 7 of Example A1) and 4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-(piperidin-4-yloxy)-6-(trifluoromethyl)pyridine (60. mg, 0.12 mmol, from Step D) were combined in methanol (2.0 mL) to dissolve, then the above generated reducing mixture was added. The reaction was stirred overnight. An additional 0.3 eq of the prestirred NaCNBH3/ZnCl2 mixture was added. After stirring for 3 hours, the mixture was diluted with EtOAc and was washed with saturated sodium bicarbonate solution, followed by brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel, eluting with a gradient from 0-80% EtOAc in hexanes afforded product as a mixture of cis- and trans-isomers (43 mg, 40%). LCMS (M+2H)2+: 461.4.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[Cl:61]C1C=CC(N=C=S)=CC=1>>[Cl:61][C:6]1[CH:5]=[CH:4][C:3]([NH:8][C:9](=[S:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:25]=[C:24]4[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]4=[O:26])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:2][CH:7]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccc(Cl)cc4)cc3)cc2C1=O

Procedure:
The compound of example 61 was prepared analogous to compound of example 51 by reaction of compound of example 6 with 4-chlorophenyl isothiocyanate. The compound of example 61 was used directly without isolation for the preparation of compound of example 62.
Reaction SMILES: Cl[C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:7])=[CH:4][N:3]=1.[CH3:25][C:26]1[CH:39]=[CH:38][C:29]([C:30]([NH:32][C:33]2[S:34][CH:35]=[CH:36][N:37]=2)=[O:31])=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1>>[CH3:22][N:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:6](=[O:7])[C:5]2[CH:23]=[CH:24][C:2]([C:27]3[CH:28]=[C:29]([C:30](=[O:31])[NH:32][C:33]4[S:34][CH:35]=[CH:36][N:37]=4)[CH:38]=[CH:39][C:26]=3[CH3:25])=[N:3][CH:4]=2)[CH2:17][CH2:18]1
Reactant: Cc1ccc(C(=O)Nc2nccs2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN1CCN(Cc2ccccc2NC(=O)c2ccc(Cl)nc2)CC1
Product: Cc1ccc(C(=O)Nc2nccs2)cc1-c1ccc(C(=O)Nc2ccccc2CN2CCN(C)CC2)cn1

Procedure:
N-[2-(4-Methylpiperazin-1-ylmethyl)phenyl]-6-[2-methyl-5-(thiazol-2-ylcarbamoyl)-phenyl]-nicotinamide was prepared from 6-chloro-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]nicotinamide (Intermediate 5) and 4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-N-(thiazol-2-yl)-benzamide (Intermediate 11) using General Method B. LCMS: retention time 2.53 min, MH+527. NMR: δH [2H6]-DMSO 12.73, (1H, b), 11.70, (1H, b), 9.26, (1H, d), 8.43, (1H, dd), 8.33, (1H, d), 8.25, (1H, s), 8.10, (1H, d), 7.93, (1H, d), 7.58, (1H, d), 7.54, (1H, d), 7.36, (1H, t), 7.30, (2H, m), 7.12, (1H, t), 3.78, (2H, s), 2.67-2.25, (11H, b), 2.14, (3H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][C:7]=1[CH:15]=O.[CH3:18][NH:19][S:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2)(=[O:22])=[O:21].N1CCCCC1>C(O)C>[CH3:18][NH:19][S:20]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])/[C:26]/2=[CH:15]\[C:7]1[NH:8][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[C:6]=1[CH2:5][CH2:4][CH2:3][N:2]([CH3:17])[CH3:1])(=[O:22])=[O:21]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CN(C)CCCc1c(C=O)[nH]c2c1CCCC2
Solvent: C1CCNCC1
Solvent: CCO
Product: CNS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN(C)C)CCCC3)C(=O)N2
Yield: 70 %

Procedure:
3-(3-Dimethylaminopropyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (71 mg, 0.3 mmol), 5-methylaminosulfonyloxindole (68 mg, 0.3 mmol) and piperidine (0.03 ml) in 1 ml of ethanol was stirred at 60° C. for over night. The mixture was cooled and the solids collected by vacuum filtration and washed with ethanol to give (93 mg, 70% yield) of 3-[1-[3-(3-dimethylaminopropyl)-4,5,6,7-tetrahydro-1H-indol-2-yl]-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[CH3:12]/[C:13](/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:14]/[C:15](O)=[O:16]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:15](=[O:16])/[CH:14]=[C:13](/[CH3:12])\[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:4]2
Reactant: C/C(=C/C(=O)O)c1ccccc1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: C/C(=C/C(=O)N[C@H]1CN2CCC1CC2)c1ccccc1

