Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([C@H:7]1[C@H:11]([OH:12])[CH2:10][CH:9]=[CH:8]1)[C:3]([O:5][CH3:6])=[O:4].CC([O:17]O)(C)C>C1(C)C=CC=CC=1.C/C(/O)=C\C(C)=O.C/C(/O)=C\C(C)=O.O=[V]>[F:1][CH:2]([C@H:7]1[C@H:8]([OH:17])[CH2:9][C@H:10]2[C@@H:11]1[O:12]2)[C:3]([O:5][CH3:6])=[O:4]
Reactant: CC(C)(C)OO
Reactant: COC(=O)C(F)[C@@H]1C=CC[C@H]1O
Agent: O=[V]
Agent: CC(=O)/C=C(\C)O
Solvent: Cc1ccccc1
Product: COC(=O)C(F)[C@@H]1[C@H]2O[C@H]2C[C@H]1O
Temperature: 14 °C
Reaction time: 2 h

Procedure:
To a solution of olefin 2 (1.92 kg, 11.0 mol) in toluene (4.83 L) was added vanadyl acetylacetonate (VO(acac)2, 58.3 g, 0.22 mol) at 0° C. After a solution of TBHP (5.7 M in decane, 38.6 mL) was added to the solution at 0° C., the resulting suspension was allowed to warm to 14° C. Additional solution of TBHP (5.7 M in decane, 4.36 L) was slowly added to the reaction mixture over 50 min while maintaining the batch temperature between 14-28° C. The resulting suspension was stirred for another 2 h, and then heated at 40° C. for 8 h. Excess TBHP was quenched with aqueous Na2S2O3 solution (2.95 kg Na2S2O3 and 4.71 kg H2O), which was slowly added at 0° C. The resulting mixture was stirred at 20° C. for 1.5 h. The disappearance of peroxides was confirmed by test paper. The aqueous layer was separated and extracted with EtOAc (9.42 L×2). The combined organic solutions were washed with brine (6.33 L). The brine layer was back-extracted with EtOAc (3.42 L×4). GC assay of the combined organic solutions indicated product 3. The combined organic solutions were concentrated, and the resulting residue was purified by silica gel chromatography in a filter pot (first eluted with hexanes/EtOAc (4/1) then pure EtOAc). Analytically pure sample was prepared by flash silica gel column chromatography (hexanes/MTBE) followed by recrystallization (EtOAc) as pale yellow crystals: mp 31-33° C.; 1H NMR (400 MHz, CDCl3) δ 5.01 (dd, J=48.3, 3.9 Hz, 1H), 4.13 (br s, 1H), 3.86 (s, 3H), 3.71 (m, 1H), 3.59 (m, 1H), 2.77 (dd, J=32.8, 3.9 Hz, 1H), 2.30 (br s, 1H), 2.11 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 168.4 (d, J=24.1 Hz), 88.1 (d, J=186.1 Hz), 73.2 (d, J=1.6 Hz), 58.4, 57.1 (d, J=5.6 Hz), 52.8, 51.6 (d, J=19.3 Hz), 37.7 (d, J=1.6 Hz); 19F NMR (376 MHz, CDCl3) δ −200.8 (dd, J=48.3, 32.8 Hz); LRMS m/z 191 (M+1), 189 (M−1), 172 ([M−H2O]+), 59 ([COOCH3]+, base peak); [α]D25=−56 (c 1.0, CHCl3).
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13](=S)[C:12]3[CH:22]=[CH:23][CH:24]=[N:25][C:11]2=3)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:26](OCC)(=[O:29])[NH:27][NH2:28]>>[N:1]1([CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]3[C:26](=[O:29])[NH:27][N:28]=[C:13]3[C:12]3[CH:22]=[CH:23][CH:24]=[N:25][C:11]2=3)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)NN
Reactant: O=C(CN1CCCCC1)N1c2ccccc2NC(=S)c2cccnc21
Product: O=C(CN1CCCCC1)N1c2ccccc2-n2c(n[nH]c2=O)-c2cccnc21

