Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:35][CH2:36][CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[NH:40][CH:39]=1.C(Cl)CCl.CO>C(Cl)(Cl)Cl>[NH:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:38]([CH2:37][CH2:36][NH:35][C:12](=[O:13])[C:11]2[CH:15]=[C:16]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:17]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=2)=[CH:39]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=C(O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: Cl
Solvent: ClCCCl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NCCc1c[nH]c2ccccc12)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
2d was synthesized the condensation of 3, 4, 5-tris(benzyloxy)benzoic acid (480 mg, 1.09 mmol) and tryptamine hydrochloride (256 mg, 1.308 mmol) using standard EDC coupling method. 2d was isolated as white solid (482 mg, 76%) by elution with 0.5% methanol in chloroform. Rf: 0.538 (1.5% methanol in chloroform); mp: 105-107° C.; IR (neat) νmax 3413.77, 1637.45, 1579.59, 1496.66; 1H NMR (300 MHz, CDCl3) δ 2.96 (t, J=6.14 Hz, 2H), 3.63 (t, J=6.2 Hz, 2H), 4.89 (s, 4H), 4.96 (s, 2H), 6.08 (bs, 1H), 6.85 (S, 3H), 6.87-7.25 (m 18H), 7.54 (d, J=7.5 Hz, 1H), 8.21 (bs, 1H); 13C NMR (75 MHz, CDCl3) δ 24.90, 40.65, 71.01 (2C), 75.05, 106.44 (2C), 111.39, 118.48, 119.36, 121.98, 122.30, 126.86, 127.44 (6C), 127.88, 128.09, 128.40 (6C), 128.48, 129.97, 136.33, 136.56 (2C), 137.31, 140.69, 140.92, 152.54 (2C), 167.12; MS (ESI) m/z calcd. for C38H34N2O4: 582.25. found: 605.07 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[N:11]([CH2:19][C:20]2[O:21][CH:22]=[CH:23][N:24]=2)[C:10]=1[CH:25]([CH3:27])[CH3:26])=[O:8].[CH2:32](I)[CH2:33][CH3:34]>>[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:32][CH2:33][CH3:34])=[CH:15][CH:16]=2)[N:11]([CH2:19][C:20]2[O:21][CH:22]=[CH:23][N:24]=2)[C:10]=1[CH:25]([CH3:27])[CH3:26])=[O:8]
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ncco1
Reactant: CCCI
Product: CCCOc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ncco3)c2c1

Procedure:
The title compound was prepared from N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1-(oxazol-2-ylmethyl)-1H-indole-3-carboxamide (Compound 210) and n-propyl iodide by General Procedure N.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:48][C:49]1[S:50][CH:51]=[C:52]([CH3:54])[N:53]=1.Cl>C(Cl)Cl.O.C(OCC)(=O)C>[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35]([NH:48][C:49]2[S:50][CH:51]=[C:52]([CH3:54])[N:53]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1
Reactant: Cc1csc(N)n1
Agent: Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1csc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48.4 %

