Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]([NH:12][C:13]([N:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=2)[C:17]([NH:28][CH2:29][C:30](=[O:36])[NH:31][CH:32]2[CH2:35][NH:34][CH2:33]2)=[N:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[CH2:37]([O:39][C:40]([CH:42]1[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]1)=[O:41])[CH3:38]>>[CH2:37]([O:39][C:40]([CH:42]1[CH2:47][CH2:46][CH:45]([N:34]2[CH2:33][CH:32]([NH:31][C:30](=[O:36])[CH2:29][NH:28][C:17]3[C:18]4[C:23](=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=4)[N:15]([C:13](=[O:14])[NH:12][C:8]([CH3:11])([CH3:9])[CH3:10])[N:16]=3)[CH2:35]2)[CH2:44][CH2:43]1)=[O:41])[CH3:38]
Reactant: CC(C)(C)NC(=O)n1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: CCOC(=O)C1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCC(N2CC(NC(=O)CNc3nn(C(=O)NC(C)(C)C)c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of 3-[(azetidin-3-ylcarbamoylmethyl)-amino]-5-trifluoromethyl-indazole-1-carboxylic acid tert-butyl amide TFA salt (as prepared in Example 81, Step D) and 4-oxo-cyclohexanecarboxylic acid ethyl ester using the procedure described in Step E of Example 1.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[C:19](=O)(O)[O-].[Na+].C[N:25]1[C:29]([SH:30])=[N:28][N:27]=[N:26]1.Cl>O.CC(C)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH:5]([S:30][C:29]3[NH:28][N:27]=[N:26][N:25]=3)[CH3:19])[CH2:15][S:14][C@H:9]12
Reactant: O=C([O-])O
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cn1nnnc1S
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1

Procedure:
To a suspension of 27.2 g (0.1 mol) of 7-ACA in 200 ml of water and 100 ml of acetone was added a solution of 18.9 g of sodium bicarbonate in 200 ml of water. The resultant solution was warned on a steam bath and a solution of 14.5 g (0.125 mol) of 1-methyl-5-mercapto-1,2,3,4-tetrazole in 200 ml of acetone was added. The reaction mixture was refluxed for 3.5 hours while maintaining the pH at 7.4-8.0 by addition of 5% sodium bicarbonate solution. Acidification of the cooled reaction mixture to pH 3.5 with 6N hydrochloric acid resulted in precipitation of 7-amino-3-(1-methyl-1,2,3,4-tetrazole-5-ylthiomethyl)-3-cephem-4-carboxylic acid which was collected, washed (H2O), and air dried (16 g, 49%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH:5]([CH3:14])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][NH:9]1.C(N(CC)CC)C.[CH3:23][O:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([S:32](Cl)(=[O:34])=[O:33])=[C:27]([CH3:36])[CH:26]=1.Cl>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:15])[CH:5]([CH3:14])[CH2:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[S:32]([C:28]1[C:29]([CH3:31])=[CH:30][C:25]([O:24][CH3:23])=[CH:26][C:27]=1[CH3:36])(=[O:34])=[O:33]
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: COC(=O)C(C)CCC1CCCCN1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)CCC1CCCCN1S(=O)(=O)c1c(C)cc(OC)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 4-(piperidin-2-yl)butanoic acid methyl ester hydrochloride (1.26 g, 5.683 mmol) was dissolved in methylene chloride (25 ml) and triethylamine (4 ml, 28.417 mmol) and a solution of 4-methoxy-2,6-dimethylbenzenesulfonic acid chloride (2.67 g, 11.37 mmol) [see AC5, stage 1) in methylene chloride (10 ml) was added. The mixture was stirred at room temperature overnight. 1 mol/l HCl solution (10 ml) was added to the reaction mixture, phase separation, extraction of the aqueous phase with methylene chloride (2×20 ml). The combined organic phases were washed with sat. sodium chloride solution (20 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with hexane/methylene chloride/ether (400/100/50). The yield was 1.65 g (75%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(C(C)C)CC)(C)C.[F:32][C:33]([F:45])([F:44])[O:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:39](=[O:40])[C:38]3[CH:42]=[CH:43][C:35]([O:34][C:33]([F:32])([F:44])[F:45])=[CH:36][CH:37]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccc(OC(F)(F)F)cc4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.16 mmol) in CH2Cl2 (60 ml), was added diisopropylethylamine (0.94 mL, 5.4 mmol) and 4-trifluoromethoxybenzoyl chloride (0.6 g, 2.8 mmol). The mixture was then stirred at room temperature overnight. The reaction mixture was quenched with MeOH (1 mL), washed with water (40 mL), 1N HCl (2×40 mL), and brine (40 mL), dried over MgSO4, and concentrated in vacuo. The resulting oil was purified by ISCO silica gel flash chromatography (eluent: 0% MeOH in CH2Cl2 to 5% MeOH in 10 min then stay at this ratio for 15 min) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-4-trifluoromethoxy-benzamide as an off-white solid (0.8 g, 78%): mp, 163-165° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=7.3 min. (99%); 1H NMR (DMSO-d6): δ 2.07-2.10 (m, 1H), 2.51-2.64 (m, 2H), 2.91-2.92 (m, 1H), 4.96 (d, J=5.7 Hz, 2H), 5.15-5.21 (dd, J=5, 12 Hz, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.74-7.84 (m, 3H), 8.04-8.07 (dd, J=6.8, 1.9 Hz, 2H), 9.28 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.97, 30.92, 38.44, 118.23, 120.68, 121.64, 121.90, 127.15, 129.30, 129.67, 131.53, 133.01, 133.07, 134.80, 139.03, 150.39, 150.42, 165.39, 166.94, 167.51, 169.81, 172.74. Anal Calcd for C22H16F3N3O6: C, 55.59; H, 3.39; N, 8.84; F, 11.99. Found: C, 55.43; H, 3.00; N, 8.76; F, 11.77.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([C:18]([C:20]2[C:21]([CH2:32][O:33]C3CCCCO3)=[N:22][O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[O:19])[N:9]=[CH:8]1.C(O)(=O)C.O>C1COCC1>[F:47][C:2]([F:1])([F:48])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([C:18]([C:20]2[C:21]([CH2:32][OH:33])=[N:22][O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[O:19])[N:9]=[CH:8]1
Reactant: O=C(c1ncn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1)c1c(COC2CCCCO2)noc1-c1ccccc1Cl
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ncn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1)c1c(CO)noc1-c1ccccc1Cl
Temperature: 60 °C
Reaction time: 20 h