Procedure:
In the manner given in Example 13, 6,11-dihydro-11-(piperidinoacetyl)-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione is heated to about 200° C. with ethyl carbazate to give 2,9-dihydro-9-(piperidinoacetyl)-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[NH:6][CH:7]=1)[CH3:2].[Br:15]Br.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:15][C:7]1[NH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[N:4][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1c[nH]c(-c2ccc(F)cc2)n1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCc1nc(-c2ccc(F)cc2)[nH]c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
To a suspension of 4-ethyl-2-(4-fluorophenyl)imidazole (4.90 g) in chloroform (100 ml) was added bromine (4.53 g), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was collected. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was crystallized from chloroform to obtain 5-bromo-4-ethyl-2-(4-fluorophenyl)-imidazole (5.16 g) as colorless crystal. 53 mg of the product was treated with 4N hydrogen chloride-dioxane solution to obtain 5-bromo-4-ethyl-2-(4-fluorophenyl)imidazole (60 mg) as colorless crystal.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:11][C:10]2[CH:12]=[CH:13][C:14](=[O:18])[C:15]([OH:17])=[CH:16][C:9]=2[C:8](=[O:19])[CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].CN(C)C=O.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>O>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][N:11]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][C:8](=[O:19])[C:9]2[CH:16]=[C:15]([OH:17])[C:14](=[O:18])[CH:13]=[CH:12][C:10]1=2)[CH3:33]
Reactant: CCOC(=O)c1cc(=O)c2cc(O)c(=O)ccc2[nH]1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C(=O)OCC)cc(=O)c2cc(O)c(=O)ccc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
4,7-Dihydro-4,7-dioxo-6-hydroxy-1H-cyclohepta[b]pyridine-2-carboxylic acid ethyl ester (12.0 g, described in Example 3) is added to a stirring mixture of sodium hydride (57%, 2.8 g) and dimethylformamide (400 ml) at room temperature. Ethyl bromoacetate (15.8 g) is added. The mixture is stirred at room temperature for 20 hr and poured on ice. Water is added and the mixture is extracted with chloroform. The organic extract is dried over sodium sulfate and evaporated. The residue is crystallized from ethyl acetate to give the title compound, mp 186°-188° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=1)[S:8][C:7](=[O:19])[C:6]([C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])=[C:5]2[OH:27]>[OH-].[Na+].[Pd]>[CH2:12]([C:10]1[CH:11]=[CH:2][CH:3]=[C:4]2[C:9]=1[S:8][C:7](=[O:19])[C:6]([C:20]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])=[C:5]2[OH:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)CNC(=O)c1c(O)c2cc(Cl)cc(Cc3ccccc3)c2sc1=O
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CNC(=O)c1c(O)c2cccc(Cc3ccccc3)c2sc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[(6-Chloro-4-hydroxy-2-oxo-8-benzyl-2H-thiochromene-3-carbonyl)-amino]-acetic acid (Example 42 a) (70 mg, 0.173 mmol) was dissolved in aqueous sodium hydroxide (870 uL 1M in 8 mL of water) and 10% palladium on carbon (7 mg) was added. The reaction was vacuum-purged and placed under an atmosphere of hydrogen gas and permitted to stir overnight at ambient temperature. Upon completion, the reaction was filtered through a pad of Celite® to remove the palladium catalyst. The product was precipitated with 1N HCl, isolated via filtration and dried to provide the title compound (30 mg.) MS ESI(−) m/e: 368.093 (M−1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:25][CH2:26][CH:27]([N:48]=[N+]=[N-])[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O1CCCC1>[CH2:7]([O:25][CH2:26][CH:27]([NH2:48])[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCC/C=C\CCCCCCCCOCC(COCCCCCCCC/C=C\CCCCCCCC)N=[N+]=[N-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCCOCC(N)COCCCCCCCC/C=C\CCCCCCCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
