Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:19]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[S:26][C:16]=3[N:17]=2)[CH:21]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3cccnc3)nc2s1
Product: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-methylenedioxyphenethylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([N:8]1[C@@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=C[C:25]2[N:30]([OH:31])N=NC=2C=1.[CH2:32](Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[C@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH2:13][C@@H:9]1[C:10]([N:30]([O:31][CH3:32])[CH3:25])=[O:12])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccccc2)CC[C@H]1C(=O)O
Reactant: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)[C@H]1CC[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of racemic N-Boc-cis-5-phenylproline (2 g, 6.865 mmol) in DMF (35 mL) was added HOBt (1.05 g, 6.87 mmol), EDC (1.97 g, 10.3 mmol), O, N-dimethylhydroxylamine hydrochloride (1.00 g, 10.3 mmol) and DIEA dropwise (1.33 mL, 10.3 mmol). The reaction was stirred at ambient temperature for 30 min and then partitioned between ethyl acetate and water. The EtOAc layer was separated and washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 50:50 ethyl acetate and hexane. Collection and concentration of appropriate fractions provided the title compound. HPLC RT=3.46 min, 86% at 215 nm (Method A); ES MS (M+H)=335.3.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH2:14]Br)=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9]C)=O)([O-:3])=[O:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:27]([O:34][C:35](=[O:50])[C@H:36]([CH2:38][CH2:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])[NH2:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[CH2:27]([O:34][C:35]([CH:36]([N:37]1[CH2:14][C:5]2[C:6](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:7]1=[O:9])[CH2:38][CH2:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])=[O:50])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(CCC(C(=O)OCc1ccccc1)N1Cc2c(cccc2[N+](=O)[O-])C1=O)OCc1ccccc1
Yield: 59.5 %

Procedure:
A mixture of methyl 3-nitro-2-(bromomethyl)benzoate (2.5 g, 9.12 mmol), L-glutamic acid dibenzyl ester p-toluenesulfonate salt (3.0 g, 9.12 mmol) and triethylamine (2.0 g, 20.0 mmol) in THF (50 mL) is heated at reflux for 16 hours. The mixture is diluted with methylene chloride (150 mL) and washed with water (2×40 mL), brine (40 mL), dried and concentrated to an oil. The oil is purified by chromatography (silica gel, Hexane:ethoxyacetic acid 7:3) to give 1-(4-nitro-1-oxoisoindolin-2-yl)propane-1,3-dicarboxylic acid dibenzyl ester (2.65 g, 59%); 1H NMR (CDCl3) δ8.39 (d, J=7.8 Hz, 1H), 8.16 (d, J=7.3 Hz, 1H), 7.69 (t, J=7.9 Hz, 1H), 7.30 (m, 10H), 5.29 (s, 2H), 5.29-5.13 (m, 1H), 5.03 (s, 2H), 4.98 (d, J=19.1 Hz, 1H), 4.85 (d, J=19.2 Hz, 1H), 2.54-2.39 (m, 4H); 13C NMR (CDCl3) δ171.79, 169.92, 166.72, 143.47, 137.25, 135.49, 135.04, 134.99, 130.17, 129.67, 128.62, 128.52, 128.29, 128.25, 128.23, 127.04, 67.49, 66.58, 53.70, 48.35, 30.87, 24.79.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[OH:18])[CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[OH:18])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O[C@@H]1CCCC[C@H]1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(F)cc1O[C@@H]1CCCC[C@H]1O

Procedure:
(R,R)-4-Fluoro-2-(2-hydroxycyclohexyloxy)-nitrobenzene (1.99 g) in methanol (20.0 ml) was hydrogenated under 50 psi hydrogen for 5 h at rt using palladium on charcoal (5%) (200 mg) as catalyst. The catalyst was filtered off; the resulting solution was evaporated to dryness to yield an oil.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:20][F:21])[O:8][CH2:7][CH:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N+:14]([O-])=[C:13]([CH3:18])[C:12]=2[CH3:19])[CH2:5][O:4]1.C(OC(=O)C)(=[O:24])C>>[F:1][CH2:2][C:3]1([CH2:20][F:21])[O:8][CH2:7][CH:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:18][OH:24])[C:12]=2[CH3:19])[CH2:5][O:4]1
Reactant: Cc1c(OCC2COC(CF)(CF)OC2)cc[n+]([O-])c1C
Reactant: CC(=O)OC(C)=O
Product: Cc1c(OCC2COC(CF)(CF)OC2)ccnc1CO
Temperature: 100 °C
Reaction time: 2 h
Yield: 23.6 %