Procedure:
Dissolve [1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-imidazol-4-yl]-[5-(2-chloro-phenyl)-3-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-4-yl]-methanone (0.136 g, 0.20 mmol) in THF (1.5 mL), add acetic acid (1.5 mL) and H2O (0.5 mL). Attach a reflux condenser and stir 20 hours in a 60° C. oil bath. Concentrate under vacuum, neutralize with saturated aqueous NaHCO3, and extract with EtOAc. Dry over MgSO4, filter through paper, and concentrate under vacuum. Recrystallize in ether/hexane (1:10) to give the title compound: MS (ES) 607.1 (M+1), 1H NMR (CDCl3) δ 8.69 (br s, 1H), 8.58 (br s, 1H), 7.82 (s, 1H), 7.64 (m, 2H), 7.44–7.28 (m, 5H), 7.23 (s, 2H), 5.14 (s, 2H), 4.76 (s, 2H).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7](=[O:13])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:30](=[O:31])[O:29]1>C(Cl)(Cl)Cl>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][C:4]([C:7](=[O:13])[CH2:8][CH2:9][C:10]([O:12][CH:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:30](=[O:31])[O:29]2)=[O:11])=[CH:5][CH:6]=1
Reactant: O=C1OC(Br)c2ccccc21
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CCC(=O)c1ccc(-c2ccccc2)cc1)OC1OC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
To a solution of 7.5 g of 4-(4-biphenylyl)-4-oxobutyric acid in 40 ml of chloroform and 3.4 g of triethylamine is added a solution of 6.2 g of 3-bromophthalide in 20 ml of chloroform. The solution thus obtained is stirred 24 hours at room temperature, the organic phase is washed with an aqueous solution of sodium bicarbonate, then with water and finally it is dried on anhydrous sodium sulfate and evaporated to dryness to give the phthalidyl 4-(4-biphenylyl)-4-oxobutyrate; yield 73%.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][CH2:44][O:45][CH:46]1[CH2:51][CH2:50][CH2:49][CH2:48][O:47]1>CN(C=O)C.C(Cl)Cl>[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][N:33]([CH2:43][CH2:44][O:45][CH:46]6[CH2:51][CH2:50][CH2:49][CH2:48][O:47]6)[CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: BrCCOC1CCCCO1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(CCOC4CCCCO4)CC3)cc1OCC2
Temperature: 60 °C
Yield: 48 %