Procedure:
Prepared as a free base by a procedure analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and Z-3-methyl-3-phenylpropenoic acid; MS (ES+) 271 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].Cl[CH:12]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH:12]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[C:9]#[N:10]
Reactant: ClC(c1cccnc1)c1cccnc1
Reactant: N#CCc1ccccc1Br
Solvent: C1CCOC1
Product: N#CC(c1ccccc1Br)C(c1cccnc1)c1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To the solution of (2-bromophenyl)acetonitrile (1.05 g, 5.38 mmol) in THF (20 mL) at 0° C. was added L DS (5.9 mL, 1.0 M). The mixture was stirred at 0° C. for 30 min followed by the addition of a solution of 3-[chloro(pyridin-3-yl)methyl]pyridine (1.1 g, 5.38 mmol) in THF (5 mL). The mixture was stirred at 0° C. for 2 h and the reaction was quenched with water (20 mL) and extracted with CH2Cl2. The combined organic layer was dried, filtered, and concentrated to give a solid. The solid was purified by silica gel chromatography (3% MeOH in CH2Cl2) to give 2-(2-bromophenyl)-3,3-dipyridin-3-ylpropanenitrile. 1H-NMR (500 MHz, CDCl3) δ 8.57-8.54 (m, 3H), 8.26 (d, 1H, J=2.0, 2.0), 7.76 (d, 1H, J=7.8), 7.73 (d, 1H, J=8.1), 7.59 (d, 1H, J=7.8), 7.34-7.11 (m, 5H), 5.12 (d, 1H, J=6.1), 4.58 (d, 1H, J=6.1). LRMS m/z (M+H) Calcd: 364.3, found: 363.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:27])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=2)[CH:17]=1.[NH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:27])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:24])=[CH:20][N:19]=2)[CH:17]=1
Reactant: Cn1nnc(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Reactant: NN1CCOCC1
Product: Cn1nnc(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)NN3CCOCC3)cn2)cn1
Yield: 70 %

Procedure:
As described for example 22, 6-(4-(4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (69 mg, 0.189 mmol) was converted, using 4-aminomorpholine instead of 4-aminotetrahydropyran, to the title compound (59 mg, 70%) which was obtained as a white foam after purification by chromatography (silica, 0 to 10% methanol in dichloromethane). MS: m/e=449.2 [M+H]+.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21](Cl)=[O:22].[Na+].C([O-])(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([N:8]1[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][O:10][C:9]1=[O:12])=[O:22]
Reactant: O=C1N[C@H](c2ccccc2)CO1
Reactant: O=C(Cl)Cc1ccccc1F
Agent: O=C([O-])CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1F)N1C(=O)OC[C@H]1c1ccccc1
Temperature: 20 °C
Reaction time: 2.75 h

