Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].Cl.O1CCOCC1.[CH3:20][O:21][C:22](=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=O)[CH:25]=1.[BH3-]C#N.[Na+]>CO.CCOC(C)=O.[OH-].[Na+]>[CH3:20][O:21][C:22](=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][NH:10][CH2:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:12][CH:11]=2)[CH:25]=1
Reactant: CCCCc1ccc(CN)cc1
Reactant: COC(=O)Cc1cccc(C=O)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: CCCCc1ccc(CNCc2cccc(CC(=O)OC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-butyl-benzylamine (from Preparation 15, 0.918 g, 6 mmol) in MeOH was added to 4N HCl in dioxane (0.75 mL, 3 mmol) followed by addition of (3-formyl-phenyl)-acetic acid methyl ester (from Preparation 13, 0.534 g, 3.0 mmol). NaCNBH3 (0.194 mL, 3 mmol) was added and the reaction was stirred at room temperature overnight. The mixture was diluted with EtOAc and 2N NaOH was added. The organic solution was dried over MgSO4, filtered, and concentrated in vacuo. The product was purified via flash chromatography (50% hexanes, 50% EtOAc, 0.1% Et3N) to afford the title compound of Step A. 1H NMR (400 MHz, CDCl3) δ 7.08-7.38 (m, 8H), 3.75 (s, 2H), 3.73 (s, 2H), 3.70 (s, 3H), 3.62 (s, 2H), 2.61 (t, 2H), 1.58 (m, 2H), 1.37 (m, 2H), 0.92 (t, 3H); MS 326 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([N+:13]([O-])=O)=[C:10]([NH2:12])[CH:11]=1>CCO>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([NH2:13])=[CH:8][CH:7]=1
Reactant: CN(C)CCOc1ccc([N+](=O)[O-])c(N)c1
Solvent: CCO
Product: CN(C)CCOc1ccc(N)c(N)c1
Reaction time: 6 h
Yield: 90.3 %

Procedure:
5-(2-Dimethylamino-ethoxy)-2-nitro-phenylamine (0.85 g, 3.77 mmol) was dissolved in EtOH and shaken under an atmosphere of H2 for 6 hours. The catalyst was removed by filtration. Evaporation in vacuo gave 4-(2-Dimethylamino-ethoxy)-benzene-1,2-diamine as a dark yellow oil (0.665 g, 90%). MS(ESI) m/z 196.0 (M+H)+
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br:19][CH2:20][C:21](Br)=[O:22]>ClCCCl>[Br:19][CH2:20][C:21]([C:8]1[CH:9]=[CH:10][C:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:6][CH:7]=1)=[O:22]
Reactant: CCCCCCCCc1ccccc1
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCCCCCCc1ccc(C(=O)CBr)cc1
Reaction time: 2 h
Yield: 56.8 %

Procedure:
To a flame dried round bottom flask equipped with a magnetic stirbar under an inert atmosphere was added AlCl3 (5.47 g, 41 mmol) followed by 1,2-dichloroethane (22 mL). The stirring suspension was then brought to 0° C. and 1-phenyloctane (7.99 mL, 36 mmol) was added in one portion. Bromoacetyl bromide (3.75 mL, 43 mmol) was then added dropwise over a period of 10 minutes. Upon completing addition of the acid bromide, the reaction mixture was brought to room temperature and stirred for 2 hours. The reaction mixture was then quenched carefully by slow addition of H2O (36 mL) without ever letting the reaction mixture exceed 45° C. producing a suspension of solid white precipitate. The aqueous layer of the quenched reaction mixture was discarded and the organic phase was washed once with 10% HCl (10 mL), washed once with H2O (10 mL), and dried over magnesium sulfate. The dried organic phase was then concentrated in vacuo to a green/brown oil. Recrystallization from MeOH/H2O provided the product 1 (6.36 g, 57%) as white needles in three crops. Rf=0.21 (1:19 EtOAc/hexanes).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH3:14])[CH:3]=1.[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22](B3OC(C)(C)C(C)(C)O3)[CH:23]=2)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(Cl)Cl.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][N:4]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[C:10]2[C:2]([C:22]2[CH:23]=[C:24]3[C:19]([CH2:18][CH2:17][N:16]3[CH3:15])=[CH:20][CH:21]=2)=[CH:3]1
Reactant: Cn1cc(I)c2c([N+](=O)[O-])ccnc21
Reactant: CN1CCc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CN1CCc2ccc(-c3cn(C)c4nccc([N+](=O)[O-])c34)cc21
Temperature: 65 °C
Yield: 49.8 %

