Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:13])[C:5](=[CH:11][NH2:12])[C:6]([O:8]CC)=[O:7])C.[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:23](N(CC)C(C)C)(C)[CH3:24].CC[O-].[Na+].C(O)C>ClCCCl>[CH2:23]([N:12]1[CH:11]=[C:5]([C:6]([OH:8])=[O:7])[C:4](=[O:13])[N:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:21]1=[O:22])[CH3:24]
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(=O)C(=CN)C(=O)OCC
Reactant: CCN(C(C)C)C(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCO
Product: CCn1cc(C(=O)O)c(=O)n(-c2ccccc2)c1=O
Temperature: 100 °C

Procedure:
To a solution of 2-aminomethylene-malonic acid diethyl ester (0.75 g, 4.0 mmol) and phenyl isocyanate (0.57 g, 4.4 mmol) in 1,2-dichloroethane (20 mL) was added N,N-diisopropylethylamine (0.77 mL, 4.4 mmol) and heated at 100° C. 6 h. The mixture was cooled and filtered. The solids were purified by column chromatography with 0-5% MeOH in methylene chloride. This intermediate urea was suspended in ethanol (10 mL) and 21% NaOEt in ethanol (1.29 mL, 4.0 mmol) was added. After 18 h the solvent was removed under vacuum and the residue was slurred in ethyl acetate. The organics were washed with 1M citric acid solution, water and brine. The solvent was removed under vacuum and the residue was purified by chromatography with 0-5% MeOH in dichloromethane to give 0.50 g (40%). The ester was alkylated and hydrolyzed using methods for example 92 to give 1-ethyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid. 1H NMR (DMSO) δ: 12.65 (bs, 1H), 8.82 (s, 1H), 7.54-7.43 (m, 3H), 7.32-7.29 (m, 2H), 4.02 (q, 2H, J=7.1 Hz), 1.26 (t, 3H, J=7.1 Hz).
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([O:10][C:11](Cl)=[O:12])[CH:2]=1.[CH3:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:26][N:25]=2)=[CH:20][CH:19]=1)(=[O:17])=[O:16].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]=[CH:26][C:27]([O:30][CH2:31][CH:32]3[CH2:37][CH2:36][N:35]([C:11]([O:10][C:3]4[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=4)=[O:12])[CH2:34][CH2:33]3)=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)(=[O:16])=[O:17]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cn2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)Oc4ccc([N+](=O)[O-])cc4)CC3)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
4-Nitrophenyl chloridocarbonate (268 mg, 1.33 mmol) was added to a mixture of 2-[4-(methylsulfonyl)phenyl]-5-[(4-piperidinylmethyl)oxy]pyridine (460 mg, 1.33 mmol), diisopropylethylamine (0.695 mL, 4 mmol) in CH2Cl2 (20 mL) at ambient temperature. The mixture was stirred at ambient temperature for 30 min, then concentrated, and the crude product was purified by chromatography on a silica gel column using 0 to 5% MeOH/CH2Cl2 give 456 mg (67%) of 4-nitrophenyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.43 (d, 1H, J=2.7 Hz), 8.25 (d, 2H, J=9.2 Hz), 8.14 (d, 2H, J=8.5 Hz), 8.02 (d, 2H, J=8.5 Hz), 7.76 (d, 1H, J=8.7 Hz), 7.37-7.27 (m, 3H), 4.45-4.30 (m, 2H), 3.98 (d, 2H, J=5.1 Hz), 3.16-3.03 (m, 4H), 3.00-2.88 (m, 1H), 2.21-2.06 (m, 1H), 2.04-1.92 (m, 2H), 1.55-1.35 (m, 2H); LRMS (ESI), m/z 512 (M+H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]([F:34])=[C:24]([N:26]([CH2:31][C:32]#[CH:33])[S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[F:34][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)=[CH:25][C:24]=1[N:26]([CH2:31][C:32]#[CH:33])[S:27]([CH3:30])(=[O:29])=[O:28]
Reactant: C#CCN(c1cc(C(=O)C=CN(C)C)ccc1F)S(C)(=O)=O
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C#CCN(c1cc(-c2ccnc3c(C(=O)c4cccs4)cnn23)ccc1F)S(C)(=O)=O
Yield: 61.3 %

Procedure:
A mixture of 0.108 g (0.56 mmol) of (5-amino-1H-pyrazol-4-yl)-thiophene-2-yl-methanone and 0.198 g (0.61 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-prop-2-ynyl-methanesulfonamide in 10 ml of glacial acetic acid was refluxed for 2 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 ml of dichloromethane and 10 ml of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 ml of dichloromethane. The organic layers were washed with 10 ml of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 156 mg of N-{2-fluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-prop-2-ynyl-methanesulfonamide as a solid (yield 61%).