Procedure:
To a stirred suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoro acetate (300 mg, 0.61 mmol) in DMF (3.5 mL) was added potassium carbonate (290 mg, 2.1 mmol) and 2-(2-bromoethoxy)tetrahydro-2H-pyran and the mixture heated at 60° C. for 18 h before being diluted with DCM. The resultant solution was washed with saturated aqueous sodium hydrogen carbonate, water and then brine before being dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 8% methanol in DCM) to give 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-piperidin-4-yl}-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene as a cream solid (147 mg, 48%). 1H NMR 400 MHz (CDCl3) δ: 8.44 (1 H, d, J=8.29 Hz), 7.87 (1 H, s), 7.63 (1 H, s), 7.04 (1 H, dd, J=8.33, 1.81 Hz), 6.92 (1 H, d, J=1.75 Hz), 6.01-6.00 (1 H, m), 4.63 (1 H, t, J=3.54 Hz), 4.46-4.45 (4 H, m), 3.92-3.91 (2 H, m), 3.65 (1 H, m), 3.57-3.49 (1 H, m), 3.15 (2 H, m), 2.73 (2 H, m), 2.53 (1 H, m), 2.25 (2 H, m), 1.87 (5 H, m), 1.73-1.69 (3 H, m), 1.60 (8 H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17](=O)[NH:18][CH2:19][C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:33].CC(O)=O.C1(C)C(C)=CC=CC=1>[Cl-].[Na+].O>[C:21]1([C:20]2[N:33]=[C:17]([CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][NH:11]3)[NH:18][CH:19]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17]1[NH:18][CH:19]=[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:33]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CNC(=O)C1CCCCN1C(=O)OCc1ccccc1)c1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CCCCC1c1nc(-c2ccccc2)c[nH]1
Product: c1ccc(-c2c[nH]c(C3CCCCN3)n2)cc1
Temperature: 165 °C

Procedure:
2-(2-Oxo-2-phenyl-ethylcarbamoyl)-piperidine-1-carboxylic acid benzyl ester (22.83 g, 60 mmol), NH4OAc (ammonium acetate) (63.5 g, 824 mmol), AcOH (acetic acid) (30 mL), and xylene (350 mL) were mixed at room temperature, and with stirring the reaction mixture was warmed in an oil bath at 165° C. for about 6 hours. The reaction mixture was then cooled to room temperature and poured into brine. The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to yield 31.24 g of off white powder. This sample was triturated in ethyl ether (100 mL), filtered, and rinsed liberally with ethyl ether to yield 15.12 g (70% over two steps) of the desired product 2-(4-phenyl-1H-imidazol-2-yl)-piperidine-1-carboxylic acid benzyl ester as a white solid. HPLC analysis showed the compound to be 100% pure at 254 nm and 98.1% pure at 214 nm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:23](=[O:24])[CH:22]=[C:21]3[C:16]([CH:17]=[C:18](Br)[CH:19]=[CH:20]3)=[CH:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:34]1([CH2:40][C:41]#[CH:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C)C=O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:23](=[O:24])[CH:22]=[C:21]3[C:16]([CH:17]=[C:18]([C:42]#[C:41][CH2:40][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:19]=[CH:20]3)=[CH:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(Cn2cc3cc(Br)ccc3cc2=O)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(Cn2cc3cc(C#CCc4ccccc4)ccc3cc2=O)cc1
Temperature: 65 °C