Procedure:
The 4-((2,2-bis(fluoromethyl)-1,3-dioxan-5-yl)methoxy)-2,3-dimethylpyridine 1-oxide (1.63 g, 5.37 mmol) obtained in the step (7b) was mixed with acetic anhydride (8 ml). The mixture was stirred at 100° C. for 2 hours, cooled to room temperature, and then, concentrated under reduced pressure. To the residue, methanol (10 ml) and a 5N aqueous sodium hydroxide solution (5 ml) were added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and the residue was separated between a saturated saline solution and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated and the residue was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate, ethyl acetate/methanol) to obtain the title compound (385 mg, yield 23.6%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:22][N:23]1[C:27]([Sn](CCCC)(CCCC)CCCC)=[CH:26][N:25]=[CH:24]1>O1CCOCC1.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>[CH3:22][N:23]1[C:27]([C:2]2[C:3]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:26][N:25]=[CH:24]1
Reactant: Clc1nccnc1Oc1ccc(Nc2ccccn2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cn1cncc1-c1nccnc1Oc1ccc(Nc2ccccn2)cc1
Temperature: 160 °C

Procedure:
A suspension of N-(4-(3-chloropyrazin-2-yloxy)phenyl)pyridin-2-amine (350 mg, 1172 μmol), 1-methyl-5-(tributylstannyl)-1H-imidazole (870 mg, 2343 μmol), and tetrakis(triphenylphosphine)palladium (0) (271 mg, 234 μmol) in 1,4-dioxane (4 mL) was sparged with argon for 3 minutes then the vessel was appropriately sealed. The vessel was then heated to 160° C. with microwaves (3 bar; 130 watts) for 20 minutes. The solvents were removed under reduced pressure and the residue was purified on silica (40 g) eluting products with 2-4% of MeOH/DCM to afford the title compound as a white solid. MS (ESI pos. ion) m/z: 345.1 (M+1). IC50 (uM) 0.034.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]2[NH:32][C:31](=[O:33])[N:30]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[CH2:29][CH2:28][C:27]=2[CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[F:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:11]([C:9]([C:4]1[N:5]=[C:6]([CH3:8])[CH:7]=[C:2]([N:37]3[CH2:36][CH2:35][CH:34]([N:30]4[CH2:29][CH2:28][C:27]5[CH:40]=[C:23]([O:22][CH3:21])[CH:24]=[CH:25][C:26]=5[NH:32][C:31]4=[O:33])[CH2:39][CH2:38]3)[CH:3]=1)=[O:10])[CH2:12][CH2:13]2
Reactant: Cc1cc(Cl)cc(C(=O)N2CCc3cc(F)ccc32)n1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C)nc(C(=O)N4CCc5cc(F)ccc54)c3)CC1)C(=O)N2

Procedure:
125 mg (0.43 mmol) (4-chloro-6-methyl-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone, 118 mg (0.43 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one and 89 mg (0.65 mmol) potassium carbonate in 2.0 mL NMP were stirred for 10 h at 130° C. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[Br-:12].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Br:12][C:10]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:11]=1
Reactant: [Br-]
Reactant: CC(C)(C)c1ccccc1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(Br)ccc1N
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
To a solution of 2-tert-butylaniline (50 g, 335 mmol) in THF (500 mL) was added tetrabutylammonium tribromide (234.5 g, 335 mmol) at 0° C. After the solution was stirred for 30 minutes at that temperature, it was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated Na2S2O3 solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the crude product. The product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=100:0 to 20:80) to provide 4-bromo-2-tert-butylaniline (74.6 g, 98%) as a pink oil.
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][S:5]([O:8][CH2:9][C@:10]1([CH2:43][CH:44]=C)[CH2:15][C@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C@@H:13]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N:12]([C@@H:30]([CH2:40][CH3:41])[CH2:31][N:32]([CH3:39])[S:33]([CH:36]2[CH2:38][CH2:37]2)(=[O:35])=[O:34])[C:11]1=[O:42])(=[O:7])=[O:6].CSC>CO.C(Cl)Cl>[CH3:4][S:5]([O:8][CH2:9][C@:10]1([CH2:43][CH:44]=[O:1])[CH2:15][C@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[C@@H:13]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[N:12]([C@@H:30]([CH2:40][CH3:41])[CH2:31][N:32]([CH3:39])[S:33]([CH:36]2[CH2:37][CH2:38]2)(=[O:35])=[O:34])[C:11]1=[O:42])(=[O:7])=[O:6]
Reactant: C=CC[C@@]1(COS(C)(=O)=O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C2CC2)C1=O
Reactant: O=[O+][O-]
Solvent: CO
Solvent: CSC
Solvent: ClCCl
Product: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@](CC=O)(COS(C)(=O)=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
Ozone was bubbled through a solution of ((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)methyl methanesulfonate (Example 414, Step E, 1.12 g, 1.703 mmol) in 10% MeOH-DCM at −78° C. until a blue color developed. The reaction was purged with nitrogen gas followed by addition of dimethyl sulfide (1.251 ml, 17.03 mmol). The reaction was warmed to room temperature. The crude material was purified by chromatography on a RediSep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.) (12 g), eluting with a gradient of 0% to 80% EtOAc in hexane, to provide the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][N:7]=1.[O-:9][Mn](=O)(=O)=O.[K+].[OH2:15]>>[CH3:1][C:2]1[C:3]([C:8]([OH:9])=[O:15])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1nccnc1C
Reactant: O
Agent: [K+]
Product: Cc1nccnc1C(=O)O
Yield: 30 %