Procedure:
To a stirred solution of 3-iodo-1-methyl-4-nitro-1H-pyrrolo[2,3-b]pyridine (D17) (6.2 g, 20.46 mmol) in ACN (108 mL) was added 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline (7.95 g, 30.7 mmol), bis(triphenylphosphine)palladium(II) chloride (1.436 g, 2.046 mmol) and 2M sodium carbonate aq. solution (108 mL, 217 mmol). The resulting mixture was heated at 65° C. for ca. 1 hour. After being cooled to RT, the reaction mixture was diluted with DCM (150 mL) and water (200 mL). The organic phase was separated and the aqueous phase was further extracted with DCM (80 mL×4). The combined organics were dried and concentrated. The residue was purified by chromatography on silica, eluting with a gradient of 0-100% ethyl acetate in cyclohexane to give an impure fraction which was re-purified by chromatography on silica, eluting with a gradient of 0-20% ethyl acetate in DCM to give the title compound (3.14 g). LCMS (A): m/z (M+H)+ 309, C17H16N4O2 requires 308 (acidic).
Reaction SMILES: COC([C:5]1[C:6]([CH2:26][O:27][CH3:28])=[N:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:16]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=1)[N:9]=2)=O>Cl>[CH3:28][O:27][CH2:26][C:6]1[CH:5]=[C:14]([OH:15])[C:13]2[C:8](=[N:9][C:10]([C:16]3[C:21]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:12]=2)[N:7]=1
Reactant: COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(O)c1C(=O)OC
Agent: Cl
Product: COCc1cc(O)c2ccc(-c3ncccc3C(F)(F)F)nc2n1
Temperature: 110 °C

Procedure:
4-Hydroxy-2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-[1,8]napthyridine-3-carboxylic acid methyl ester (200 mg, 0.508 mmol) is dissolved in 12 M HCl (20 mL) and heated at 110° C. for 6 hours. The reaction mixture is poured onto ice (100 g) and extracted with CH2Cl2 (4×150 mL). The combined organic extracts are dried over Na2SO4 and the solvent removed under reduced pressure. The crude product is purified by silica gel preparatory TLC eluting with hexanes/acetone (3:1) yielding the title compound as a white solid.
Reaction SMILES: [CH:1]([NH:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH2:16][CH2:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)=[CH:13][C:12]2=[O:27])[C@H:7]([CH2:28][S:29]([C:32]2[CH:37]=[CH:36][C:35](SC)=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:6]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>CO.[Pd]>[CH:1]([NH:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:24])[F:26])[CH:18]=3)[CH2:13][C:12]2=[O:27])[C@H:7]([CH2:28][S:29]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)(=[O:30])=[O:31])[CH2:6]1)([CH3:3])[CH3:2]
Reactant: CSc1ccc(S(=O)(=O)C[C@@H]2C[C@H](NC(C)C)CC[C@@H]2N2CCC(c3cccc(C(F)(F)F)c3)=CC2=O)cc1
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N[C@@H]1CC[C@H](N2CCC(c3cccc(C(F)(F)F)c3)CC2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Reaction time: 12 h

