Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH2:43]C)=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.N[C:46]1[CH:53]=[CH:52]C=C[C:47]=1[CH2:48][OH:49].NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[CH:52][CH:53]=[CH:46][C:47]=4[CH2:48][OH:49])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:35][CH2:36][N:37]([C:40]([O:42][CH3:43])=[O:41])[CH2:38][CH2:39]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: Nc1ccccc1CO
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: COC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(NC(=O)Nc5ccccc5CO)cc4)nc32)CC1

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 2-aminobenzylalcohol as the aniline component. (12%, MS=613.3 (M+H))
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N+:8]([C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]=1Cl)[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15])([O-:10])=[O:9]>>[N+:8]([C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]=1[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15])([O-:10])=[O:9]
Reactant: CN1CCNCC1
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Product: CN1CCN(c2ccc(C(=O)c3ccccc3)cc2[N+](=O)[O-])CC1
Yield: 90 %

Procedure:
N-methyl-piperazine is reacted with 3-nitro-4-chloro-benzophenone as described in Example 7 or 8 to obtain 3-nitro-4-(N-methyl-piperazino)-benzophenone with a yield of 90 %. The product melts at 94 °C.
Reaction SMILES: C(O[C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([Cl:17])=[CH:11][C:10]=1[CH2:18][CH:19]([OH:22])[CH2:20][OH:21])C1C=CC=CC=1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.CC1C=CC(S(OCC(O)CC2C=C(Cl)C=C(OC)C=2OCC2C=CC=CC=2)(=O)=O)=CC=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.CC1C=CC(S(OCC(O)CC2C=C(Cl)C=C(OC)C=2O)(=O)=O)=CC=1.C1(O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>N1C=CC=CC=1.[Pd]>[CH3:33][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O:21][CH2:20][CH:19]2[CH2:18][C:10]3[CH:11]=[C:12]([Cl:17])[CH:13]=[C:14]([O:15][CH3:16])[C:9]=3[O:22]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc(Cl)cc(CC(O)CO)c1OCc1ccccc1
Agent: [Pd]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: COc1cc(Cl)cc(CC(O)COS(=O)(=O)c2ccc(C)cc2)c1O
Solvent: c1ccncc1
Solvent: Oc1ccccc1
Product: COc1cc(Cl)cc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Yield: 75.9 %

Procedure:
Treatment of (±)-3-[2-(benzyloxy)-5-chloro-3-methoxyphenyl]-1,2-propanediol (32 g, 0.1 mol) with p-toluenesulfonyl chloride (21 g, 0.11 mol) in pyridine generally according to the procedure described for intermediate 3 provided (±)-3-[2-(benzyloxy)-5-chloro-3-methoxyphenyl]-2-hydroxypropyl 4-methylbenzenesulfonate. Treatment of the tosylate with palladium on carbon (2.32 g, 5 wt. %) generally according to the procedure described for Intermediate 4 afforded (±)-3-(5-chloro-2-hydroxy-3-methoxyphenyl)-2-hydroxypropyl 4-methylbenzenesulfonate. Treatment of the phenol with triphenylphosphine (23.6 g, 0.09 mol) and diisopropyl azodicarboxylate (18.2 g, 0.09 mol) generally according to the procedure described for Intermediate 5 afforded 28 g (76%) of (±)-(5-chloro-7-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a pale yellow solid. mp 99-102° C.; Anal. calcd. for C17H17ClO5S: C, 55.36; H, 4.65. Found: C, 55.35; H, 4.62.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1>C(OCC)(=O)C>[CH3:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1cccc(-c2csc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2csc(N3CCNCC3)n2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.1 %

Procedure:
A 4 N solution (50 ml) of hydrogen chloride in ethyl acetate was added to a solution of tert-butyl 4-[4-(3-methylphenyl)-1,3-thiazol-2-yl]piperazine-1-carboxylate (2.00 g, 5.56 mmol) in ethyl acetate (50 ml), the mixture was stirred at room temperature for 12 hours, and the solvent was distilled off under reduced pressure. The residue was dissolved in water, neutralized with a 1 N sodium hydroxide aqueous solution, and extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 910 mg (62.9%) of the desired product as an oil.
Reaction SMILES: [NH:1]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[NH2:2].[C:10]1([S:16]([CH:19]=[CH2:20])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[C:10]1([S:16]([CH2:19][CH2:20][NH:2][NH:1][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=CS(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)NN
Solvent: CCO
Product: CC(C)(C)OC(=O)NNCCS(=O)(=O)c1ccccc1