Procedure:
A solution of 4-(7-bromo-3-oxo-2H-isoquinolin-2-ylmethyl)benzoic acid tert-butyl ester (1.50 g, 3.62 mmol) in dimethylformamide (10 mL) is degassed with nitrogen, then treated with triethyl-amine (2.07 mL, 14.8 mmol), CuI (0.050 g, 0.26 mmol), Pd(Ph3P)4 (0.173 g, 0.15 mmol), and 3-phenyl-1-propyne (1.13 mL, 9.05 mmol). The reaction mixture is heated in an oil bath at 65° C. for 5 hours, cooled to room temperature, the DMF is evaporated, and the residue is dissolved in ethyl acetate. The solution is washed with 1N HCl, brine, dried over MgSO4 and evaporated onto silica gel. Purification on a 3.5×18 cm silica gel column eluted with hexane/ethyl acetate 4:1, followed by drying, will afford the desired product.
Reaction SMILES: O.C([O:4][C:5](=O)[CH2:6][S:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=1[N+:17]([O-])=O)C>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]2[S:7][CH2:6][C:5](=[O:4])[NH:17][C:9]=2[CH:10]=1
Reactant: CCOC(=O)CSc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)NC(=O)CS2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of iron (30.2 g, 540 mmol), glacial acetic acid (2 mL), and water (40 mL) was prepared in a 500 mL 3-necked round bottom flask equipped with a dropping funnel and an overhead stirrer. A solution of (2,4-dinitro-phenylsulfanyl)-acetic acid ethyl ester (11.79 g, 41.2 mmol) in glacial acetic acid (40 mL) and ethyl acetate (40 mL) was added dropwise. After addition the dropping funnel was replaced with a condenser and the solution heated at 80° C. for 3.5 hrs, then allowed to stir overnight at room temperature. The mixture was filtered through Celite and the Celite washed with ethyl acetate and water. The layers were separated in a separatory funnel and the aqueous layer extracted twice with ethyl acetate. The organic layers were washed with water, twice with saturated sodium bicarbonate, then dried over magnesium sulfate, filtered, and evaporated under vacuum to yield a 6-amino-4H-benzo[1,4]thiazin-3-one as a brown solid.
Reaction SMILES: [OH:1][C@@H:2]([CH2:12]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:3][P:4]([CH3:11])(=[O:10])[O:5][CH2:6][CH:7]([CH3:9])[CH3:8].[N-:24]=[N+:25]=[N-:26].[Na+].O>CN(C)C=O>[N:24]([CH2:12][C@H:2]([OH:1])[CH2:3][P:4]([CH3:11])(=[O:10])[O:5][CH2:6][CH:7]([CH3:9])[CH3:8])=[N+:25]=[N-:26]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)CP(C)(=O)OCC(C)C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COP(C)(=O)C[C@@H](O)CN=[N+]=[N-]
Temperature: 25 °C

Procedure:
To a solution of 4.55 g of isobutyl O-trimethylsilyl-P-methyl-phosphonite in 100 ml of dry tetrahydrofuran are added 5.0 g of (2R)-glycidyl tosylate followed by 0.2 g of dry zinc chloride. The mixture is heated to reflux for a period of 3 hours under an inert gas atmosphere. The mixture is allowed to cool to room temperature, the solvent is evaporated under reduced pressure, the residue dissolved in 50 ml of chloroform, and this is stirred vigorously with 25 ml of water for a period of 0.5 hours. The organic layer is separated, dried over magnesium sulphate and the solvent is removed under reduced pressure. The residue is chromatographed on silica gel using 5 parts of ethyl acetate and 1 part of ethanol as eluent. There is obtained isobutyl P-[2(S)-hydroxy-3-tosyloxy-propyl]-P-methyl-phosphinate as a viscous oil, 31P-NMR spectrum: δ=+54.5 and +53.4 ppm (CDCl3), [α]D25 =+6.5(c=0.54% in ethanol). A solution of 3.32 g of isobutyl P-[2(S)-hydroxy-3-tosyloxy-propyl]-P-methyl-phosphinate and 1.19 g of sodium azide in 25 ml of dry dimethylformamide is heated to a temperature of 120° for a period of 3 hours, under an inert gas atmosphere. The reaction mixture is allowed to cool to room temperature, poured onto 50 ml of water and extracted twice with 100 ml of ethyl acetate. The organic extract is dried over magnesium sulphate and the solvent removed under reduced pressure. The residue is chromatographed on silica gel using 5 parts of ethyl acetate to 1 part of ethanol as eluent. There is obtained isobutyl P-[3-azido-2(S)-hydroxy-propyl]-P-methyl-phosphinate as a viscous oil, 1P-NMR spectrum: δ=+54.8 and +53.7 ppm (CDCl3), [α]D25 =+18.6(0.56% in ethanol
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH2:24])=[O:23])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.C1(S(Cl)(=O)=O)C=CC=CC=1.[OH-].[NH4+:47]>>[NH2:47][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH2:24])=[O:23])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCCCC(N)=O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [OH-]
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCCC(N)=O