Procedure:
The product of procedure (28e), (±) 1-[(1S*,2R*,4R*)-4-isopropylamino-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-4-(3-trifluoromethyl-phenyl)-5,6-dihydro-lH-pyridin-2-one (-10 mg), was dissolved in MeOH. The resulting solution was charged with ˜20 mg 10% Pd/C, stirred under 1 atm of H2 for 12 h, filtered, and concentrated in vacuo. The residue was redissolved in MeOH. The resulting solution was charged with ˜40 mg 10% Pd/C, stirred under 55 atm of H2 for 12 h, filtered, and concentrated in vacuo. The residue was redissolved in MeOH. The resulting solution was charged with ˜50 mg 10% Pd/C, stirred under 55 atm of H2 for 36 h, filtered, and concentrated in vacuo. The residue was dissolved in 0.5% TFA/MeCN and concentrated in vacuo to afford a mixture of diastereomers as the title compound as its TFA salt (10 mg). MS found: (M+H)+=537.
Reaction SMILES: C([O:8][C:9](=[O:36])[C@H:10]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH:11][C:12]([N:14]([CH2:16][CH2:17][N:18]([C:20]([N:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21])[CH3:19])[CH3:15])=[O:13])C1C=CC=CC=1.[H][H]>CO.[Pd]>[N:22]1([C:20]([N:18]([CH2:17][CH2:16][N:14]([CH3:15])[C:12]([NH:11][C@H:10]([C:9]([OH:36])=[O:8])[CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:13])[CH3:19])=[O:21])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: [H][H]
Reactant: CN(CCN(C)C(=O)N1CCCCCC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CN(CCN(C)C(=O)N1CCCCCC1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Yield: 107.2 %

Procedure:
A solution of N-[N-{2-[N-(hexahydro-1H-azepin-1-ylcarbonyl)-N-methylamino]ethyl}-N-methylaminocarbonyl]-L-phenylalanine benzyl ester (1.46 g) in methanol (20 ml) was hydrogenated over 10% palladium on carbon (146 mg) at 3 atmospheric pressure of hydrogen gas for 1 hour at ambient temperature. The solution was filtered and concentrated in vacuo to give N-[N-{2-[N-(hexahydro-1H-azepin-1-ylcarbonyl)-N-methylamino]ethyl}-N-methylaminocarbonyl]-L-phenylalanine (1.28 g) as an oil. Rf: 0.35 (chloroform:methanol:acetic acid, 16:1:1, V/V)
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:15])[Cl:14])=[O:10])[N:6]2[C:17](=[O:20])[CH:18]([NH2:19])[C@H:5]2[S:4]1.CN(C)C1C=CC=CC=1.[S:30]1[CH:34]=[N:33][N:32]=[C:31]1[S:35][CH2:36][C:37](O)=[O:38].C1(N=C=NC2CCCCC2)CCCCC1.Cl>ClCCl.C(N(CC)CC)C>[CH3:2][CH:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][C:13]([Cl:16])([Cl:14])[Cl:15])=[O:10])[N:6]2[C:17](=[O:20])[CH:18]([NH:19][C:37](=[O:38])[CH2:36][S:35][C:31]3[S:30][CH:34]=[N:33][N:32]=3)[C@H:5]2[S:4]1
Reactant: O=C(O)CSc1nncs1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)c1ccccc1
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)CSc3nncs3)[C@H]2S1
Yield: 89.3 %