Procedure:
A solution of 0.79 g tert-butyl hydrazinecarboxylate and 1.00 g phenylvinylsulphone in 8 ml of ethanol is refluxed for 5 h with stirring. Then the solvent is removed completely and the residue is chromatographed over silica gel (cyclohexane/ethyl acetate).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH:14]=C)[C:7]([O:9][CH3:10])=[O:8])[CH2:2][CH3:3].[O:16]=[O+][O-].CSC>CO.C(Cl)Cl>[CH:14]([C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[CH2:1][CH2:2][CH3:3])=[O:16]
Reactant: O=[O+][O-]
Reactant: C=Cc1ccc(C(=O)OC)cc1CCC
Solvent: CSC
Solvent: ClCCl
Solvent: CO
Product: CCCc1cc(C(=O)OC)ccc1C=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 59 %

Procedure:
To a magnetically stirred solution of 2.796 g (14.0 mmol) of the product of Step B dissolved in a mixture of 15 mL methanol and 5 mL methylene chloride was introduced a slow stream of ozone at -78° C. After 15 minutes a persistent blue color of excess ozone was observed and the flow of ozone was stopped. Excess methylsulfide (2 mL) was added via syringe, the reaction mixture was allowed to warm to room temperature, and stirring was continued for 12 hours. The reaction mixture was then concentrated on a rotary evaporator and then purified on a silica gel flash chromatography column eluted with 5% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded 1.677 g (59%) of the title compound as a clear oil.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]=[C:10]1[NH:16][CH2:15][CH2:14][N:13]([CH3:17])[C:12]2[CH:18]=[C:19](Cl)[CH:20]=[CH:21][C:11]1=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[F-].[Cs+]>O1CCOCC1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[CH2:1]([O:3][P:4]([CH:9]=[C:10]1[NH:16][CH2:15][CH2:14][N:13]([CH3:17])[C:12]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:20]=[CH:21][C:11]1=2)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(C=C1NCCN(C)c2cc(Cl)ccc21)OCC
Reactant: OB(O)c1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: CCOP(=O)(C=C1NCCN(C)c2cc(-c3ccccc3)ccc21)OCC
Temperature: 80 °C
Yield: 70.8 %

Procedure:
To 286 mg (0.83 mmol) of (8-chloro-1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester (prepared as described in Example 48) in 1 ml of dioxane was added 106 mg (0.87 mmol) of phenylboronic acid, 8.4 mg (0.03 mmol) of tricyclohexylphosphine, 11.5 mg 0.013 mmol)of tris-(dibenzylideneacetone)-palladium (0) and 152 mg of caesium fluoride. The mixture was heated at 80° C. for 14 hours. The mixture was purified by column chromatography (20 g IST pre-packed column) eluting with acetone—petroleum ether (40-60° C.) (1:2) to give 227 mg of (1-methyl-8-phenyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester as a yellow oil; MS: m/e 387 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:26])([CH2:18][O:19]C(=O)CCCC)[CH2:10][O:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16]>C([O-])(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:26])([CH2:10][O:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])[CH2:18][OH:19]
Reactant: CCCCC(=O)OCC(O)(COC(=O)CCCC)c1ccc(F)cc1F
Agent: CC(=O)[O-]
Product: CCCCC(=O)OC[C@](O)(CO)c1ccc(F)cc1F
Temperature: 30 °C
Yield: 65.2 %