In 3 ml of tetrahydrofuran was suspended 8 mg (0.2 mmol) of lithium aluminum hydride. While this suspension was maintained under ice-cooling, 125 mg (0.2 mmol) of 1,3-dioleyloxy-2-propyl azide was added dropwise and the mixture was stirred at 0° C. for 2 hours. The reaction mixture was then poured in ice-water and extracted with ether. The extract was washed with water, dried, and concentrated. The residue was subjected to column chromatography (silica gel/methylene chloride-methanol) to provide 104 mg (89%) of the title compound as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[N:8]([Si](C(C)C)(C(C)C)C(C)C)[CH:9]=[CH:10][CH:11]=2)=[N:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([C:7]2[NH:8][CH:9]=[CH:10][CH:11]=2)=[N:4][CH:3]=1
Reactant: Cc1cnc(-c2cccn2[Si](C(C)C)(C(C)C)C(C)C)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(-c2ccc[nH]2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
5-Methyl-2-[1-(triisopropylsilyl)-1H-pyrrol-2-yl]-1,3-thiazole (215 mg, 0.67 mmol) synthesized in Example (3b) was dissolved in tetrahydrofuran (8 mL), and tetrabutylammonium fluoride (1M tetrahydrofuran solution, 0.87 mL, 0.87 mmol) was added, followed by stirring at room temperature for 30 minutes under nitrogen atmosphere. Water (10 mL) was added, and extraction was carried out with diethyl ether (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=5%-30%) to afford the desired compound (100 mg, yield 91%) as a white solid.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH3:7])[CH:4]=[O:5])[CH3:2].[CH2:8](O)[CH:9]=[CH:10][CH2:11][OH:12].C1CCCCC1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH3:2][CH2:1][CH:3]([CH:4]1[O:12][CH2:11][CH:10]=[CH:9][CH2:8][O:5]1)[CH2:6][CH3:7]
Reactant: CCC(C=O)CC
Reactant: OCC=CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: O
Product: CCC(CC)C1OCC=CCO1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a one liter flask equipped with heating jacket, agitator and condenser fitted with a Dean-Stark trap was charged 100 grams (1.0 mole), 2-ethyl-butanal, 97 grams(1.1 mole) 2-butene-1,4-diol, 80 grams cyclohexane and 0.2 grams p-toluenesulfonic acid monohydrate. The mixture was heated with vigorous agitation at reflux (84° - 99°C.) until water no longer continued to be distilled from the reaction mixture (1.2 hours). The reaction mixture was cooled to room temperature and the p-toluenesulfonic acid neutralized by washing with reaction mixture with a 5% aqueous solution of sodium hydroxide. The reaction mixture was then washed neutral with water and distilled to remove the cyclohexane. The oil was vacuum distilled to obtain 146 grams (86% of theoretical) of 4,7-dihydro-2-(3-pentyl)-1,3-dioxepin having a boiling point of 47°C. at a pressure of 1.0 millimeter of mercury, (refractive index, ND20 = 1.457). Analysis for carbonyl content of IR showed 0.0% carbonyl and VPC analysis showed the compound to have a purity of 100%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[S:16][C:15]([S:17]([N:20]2[CH:24]=[CH:23][CH:22]=[CH:21]2)(=[O:19])=[O:18])=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[S:16][C:15]([S:17]([N:20]3[CH:24]=[CH:23][CH:22]=[CH:21]3)(=[O:18])=[O:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Product: Cc1ccc(-c2ccc(S(=O)(=O)n3cccc3)s2)cc1