Procedure:
A solution of triphenylphosphine (345 mg, 1.31 mmol) in methylene chloride (4 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (234 mg, 1.31 mmol). The reaction mixture was stirred at 0° C. for 15 min and then treated with 3-cyclopentyl-2(R)-(4-methanesulfonylphenyl)propionic acid (300 mg, 1.01 mmol). The resulting reaction mixture was stirred at 0° C. for 5 min and then allowed to warm to 25° C. where it was stirred for 25 min. The reaction mixture was then treated with 2-amino-4-methylthiazole (288 mg, 2.52 mmol). The resulting reaction mixture was allowed to stir at 25° C. for 20 h. The reaction mixture was then diluted with water (30 mL), a 1N aqueous hydrochloric acid solution (5 mL), and ethyl acetate (30 mL). The layers were separated, and the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-N-(4-methyl-thiazol-2-yl)-propionamide (192 mg, 48%) as an off-white foam: mp 83-87° C. (foam to gel); [α]23589=−35.7° (c=1.01, chloroform); EI-HRMS m/e calcd for C19H24N2O3S2 (M+) 392.1228, found 392.1227.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16]>C(O)C>[N+:15]([C:6]1[CH:7]=[C:8]([S:11](=[O:13])(=[O:12])[NH2:14])[CH:9]=[CH:10][C:5]=1[NH:2][NH2:3])([O-:17])=[O:16]
Reactant: NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
20 ml of hydrazine hydrate were added to a suspension of 47.33 g of 4-chloro-3-nitrobenzenesulfonamide [prepared as described in: J. Am. Chem. Soc. 73, 2558 (1951)] in 200 ml of abs. ethanol. The mixture was boiled under stirring for 30 minutes, then cooled down. The crystals were filtered by suction and thoroughly washed with water to obtain 43.38 g (93.4%) of 2-nitro-4-sulfamoylphenylhydrazine, m.p.: 217°-218° C. (with decomposition).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH3:10][C:11]1([CH3:33])[CH:16]2[CH2:17][CH:13]([CH2:14][CH2:15]2)[CH:12]1[CH2:18][CH2:19][C:20](=O)[CH2:21][CH2:22][CH:23]1[C:28]([CH3:30])([CH3:29])[CH:27]2[CH2:31][CH:24]1[CH2:25][CH2:26]2.[C:34](#[N:37])[CH:35]=[CH2:36]>>[NH2:37][CH2:34][CH2:35][CH2:36][N:7]1[CH2:8][CH2:9][CH:4]([CH2:3][CH2:2][NH:1][CH:20]([CH2:21][CH2:22][CH:23]2[C:28]([CH3:29])([CH3:30])[CH:27]3[CH2:31][CH:24]2[CH2:25][CH2:26]3)[CH2:19][CH2:18][CH:12]2[C:11]([CH3:33])([CH3:10])[CH:16]3[CH2:15][CH:14]2[CH2:13][CH2:17]3)[CH2:5][CH2:6]1
Reactant: CC1(C)C2CCC(C2)C1CCC(=O)CCC1C2CCC(C2)C1(C)C
Reactant: C=CC#N
Reactant: NCCC1CCNCC1
Product: CC1(C)C2CCC(C2)C1CCC(CCC1C2CCC(C2)C1(C)C)NCCC1CCN(CCCN)CC1

Procedure:
As an alternative to obtaining a mixture of Schiff bases VI and VI(a) or VI(b), the reaction can be conducted stepwise. For example, 4-(2-aminoethyl)piperidine may be converted to a Schiff base with 1,5-di-[3,3-dimethylbicyclo[2.2.1]hept-2-yl]pentan-3-one, catalytically reduced, the ring nitrogen selectively cyanoethylated with acrylonitrile, followed by catalytic hydrogenation to furnish 1-(3-aminopropyl)-4-[2-(1,5-di-[3,3-dimethylbicyclo[2.2.1]hept-2-yl]-3-pentylamino)ethyl]piperidine.
Reaction SMILES: C(N(CC)CC)C.O=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].Cl.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30]N)=[CH:26][CH:25]=1.CCOCC>C(O)C>[CH3:23][C:24]1[CH:25]=[C:26]2[C:27](=[CH:28][CH:29]=1)[NH:30][C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:10]2[CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: Cc1ccc(NN)cc1
Reactant: O=C(O)CCCC(=O)c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc2[nH]c(-c3ccccc3)c(CCC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.1 %