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH2:11][CH2:12][CH3:13])=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[C:17]1([C:23](=O)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH2:32][C:33]([NH2:35])=[O:34].Cl>C(O)C>[OH:1][C:2]1[C:9]([O:10][CH2:11][CH2:12][CH3:13])=[CH:8][C:5]([CH:6]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:35][C:33](=[O:34])[NH:32]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: CCCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: NC(N)=O
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CCCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Temperature: 110 °C
Yield: 10.8 %

Procedure:
The mixture of 4-hydroxy-3-nitro-5-propoxybenzaldehyde (Intermediate 65) (126 mg, 0.56 mmol), 1,2-diphenylethanone (131 mg, 0.672 mmol), urea (100 mg, 1.68 mmol) and concentrated hydrochloric acid (0.1 mL) in ethanol (5 mL) was stirred at reflux (110° C.) under N2 overnight. The reaction was concentrated and purified by silica gel column chromatography, followed by preparative HPLC to give Compound 130 (27 mg, yield 10.8%) as a solid. 1H NMR (DMSO-d6 400 MHz): δ 10.27 (s, 1H), 8.72 (d, J=1.6 Hz, 1H), 7.54 (s, 1H), 7.45 (d, J=2.0 Hz, 1H), 7.18-7.27 (m, 6H), 7.00-7.06 (m, 3H), 6.82-6.84 (m, 2H), 5.197 (d, J=2.8 Hz, 1H), 3.90-3.97 (m, 2H), 1.71-1.76 (m, 2H), 0.970 (t, J=7.6 Hz, 3H); MS (ESI): m/z 446.3 [M+1]+.
Reaction SMILES: Cl[C:2]([N:4]1[CH2:10][C:9]2[CH:11]=[C:12]([C:15]3[CH:16]=[CH:17][C:18]4[N:22]=[CH:21][N:20](C(OC(C)(C)C)=O)[C:19]=4[CH:30]=3)[CH:13]=[CH:14][C:8]=2[O:7][CH2:6][CH2:5]1)=[O:3].[N:31]1([C:37]2[N:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.[CH3:43]N1C2C=CC(Cl)=CC=2C(C2C=CC=CC=2)=NCC1=O>C(Cl)Cl>[CH3:43][C:21]1[NH:20][C:19]2[CH:30]=[C:15]([C:12]3[CH:13]=[CH:14][C:8]4[O:7][CH2:6][CH2:5][N:4]([C:2]([N:34]5[CH2:35][CH2:36][N:31]([C:37]6[N:38]=[CH:39][CH:40]=[CH:41][N:42]=6)[CH2:32][CH2:33]5)=[O:3])[CH2:10][C:9]=4[CH:11]=3)[CH:16]=[CH:17][C:18]=2[N:22]=1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: CC(C)(C)OC(=O)n1cnc2ccc(-c3ccc4c(c3)CN(C(=O)Cl)CCO4)cc21
Solvent: ClCCl
Product: Cc1nc2ccc(-c3ccc4c(c3)CN(C(=O)N3CCN(c5ncccn5)CC3)CCO4)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,1-dimethylethyl 6-[4-(chlorocarbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazole-1-carboxylate (5.5 mg, 16 μmol) and 2-(piperazin-1-yl)pyrimidine (7.9 mg, 48 μmol) in anhydrous DCM (2 mL) was added PL-DIPAM (85 mg, 3.27 mmol/g loading, 315 μmol, Polymer Labs) and the reaction mixture was