Procedure:
A 200 ml reaction vessel was charged with 2 g of 2-(2,4-difluorophenyl)-1,3-di-n-pentanoyloxy-2-propanol, 100 mg of Lipase D made by Amano Pharmaceutical Co., Ltd. (derived from Rhizopus delemer, Enzyme No. 6) and 100 ml of 50 mM acetate buffer (pH 5). The resulting mixture was stirred at 30° C. to react for 18 hours. After the reaction liquid was extracted three times with 50 ml of ethyl acetate, the organic layers were combined and the combined organic layer was washed with saturated aqueous solution with sodium bicarbonate and with saturated aqueous solution with sodium chloride and further dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/2) to give 1.01 g of oily (R)-2-(2,4-difluorophenyl)-3-n-pentanoyloxy-1,2-propanediol. An optical purity thereof was determined in the same manner as Example 35. (Elution time: 13.7 minutes ((R)-form) and 11.1 minutes ((S)-form)).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH3:5].C([Li])CCC.[C:11]([C:15]1([C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:17][O:16]1)([CH3:14])([CH3:13])[CH3:12].C(OCC)C>CCCCC.CN(P(N(C)C)(N(C)C)=O)C>[C:11]([C:15]([OH:16])([CH2:17][C:1]#[C:2][CH2:3][CH2:4][CH3:5])[C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)C1(C(C)(C)C)CO1
Reactant: C#CCCC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCC#CCC(O)(C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 84.3 %

Procedure:
1.26 ml (12.8 mmol) 1-pentyne were added dropwise at 0° C. under argon for 5 minutes to 8.0 ml (12.8 mmol) of a 1.6-molar n-butyllithium solution in pentane. The solution obtained was cooled for another 15 minutes, and then the solvent was withdrawn under reduced pressure. 5 ml HMPA and a solution of 1.0 g (6.4 mmol) 2,2-di-tert-butyloxirane in 2 ml HMPA were added. The reaction solution was stirred for 20 hours at room temperature. Subsequently, it was processed analogous to Example 1. The raw product obtained was cleaned by means of a silica column with 2% diethyl ether/light gasoline. There were obtained 1.21 g (84%) 3-tert-butyl-2,2-dimethylnon-5-in-3-ol
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:3]1.CCN(C(C)C)C(C)C.Cl.Cl.[N:36]1([CH:41]2[CH2:45][CH2:44][NH:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:43]4[CH2:44][CH2:45][CH:41]([N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)[CH2:42]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:3]1
Reactant: C1CCN(C2CCNC2)C1
Reactant: O=C(NCC1CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCCC(F)(F)C1)c1c(Cl)ccc2nc(N3CCC(N4CCCC4)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-cyclohexylmethyl)-amide, DIPEA and 3-pyrrolidinyl-pyrrolidine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1H), 7.48 (2H), 6.69 (1H), 3.89 (m, 1H), 3.70 (m, 1H), 3.45 (m, 1H), 3.26 (m, 2H), 2.85 (m, 1H), 2.54 (m, 4H), 2.15 (m, 1H), 2.06 (m, 2H), 1.85 (m, 3H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 478 [M+H]
Reaction SMILES: [CH2:1]([CH:8]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)([O-])=O.[OH-].[K+]>>[CH2:1]([CH:8]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH2:24][C:23]2[CH:26]=[CH:27][C:20]([NH2:17])=[CH:21][CH:22]=2)[C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCCCCCC1Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Product: Nc1ccc(CC2CCCCCC(Cc3ccccc3)C2=O)cc1

Procedure:
This example illustrates the preparation of benzylcyclooctanones wherein the aromatic ring is substituted with an amino group. 2-Benzylcyclooctanone is allowed to react with equimolar amounts of p-nitrobenzaldehyde in refluxing methanolic potassium hydroxide for 3 hours. The 2-benzyl-8-(p-nitrobenzylidene)cyclooctanone which forms is removed by filtration and subjected to hydrogenation at 50 p.s.i.g. in the presence of 10 percent palladium on carbon using a solvent system comprising equal portions of ethyl acetate and acetic acid. The 2-benzyl-8-(p-aminobenzyl)cyclooctanone which is obtained from the hydrogenation is purified by converting it to the hydrochloride salt by means of hydrogen chloride introduced into an ethereal solution of the crude product. The melting point of the crude 2-benzyl8-(p-aminobenzyl)cyclooctanone hydrochloride is 175°-195° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:18]([OH:48])[CH:19]([CH2:45][CH2:46]O)[CH2:20][C:21]3[CH:22]=[C:23]([O:27][Si:28]([C:41]([CH3:44])([CH3:43])[CH3:42])([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:24]=[CH:25][CH:26]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH:19]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][Si:28]([C:41]([CH3:44])([CH3:43])[CH3:42])([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH:22]=4)[CH2:45][CH2:46][O:48]3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)[Si](Oc1cccc(CC(CCO)C(O)c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](Oc1cccc(CC2CCOC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1)(c1ccccc1)c1ccccc1
Yield: 118.7 %

