Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]1([NH:14][NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:16][O:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=1[S:24]([O:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=O)(=[O:26])=[O:25]>C1C=CC=CC=1>[C:8]1([NH:14][N:15]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][O:27][S:24]([C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:17][CH3:16])(=[O:26])=[O:25])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COc1ccccc1S(=O)(=O)OCC(=O)c1ccccc1
Reactant: NNc1ccccc1
Solvent: c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: COc1ccccc1S(=O)(=O)OCC(=NNc1ccccc1)c1ccccc1

Procedure:
Into a reactor, equipped with a Dean-Stark separator, were introduced 100 ml of benzene, 1 ml of acetic anhydride, 10.8g (0.1 mol) of phenylhydrazine and 30.6 g (0.1 mol) of 3-methoxy-4-benzenesulphonyloxy-acetophenone. The reaction medium was stired and refluxed for 1 hour.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].CC(=CC)C.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH:36]=[O:37])[CH:25]([F:38])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>O.O1CCOCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]([OH:6])=[O:37])[CH:25]([F:38])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=P([O-])(O)O
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C=O)C(F)C1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2C(=O)O)C(F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A solution of sodium chlorite (274 mg; 3.03 mmol; 5 eq.) and sodium dihydrogen phosphate (291 mg; 2.42 mmol; 40 eq.) in water (4 mL) was added dropwise to a solution of 2-methyl-but-2-ene (0.5 mL) and 3-fluoro-4-(2-formyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (196 mg; 0.61 mmol; 1 eq.) in 1,4-dioxane (4 mL) and the resulting mixture was stirred a room temperature for 3 hours. The dioxane was evaporated in vacuo and the pH made acidic with 1M HCl. The solution was extracted with ethyl acetate (2×), washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (205 mg, 100%) as a yellow oil. UPLC/MS: (MS−) 338.2 ([M−H]−).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([C:13](=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].C(N(CC)CC)C.[C:30](Cl)(=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].O>C(Cl)Cl>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:22])[C:13](=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:30](=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:15]=1)[CH3:12]
Reactant: CCOC(=O)CN(CC(=O)OCC)C(=O)c1cccc(N)c1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)Nc1cccc(C(=O)N(CC(=O)OCC)CC(=O)OCC)c1
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To an ice bath cooled solution of 3.1 g (10.06 mmol) of N-(3-aminobenzoyl)-N-(2-ethoxy-2-oxoethyl)glycine ethyl ester and 2.6 ml (19 mmol) of triethylamine in 60 ml of methylene chloride was added dropwise 3.2 ml (9.6 mmol) of stearoyl chloride. The reaction mixture was stirred in the cold for 30 minutes and then at room temperature for 5 hours. The mixture was poured into water containing 1N HCl and the product was extracted with ethyl acetate. The dried extract was concentrated to a solid which was purified by chromatography on 70 g of silica gel using 35% ethyl acetate: 10% methylene chloride: 55% hexane and then recrystallization from ethyl acetate-hexane to give 4.5 g (78% yield, mp 76°-79°) of N-(2-ethoxy-2-oxoethyl)-N-[3-(1-oxooctadecylamino)benzoyl]glycine ethyl ester.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:11]1[N:12]=[N+:13]([O-:24])[C:14]2[C:23]3[CH2:22][CH2:21][CH2:20][C:19]=3[CH:18]=[CH:17][C:15]=2[N:16]=1>COCCOC>[N:1]1([CH2:7][CH2:8][NH:9][C:11]2[N:12]=[N+:13]([O-:24])[C:14]3[C:23]4[CH2:22][CH2:21][CH2:20][C:19]=4[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [O-][n+]1nc(Cl)nc2ccc3c(c21)CCC3
Reactant: NCCN1CCCCC1
Solvent: COCCOC
Product: [O-][n+]1nc(NCCN2CCCCC2)nc2ccc3c(c21)CCC3
Yield: 93.4 %