Procedure:
A solution of 46.0 g of (R)-4-phenyl-2-oxazolidinone in 300 g (338 mL) of peroxide-free tetrahydrofuran is cooled to -5 to 0° C. (bath temperature -10 to -5° C.) over a period of 15 minutes. 145.2 g (166.8 mL) of 25% w/w potassium t-amylate/toluene solution is added over a period of 25 minutes while maintaining an internal temperature below 0° C. The reaction mixture is warmed to 20±5° C. within 1 hour and stirred at this temperature for 2.5-3 hours. The mixture is cooled to -15 to -5° C. over a period of 30 minutes, and crude 2-fluorobenzenacetyl chloride (obtained above) is added over a period of 45 minutes while maintaining an internal temperature below -5° C. (bath temperature -15 to -10° C.). After the addition is completed, the mixture is warmed to 20±5° C. over a period of 1 hour, and diluted with 100 mL of toluene. This is added to 500 mL of saturated citric acid monosodium salt solution (100 g in 450 g of water) and the mixture is stirred for 5 minutes. The organic layer is separated, and washed with 1 L of sodium chloride solution (200 g in 800 g of water) in two equal portions of 500 mL each. The solution is concentrated to dryness under reduced pressure (66-76 mm Hg, bath temperature 65-70° C.) to obtain 3-[2-(2-fluorophenyl)-1-oxoethyl]-4(R)-phenyl-2-oxazolidinone as a semi-solid. The semi-solid is suspended in 450 mL of t-butyl methyl ether and the mixture is heated to reflux (53-58° C.) to obtain a solution; 225 mL of t-butyl methyl ether is then distilled off at atmospheric pressure (bath temperature 60-65° C.). The resulting mixture is cooled to 20-25° C., and stirred at this temperature for 16 hours, then cooled to -5 to 0° C. and stirred at this temperature for additional 2 hours and filtered. The resulting solid is dried under vacuum (66-76 mm Hg) at 45-50° C. for 12 hours to obtain 3-[2-(2-fluorophenyl)-1-oxoethyl]-4(R)-phenyl-2-oxazolidinone as a white crystalline solid. Alternately, 3-[2-(2-fluorophenyl)-1-oxoethyl]-4-(R)-phenyl-2-oxazolidinone is prepared as follows:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18]([CH3:19])=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:20])=[CH:5][CH:4]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18]([CH3:19])=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2c(C)cc3ccccc3c2=O)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc2ccccc2c(=O)n1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
2-(4-methoxyphenyl)-3-methyl-1(2H)-isoquinolinone (56 mg, 0.21 mmol) was dissolved in dry methylene chloride, a 1M methylene chloride solution (0.63 mL) of boron tribromide was slowly added at −10° C., and stirred at room temperature for 2 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the methylene chloride distilled off under reduced pressure. 8N hydrochloric acid aqueous solution was added, and the solid precipitate was filtered off and dried to obtain the target compound (48 mg, 91%) as a colorless solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[N:18])=[C:12]([Cl:19])[CH:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:31][CH2:32][CH2:33][CH2:34]Br>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:17]#[N:18])[CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:12]([Cl:19])[CH:11]=1
Reactant: BrCCCCBr
Reactant: N#CCc1ccc(-c2nc3ccccc3o2)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC1(c2ccc(-c3nc4ccccc4o3)cc2Cl)CCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of [4-(1,3-benzoxazol-2-yl)-2-chlorophenyl]acetonitrile (270 mg, 1.0 mmol) and THF (20 mL) was cooled to −78° C. A solution of NaHMDS (3.7 mL, 2.2 mmol, 0.6M solution in PhMe) was added dropwise via syringe to the reaction. After 15 min at −78° C., 1,4-dibromobutane (143 μL, 1.2 mmol) was added dropwise via syringe. The cooling bath was removed, and the reaction was allowed to warm to rt. The reaction was quenched by the addition of silica gel (600 mg) and concentrated to dryness. The residue was purified by flash chromatography on silica gel (EtOAc:hexanes 1:5) to afford the desired 1-[4-(1,3-benzoxazol-2-yl)-2-chlorophenyl]cyclopentanecarbonitrile as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.34 (s, 1H), 8.12 (dd, 1H), 7.77–7.80 (m, 1H), 7.56–7.62 (m, 2H), 7.35–7.42 (m, 2H), 2.71–2.78 (m, 2H), 2.14–2.26 (m, 2H), 1.89–2.01 (m, 4H). MS (ESI) 323 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH2:8]([S:10](Cl)(=[O:12])=[O:11])[CH3:9]>>[CH2:8]([S:10]([NH:1][CH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])(=[O:12])=[O:11])[CH3:9]
Reactant: CCS(=O)(=O)Cl
Reactant: COC(=O)CCN
Product: CCS(=O)(=O)NCCC(=O)OC

Procedure:
N-(ethylsulfonyl)-β-alanine, methyl ester (21) was prepared from methyl β-alaninate and ethanesulfonyl chloride on a 32 mmol scale in the manner described in Example 13 above to yield 1.53 g (24%) of product. Analysis calculated for C6H13NO4S 0.25 H2O (M.W. 199.74): C, 36.08; H, 6.81; N, 7.01; S, 16.05. Found: C, 36.03; H, 6.82; N, 6.97; S, 15.59.
Reaction SMILES: C[O:2][C:3](=[O:46])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[O:11][C:12]([C:15]3[N:16]([O:38]CC4C=CC=CC=4)[CH:17]([CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[NH:18][C:19]=3[CH2:20][O:21][C:22]34[CH2:31][CH:26]5[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]5)[CH2:23]3)[CH2:29]4)=[N:13][N:14]=2)[CH:5]=1.COC(=O)C1C=CC=C(C(N(C(C2N(OCC3C=CC=CC=3)C(C3CCCCC3)NC=2COC23CC4CC(CC(C4)C2)C3)=O)N)=O)C=1>>[C:22]12([O:21][CH2:20][C:19]3[NH:18][CH:17]([CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[N:16]([OH:38])[C:15]=3[C:12]3[O:11][C:10]([C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([OH:46])=[O:2])=[N:14][N:13]=3)[CH2:23][CH:24]3[CH2:30][CH:28]([CH2:27][CH:26]([CH2:25]3)[CH2:31]1)[CH2:29]2
Reactant: COC(=O)c1cccc(-c2nnc(C3=C(COC45CC6CC(CC(C6)C4)C5)NC(C4CCCCC4)N3OCc3ccccc3)o2)c1
Agent: COC(=O)c1cccc(C(=O)N(N)C(=O)C2=C(COC34CC5CC(CC(C5)C3)C4)NC(C3CCCCC3)N2OCc2ccccc2)c1
Product: O=C(O)c1cccc(-c2nnc(C3=C(COC45CC6CC(CC(C6)C4)C5)NC(C4CCCCC4)N3O)o2)c1