Procedure:
A mixture of 3-[3-(4,5-diphenyloxazol-2-yl)-3-hydroxy-2-(2-hydroxyethyl)propyl]-1-(t-butyldiphenylsilyloxy)benzene (1.3 g) and p-toluenesulfonic acid (100 mg) in toluene (20 ml) was stirred under reflux for 6 hours. The solution was washed with sat. NaHCO3 and brine, dried over MgSO4, and evaporated in vacuo to afford crude 2-(4,5-diphenyloxazol-2-yl)-3-(3-t-butyldiphenylsilyloxybenzyl)tetrahydrofuran (1.5 g).
Reaction SMILES: BrC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]4)(=O)=O)=CC=1.Cl.Cl.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1.C(N(CC)C(C)C)(C)C>CS(C)=O.C(=O)(O)[O-].[Na+]>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([N:37]2[CH2:42][CH2:41][N:40]([CH2:12][C@@H:13]3[O:27][C:17]4=[C:18]5[C:23](=[CH:24][CH:25]=[C:16]4[O:15][CH2:14]3)[N:22]=[C:21]([CH3:26])[CH:20]=[CH:19]5)[CH2:39][CH2:38]2)=[CH:35][CH:36]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CN1CCN(c2ccc(Cl)cc2)CC1)O3
Temperature: 75 °C
Yield: 49.6 %

Procedure:
To a mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromobenzenesulfonate (577 mg, 1.28 mmol) and 4-chlorophenylpiperazine dihydrochloride (1.03 g, 3.81 mmol) in anhydrous DMSO (10 mL) was added N,N-diisopropylethylamine (1.33 mL, 3.81 mmol). The reaction mixture was heated at 75° C. overnight. The cooled reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Flash chromatography on silica gel (50% hexanes/EtOAc) afforded 260 mg (15%) of the title compound as a tan solid: MS EI m/z 410.09 [M+H]+.
Reaction SMILES: ClCC1N=NC=CC=1.C(N)CN.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][NH:20][CH2:21][CH2:22][NH2:23])[N:14]=1.[CH3:24][N:25]=[C:26]=[S:27]>>[CH3:24][NH:25][C:26]([NH:23][CH2:22][CH2:21][NH:20][CH2:19][C:15]1[N:14]=[N:13][CH:18]=[CH:17][CH:16]=1)=[S:27]
Reactant: NCCNCc1cccnn1
Reactant: CN=C=S
Agent: ClCc1cccnn1
Solvent: NCCN
Product: CNC(=S)NCCNCc1cccnn1

Procedure:
Reacting 3-chloromethylpyridazine with ethylenediamine by the procedure of Example 34 and reacting the resulting N-(3-pyridazinylmethyl)ethylenediamine with methyl isothiocyanate by the procedure of Example 3(b), then chromatographing gives N-methyl-N'-[2-(3-pyridazinylmethylamino)ethyl]thiourea. This intermediate is reacted with lead cyanamide by the procedure of Example 3(b) to give N-cyano-N'-methyl-N"-[2-(3-pyridazinylmethylamino)ethyl]guanidine. Hydrolysis of this compound by the procedure of Example 3(e) gives N-methyl-N'-[2-(3-pyridazinylmethylamino)ethyl]guanidine dihydrochloride.
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.C(CN)O.O>COCC(O)CO>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH2:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: COCC(O)CO
Solvent: O
Solvent: NCCO
Product: COC1=CC[C@H]2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Temperature: 20 °C
Reaction time: 1.25 h
Yield: 80.6 %