Procedure:
N-[5-(4-methylphenyl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as described in Example 32C using 4-methyl-phenylboronic acid and N-(5-bromothiophenesulfonyl)pyrrole. Purification by column chromatography using 2% ethyl acetate/hexanes gave N-[5-(4-methylphenyl)thiophene-2-sulfonyl]pyrrole as a pale yellow solid in 77% yield.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:13])=[C:6]([Cl:12])[CH:7]=[C:8]([O:10]C)[CH:9]=1)(=[O:3])[CH3:2]>Br>[C:1]([C:4]1[C:5]([OH:13])=[C:6]([Cl:12])[CH:7]=[C:8]([OH:10])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(Cl)c(O)c(C(C)=O)c1
Agent: Br
Product: CC(=O)c1cc(O)cc(Cl)c1O
Temperature: 85 °C
Reaction time: 15 h

Procedure:
8.7 g of 3-acetyl-1-chloro-2-hydroxy-5-methoxybenzene were taken up in 150 ml of hydrobromic acid (48% strength in water). 1.69 g of red phosphorus were added, and the mixture was then stirred at 85° C. for 15 hours. After cooling, the reaction mixture was poured into about 1 liter of ice-cold water and extracted with ethyl acetate. The crude product obtained after drying and concentration of the ethyl acetate phase was purified by column chromatography. Yield: 2.9 g (36%)
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Cl)=[CH:9][CH:8]=1.C1(C)C(C)=CC=CC=1>Cl>[Cl:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][N:2]([CH3:1])[CH2:3][CH2:4][OH:5])=[CH:9][CH:8]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CNCCO
Agent: Cl
Solvent: Cc1ccccc1C
Product: CN(CCO)Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of N-methylethanolamine (21.2 g), 4-chlorobenzyl chloride (35.0 g) and xylene (100 ml) was stirred and boiled under reflux for 7 hours. The mixture was allowed to cool to ambient temperature and the solid mass was dissolved in 2M hydrochloric acid. The aqueous phase was separated off, washed with ether, basified with 2M sodium hydroxide solution and extracted with dichloromethane to give an oil which was distilled at 120°-125° C. at 0.3 mbar to give N-(4-chlorobenzyl)-N-methylethanolamine.
Reaction SMILES: [CH2:1]([NH2:4])[C:2]#[CH:3].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:42]3[N:47]=[CH:46][C:45]4=[CH:48][CH:49]=[C:50]([C:51]5[CH:52]=[C:53]([CH:57]=[CH:58][CH:59]=5)[C:54](O)=[O:55])[N:44]4[N:43]=3)=[CH:37][CH:36]=2)[CH2:31][CH2:30]1.CN1CCOCC1>CN(C)C=O.C([O-])(O)=O.[Na+]>[CH3:28][N:29]1[CH2:30][CH2:31][N:32]([C:35]2[CH:40]=[CH:39][C:38]([NH:41][C:42]3[N:47]=[CH:46][C:45]4=[CH:48][CH:49]=[C:50]([C:51]5[CH:52]=[C:53]([CH:57]=[CH:58][CH:59]=5)[C:54]([NH:4][CH2:1][C:2]#[CH:3])=[O:55])[N:44]4[N:43]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cccc(C(=O)O)c5)n4n3)cc2)CC1
Reactant: C#CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C#CCNC(=O)c1cccc(-c2ccc3cnc(Nc4ccc(N5CCN(C)CC5)cc4)nn23)c1
Reaction time: 0.08 h
Yield: 34.1 %

Procedure:
Into a 8-dram vial, Prop-2-ynylamine (0.0643 g, 0.00117 mol) was dissolved in N,N-Dimethylformamide (1.75 mL), and 1-Hydroxybenzotriazole hydrate (0.0429 g, 0.000280 mol), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (53.7 mg, 0.280 mmol) were added. After stirring for 5 min, 3-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-benzoic acid (100 mg, 0.233 mmol) was added followed by 4-Methylmorpholine (0.0308 mL, 0.280 mmol). The reaction was stirred at rt for 1 hour. The reaction mixture was diluted with NaHCO3 and the resulting ppt was filtered, washed with NaHCO3 and water. The solid was dried under vacuum to give 3-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-prop-2-ynyl-benzamide as a yellow solid (37 mg, 34%). LCMS (E/I+) 466.19 (M+H). MP 185-187° C. NMR 1H (DMSO-d6)-9.25 (s, 1H), 9.03 (t, 1H, J=4.84 Hz), 8.96 (s, 1H), 8.57 (s, 1H), 8.39 (d, 1H, J=8.02 Hz), 7.84 (d, 1H, J=8.02 Hz), 7.65 (d, 1H, J=8.02 Hz), 7.62 (d, 2H, J=8.32 Hz), 7.20 (d, 1H, J=4.75 Hz), 6.95 (d, 1H, J=4.75 Hz), 6.89 (d, 2H, J=8.00 Hz), 4.11 (s, 2H), 3.14 (s, 1H), 3.06 (bs, 4H), 2.46 (bs, 4H), 2.22 (s, 3H).
Reaction SMILES: [Br:1]Br.O.[NH2:4][C:5]1[C:12]([F:13])=[CH:11][C:8]([C:9]#[N:10])=[C:7]([F:14])[CH:6]=1>C(O)(=O)C>[NH2:4][C:5]1[C:12]([F:13])=[CH:11][C:8]([C:9]#[N:10])=[C:7]([F:14])[C:6]=1[Br:1]
Reactant: N#Cc1cc(F)c(N)cc1F
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cc(F)c(N)c(Br)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.9 %