shaken overnight at room temperature. The resulting mixture was drained into PL-PETA (55 mg, 2.7 mmol/g loading, 175 μmol, Polymer Labs) and PL-MIA, (35 mg, 2.65 mmol/g loading, 104 μmol, Polymer Labs). The reaction mixture was shaken overnight at room temperature, drained and the resin was washed with 3.0 mL of methanol. The combined methanol solution was transferred to a 2 dram vial and concentrated under reduced pressure. The resulting oil was dissolved in methanol (2 mL) followed by the addition of 4 N anhydrous hydrogen chloride in dioxane (0.5 mL, Aldrich). The mixture was shaken at room temperature for an additional 18 hours. The resulting solution was concentrated under reduced pressure to give 7-(2-methyl-1H-benzimidazol-6-yl)-4-[(4-pyrimidin-2-ylpiperazin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine. MS (EI) for C26H27N7O2: 470.5 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]2[S:23][C:22]3[CH:24]=[C:25](S[Si](C(C)C)(C(C)C)C(C)C)[CH:26]=[CH:27][C:21]=3[CH:20]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[N:6][CH:7]=1.[N+]([O-])([O-])=O.[K+].[S:44](Cl)(Cl)(=[O:46])=[O:45].[OH-].[NH4+:50]>C(#N)C.O>[Cl:1][C:2]1[C:3]([C:19]2[S:23][C:22]3[CH:24]=[C:25]([S:44]([NH2:50])(=[O:46])=[O:45])[CH:26]=[CH:27][C:21]=3[CH:20]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[N:6][CH:7]=1
Reactant: CC(C)[Si](Sc1ccc2cc(-c3nc(NCCCN4CCN(C)CC4)ncc3Cl)sc2c1)(C(C)C)C(C)C
Reactant: O=S(=O)(Cl)Cl
Reactant: [NH4+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4ccc(S(N)(=O)=O)cc4s3)n2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 6.9 %

Procedure:
To a suspension of [5-chloro-4-(6-triisopropylsilanylsulfanylbenzo[b]thiophen-2-yl)-pyrimidin-2-yl]-[3-(4-methylpiperazin-1-yl)-propyl]-amine (463 mg, 0.784 mmol) in acetonitrile (4 mL) is added potassium nitrate (198 mg, 1.96 mmol) followed by the dropwise addition of sulfuryl chloride (0.157 mL, 1.96 mmol). The mixture is stirred at room temperature for 1.5 hours. After filtration, the solid is suspended in acetone (5 mL) and a solution of ammonium hydroxide (0.926 mL, 15.7 mmol) is added dropwise at 0° C. After stirring at 0° C. for 1 hour, water (40 mL) is added and the mixture is extracted with EtOAc (3×50 mL). The organic layers are concentrated and the crude product is purified on silica gel, eluting with dichloromethane in MeOH 10:0 to 6:4. The solid obtained is washed with MeOH to give the title compound as a yellow solid (26 mg, 7% yield). ES+(m/z) 481 (35Cl) and 483 (37Cl) [M+H].