Procedure:
5-[2-(Ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]pentanamide (2.25 g, 6.89 mmol) was treated with mCPBA (2.77 g, 12.0 mmol), ammonium hydroxide (40 mL), and benzenesulfonyl chloride (1.71 mL, 13.4 mmol) according to the method described in Part D of Example 36. The crude product was purified by column chromatography on silica gel (eluting with dichloromethane:methanol in a gradient from 90:10 to 85:15). The resulting product was triturated with 10% aqueous sodium hydroxide, isolated by filtration, washed with water, and dried overnight in a vacuum oven to provide 0.752 g of 5-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]pentanamide as a tan solid, mp 198-200° C.
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].[CH3:8][O:9][C:10]1[CH:29]=[CH:28][C:13]2CO[C:16](=[O:27])[N:17]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:12]=2[CH:11]=1.C(N(CC)C(C)C)(C)C.[O:39]1[C:48]2[CH:47]=[C:46]([CH:49]=O)[N:45]=[CH:44][C:43]=2[O:42][CH2:41][CH2:40]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[O:39]1[C:48]2[CH:47]=[C:46]([CH2:49][N:24]3[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][CH2:18][N:17]4[C:12]5[CH:11]=[C:10]([O:9][CH3:8])[CH:29]=[CH:28][C:13]=5[O:4][CH2:3][C:16]4=[O:27])[CH2:26][CH2:25]3)[N:45]=[CH:44][C:43]=2[O:42][CH2:41][CH2:40]1
Reactant: COc1ccc2c(c1)N(CCCN1CCNCC1)C(=O)OC2
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: O=C(O)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)N(CCCN1CCN(Cc3cc4c(cn3)OCCO4)CC1)C(=O)CO2

Procedure:
7-Methoxy-1-(3-piperazin-1-ylpropyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one trifluoroacetate (Intermediate 118, crude, 963 mg, 1.81 mmol) was converted to the free base with N,N-diisopropylethylamine and reacted with 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (203 mg, 123 mmol) and sodium triacetoxy borohydride (240 mg, 1.10 mmol) as described for Example 55 to give the free base of the product as an oil after chromatography on silica gel with dichloromethane/methanol (93:7), 125 mg (22%).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[CH:26]=[N:27][CH:28]=[C:29]([CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH:30]=1>>[Si:33]([O:32][CH2:31][C:29]1[CH:30]=[C:25]([C:20]2([OH:23])[CH2:21][CH2:22][N:17]([CH2:16][C:13]34[CH2:15][CH:6]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=53)[C:5]3[C:14]4=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:18][CH2:19]2)[CH:26]=[N:27][CH:28]=1)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: CC(C)(C)[Si](C)(C)OCc1cncc(Br)c1
Product: CC(C)(C)[Si](C)(C)OCc1cncc(C2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)c1
Yield: 62 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 3-bromo-5-(tert-butyldimethylsilyl)oxymethylpyridine (described in example 69b), the title compound was formed in 62% yield as an oil. TLC analysis (Rf 0.25, 30% ethyl acetate in hexane). MS (CI, CH4) m/z 27 (M+1,100), 555 (M+29,14), 509 (20),395 (20).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[Br:20]Br>C(Cl)Cl.C(O)(=O)C>[Br:20][C:10]1[S:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: BrBr
Reactant: Fc1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: Fc1ccc(-c2cc(Br)sc2-c2ccc(F)cc2)cc1
Reaction time: 4 h
Yield: 83.7 %

Procedure:
A solution of 2,3-bis(4-fluorophenyl)thiophene (13.6 g, 50 mmole) in 120 ml methylene chloride and 150 ml acetic acid was cooled to ~5° and treated with bromine (2.8 ml, 55 mmole). After 4 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine, dried and concentrated in vacuo. Recrystallization from ethanol gave the title compound (14.7 g), m.p. 91°-93°.