Procedure:
2-(1-Piperidinyl)ethylamine (0.32 mL, 2.2 mmol) was added to a stirred solution of chloride 5 (165 mg, 0.7 mmol) in DME (30 mL) and the solution stirred at reflux temperature for 5 h. The solvent was evaporated and the residue was partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 12 (205 mg, 88%) as a pale yellow solid: mp (MeOH) 152-155° C.; 1H NMR δ 7.53 (d, J=8.4 Hz, 1H, H-5), 7.38 (d, J=8.4 Hz, 1H, H-6), 5.90 (br s, 1H, NH), 3.60-3.66 (m, 2H, H-9), 3.48-3.54 (m, 2H, CH2N), 2.97 (br t, J=7.7 Hz, 2H, H-7), 2.57 (dd, J=6.1, 5.9 Hz, 2H, CH2N), 2.38-2.45 (m, 4H, 2×CH2N), 2.17 (br p, J=7.7 Hz, 2H, H-8), 1.55-1.61 (m, 4H, 2×CH2), 1.41-1.48 (m, 2H, CH2); 13C NMR δ 158.4, 149.0, 142.0, 137.3, 132.2, 129.1, 124.6, 56.9, 54.2 (2), 37.9, 35.3, 32.8, 25.9 (2), 24.8, 24.4. Anal. calcd for C17H23N5O: C, 65.2; H, 7.4; N, 22.4. Found: C, 65.1; H, 7.2; N, 22.5%.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[N:34]=[C:35]([CH2:38][CH3:39])[O:36][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:38]([C:35]1[O:36][CH:37]=[C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])[N:34]=1)[CH3:39]
Reactant: CCc1nc(CCl)co1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)co1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (590 mg; compound B50) is reacted with 4-(chloromethyl)-2-ethyl-1,3-oxazole (200 mg; compound D15) in the presence of potassium carbonate (190 mg) in DMF (15 ml). Using WU2 the title compound is obtained after flash column chromatography [silica gel, eluent: cyclohexane/EtOAc, 3/2 (v/v)] as a solid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Mg]Cl)(C)C.[Br:12][C:13]1[C:14]([F:21])=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17]>C1COCC1>[Br:12][C:13]1[C:14]([F:21])=[C:15]([CH:16]([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[OH:17])[CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1cccc(Br)c1F
Reactant: Brc1nccs1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC(c1nccs1)c1cccc(Br)c1F
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 2-bromothiazole (0.088 mL, 0.985 mmol) in THF (2.99 mL) cooled to 0° C. was added isopropylmagnesium chloride (0.493 mL, 0.985 mmol). After 50 min, 3-bromo-2-fluorobenzaldehyde (0.200 g, 0.985 mmol) was added. The reaction mixture was allowed to warm to room temperature overnight. After 12 hr, the reaction was quenched with saturated aqueous NH4Cl. The reaction mixture was diluted with CH2Cl2. The layers were separated. The aqueous phase was extracted with CH2Cl2 (2×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford the title compound as a brown liquid.
Reaction SMILES: [C:1]([CH2:3][C@@H:4]([OH:24])[CH2:5][C:6](=[O:23])[CH2:7][C:8]([N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])#[N:2].CO.COB(CC)CC.[BH4-].[Na+]>O1CCCC1.C(OCC)(=O)C>[C:1]([CH2:3][CH:4]([OH:24])[CH2:5][CH:6]([OH:23])[CH2:7][C:8]([N:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:9])#[N:2]
Reactant: N#CC[C@@H](O)CC(=O)CC(=O)N(c1ccccc1)c1ccccc1
Agent: CCB(CC)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: N#CCC(O)CC(O)CC(=O)N(c1ccccc1)c1ccccc1
Temperature: -20 °C
Reaction time: 10 h

Procedure:
Crude (R)-6-cyano-5-hydroxy-3-oxo-N,N-diphenylhexanamide, approximately 0.2 mol, is dissolved in tetrahydrofuran (200 mL) and methanol (100 mL) under a nitrogen atmosphere. The solution is cooled to -20° C., and a 50% solution of methoxydiethylborane in tetrahydrofuran (105 mL) is added. The reaction is cooled to -78° C., and sodium borohydride (24 g, 0.63 mol) is added over 30 minutes. The reaction mixture is maintained at -78° C. for 5 hours, allowed to warm to room temperature, and stand for 10 hours under a nitrogen atmosphere. The reaction is quenched by the addition of acetic acid (40 mL) and concentrated by vacuum distillation to an oil. The residue is dissolved with methanol (400 mL), concentrated by vacuum distillation, redissolved with methanol (300 mL), and reconcentrated by vacuum distillation to give a yellow oil. The oil is taken up in ethyl acetate (300 mL) and washed with deionized water (500 mL). The ethyl acetate solution is concentrated by vacuum distillation to give [R-(R*,R*)])-6-cyano-3,5-dihydroxy-N,N-diphenylhexanamide as an oil which is used without further purification. A small sample is purified by column chromatography on flash silica gel (60:40 hexane:ethyl acetate) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.Cl.[CH3:18][NH:19][O:20][CH3:21]>>[CH3:21][O:20][N:19]([CH3:18])[C:10](=[O:11])[CH2:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CNOC
Reactant: CC(C)(C)C(CC(=O)O)c1ccc(Br)cc1
Agent: Cl
Product: CON(C)C(=O)CC(c1ccc(Br)cc1)C(C)(C)C