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:23])([CH2:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:6]1=[O:24])CCC.[CH2:25](N1C2C(=CC=CC=2)C(=O)C1=O)[CH:26](C)[CH3:27].C(C1C=CC=CN=1)(=O)C>>[OH:23][C:7]1([CH2:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([CH2:1][CH:26]([CH3:27])[CH3:25])[C:6]1=[O:24]
Reactant: CCCCN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21
Reactant: CC(C)CN1C(=O)C(=O)c2ccccc21
Agent: CC(=O)c1ccccn1
Product: CC(C)CN1C(=O)C(O)(CC(=O)c2ccccn2)c2ccccc21

Procedure:
This compound was made in a similar manner to 1-butyl-3-hydroxy-3-(2-oxo-2-(pyridin-2-yl)ethyl)indolin-2-one using 1-isobutylindoline-2,3-dione and commercially available 2-acetyl pyridine (Fisher Scientific). 1H-NMR δ 8.70 (ddd, 1H), 8.13 (td, 1H), 7.92 (dd, 1H), 7.56 (ddd, 1H), 7.34-7.28 (m, 2H), 7.07-7.02 (m, 2H), 6.85 (d, 1H), 3.77 (d, 1H), 3.56-3.42 (m, 3H), 2.15 (m, 1H), 0.97 (dd, 6H). calculated mass for C19H20N2O3, 324.15. Observed, 325.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[Br:16]Br>C(Cl)Cl>[NH2:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][C:12]=1[Br:16]
Reactant: CCOC(=O)c1ccc(N)c([N+](=O)[O-])c1
Reactant: BrBr
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)c(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
To a solution of ethyl 4-amino-3-nitrobenzoate (D212) (21.0 g, 100 mmol, 1 equiv) in CH2Cl2 (500 ml) at room temperature was added bromine (6.7 ml, 130 mmol, 1.3 equiv) and the resulting mixture was refluxed for 4 h then bromine (2 ml, 40 mmol, 0.4 equiv) was added and the resulting mixture refluxed for another 3 h then cooled to room temperature. The organic phase was washed twice with a 10% aqueous Na2S2O3 solution and twice with H2O, dried over MgSO4 and concentrated in vacuo to give ethyl 4-amino-3-bromo-5-nitrobenzoate (D213) (27.1 g, 94%) as a yellow solid which was used in the next step without further purification.
Reaction SMILES: N[C@H]1C2C(=CC=CC=2)C[C@H]1O.[Br:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:18]([N+:30]([O-:32])=[O:31])[CH:17]=1)=[O:15]>C1COCC1>[N+:30]([C:18]1[CH:17]=[C:16]([C@H:14]([OH:15])[CH2:13][Br:12])[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([O-:32])=[O:31]
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: N[C@H]1c2ccccc2C[C@H]1O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc([C@H](O)CBr)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A cold (5° C.) solution of (1S,2R)-1-amino-2-indanol (400 mg, 2.68 mmol) in THF (160 mL) was added dropwise to a cold (0° C.) solution of borane-diethylaniline complex (7.0 g, 43 mmol) in THF (20 mL). After complete addition, the resulting solution was stirred at (0° C.) for 30 min then 2-bromo-4′-benzyloxy-3′-nitroacetophenone (20.0 g, 57.1 mmol) was added in three portions over a 30 min period. The resulting solution was stirred at <5° C. for 1 h, quenched by dropwise addition of acetone (17 mL) then allowed to warm to ambient temperature overnight. The reaction mixture was concentrated in vacuo to a residue, which was dissolved in toluene (100 mL) and washed in succession with 10% H2SO4 (2×45 mL), H2O (2×45 mL) and sat. brine (1×40 mL). The organic layer was dried over MgSO4, clarified then concentrated in vacuo to a volume of ˜40 mL. Heptane (45 mL) was slowly added to give a thick slurry. The solid was collected on a filter and washed with heptane (2×5 mL). This material was dissolved in warm toluene (˜50 mL), the solution was clarified then diluted with heptane (50 mL). The resulting mixture was stirred for 30 min, the solids were collected, washed with heptane (2×5 mL) then dried to constant weight in vacuo to give 18.9 g (94.0%) of the title compound.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][OH:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.N1C=CC=CC=1.[C:30](Cl)(=[O:34])[C:31]([CH3:33])=[CH2:32]>C1COCC1>[C:30]([O:16][CH2:15][C:13]1[C:12]2[C:7]([CH:6]=[C:5]3[C:14]=1[CH:1]=[CH:2][CH:3]=[CH:4]3)=[CH:8][CH:9]=[CH:10][CH:11]=2)(=[O:34])[C:31]([CH3:33])=[CH2:32]
Reactant: C=C(C)C(=O)Cl