Procedure:
A solution of dimethylpyrazine (25 g, 231 mmol) in water (250 mL) was heated at 70° C. and a solution of KMnO4 (82.2 g, 520 mmol) in water was added at such a rate to maintain the temperature between 70 and 75° C. The mixture was stirred until the purple color vanished and was filtered over Celite. The aqueous solution was extracted with EtOAc (6×800 mL), dried over Na2SO4 and concentrated in vacuo. The residue was titrated with TBME to afford 3-methylpyrazine-2-carboxylic acid (9.3 g, 67 mmol) as a white solid in 30% yield.
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.CC([Li])CC.[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C:16](=[O:22])[CH2:15]2.Cl>O1CCCC1.C1CCCCC1.O>[OH:8][C:7]1[C:2]([CH2:1][C:16]2([OH:22])[CH:17]3[CH2:20][CH2:21][N:14]([CH2:19][CH2:18]3)[CH2:15]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CN2CCC1CC2
Reactant: Cc1ncccc1O
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Solvent: C1CCCCC1
Product: Oc1cccnc1CC1(O)CN2CCC1CC2
Temperature: -56 °C
Yield: 55.1 %

Procedure:
52.9 g (484 mmol) of 2-methyl-3-hydroxypyridine dissolved in 1300 ml of tetrahydrofuran are introduced into a 2000 ml three-neck flask under argon. The solution is cooled to −56° C. and 750 ml (975 mmol) of a 1.3 M 1-methylpropyllithium solution in cyclohexane is added dropwise in the course of 3 h, keeping the temperature lower than −50° C. At the end of the addition, the temperature is allowed to rise to −4° C. in the course of 45 min and the mixture is then again cooled to −58° C. to add 60.6 g (484 mmol) of 1-azabicyclo[2.2.2]octan-3-one dissolved in 250 ml of tetrahydrofuran dropwise in the course of 40 min. The temperature is allowed to rise to ambient and stirring is maintained for 20 h. The reaction mixture is cooled to 4° C. and hydrolysed by addition of 110 ml of an aqueous solution of 36% hydrochloric acid. 400 ml of water are added, the two phases are allowed to settle and the organic phase is extracted with water. The aqueous phases are reunited, the mixture is cooled to 4° C. and a concentrated aqueous solution of sodium hydroxide is added to pH 8.4. The precipitate obtained is filtered and dried in vacuo at 80° C. 62.5 g of product are thus obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]1[S:12][CH:13]=[CH:14][C:15]=1[CH:16]1OCCO1)([O-])=O>CC(C)=O.C(O)(=O)C.[Zn]>[S:12]1[C:11]2[CH2:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[NH:1][CH2:16][C:15]=2[CH:14]=[CH:13]1
Reactant: O=[N+]([O-])c1ccccc1Cc1sccc1C1OCCO1
Agent: [Zn]
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: c1ccc2c(c1)Cc1sccc1CN2
Reaction time: 6 h
Yield: 72.4 %