Procedure:
A mixture of bromine (1.65 mL, 32 mmol), water (2 mL), and 4-amino-2,5-difluorobenzonitrile (5 g, 32 mmol) in acetic acid (50 mL) was stirred at RT for 16 h. The mixture was poured into ice cooled saturated sodium bicarbonate solution, causing a solid to separate out. The solid was filtered and washed with water. The solid was then dissolved in DCM, washed with water, dried over sodium sulfate, filtered, and concentrated to afford 7 g (92%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.18-7.21 (m, 1H), 4.80 (br. s, 2H).
Reaction SMILES: Cl[C:2]1[C:3]([F:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].CC(C)([O-])C.[K+].[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.O>CN(C)C=O>[NH2:7][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]([F:12])=[C:2]([O:19][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=2)[CH:8]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Nc1cc(Cl)c(F)cc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc(C=O)cc2)c(F)cc1[N+](=O)[O-]
Yield: 85.1 %

Procedure:
A solution of 5-chloro-4-fluoro-2-nitroaniline (0.380 g, 1.99 mmol), potassium t-butoxide (0.269 g, 2.39 mmol), and 4-hydroxybenzaldehyde (0.292 g, 2.39 mmol) in dimethylformamide (5 mL) was heated to 80 degrees Centigrade for 6 hours and then cooled. Water was added and the organics extracted using ethyl acetate (2×50 mL). The combined organics were then washed one time in brine and then dried (Na2SO4), filtered and concentrated. Chromatography on silica gel using a gradient of 20%-30% ethyl acetate/hexanes eluted the product to give 0.468 g of 4-[(5-amino-2-fluoro-4-nitrophenyl)oxy]benzaldehyde as an orange solid.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:33][CH3:34])=[C:10]([CH:32]=1)[C:11]([NH:13][CH:14]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:28][CH3:29])=[C:20]([S:24](=[O:27])(=[O:26])[NH2:25])[CH:21]=2)[O:16][C:15]1([CH3:31])[CH3:30])=[O:12].C(=O)([O-])[O-].[K+].[K+].C>CS(C)=O>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:33][CH3:34])=[C:10]([CH:32]=1)[C:11]([NH:13][CH:14]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:28][CH3:29])=[C:20]([S:24]([NH:25][C:3]([NH:2][CH3:1])=[S:4])(=[O:27])=[O:26])[CH:21]=2)[O:16][C:15]1([CH3:31])[CH3:30])=[O:12]
Reactant: CN=C=S
Reactant: COc1ccc(Cl)cc1C(=O)NC1Cc2cc(S(N)(=O)=O)c(OC)cc2OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNC(=S)NS(=O)(=O)c1cc2c(cc1OC)OC(C)(C)C(NC(=O)c1cc(Cl)ccc1OC)C2
Temperature: 80 °C
Reaction time: 0.42 h