Procedure:
2,2,2-Trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (3.82 g) was suspended in dried dichloromethane (80 ml) and dissolved by adding under stirring and ice-cooling a solution of triethylamine (0.9 g) and dimethylaniline (0.15 g) in dichloromethane (20 ml). To the solution were added (1,3,4-thiadiazol-2-ylthio)acetic acid (1.8 g) and dicyclohexylcarbodimide (2.25 g) under stirring and ice-cooling, and the mixture was stirred for 1 hour under ice-cooling. To the reaction mixture, was added 5% hydrochloric acid (50 ml), and the mixture was stirred for 30 minutes, after which the organic layer was separated, washed in turn with 5% hydrochloric acid, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, and then dried over magnesium sulfate. The solvent was distilled off to give pale brown powder of 2,2,2-trichloroethyl 2-methyl-7-[2-(1,3,4-thiadiazol-2-ylthio)acetamido]-3-cephem-4-carboxylate (4.5 g), mp 130° to 140° C. (dec.).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:13]([C@@H:14]([CH2:23][OH:24])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@@H:10]1[OH:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35]1([CH3:45])[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>ClCCl>[CH2:1]([O:8][C@@H:9]1[C@@H:13]([C@@H:14]([CH2:23][O:24][S:41]([C:38]2[CH:39]=[CH:40][C:35]([CH3:45])=[CH:36][CH:37]=2)(=[O:43])=[O:42])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@@H:10]1[O:34][S:41]([C:38]1[CH:39]=[CH:40][C:35]([CH3:45])=[CH:36][CH:37]=1)(=[O:43])=[O:42])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cn([C@@H]2O[C@H]([C@@H](CO)OCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]c1=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@@H](OCc2ccccc2)[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](OS(=O)(=O)c3ccc(C)cc3)[C@@H]2OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of nucleoside 16 (0.60 g, 1.28 mmol) in dichloromethane (70 cm3) at room temperature was added 4—N,N-(dimethylamino)pyridine (0.63g, 5.12 mmol) and p-toluenesulphonyl chloride (0.73 g, 3.84 mmol). After stirring for 3 h, ice-cold H2O (50 cm3) was added and extraction was performed using dichloromethane (3×75 cm3). The combined organic phase was dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol (99.5:0.5, v/v) as eluent to give nucleoside 17 as white solid material (0.71 g, 71%) after evaporation of the solvents under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:3]=1[O:4][C:5]1[C:13]2[NH:12][C:11](=[O:14])[N:10]([CH3:15])[C:9]=2[CH:8]=[CH:7][C:6]=1[C:16]1[C:17]2[CH:26]=[CH:25][N:24](S(C3C=CC(C)=CC=3)(=O)=O)[C:18]=2[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1.[H-].[Na+].CI.[OH-].[Na+].O.[C:49](O)(=O)C>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:3]=1[O:4][C:5]1[C:13]2[N:12]([CH3:49])[C:11](=[O:14])[N:10]([CH3:15])[C:9]=2[CH:8]=[CH:7][C:6]=1[C:16]1[C:17]2[CH:26]=[CH:25][NH:24][C:18]=2[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1
Reactant: CC(=O)O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc5c([nH]c(=O)n5C)c4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CI
Product: Cn1cc(-c2ccc3c(c2Oc2ccc(F)cc2F)n(C)c(=O)n3C)c2cc[nH]c2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
A solution of 4-(2,4-difluorophenoxy)-1-methyl-5-{6-methyl-1-[(4-methylphenyl)sulfonyl]-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one (30.0 mg, 0.0520 mmol) in N,N-dimethylformamide (0.25 mL) was treated with sodium hydride (4.2 mg, 0.104 mmol) and stirred at RT for 30 min. The reaction mixture was treated with methyl iodide (4.9 μL, 0.0780 mmol) and stirred at RT for 1 h. Analytical LCMS indicated the reaction was complete. The reaction mixture was diluted with ethanol (3.0 mL), treated with 3.0 M sodium hydroxide in water (0.175 mL, 0.525 mmol), and stirred at RT overnight. The reaction was quenched with acetic acid (0.044 mL, 0.780 mmol) and purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) to give the desired product (14.5 mg, 64%). 1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 7.25-7.10 (m, 5H), 6.74-6.62 (m, 1H), 6.56-6.42 (m, 1H), 6.16-6.05 (m, 1H), 3.44 (s, 3H), 3.39 (s, 3H), 3.32 (s, 3H); LCMS calculated for C23H19F2N4O3 (M+H)+: m/z=437.1. found: 437.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12]([CH3:23])=[N:13][C:14]([S:17]([CH2:19][C:20](=[O:22])[NH2:21])=[O:18])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1.CN(C=O)C>ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12]([CH3:23])=[N:13][C:14]([S:17]([CH2:19][C:20](=[O:22])[NH2:21])(=[O:32])=[O:18])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1nc(S(=O)CC(N)=O)ncc1C(=O)Nc1ccc(F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(S(=O)(=O)CC(N)=O)ncc1C(=O)Nc1ccc(F)cc1
Yield: 18.9 %