Procedure:
Triethylamine (1.4 mL, 10 mmol) was added to a stirred suspension of δ-oxobenzenepentanoic acid (1.92 g, 10 mmol) and (4-methylphenyl)hydrazine hydrochloride (1.59 g, 10 mmol) in ethanol (16 mL) and the mixture was stirred at room temperature for 4 h. Ether (100 mL) was added, the mixture was filtered and the solvent was evaporated under reduced pressure. The residue was added slowly to trifluoroacetic acid (15 mL) and the mixture was heated under reflux for 2 h. The mixture was cooled, water (100 mL) was added and the mixture was extracted with ethyl acetate (100 mL). The organic fraction was washed with brine (30 mL), dried (MgSO4) and the volume was reduced to Ca. 10 mL by evaporation under reduced pressure. The precipitate was collected and recrystallized from ether to give the title compound as a pale solid (1.51 g, 54%). 1H NMR (360 MHz, DMSO-d6) δ2.39 (3H, s), 2.50-2.58 (2H, m), 3.03-3.09 (2H, m), 6.91-6.95 (1H, m), 7.23-7.25 (1H, m), 7.34-7.40 (2H, m), 7.47-7.63 (4H, m), 11.4 (1H, br s), and 12.25 (1H, br s). m/z (ES+) 280 (M+1).
Reaction SMILES: C1(OC)C=CC=CC=1.[CH3:9][O:10][N:11]=[C:12]([C:51]1[N:52]=[N:53][S:54][CH:55]=1)[C:13]([NH:15][C:16]1([O:49][CH3:50])[C:47](=[O:48])[N:18]2[C:19]([C:31]([O:33]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:32])=[C:20]([CH2:23][S:24][C:25]3[N:29]([CH3:30])[N:28]=[N:27][N:26]=3)[CH2:21][S:22][C@H:17]12)=[O:14].FC(F)(F)C(O)=O>ClCCCl>[CH3:9][O:10][N:11]=[C:12]([C:51]1[N:52]=[N:53][S:54][CH:55]=1)[C:13]([NH:15][C:16]1([O:49][CH3:50])[C:47](=[O:48])[N:18]2[C:19]([C:31]([OH:33])=[O:32])=[C:20]([CH2:23][S:24][C:25]3[N:29]([CH3:30])[N:28]=[N:27][N:26]=3)[CH2:21][S:22][C@H:17]12)=[O:14]
Reactant: CON=C(C(=O)NC1(OC)C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nnnn3C)CS[C@@H]21)c1csnn1
Solvent: ClCCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CON=C(C(=O)NC1(OC)C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@@H]21)c1csnn1
Reaction time: 2 h
Yield: 32.1 %

Procedure:
Anisole (0.86 ml.) was added at ambient temperature to a solution of diphenylmethyl 7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-7-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer) (0.86 g.) in dry 1,2-dichloroethane (10 ml.), and then trifluoroacetic acid (1.68 g.) was added dropwise thereto under ice-cooling. The resulting mixture was stirred for 2 hours under ice-cooling and the reaction mixture was concentrated under reduced pressure. To the residue were added ethyl acetate (20 ml.) and water (20 ml.). After shaking the mixture, the ethyl acetate layer was separated. The remaining aqueous layer was further extracted with ethyl acetate (10 ml. and 5 ml.). The ethyl acetate layers were combined and 10% aqueous solution of dipotassium hydrogen phosphate (20 ml.) was added thereto. The mixture was shaken and the aqueous layer was separated. The ethyl acetate layer was further extracted with 10% aqueous solution of dipotassium hydrogen phosphate (10 ml. and 5 ml.). The aqueous layers were combined and washed in turn with ethyl acetate (10 ml. and 5 ml.) and ether (10 ml.). The remaining solvent in the aqueous layer was removed by bubbling of nitrogen gas. The resulting aqueous layer was adjusted to pH 2 with 10% hydrochloric acid under ice-cooling. Precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-7-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.21 g.).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:22]>C(Cl)Cl>[F:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:22])=[CH:7][CH:8]=1
Reactant: Fc1ccc(SCc2ccccn2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: O=S(Cc1ccccn1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.3 %