Procedure:
A stirred solution of 4 gms of 2-[2-[(2-nitrophenyl)methyl]-3-thienyl]-1,3-dioxolane in acetone (50 ml) and acetic acid (90% 50 ml) is heated to 60° C. Zinc dust (10 gms) is slowly added and after the addition, reaction mixture is stirred for 6 hours. At the end, reaction mixture is filtered and the residue washed with acetone and concentrated. The brown residue is extracted with chloroform and washed well with water. The organic layer is dried (Na2SO4) and filtered and concentrated. The product is isolated by silica gel column chromatography by eluting with 20% ethyl acetate:hexane to give 2.0 g of the desired product ZLs a pale yellow crystalline solid, m.p. 86° C. Mass Spectrum; M+ 202.
Reaction SMILES: [NH:1]1[C:5]([NH2:6])=[CH:4][CH:3]=[N:2]1.O.[N+:8]([CH:11]([CH:14]=O)[CH:12]=O)([O-:10])=[O:9].[Na].O>C(O)(=O)C>[N+:8]([C:11]1[CH:12]=[C:4]2[CH:3]=[N:2][NH:1][C:5]2=[N:6][CH:14]=1)([O-:10])=[O:9]
Reactant: O=CC(C=O)[N+](=O)[O-]
Reactant: Nc1ccn[nH]1
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cnc2[nH]ncc2c1
Temperature: 90 °C
Yield: 90 %

Procedure:
A suspension of 1H-pyrazol-5-amine (0.804 g, 9.48 mmol) and sodium nitromalonaldehyde monohydrate (1.56 g, 9.96 mmol) in acetic acid (12 mL) was heated to 90° C. overnight. The reaction mixture was cooled to room temperature and poured into water (50 mL). The resulting solids were collected by filtration. The solids were washed with water (3×20 mL) and dried in vacuo to give 5-nitro-1H-pyrazolo[3,4-b]pyridine (1.40 g, 84%) as a solid.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([O:17][CH3:18])[CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[CH:5]=[C:4]([OH:19])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>CC(C)=O>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([O:17][CH3:18])[CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[CH:5]=[C:4]([O:19][CH2:26][CH:28]2[CH2:29][O:30]2)[CH:3]=1
Reactant: COc1cccc2c(=O)c3c(O)cc(O)cc3oc12
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cccc2c(=O)c3c(O)cc(OCC4CO4)cc3oc12
Temperature: 57.5 °C
Yield: 32.1 %

Procedure:
A mixture of 1,3-dihydroxy-5-methoxy-9H-xanthen-9-one (1.13 g, 4.39 mmol) prepared in Step 1 of Example 1 and K2CO3 (1.52 g, 10.98 mmol) in anhydrous acetone (25 mL) was charged to a dry round-bottom flask, and epichlorohydrin (1.73 mL, 21.95 mmol) was added thereto, followed by stirring under reflux at a temperature of 55 to 60° C. for 6 hours. Solid of the reaction mixture was filtered, and the solvent was removed under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:1 (v/v)) to give the title compound (443.2 mg, 32%) as a light yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:5])C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:12][O:13][N:14]=[C:15]([C:32]1[NH:36][N:35]=[N:34][N:33]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][O:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=1[CH3:31].S(OC)(OC)(=O)=O>CCOCC>[CH3:12][O:13][N:14]=[C:15]([C:32]1[N:36]([CH3:1])[N:35]=[N:34][N:33]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][O:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=1[CH3:31].[CH3:12][O:13][N:14]=[C:15]([C:32]1[N:33]=[N:34][N:2]([CH3:5])[N:36]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][O:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=1[CH3:31]
Reactant: CON=C(c1nnn[nH]1)c1ccccc1COc1cc(C)ccc1C
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: COS(=O)(=O)OC
Product: CON=C(c1ccccc1COc1cc(C)ccc1C)c1nnnn1C
Product: CON=C(c1nnn(C)n1)c1ccccc1COc1cc(C)ccc1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 19 %
Yield: 37.9 %