Reactant: OCc1c2ccccc2cc2ccccc12
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCc1c2ccccc2cc2ccccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
9-Anthracenemethanol (30 g) was dissolved in freshly distilled THF (150 mL). To the solution triethylamine (30 mL) and pyridine (20 mL) were added and the mixture was cooled down to 0° C. Then methacryloyl chloride (21 mL) was added dropwise. After the addition, ice-water bath was removed and the mixture was stirred for 1 hour. After water (75 mL) was added to the reaction flask, the solution was transferred into separatory funnel and extracted with diethyl ether (500 mL). The extract was washed with aqueous HCl (1 M, 150 mL), aqueous NaHCO3 (5%, 150 mL), and brine (150 mL), respectively. The solvent was evaporated in vacuum and recrystallized with methanol. (Product: 21 g) 1H NMR (500 MHz, CDCl3): δ 8.55 (s, 1H), 8.41 (d, J=8.9 Hz, 2H), 8.07 (d, J=8.4 Hz, 2H), 7.61 (t, J=7.7 Hz, 2H), 7.53 (t, J=7.9 Hz, 2H), 6.25 (s, 2H), 6.08 (s, 1H), 5.54 (s, 1H), 1.95 (s, 3H) ppm.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:22]=[CH:21][C:9]([C:10]([NH:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][S:18][CH2:17][CH2:16]2)=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl.OO.S([O-])([O-])=[O:27].[Na+].[Na+]>O.CO>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:12][CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][S:18](=[O:27])[CH2:19][CH2:20]2)=[O:11])=[CH:21][CH:22]=1)(=[O:3])=[O:4]
Reactant: O=S([O-])[O-]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)NCCN2CCSCC2)cc1
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(C(=O)NCCN2CCS(=O)CC2)cc1
Temperature: 0 °C

Procedure:
To 50 ml of methanol add 1.0 g (2.93 mmole) of 4-[(methylsulfonyl)amino]-N-[2-(thiomorpholin-4-yl)ethyl]benzamide. Add dropwise 3.08 ml (3.08 mmole) of 1.0N hydrochloric acid. Cool the solution to 0° C. Slowly add 0.70 ml (6.16 mmole) of 30% w/v hydrogen peroxide. Stir the reaction at ambient temperature. Monitor the progress of the reaction by thin layer chromatography on silica gel (methanol:1M NaCl; 95:5). Upon the completion of the reaction, add 25 ml of 10% sodium sulfite to the stirring solution. Filter the resulting solid. Evaporate the filtrate in vacuo to yield a solid. Stir this solid in H2O overnight, then filter the solid and recrystallize it from methanol to yield the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@@H:7]1[CH2:12][CH2:11][C@H:10]([O:13]C(=O)C2C=CC([N+]([O-])=O)=CC=2)[CH2:9][CH2:8]1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:13][C@@H:10]1[CH2:9][CH2:8][C@H:7]([N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[O:1])[CH2:12][CH2:11]1
Reactant: O=C(O[C@H]1CC[C@@H](N2CCCC2=O)CC1)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C1CCCN1[C@H]1CC[C@@H](O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve cis-4-nitro-benzoic acid 4-(2-oxo-pyrrolidin-1-yl)-cyclohexyl ester (preparation 2) (87.9 g; 264 mmol) in methanol (1.35 L) and water (150 mL) and add potassium carbonate (109.5 g; 800 mmol). Stir at room temperature overnight to give a white precipitate. Evaporate to dryness. Azeotrope with ethanol (×2). Stir in tetrahydrofuran (1 L) for 1 hour then filter. Evaporate the filtrate to an oil and crystallize from diethyl ether (100 mL) to afford 40 g (83%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[C:11]([C:16]#N)=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[Mg]Cl.[OH2:27]>C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[C:11]([C:16]([CH:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)=[O:27])=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ncccc1CCc1cccc(Cl)c1
Reactant: CN1CCCCC1[Mg]Cl
Reactant: O
Solvent: C1CCOC1
Product: CN1CCC(C(=O)c2ncccc2CCc2cccc(Cl)c2)CC1
Product: Cl