Procedure:
In analogy to example 74, step 4, from 3-(4-bromo-phenyl)-4,4-dimethyl-pentanoic acid (CAS RN: [1017356-66-9]) and N,O-dimethylhydroxylamine hydrochloride was prepared the title compound as a white solid, MS (ESI+): m/z=328.0895 ([M+H]+, 1Br).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[CH2:15][CH2:14][CH2:13]3)[N:4]=[CH:3]1.[Cl:21][C:22]1[S:26][C:25]([CH:27]=O)=[CH:24][CH:23]=1>[OH-].[K+].CCO>[ClH:21].[Cl:21][C:22]1[S:26][C:25]([CH:27]=[C:15]2[CH2:14][CH2:13][C:12]3[C:17](=[CH:18][CH:19]=[C:10]([O:9][CH2:8][CH2:7][C:5]4[N:4]=[CH:3][NH:2][CH:6]=4)[CH:11]=3)[C:16]2=[O:20])=[CH:24][CH:23]=1
Reactant: O=C1CCCc2cc(OCCc3c[nH]cn3)ccc21
Reactant: O=Cc1ccc(Cl)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccc(Cl)s2)CCc2cc(OCCc3c[nH]cn3)ccc21
Yield: 114.3 %

Procedure:
According to the method of Example 34, 6-[2-(1H-imidazole-4-yl)-ethoxy]-3,4-dihydro-2H-naphthalen-1-one, monohydrochloride (0.313 g, 1.07 mmol) was reacted with 5-chloro-2-thiophene carboxaldehyde (0.165 g, 1.13 mmol) in 5 mL of 4% KOH in EtOH overnight to afford 0.272 g (60%) of the title compound as a dull yellow powder, mp dec. >210° C.: CI-MS m/e 385, 387 (M+—Cl).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]([N:25]([CH3:27])[CH3:26])[CH:5]=2.[Cl:28][CH2:29][C:30](Cl)=[O:31]>>[Cl:28][CH2:29][C:30]([NH:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([Br:24])[CH:15]=3)[C:11]=1[C:12]#[N:13])=[CH:8][CH:7]=[C:6]([N:25]([CH3:27])[CH3:26])[CH:5]=2)=[O:31]
Reactant: COc1cc(C2C(C#N)=C(N)Oc3cc(N(C)C)ccc32)cc(Br)c1OC
Reactant: O=C(Cl)CCl
Product: COc1cc(C2C(C#N)=C(NC(=O)CCl)Oc3cc(N(C)C)ccc32)cc(Br)c1OC

Procedure:
The title compound was prepared from 2-amino-3-cyano-7-dimethylamino-4-(3-bromo-4,5-dimethoxyphenyl)-4H-chromene and chloroacetyl chloride as a yellow solid by a procedure similar to that described for Example 80. 1H NMR (CDCl3): 8.26 (s, 1H), 6.97-6.80 (m, 3H), 6.50-6.46 (m, 1H), 6.33 (d, J=2.4, 1H), 4.73 (s, 3H), 4.23 (s, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 2.95 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20])([O-:12])=[O:11]>O1CCCC1>[C:2]1([CH2:1][O:8][NH:9][S:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N+:10]([O-:12])=[O:11])(=[O:20])=[O:21])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NOCc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.2 %

Procedure:
A solution of 96.4 g of O-benzylhydroxylamine in 80 ml of tetrahydrofuran was added to a solution of 86.8 g of o-nitrobenzenesulfonyl chloride in 400 ml of tetrahydrofuran at 5°-10°. After stirring at ambient temperature for 16 hours the solvent was evaporated. The residue was washed with water, filtered and dried to give 112.6 g of N-(phenylmethoxy)-2-nitrobenzenesulfonamide, m.p. 148°-151°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][CH:10]=2)[C:5]([Cl:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:33]=[CH:32][C:23]2[CH2:24][CH2:25][CH2:26][C:27](=[O:31])[N:28]([CH2:29][CH3:30])[C:22]=2[CH:21]=1>>[Cl:18][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][CH:10]=2)=[N:7][C:2]([NH:19][C:20]2[CH:33]=[CH:32][C:23]3[CH2:24][CH2:25][CH2:26][C:27](=[O:31])[N:28]([CH2:29][CH3:30])[C:22]=3[CH:21]=2)=[N:3][CH:4]=1
Reactant: CCN1C(=O)CCCc2ccc(N)cc21
Reactant: N#CCc1ccc(Nc2nc(Cl)ncc2Cl)cc1
Product: CCN1C(=O)CCCc2ccc(Nc3ncc(Cl)c(Nc4ccc(CC#N)cc4)n3)cc21