Procedure:
A stirred suspension of 2-(((4-fluorophenyl)thio)methyl)pyridine, hydrochloride (2 g) in methylene chloride (50 ml) at 0° C. was treated portionwise with m-chloroperoxybenzoic acid (1.8 g) over 1/2 hour. The mixture was allowed to warm to ambient temperature and the mixture was stirred for a further 4 hours. The solution was washed with saturated Na2CO3 solution and water, dried (MgSO4) and evaporated. The residue was recrystallised from diisopropyl ether to give the title compound (1.0 g) mp 92°-4° C. (Found: C,60.9; H,4.6; N,5.6 C12H10FNOS requires C,61.3; H,4.3; N,5.95%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:14]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:15]([CH:20]=O)=[CH:16][CH:17]=[CH:18][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:14]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][N:11]1[CH2:12][CH2:13][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:9][CH2:10]1
Reactant: O=Cc1ccccc1-c1ccccc1
Reactant: Fc1cccc(N2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Fc1cccc(N2CCN(Cc3ccccc3-c3ccccc3)CC2)c1

Procedure:
80 mg of the target compound (0.23 mmol, 28.0%) was obtained using 1-(3-fluorophenyl)piperazine (296 mg, 1.64 mmol), biphenyl-2-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(O)C[OH:15]>>[CH:2]([OH:15])([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:1]
Reactant: C=CCCCCCCCCCC
Reactant: OCCO
Product: CCCCCCCCCCC(C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.4 %

Procedure:
A reaction vessel of glass, 3000 ml in inner volume, provided with stirring vanes and a reflux condenser was charged with 810 g (4.82 mols) of 1-dodecene, 900 g (14.52 mols) of monoethylene glycol, and 100 g of the BEA type zeolite (produced by PQ Corp. and marketed under trademark designation of "VALFOR CP 811 BL-25"). The vapor-phase part of the reaction vessel was displaced with nitrogen and then retained in the atmosphere of nitrogen at normal pressure. The reaction mixture was heated to and kept at 150° C. for three hours and meanwhile kept stirred at 600 rpm to induce reaction. The reaction solution was cooled to room temperature. The dodecene phase in the upper layer was separated and distilled to expel the unaltered dodecene. The residue of the distillation was treated under a reduced pressure of 2 mmHg in a boiling point range of 129° to 131° C. to obtain 255 g of a secondary dodecanol ethoxylate composition.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[CH:5]=[O:6].[H-].[Na+].I[CH3:15]>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[O:10][CH3:15])[CH:5]=[O:6]
Reactant: Cc1cc(C=O)cc(I)c1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1c(C)cc(C=O)cc1I
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
At 5° C., to a stirred solution of 3-iodo-4-hydroxy-5-methylbenzaldehyde (3.53 g, 13.5 mmol) in THF (67.4 mL) was added 60% sodium hydride/mineral oil (0.701 g, 17.5 mmol). After 0.5 h, to the reaction was added dropwise iodomethane (1.34 mL, 21.6 mmol). After 2 h, the reaction was heated at 60° C. After 3 days, the reaction was cooled to ambient temperature, quenched with H2O (100 mL) and extracted with ether. The ethereal extracts were washed with 1N NaOH (3×), with brine (3×), dried (K2CO3) and concentrated. Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave 2.24 g (60%) of the title compound. 1H NMR (DMSO-d6) δ 2.37 (s, 3 H), 3.77 (s, 3 H), 7.78 (s, 1 H), 8.17 (s, 1 H), 9.86 (s, 1 H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:12]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([NH:34][C:35]3[S:36][CH:37]=[CH:38][N:39]=3)(=[O:33])=[O:32])=[CH:27][CH:26]=2)[N:11]=1.CO>ClCCl>[ClH:9].[ClH:9].[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:12]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([S:31]([NH:34][C:35]4[S:36][CH:37]=[CH:38][N:39]=4)(=[O:33])=[O:32])=[CH:27][CH:26]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=S(=O)(Nc1nccs1)c1ccc(Nc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Solvent: ClCCl
Solvent: CO
Product: Cl
Product: N[C@H]1CC[C@H](Nc2nc(Nc3ccc(S(=O)(=O)Nc4nccs4)cc3)c3ncn(C4CCCC4)c3n2)CC1
Reaction time: 3 h