Procedure:
A solution of 2-carbamoylmethylsulfinyl-4-methylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (as prepared above, 42 mg, 0.12 mmol) and m-CPBA (47 mg, 0.27 mmol) in 2 mL of 1:1 dichloromethane:DMF was stirred at ambient temperature for 3 days. The solution was diluted with 40 mL of 1:1 ethyl acetate:hexane and sequentially washed with 2×10 mL 5% NaHCO3(aq), 10 mL 0.1 M HCl(aq) and 10 mL brine. The organic layer was dried using Na2SO4 and concentrated to a white solid which was triturated with 10 mL of 1:1 dichloromethane:hexane, yielding 8 mg (19%) of the titled compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH3:18][N:19]([CH3:24])[S:20](Cl)(=[O:22])=[O:21].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:10]=[CH:9][N:8]([S:20](=[O:22])(=[O:21])[N:19]([CH3:24])[CH3:18])[N:7]=1)=[O:5])[CH3:2]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCOC(=O)c1nc[nH]n1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncn(S(=O)(=O)N(C)C)n1
Yield: 81.3 %

Procedure:
To a solution of 1.02 g (7.23 mmol) of 1H-1,2,4-triazole-3-carboxylic acid ethyl ester in 6 ml of DMF was added 1.46 g (1.44 mmol) of triethylamine. To the solution was added dropwise with stirring under ice-cooling 1.14 g (7.94 mmol) of dimethylsulfamoyl chloride. The mixture was stirred at room temperature for 8 hours. 30 ml of Water was added thereto and extracted with 20 ml of ethylacetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and water, dried over Na2SO4 and evaporated under reduced pressure to give an oil. The obtained oil was purified with silica gel chromatography (eluate: hexane/ethylacetate=2:1) to give 1.46 g of 1-dimethylsulfamoyl-1,2,4-triazole-3-carboxylic acid ethyl ester as a white crystal. Yield: 82%.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH2:35]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:35][C:34]3[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:32]([F:31])[CH:33]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CBr)cc1F
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: COc1ccc(Cn2ccc3c(-c4ccc5c(c4)CCCO5)c(C(OC(C)(C)C)C(=O)O)c(C)nc32)cc1F

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 3-fluoro-4-methoxybenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.51-7.41 (m, 1 H), 7.25-7.18 (m, 1 H), 7.07-6.99 (m, 3 H), 6.97-6.88 (m, 2 H), 6.31-6.23 (m, 1 H), 5.63-5.56 (m, 1 H), 5.53-5.36 (m, 2 H), 4.32-4.26 (m, 2 H), 3.90-3.86 (m, 3 H), 2.96-2.80 (m, 2 H), 2.75 (s, 3 H), 2.14-2.04 (m, 2 H), 0.97 (s, 9H); LC/MS (m/z) ES+=533.28 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=[CH2:8])[C:3]([OH:5])=[O:4].[CH3:10]O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=[CH2:8])[C:3]([O:5][CH3:10])=[O:4]
Reactant: CO
Reactant: C=CCC(C)(C)C(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: C=CCC(C)(C)C(=O)OC

Procedure:
2,2-Dimethyl-4-pentenoic acid (15 g, 0.117 mol) was mixed with 70 mL anhydrous methanol and 50 mL toluene. Concentrated sulfuric acid (0.1 mL) was added. The solution was refluxed for 24 h. Solvents were then removed. The crude product was distilled under reduced pressure to gave 6 g pure product. 1H NMR(CDCl3) δ1.28(s, 6H, —CMe2—); 2.37(d, 2H, CH2═CHCH2—); 3.77(s, 3H, —CO2Me); 5.15(m, 2H, CH2═CH—); 5.84(m, 1H, CH2═CH—)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[OH:17])=[C:4]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:3]=1.C([O-])(O)=O.[Na+].[N:32]1[C:39]([Cl:40])=[N:38][C:36](Cl)=[N:35][C:33]=1[Cl:34]>C1COCC1>[CH2:20]([O:19][C:4]1[CH:3]=[C:2]([NH:1][C:36]2[N:38]=[C:39]([Cl:40])[N:32]=[C:33]([Cl:34])[N:35]=2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[OH:17])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Nc1ccc(NC(=O)c2ccc(F)cc2O)c(OCc2ccccc2)c1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1OCc1ccccc1)c1ccc(F)cc1O
Temperature: 25 °C