Procedure:
{4-[5-Chloro-2-(1-ethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ylamino)-pyrimidin-4-ylamino]-phenyl}-acetonitrile was prepared from [4-(2,5-Dichloro-pyrimidin-4-ylamino)-phenyl]-acetonitrile and 8-Amino-1-ethyl-1,3,4,5-tetrahydro-1-benzazepin-2-one in an analogous manner to Example 1d. White solid 130 mg (96%), MP: 163-164, HPLC purity 94%, LCMS: 447.25 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.12 (s, 1H), 7.74 (s, 1H), 7.58 (d, J=8.2 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 7.08-7-11 (m, 3H), 7.01 (s, 1H), 3.84 (s, 2H), 2.67 (bs, 2H), 2.34-2.31 (m, 2H), 2.29-2.18 (m, 2H), 1.58 (s, 2H), 1.02 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]([CH:20]2[CH2:22][CH2:21]2)[CH2:18][CH3:19])[C:11]=1[N+:23]([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]([CH:20]2[CH2:21][CH2:22]2)[CH2:18][CH3:19])[C:11]=1[NH2:23]
Reactant: CCC(Nc1nccc(-c2ccc(OC)cc2Cl)c1[N+](=O)[O-])C1CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CCC(Nc1nccc(-c2ccc(OC)cc2Cl)c1N)C1CC1
Yield: 95.3 %

Procedure:
[4-(2-Chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine (0.56 g, 1.55 mmol) and Na2S2O4 (2.17 g, 12.5 mmol) were treated substantially as described in Part E of Example 9 to give 0.49 g (96%) of crude 4-(2-chloro-4-methoxy-phenyl)-N2-(1-cyclopropyl-propyl)-pyridine-2,3-diamine: MS (AP) m/z 331.8 [(M+H)+, 100].
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][N:17]([CH3:36])[CH2:18][CH2:19][NH:20][C:21]1[N:22]=[N+:23]([O-:35])[C:24]2[CH:34]=[C:33]3[C:28]([CH2:29][CH2:30][CH2:31][O:32]3)=[CH:27][C:25]=2[N:26]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[O-:35][N+:23]1[C:24]2[CH:34]=[C:33]3[C:28](=[CH:27][C:25]=2[N+:26]([O-:4])=[C:21]([NH:20][CH2:19][CH2:18][N:17]([CH3:36])[CH3:16])[N:22]=1)[CH2:29][CH2:30][CH2:31][O:32]3
Reactant: CN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)OCCC3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CCCO3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 25.8 %

Procedure:
H2O2 (70%, 0.47 mL, ca. 9.3 mmol) was added dropwise to a stirred solution of TFAA (1.3 mL, 9.3 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 241 (270 mg, 0.9 mmol) and TFA (0.36 mL, 4.7 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 20° C. for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 242 (71 mg, 22%) as a red solid: mp (MeOH/EtOAc) 152-154° C.; 1H NMR δ 7.99 (s, 1H, H-5), 7.61 (s, 1H, H-10), 7.27 (br s, 1H, NH), 4.30 (br dd, J=5.3, 5.2 Hz, 2H, H-8), 3.62 (br t, J=5.9 Hz, 2H, CH2N), 3.05 (br t, J=6.3 Hz, 2H, H-6), 2.62 (t, J=6.0 Hz, 2H, CH2N), 2.31 [s, 6H, N(CH3)2], 2.05-2.12 (m, 2H, H-7); 13C NMR δ 154.7, 148.7, 136.2, 133.2, 130.1, 117.4, 105.2, 67.1, 57.6, 45.1 (2), 38.8, 26.1, 21.3. Anal. calcd for C14H19N5O3.½H2O: C, 52.7; H, 6.5; N, 22.0. Found: C, 53.0; H, 5.9, 21.6%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]=O)[CH:7]=[CH:6]2.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[Na]>O1CCCC1.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C=O)ccc2c1
Reactant: C1CCNC1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc2cc(CN3CCCC3)ccc2c1
Temperature: 0 °C
Reaction time: 7 h
Yield: 100.1 %