Procedure:
N,N-Dimethylformamide (3 ml) and potassium carbonate (0.33 g, 2.4 mmol) were added to 2-(2,5-dimethylphenoxymethyl)phenyl 1H-tetrazol-5-yl ketone O-methyloxime (0.40 g, 1.2 mmol), and the mixture was stirred at room temperature for 5 minutes. Then, dimethyl sulfate (0.23 g, 1.8 mmol) was added under ice-cooling, and the mixture was stirred at room temperature overnight. After completion of the reaction, ether (150 ml) was added, and the mixture was washed with brine (50 ml) twice. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 2-(2,5-dimethylphenoxymethyl)phenyl 1-methyl-1H-tetrazol-5-yl ketone O-methyloxime as colorless crystals (0.16 g, 37.9%) [mp. 115.5-116.5° C.; 1H-NMR(CDCl3) δ ppm: 1.97(3H,s), 2.26(3H,s), 4.06(3H,s), 4.13(3H,s), 4.89(2H,s), 6.50(1H,s), 6.65(1H,d,J=7.9), 6.97(1H,d,J=7.9), 7.34-7.58(4H,m)] and 2-(2,5-dimethylphenoxymethyl)phenyl 2-methyl-2H-tetrazol-5-yl ketone O-methyloxime as colorless crystals (0.08 g, 19.0%) [mp. 131-132° C.; 1H-NMR(CDCl3) δ ppm: 2.12(3H,s), 2.24(3H,s), 4.09(3H,s), 4.34(3H,s), 4.96(2H,s), 6.54(1H,s), 6.64(1H,d,J=7.9), 6.98(1H,d,J=7.3), 7.29-7.53(3H,m), 7.69(1H,d,J=7.3)].
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[F:22][C:23]1[CH:30]=[CH:29][C:26]([NH:27][CH3:28])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:30]=[CH:29][C:26]([N:27]([CH3:28])[S:2]([C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9]4[NH:16][CH:17]=[CH:18][C:8]=4[C:7]=3[CH:6]=2)(=[O:3])=[O:4])=[CH:25][CH:24]=1.[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: CNc1ccc(F)cc1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Product: CCC(=O)[O-]
Product: CN(c1ccc(F)cc1)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Yield: 24.5 %

Procedure:
This compound is prepared according to synthesis 25, from 150 mg (0.46 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2) and 62 μL (0.55 mmol) of (4-fluoro)-N-methyl-aniline. After purification by chromatography on silica (eluent dichloromethane/methanol 95/5) then trituration in methanol, 25 mg (12%) of 8-[(4-fluorophenyl)-methyl-sulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:24])([CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[CH3:16])=[CH:11][CH:10]=1)=[O:7])([O-])=O.[H][H]>CCO.[Pd]>[NH2:1][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([CH3:24])([CH:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]2)[CH3:16])=[CH:13][CH:14]=1)=[O:7]
Reactant: [H][H]
Reactant: CN1CCC(C(C)(C)c2ccc(NC(=O)c3ccccc3[N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCC(C(C)(C)c2ccc(NC(=O)c3ccccc3N)cc2)CC1

Procedure:
2-Nitro-N-{4-[1-methyl-1-(1-methylpiperidin-4-yl)ethyl]phenyl}benzamide (Step A, 750 mg) was mixed with Pd/C (10%, 200 mg) in EtOH (80 mL) and hydrogenated under a hydrogen atmosphere for 1 h. The solution was filtered through Celite® and evaporated to give the amine used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23](C)(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[N:3]=1.C(B(CC)CC)C.C([O-])(=O)C.[Na+].[NH2:39]OS(O)(=O)=O>O1CCCC1.O>[CH3:1][C:2]1[N:3]=[C:4]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:39])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(-c2nc(C(F)(F)F)cn2-c2ccc(S(C)(=O)=O)cc2)n1
Reactant: NOS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: CCB(CC)CC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(-c2nc(C(F)(F)F)cn2-c2ccc(S(N)(=O)=O)cc2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a clear solution of Example 34 (10 mmol) in tetrahydrofuran (60 ml) at 0° C., n-BuMgcl (2M solution in THF, 25 ml, 50 mmol) is added over 10 minutes. After stirring for an additional 20 minutes, the ice bath is removed and the solution is stirred for 2 hours. The reaction mixture is recooled to 0° C. and triethylborane (1M solution in THF, 60 ml, 60 mmol) is added. After stirring for 1 hour, the reaction is heated to reflux for 72 hours. The reaction mixture is cooled to room temperature and treated with aqueous sodium acetate (5.5 g in 22 ml water). After stirring for 5 minutes, solid hydroxylamine-O-sulfonic acid (5.5 g) is added and the mixture stirred for 24 hours. The reaction mixture is diluted with water and extracted with ether. The ethereal layer is dried over sodium sulfate, filtered and concentrated. The crude solid is chromatographed on silica gel using mixtures of hexane and isopropanol to give the desired product.