Procedure:
3-{5-[5-(Adamantan-1-yloxymethyl)-3-benzyloxy-2-cyclohexyl-1H-imidazol-4-yl]-[1,3,4]oxadiazol-2-yl}-benzoic acid methyl ester. The title compound was prepared essentially using the procedure in Example 9, step a, with the modification that 3-{N1-[5-(Adamantan-1-yloxymethyl)-3-benzyloxy-2-cyclohexyl-1H-imidazole-4-carbonyl]-hydrazinocarbonyl}-benzoic acid methyl ester was used instead of 3-{N1-[5-(Adamantan-1-yloxymethyl)-2-cyclohexyl-1H-imidazole-4-carbonyl]-hydrazinocarbonyl}-benzoic acid methyl ester. 1H NMR (CDCl3) 8.77 (1H, s), 8.33 (1H, d), 8.24 (1H, d), 7.63 (1H, t), 7.53 (2H, m), 7.45 (3H, m), 5.37 (2H, s), 4.77 (2H, s), 3.97 (3H, s), 2.73 (1H, m), 2.14 (3H, br s), 1.87-1.56 (19H, m), 1.27 (3H, m).
Reaction SMILES: [I-].C[S+](C)(C)=O.[H-].[Na+].[CH3:9]S(C)=O.[O:13]=[CH:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:19][CH2:18]1>O>[O:13]1[CH2:9][CH:14]1[CH2:15][O:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])[CH2:19][CH2:18]1
Reactant: CS(C)=O
Reactant: O=CCOC1CCN(C(=O)OCc2ccccc2)CC1
Agent: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(OCC2CO2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of trimethylsulfoxonium iodide (2.17 g), sodium hydride (oil, 60%, 395 mg) and dimethyl sulfoxide (20 mL) was stirred at room temperature for 1 hr, and benzyl 4-(2-oxoethoxy)piperidine-1-carboxylate (2.28 g) was added thereto. The obtained mixture was stirred at room temperature for 3 days. Water was added thereto, and the obtained mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (208 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][O:20][CH3:21]>CN(C)C=O.C(OCC)(=O)C>[CH3:19][O:20][CH2:21][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: COCCl
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCOc1cc([N+](=O)[O-])ccc1N
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 2-amino-5-nitrophenol (4.62 g) in N,N-dimethylformamide (150 no) was added potassium carbonate (12.44 g), and thereto was added dropwise chloromethylmethylether (2.73 mL). The mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on NH-silica gel (Chromatorex NH-silica gel; solvent; n-hexane/ethyl acetate=2/1) to give [2-(methoxymethoxy)-4-nitrophenyl]amine (4.76 g) as a yellow oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:9]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:8][C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:6][C:5]=1[OH:18].[CH:19](=O)[CH2:20][CH2:21][CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C.C(Cl)Cl>[C:10]([C:9]1[C:4]([CH2:3][NH:2][CH2:19][CH2:20][CH2:21][CH3:22])=[C:5]([OH:18])[CH:6]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:8]=1)([CH3:11])([CH3:12])[CH3:13]
Reactant: CCCC=O
Reactant: CC(C)(C)c1cc(O)c(CN)c(C(C)(C)C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCNCc1c(O)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 0.47 g (2.0 mmol) of the product of Example 19 and 0.15 g (2.1 mmol) of n-butyraldehyde in 10 mL of 1,2-dichloroethane was added 25 drops of acetic acid and 3 g of finely powdered 4 Å molecular sieves. The mixture was stirred 5 h at room temperature at which point 1 g of sodium triacetoxyborohydride was added. The reaction mixture was stirred overnight at room temperature, then diluted with 10 mL CH2Cl2 and filtered through a layer of Celite filter aid. The filtrate was washed with excess saturated aq. NaHCO3, the aqueous layer was extracted with CH2Cl2, then the organic layers were combined, dried (Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 0-10% EtOAc in CH2Cl2. Evaporation of the purified fractions and drying in vacuo afforded the title compound.