Procedure:
To a solution of 6-methoxy-2-naphthaldehyde (3.00 g, 16.1 mmol) and pyrrolidine (2.69 ml, 32.2 mmol) in tetrahydrofuran (32 ml) and acetic acid (16 ml) was added sodium triacetoxyhydroborate. (6.83 g, 32.2 mmol) at 0° C., and the mixture was stirred at room temperature for 7 hours. The solvent was distilled off under reduced pressure, 1N hydrochloric acid was added to the resulting oil, and the mixture was washed with diethyl ether. An 8N aqueous sodium hydroxide solution was added to the aqueous layer, followed by extraction with ethyl acetate. The extract was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to obtain the titled compound (3.89 g).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[O:18]=[C:19]1[C:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:21][N:20]1[CH2:36][C:37](O)=[O:38].C(N(C(C)C)CC)(C)C>ClCCl>[O:38]=[C:37]([N:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:13]=[CH:14][CH:15]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:4]=2)[CH2:8][CH2:9]1)[CH2:36][N:20]1[CH2:21][CH2:22][C:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]1=[O:18]
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: FC(F)(F)c1cccc(CN2CCNCC2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(Cc2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-(3-(trifluoromethyl)benzyl)piperazine (0.090 g, 0.368 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.140 g, 0.368 mmol) and 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.099 g, 0.335 mmol) in dichloromethane (1.0 mL) was added diisopropylethylamine (0.088 mL, 0.502 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction was concentrated and loaded onto silica gel. The product was eluted using a gradient of 5% to 100% ethyl acetate/hexanes giving incomplete purification. A second chromatography over silica gel using a gradient of 0.5% to 5% methanol/dichloromethane gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.41-7.58 (m, 4H), 7.20-7.37 (m, 10H), 4.19 (s, 2H), 3.60 (t, J=4.8 Hz, 2H), 3.52 (t, J=6.5 Hz, 2H), 3.51 (s, 2H), 3.41 (t, J=4.8 Hz, 2H), 2.81 (t, J=6.5 Hz, 2H), 2.40 (t, J=4.9 Hz, 2H), 2.28 (t, J=4.8 Hz, 2H); MS (ESI−) m/z 520 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][N:3]=1
Reactant: C1CCNCC1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccc(CN2CCCCC2)cn1
Temperature: 80 °C
Yield: 77.2 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (578 mg, 3.57 mmole) in 7 mL of dry acetonitrile is added 0.71 mL (7.14 mmol) of piperdine followed by 493 mg (3.57 mmol) of potassium carbonate. The reaction is heated at 80° C. for 20 h. After cooling, the reaction mixture is quenched with 5 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 581 mg (77% yield) of 2-Chloro-5-piperidin-1-ylmethyl-pyridine. Diagnostic 1H NMR (400 MHz, CDCl3) 1.40–1.65 (m, 6H), 2.20–2.39 (s, 4H), 3.47 (s, 2H), 7.28 (d, 1H, J=7.9 Hz), 8.60–8.69 (m, 1H), 8.28 (d, 1H, J=2.1 Hz); MS 211.3 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([Cl:22])[CH:13]=1)[CH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][S:8][CH2:7]1.[OH-].[Li+]>CO>[Cl:22][C:14]1[CH:13]=[C:12]([CH:4]([CH2:5][C@H:6]2[CH2:11][CH2:10][CH2:9][S:8][CH2:7]2)[C:3]([OH:23])=[O:2])[CH:17]=[CH:16][C:15]=1[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: COC(=O)C(C[C@H]1CCCSC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCCSC2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.5 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3(R)-(tetrahydro-thiopyran-3-yl)-propionic acid methyl ester (247 mg, 0.655 mmol) in methanol (4.75 mL) was treated with a 0.8M aqueous lithium hydroxide solution (7.27 mL, 5.895 mmol). The reaction mixture was stirred at 25° C. for 1.5 h and then concentrated in vacuo to remove methanol. The remaining aqueous layer was acidified to pH=2 with a 10% aqueous hydrochloric acid solution and then extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford pure 2-(3-chloro-4-methanesulfonyl-phenyl)-3(R)-(tetrahydro-thiopyran-3-yl)-propionic acid (227.0 mg, 95.5%) as a light yellow foam: [α]23589=+12.21° (c=0.79, methanol).