Procedure:
0.26 g (3.5 mmol) of methyl isothiocyanate was added to a suspension of 1.14 g (2.5 mmol) of 3-(5-chloro-2-methoxybenzamido)-2,2-dimethyl-6-sulfamoyl-7-methoxychroman and 1.04 g (7.5 mmol) of finely powdered potassium carbonate in 10 ml of DMSO. After the mixture had been stirred at 80° C. for 25 minutes, it was cooled, introduced into ice/water, clarified with charcoal and acidified to pH 1. The precipitate was filtered off with suction and recrystallized from methanol/DMF. The product had a melting point of 234°-235° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1)(=[O:20])=[O:19].[ClH:34]>>[ClH:34].[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1)(=[O:19])=[O:20]
Reactant: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(CN4CCCCC4)cc3)c(C)o2)cc1
Agent: Cl
Product: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(CN2CCCCC2)cc1
Yield: 68 %

Procedure:
A solution of methyl 4-(5-methyl-4-((4-(piperidin-1-ylmethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoate (2 g, 2.65 mmol, 1.00 equiv, 62%) in 6N hydrochloric acid (50 mL) was refluxed overnight. The resulting mixture was concentrated under vacuum and the residue was washed with 20 mL of ethyl acetate and 20 mL of ether. The solid was dried in a vacuum oven to give 1.2 g (68%) of 4-(5-methyl-4-((4-(piperidin-1-ylmethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoic acid hydrochloride as an off-white solid. LC-MS: (ES, m/z): 496 [M+CH3CN+H]+, 455 [M+H]+
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:34])[NH:13][C:14](=[O:33])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH2:27]OS(C)(=O)=O)[CH:17]=2)=[CH:3]1.[Na].[SH:36][C:37]1[N:41]([CH3:42])[N:40]=[N:39][N:38]=1.O>CS(C)=O>[CH3:1][N:2]1[C:10]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:4]([C:11]2[C:12](=[O:34])[NH:13][C:14](=[O:33])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][CH2:27][S:36][C:37]3[N:41]([CH3:42])[N:40]=[N:39][N:38]=3)[CH:17]=2)=[CH:3]1
Reactant: Cn1nnnc1S
Reactant: Cn1cc(C2=C(c3cn(CCCOS(C)(=O)=O)c4ccccc34)C(=O)NC2=O)c2ccccc21
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: Cn1nnnc1SCCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 55 °C
Yield: 46.1 %

Procedure:
100 mg of the product of Example 58 in 10 ml of DMSO were treated with 120 mg of 5-mercapto-1-methyltetrazole sodium salt. The solution was heated at 55° C. for 6 hours, then cooled and poured into water. The aqueous phase was extracted with ethyl acetate. The ethyl acetate extracts were dried and concentrated. Chromatography on silica gel with dichloromethane/ethyl acetate (4:1) gave 48 mg of 3-(1-methyl-3-indolyl)-4-[1-[3-(1-methyl-5-tetrazolylthio)propyl]-3-indolyl]-1H-pyrrole-2,5-dione, m.p. 95°-97° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[C:21]3[N:28]([CH2:29][CH2:30][O:31][CH2:32][CH2:33][N:34]4C(=O)C5[C:36](=CC=CC=5)[C:35]4=[O:44])[CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.O.NN.C(=O)([O-])O.[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[C:21]3[N:28]([CH2:29][CH2:30][O:31][CH2:32][CH2:33][NH:34][C:35](=[O:44])[CH3:36])[CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=1
Reactant: O=C1c2ccccc2C(=O)N1CCOCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)NCCOCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Reaction time: 1 h
Yield: 85 %

Procedure:
2-(2-{2-[4-({3-Chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl)-1H-isoindole-1,3(2H)-dione (200 mg) was dissolved in ethanol (5.0 mL), hydrazine monohydrate (3.0 mL) was added, and the mixture was stirred for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate under ice-cooling and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→ethyl acetate:methanol=95:5). The title compound (146.0 mg) was obtained as colorless crystals by the reaction in the same manner as in Example 180 using the obtained oil, acetic anhydride (1.0 mL), N-methylmorpholine (1.0 mL) and tetrahydrofuran (5.0 mL).