Procedure:
Thebaine (4.0 g dry basis, 12.9 mmol) is placed in a mixture of 3-methoxy-1,2-propanediol (13.0 g) and ethanolamine (1.3 g, 21.3 mmol, 1.65 equiv) and is heated at 110 to 114° C. p-Toluenesulfonylhydrazide (4.8 g, 25.8 mmol, 2.0 equiv) is dissolved at 15 to 25° C. in a mixture of ethanolamine (9.6 g, 157.2 mol, 12.2 equiv) and 3-methoxy-1,2-propanediol (0.8 g) and the solution is added in portions to the thebaine mixture over 1.25 hours. The reaction mixture is held at 110 to 114° C. for 1.25 hours then cooled to 15 to 25° C. and water (24 g) added while maintaining the batch temperature at ≦30° C. The resulting slurry (pH 10.9) is stirred, further cooled to 0 to 5° C. and then filtered. The product is washed with water (3×8 g) and dried at 40° C. to a constant weight to give 8,14-dihydrothebaine (3.26 g, 81.0% yield; 97.0 area % purity by HPLC).
Reaction SMILES: CN(C)C=O.[C:6]([C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][C:16]([OH:18])=O)=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7].Cl.[NH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[C:26]([F:35])[CH:25]=1.Cl.C(N=C=NCCCN(C)C)C>C(N(CC)CC)C>[C:6]([C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][C:16]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[C:26]([F:35])[CH:25]=2)=[O:18])=[CH:19][CH:20]=1)([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(OCC(=O)NCc2ccc(NS(C)(=O)=O)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 722.2 %

Procedure:
To a N,N-dimethylformamide (DMF) (10 ml) solution of (4-tert-butylphenoxy)acetic acid (50 mg, 0.2 mmol) and N-[4-(aminomethyl)-2-fluorophenyl]methanesulfonamide hydrochloride (40.4 mg, 0.2 mmol, J. Med. Chem. 2003, 46, 3116–3126), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (112 mg, 0.6 mmol), 1-hydroxybenzotriazole(HOBt) monohydrate (catalytic amount 5 mg) and triethylamine (0.3 ml) were added and the mixture was stirred for 3 hours at ambient temperature. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate and then crude products were extracted with methylene dichloride. The organic layer was then washed with brine and dried over sodium sulfate. After filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with methylene dichloride/methanol=9/1 to furnish 0.59 g (75% yield) of the title compound as a white solid.
Reaction SMILES: [NH3:1].[N+:2]([C:5]1[C:6](F)=[CH:7][C:8]([Cl:24])=[C:9]([CH:23]=1)[C:10]([NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([F:22])([F:21])[F:20])[CH2:15][CH2:14]1)=[O:11])([O-:4])=[O:3].C1COCC1>O>[N+:2]([C:5]1[C:6]([NH2:1])=[CH:7][C:8]([Cl:24])=[C:9]([CH:23]=1)[C:10]([NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([F:22])([F:21])[F:20])[CH2:15][CH2:14]1)=[O:11])([O-:4])=[O:3]
Reactant: N
Reactant: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1cc([N+](=O)[O-])c(F)cc1Cl
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(Cl)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Conc. ammonia (0.8 ml) was added portionwise at −10° C. to a mixture of 5-nitro-2-chloro-4-fluoro-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-benzamide (0.20 g, 0.54 mmol) and 10 ml THF and it was stirred overnight at room temperature. Water was added and the mixture was conc. i.vac. The residue was triturated with water and filtered. The filter cake was washed with water and dried to obtain the crude subtitle compound (MS m/z: 366 [M+H]+).
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:10].[H-].[Na+].F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1>CN(C=O)C.C(OCC)(=O)C>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([N:3]2[C:4]3=[N:5][CH:6]=[CH:7][CH:8]=[C:9]3[O:1][C:2]2=[O:10])=[CH:15][CH:16]=1)([O-:22])=[O:21]
Reactant: O=c1[nH]c2ncccc2o1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1oc2cccnc2n1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 19.3 %

Procedure:
A solution of oxazolo[4,5-b]pyridin-2(3H)-one (200 mg) in DMF (3.5 mL) was treated with a 60% dispersion of sodium hydride in mineral oil (62 mg) and the resulting mixture stirred at ambient temperature for 5 min. The mixture was treated with 1-fluoro-4-nitrobenzene (248 mg) then stirred at 100° C. for 17 h. After this time, the reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (100 mL), washed with water (2×50 mL), 5% aqueous lithium chloride (50 mL) then brine (50 mL), dried over sodium sulfate, and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, heptane to 1:1 ethyl acetate/heptane) to afford 3-(4-nitrophenyl) [1,3]oxazolo[4,5-b]pyridin-2(3H)-one (73 mg) as a yellow solid.