Procedure:
400 mg of trans-1,4-diaminocyclohexane is taken to approximately 150° C. then 333 mg of the product obtained in Stage 1 above is added, the reaction medium is left under agitation for 3 hours then left to return to ambient temperature and diluted with 30 ml of dichloromethane. 10 ml of methanol is added, followed by washing with 10 ml of water, drying and evaporating the solvents. Chromatography on silica is carried out (eluent: MeOH/NH4OH 98/2), the residue is taken up in an ethanolic solution of hydrochloric acid, followed by evaporating the solvents, impasting in ether, separating, drying under reduced pressure at ambient temperature and 66 mg of expected product is recovered.
Reaction SMILES: [F:1][CH:2]([F:15])[C@H:3]1[CH2:8][N:7](S(C)(=O)=O)[CH2:6][C@@H:5]([OH:13])[C@@H:4]1[OH:14].CS([Cl:20])(=O)=O>>[ClH:20].[F:15][CH:2]([F:1])[C@H:3]1[CH2:8][NH:7][CH2:6][C@@H:5]([OH:13])[C@@H:4]1[OH:14]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)N1C[C@@H](O)[C@H](O)[C@@H](C(F)F)C1
Product: Cl
Product: O[C@H]1[C@H](O)CNC[C@@H]1C(F)F

Procedure:
(3R,4R,5S)-5-(Difluoromethyl)-1-(methanesulfonyl)piperidine 3,4-diol (8b; Z=SO2; R5=Me). Following General Procedure D except that the reaction was run at room temperature and using methanesulfonyl chloride (0.16 g, 1.4 mmol), the title compound was obtained as a white solid (0.17 g, 51%). 1H NMR (DMSO-d6) 6.2 (t, 1H, J=53 Hz), 5.43 (d, 1H, ex), 5.38 (d, 1H, ex), 3.2-3.7 (m, 4H), 2.95 (s, 3H), 2.85 (m, 1H), 2.7 (t, 1H), 2.1 (br s, 1H). (3R,4R,5S)-5-(Difluoromethyl)-1-tosylpiperidine 3,4-diol (8b; Z=SO2; R5=Ph) Following General Procedure D except that the reaction was run at room temperature and using toluenesulfonyl chloride (0.26, 1.4 mmol), the title compound was obtained as a white solid (0.35 g, 67%). 1H NMR (DMSO-d6) 7.6 (d, 2H), 7.45 (d, 2H), 6.25 (t, 1H, J=53 Hz), 5.4 (2d, 2H, ex), 3.3-3.55 (m, 4H), 3.2 (m, 1H), 2.5 (m, 3H), 2.4 (t, 1H), 2.1 (m, 1H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:2].[CH3:11][S:12]([NH:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([N:22]2[CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1)(=[O:14])=[O:13].[OH-].[NH4+].[P:29](=[O:33])([OH:32])([OH:31])[OH:30]>C(#N)C.CO>[P:29](=[O:30])([OH:33])([OH:32])[OH:31].[CH2:1]([N:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:24][CH2:23][NH:22][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([NH:15][S:12]([CH3:11])(=[O:13])=[O:14])=[CH:26][CH:25]=1)[CH3:2]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)N2CC2)cc1
Reactant: CCCCCCCNCC
Agent: O=P(O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: CCCCCCCN(CC)CCNC(=O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
0.60 g (4.16 mmol) of N-ethylheptanamine and 0.50 g (2.08 mmol) of 1-[4-[(methylsulfonyl)amino]benzoyl]aziridine are dissolved in 10 mL of acetonitrile and the solution is warmed to 50° C. for 48 hours. The reaction is monitored by thin-layer chromatography (silica gel (EM); acetonitrile:conc. ammonium hydroxide (90:10)). After 48 hours, the reaction mixture is evaporated and the resultant solid is dissolved in 20 mL of methylene chloride. This solution is extracted with 2×10 mL of 1N aq. sodium hydroxide. The aqueous extract is acidified to pH=1 with 6N aq. hydrochloric acid and extracted with 2×15 mL of methylene chloride. The combined organic extracts are neutralized with saturated aqueous sodium bicarbonate and washed with 10 mL of water. The organic layer is dried over sodium sulfate, filtered and evaporated on a rotary evaporator to provide an oil. This oil is dissolved in 20 mL of 50% aqueous methanol and titrated to pH=4.5 with 0.1N aq. phosphoric acid. This solution is evaporated on the rotary evaporator and residual water is removed by azeotroping with 20 mL of alcohol. This residue is crystallized from 8 mL of reagent alcohol to provide the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:16])[C:9](=[O:15])[N:10]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:5]2=[CH:4][CH:3]=1.[C:17]([Si:21]([CH3:37])([CH3:36])[O:22][CH2:23][CH2:24]/[CH:25]=[CH:26]/B1OC(C)(C)C(C)(C)O1)([CH3:20])([CH3:19])[CH3:18].[C:38]([O-])([O-])=O.[Cs+].[Cs+].O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O1CCOCC1>[Si:21]([O:22][CH2:23][CH2:24]/[CH:25]=[CH:26]/[C:2]1[N:7]=[C:6]2[N:8]([CH3:16])[C:9](=[O:15])[N:10]([CH2:11][C:12]([CH3:13])([CH3:14])[CH3:38])[C:5]2=[CH:4][CH:3]=1)([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:36])[CH3:37]
Reactant: CC1(C)OB(/C=C/CCO[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: O=C([O-])[O-]
Reactant: Cn1c(=O)n(CC2CC2)c2ccc(Cl)nc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(/C=C/CCO[Si](C)(C)C(C)(C)C)nc21
Temperature: 100 °C
Reaction time: 18 h