Procedure:
N-(4-Amino-2-benzyloxy-phenyl)-4-fluoro-2-hydroxy-benzamide (76) (0.060 g, 0.170 mmol) was dissolved in THF (3.4 mL), NaHCO3 (0.086 g, 1.02 mmol) was added and the mixture was chilled on a dry-ice/acetone bath. Cyanuric chloride (5) (0.032 g, 0.184 mmol) was dissolved in THF (2 mL) and added directly to the chilled solution while stirring. The ice bath was removed and the mixture continued to stir while warming to room temperature for 1 h. TLC (Rf: 0.8 compared to Rf: 0.35 for compound 76 in 1:1 hexane/EtOAc, single spot) indicated complete reaction at this point. The reaction mixture was used immediately in the next step without purification or characterization.
Reaction SMILES: [ClH:1].Cl.[N:3]1([CH2:8][CH2:9][O:10][C:11]2[CH:40]=[CH:39][C:14]([CH2:15][C:16]3[C:17]4[CH:38]=[CH:37][CH:36]=[CH:35][C:18]=4[S:19][C:20]=3[C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]4[N:31]=CN[CH:34]=4)=[O:29])=[CH:23][CH:22]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.[NH:41]1[CH:45]=CC(C(O)=O)=N1.[NH4+].[OH-].Cl>C(Cl)(Cl)Cl.CO>[ClH:1].[ClH:1].[N:3]1([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:15][C:16]3[C:17]4[CH:38]=[CH:37][CH:36]=[CH:35][C:18]=4[S:19][C:20]=3[C:21]3[CH:22]=[CH:23][C:24]([NH:27][C:28]([C:30]4[CH:34]=[CH:45][NH:41][N:31]=4)=[O:29])=[CH:25][CH:26]=3)=[CH:39][CH:40]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(O)c1cc[nH]n1
Reactant: O=C(Nc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1)c1c[nH]cn1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(Nc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1)c1cc[nH]n1
Yield: 48 %

Procedure:
By essentially following the conditions described in Example 16, Part E, the free base of the title compound was prepared as a solid from 2-(4-aminophenyl)-3-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzo[b]thiophene (Example 16; Part D) and 3-pyrazole carboxylic acid in 48% yield following radial chromatography (SiO2; 1% then 3% then 5% MeOH in CHCl3 sat'd with NH4OH). The solid was taken up in 5 mL MeOH, and the solution was treated with 1 mL of 1 N HCl. The solution was concentrated to give the title compound.
Reaction SMILES: COC1C(OC)=C(OC)C=C([N+]([O-])=O)C=1Br.[ClH:17].[CH3:18][SH:19]1(=[O:48])[C:24]2[C:25](OC)=[C:26]([O:31][CH3:32])[C:27]([O:29]C)=[CH:28][C:23]=2[N:22]=[C:21]([N:35]2[CH2:40][CH2:39][N:38]([C:41]([C:43]3[O:44][CH:45]=[CH:46][CH:47]=3)=[O:42])[CH2:37][CH2:36]2)[NH:20]1>>[ClH:17].[CH3:18][SH:19]1(=[O:48])[C:24]2[CH:25]=[C:26]3[O:31][CH2:32][O:29][C:27]3=[CH:28][C:23]=2[N:22]=[C:21]([N:35]2[CH2:36][CH2:37][N:38]([C:41]([C:43]3[O:44][CH:45]=[CH:46][CH:47]=3)=[O:42])[CH2:39][CH2:40]2)[NH:20]1
Reactant: COc1cc2c(c(OC)c1OC)[SH](C)(=O)NC(N1CCN(C(=O)c3ccco3)CC1)=N2
Agent: COc1cc([N+](=O)[O-])c(Br)c(OC)c1OC
Agent: Cl
Product: C[SH]1(=O)NC(N2CCN(C(=O)c3ccco3)CC2)=Nc2cc3c(cc21)OCO3

Procedure:
By employing 2,3,4-trimethoxy-6-nitrophenylbromide as a starting material, and following the procedures of the above examples, 1-methyl-3-[4-(2-furoyl)-piperazino]-6,7,8-trimethoxy-1H-1,2,4-benzothiadiazine-1-oxide hydrochloride was prepared. The compound melted at 130°-2° C.