Temperature: 5 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of compound 3-[2-(3-chlorophenyl) ethyl]-2-pyridinecarbonitrile (118 g; 0.49 mol) in 1.2 L of dry THF was added 395 mL (2.48 N; 0.59 mol) of N-methyl-piperidyl magnesium chloride over 0.5 h while the temperature was maintained at 40°-50° C. by cooling with water as necessary. The reaction mixture was maintained at 40°-50° C. for an additional 0.5 h. The reaction was quenched to below pH 2 by the addition of 2N hydrochloric acid and the resulting solution was stirred at 25°-30° C. for 1 h. The bulk of the THF was removed by distillation and the pH of the solution adjusted to 3.5 by the addition of aqueous sodium hydroxide. The mixture was cooled to 5° C. and the product was collected by filtration, washed with cold water and dried under vacuum at 60° C. to give 168 g (91%) of [3-[2-(3-chlorophenyl) ethyl]-2-pyridinyl]-1-methyl-4-piperidinyl methanone hydrochloride as a crystalline solid: mp 183°-185° C.; NMR (200 MHz, DMSO)δ2.72 (s,3H), 2.8-2.9 (m,2H) 3.0-3.2 (m,4H), 3.3-3.5 (m,3H), 3.9-4.1 (m, 1H), 7.2-7.3 (m,1H), 7.3-7.4 (m,3H), 7.57 (dd,1H,J=6, 4Hz), 7.84 (dd,1H, J=6, 1.2 Hz), 8.59 (dd,1H,J=4, 1.2 Hz), 10.95 (br s, 1H); mass spectrum m/e (rel intensity) 345M+2 (32), 343M+ (100). Anal. Calcd for C20H24N2OCl2 : C,63.32; H,6.38; N,7.39; Cl,18.69. Found: C,63.45; H,6.47; N,7.40; Cl, 18.49.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[CH2:19][CH2:20][CH2:21][CH2:22][OH:23].BrBr.N12CCCN=C1CCCCC2.O>C(Cl)(Cl)Cl>[C:12]1([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][N:7]=3)[C:2](=[O:1])[C:3]3([CH2:19][CH2:20][CH2:21][CH2:22][O:23]3)[C:4]2=[O:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=c1c(CCCCO)c(O)c2cccnc2n1-c1ccccc1
Agent: BrBr
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1c2cccnc2N(c2ccccc2)C(=O)C12CCCCO2

Procedure:
A suspension of 4-Hydroxy-3-(4-hydroxybutyl)-1-phenyl-(1,8)-naphthyridin-2(1H)-one (2 g.) in chloroform was stirred in an ice-bath. A solution of bromine (1 g.) in chloroform was added dropwise and the mixture was stirred overnight at room temperature. To this mixture was added a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (2 g) in chloroform at room temperature. After about 3/4 hr. water was added and the pH was adjusted to be slightly acidic. The chloroform layer was separated and washed with saturated NaCl solution. The solution was dried and evaporated to a solid which was washed with ethanol/water and dried to yield 1-phenyl-3',4', 5', 6'-tetrahydro-spiro[1,8-naphthyridine-3,2'-(2H) pyran]-2,4-dione, m.p. 213°-215° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])[C@@H:14]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[C@@:12]3([CH:38]=C)[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1.C[N+]1([O-])CC[O:44]CC1.[BH4-].[Na+]>O1CCOCC1.CCOC(C)=O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])[C@@H:14]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[C@@:12]3([CH2:38][OH:44])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C=C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: OC[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Reaction time: 14 h
Yield: 52.1 %

Procedure:
To a solution of the compound from Example 137, Step B (300 mg, 0.48 mmol) in 1,4-dioxane (5 mL) were added N-methylmorpholine-N-oxide (300 mg, 2.56 mmol) and osmium tetroxide (4% solution in water, 0.3 mL). The mixture was stirred in the dark for 14 h. The precipitate was removed by filtration through a celite plug, diluted with water (3×), and extracted with EtOAc. The EtOAc layer was dried over Na2SO4 and concentrated in vacuo. The oily residue was taken up in dichloromethane (5 mL) and stirred over NaIO4 on silica gel (3 g, 10% NaIO4) for 12 h. The silica gel was removed by filtration and the residue was evaporated and taken up in absolute ethanol (5 mL). The solution was cooled in an ice bath and sodium borohydride (300 mg, 8 mmol) was added in small portions. The resulting mixture was stirred at room temperature for 4 h and then diluted with EtOAc. The organic layer was washed with water (2×20 mL), brine (20 mL) and dried over Na2SO4. The solvent was evaporated and the residue purified by flash chromatography (SiO2, 2:1 hexanes/EtOAc) to give the title compound (160 mg, 0.25 mmol) as white flakes.