Procedure:
5-Chloro-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1-4, 1.0 g, 3.9 mmol, 1.0 equiv), tert-butyl(dimethyl){[(3E)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-1-yl]oxy}silane (32-1, 2.1 mL, 5.9 mmol, 1.5 equiv), Cs2CO3 (2.6 g, 7.9 mmol, 2.0 equiv) and Bis(tri-tert-butylphosphine)palladium(0) (0.40 g, 0.79 mmol, 0.2 equiv) were added to water (0.94 mL) and 1,4-dioxane (4.7 mL). The resulting mixture was heated to 100° C. and stirred for 18 h. Following this duration, LCMS showed consumption of 1-4. The contents were filtered through Celite and washed with ethyl acetate (10 mL). The filtrate was diluted with saturated NaHCO3 (50 mL) and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (3×20 mL) and the combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give a dark red oil. Purification by normal-phase HPLC (0-30% EtOAc:hexane) afforded 32-2 as an orange oil. MS m/z (M+H): calculated=404.2728; observed=404.2736.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:6].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:13]([NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:6])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: NCCNC(=O)c1cccnc1
Solvent: CCO
Product: O=C(NCCNCc1ccccc1)c1cccnc1
Reaction time: 1 h

Procedure:
A solution of N-(2-aminoethyl)pyridine-3-carboxamide (26.5 g.) and benzaldehyde (16.35 ml.) in ethanol (220 ml.) was kept for 48 hours. A small quantity of solid was removed by filtration. Sodium borohydride (6.1 g.) was then added to the filtrate which was stirred for 1 hour. Glacial acetic acid was then added cautiously until the solution was neutral. The solution was diluted with water (100 ml.) and basified with 2M sodium hydroxide. The mixture was extracted with ethyl acetate (3×200 ml.) and the extracted washed with saturated brine, dried (Na2SO4) and evaporated. The residue was purified by chromatography on a column of Florisil (200 g.), eluting with ethyl acetate, to yield N-[2-(benzylamino)ethyl]pyridine-3-carboxamide (29.5 g.) as a pale brown oil.