Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:24]([N:25]2[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]2)=[CH:23][C:6]2[C:7]([CH3:22])([CH3:21])[C:8]3[NH:9][C:10]4[C:15]([C:16]=3[C:17](=[O:18])[C:5]=2[CH:4]=1)=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=4)[CH3:2].[O:32]=[C:33]1[CH2:38][NH:37][CH2:36][CH2:35][NH:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(OCC)(=O)C>[CH2:1]([C:3]1[C:24]([N:25]2[CH2:26][CH2:27][CH:28]([N:37]3[CH2:36][CH2:35][NH:34][C:33](=[O:32])[CH2:38]3)[CH2:29][CH2:30]2)=[CH:23][C:6]2[C:7]([CH3:21])([CH3:22])[C:8]3[NH:9][C:10]4[C:15]([C:16]=3[C:17](=[O:18])[C:5]=2[CH:4]=1)=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=4)[CH3:2]
Reactant: O=C1CNCCN1
Reactant: CCc1cc2c(cc1N1CCC(=O)CC1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cc2c(cc1N1CCC(N3CCNC(=O)C3)CC1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 30 °C
Reaction time: 6 h
Yield: 31.8 %

Procedure:
9-Ethyl-6,6-dimethyl-11-oxo-8-(4-oxopiperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (30 mg) and 2-ketopiperazine (10 mg) were dissolved in THF (2 ml), added with sodium triacetoxy borohydride (30 mg), and the mixture was stirred at 30° C. for 6 hrs. The reaction mixture was diluted with ethyl acetate (20 ml). The organic layer was washed with 10% brine, and then concentrated under reduced pressure. The resulting residues were purified by silica gel column (dichloromethane/methanol=99/1 to 90/10) to obtain the title compound (11.5 mg, yield 32%).
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[Cl:19])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)(=[O:5])=[O:4].C(OO)(=[O:22])C>>[CH3:1][N:2]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[Cl:19])[S:3]([C:6]1[N+:7]([O-:22])=[CH:8][CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:5]
Reactant: CC(=O)OO
Reactant: CN(c1cccc(Cl)c1Cl)S(=O)(=O)c1ccccn1
Product: CN(c1cccc(Cl)c1Cl)S(=O)(=O)c1cccc[n+]1[O-]

Procedure:
N-methyl-N-(2,3-dichlorophenyl)-2-pyridinesulfonamide (1.7 g, 5.3 mmol) is treated with 40% peracetic acid (approx. 12 ml) at 35°-45° under N2 for 14 hours. The excess peracetic acid is removed under vacuum, and the residue is diluted with methylene chloride, poured into water, neutralized with aq. sodium bicarbonate, washed with brine, dried and evaporated to dryness to give, after purification, the title compound (compound 1, Table A).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)[C:9]=1[CH3:25].C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>C(Cl)Cl>[C:33]([N:20]1[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=[C:16]1[S:15][CH2:14][C:10]1[C:9]([CH3:25])=[C:8]([S:7][CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH:13]=[CH:12][N:11]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: Cc1c(SCc2ccco2)ccnc1CSc1nc2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)n1c(SCc2nccc(SCc3ccco3)c2C)nc2ccccc21
Temperature: 20 °C
Reaction time: 20 h
Yield: 97 %

Procedure:
2-{[[4-(2-Furylmethylthio)-3-methyl-2-pyridinyl]methyl]thio}-1H-benzimidazole (5.0 mmol) is suspended in anhydrous methylene chloride (50 ml), triethylamine (11 mmol and acetyl chloride (8 mmol) are added and the mixture is stirred at 20° C. for 20 h. The clear reaction solution is washed with sodium bicarbonate solution and water, dried over magnesium sulfate and concentrated and the residue is crystallized by addition of diisopropyl ether. The title compound is obtained as a colorless powder; m.p. 168-169° C. (decomp.); yield: 97% of theory.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].C(N(CC)CC)C.[CH2:21]([O:23][C:24](=[O:35])[C:25](=O)[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:22].Cl>C(O)C.[Ni]>[CH2:21]([O:23][C:24]([C@@H:25]([NH:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3])[CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:35])[CH3:22]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: [Ni]
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 2 h

Procedure:
50 mmoles (9.3 g) Ala-Pro were suspended in 100 ml ethanol, mixed with 10 moles (1 g) triethylamine, 75 mmoles (15.5 g) 2-oxo-4-phenyl-butyric acid ethyl ester and 18 g molecular sieve 3 A and agitated for 2 hours under anhydrous conditions. One teaspoon of dehydrated Raney nickel and 15 g molecular sieve 3 A were now added, briefly reacted and subsequently hydrogenated for 22 hours under an atmosphere of 4 bars of H2. The reaction mixture was filtered and evaporated to concentrate it to a small volume. Conversion (according to HPLC) relative to Ala-Pro used: 95.6%, product yield (according to HPLC): 95%. The residue was taken up in 250 ml ethanol and adjusted to pH 4.25 with conc. HCl (an aliquot was removed for this purpose, diluted with water and the pH adjusted, then the entire amount of HCl required was calculated). The solution was evaporated to low bulk under reduced pressure at 40° C. to 50 g, filtered with Celite and diluted to 100 ml total volume with ethyl acetate. 5.2 g maleic acid dissolved in ethyl acetate+ethanol were added and the mixture was seeded with enalapril maleate. The crystallizate formed was separated off and dried.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH:3]([OH:5])[CH3:4].[F:7][C:8]([F:20])([F:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15](Cl)(=[O:17])=[O:16].C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:20][C:8]([F:7])([F:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([O:6][CH2:1][CH2:2][CH:3]([OH:5])[CH3:4])(=[O:16])=[O:17]
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: CC(O)CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(O)CCOS(=O)(=O)c1ccccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a solution of 1,3-butane diol (2.18 g, 24 mmol) and TEA (1.64 g, 16 mmol) in CH2Cl2 (15 mL) at 0° C. was added o-(trifluoromethyl)benzenesulfonyl chloride (2 g, 8 mmol) dissolved in CH2Cl2 (20 mL). The solution was stirred at 0° C. for 2 h. Saturated aqueous NaHCO3 (15 mL) was added to the solution and mixture was stirred at rt for 45 min. The organics were extracted with CH2Cl2 (150 mL) and washed with 0.5 M HCl (2×80 mL) and saturated aqueous NaCl (1×50 mL). The organics were dried over Na2SO4 and concentrated to give a crude mixture. Silica gel chromatography (50% ethyl acetate in hexanes) yielded the desired product (2 g, 84%). 1H NMR (400 MHz CDCl3) δ 8.23 (m, 1H), 7.92 (m, 1H), 7.74 (m, 2H), 4.34 (m, 1H), 4.24 (m, 1H), 3.95 (m, 1H), 1.89 (m, 1H), 1.73 (m, 1H), 1.20 (d, 3H, J=6.3 Hz). Anal. Calcd. For C11H13F3O4S: C, 44.29; H, 4.39. Found: C, 44.29; H, 4.28.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([S:11](Cl)(=[O:13])=[O:12])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl.O>[C:15]([NH:19][S:11]([C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10])(=[O:13])=[O:12])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)N
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)NC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 2-(acetylamino)-4-methyl-1,3-thiazole-5-sulfonyl chloride (1.0 g) in DCM (10 ml) was added tert-butylamine (0.92 ml) and the mixture was stirred at room temperature for 2 d. The mixture was diluted with H2O and extracted with DCM (×3). The combined organic extracts were dried (MgSO4), filtered and evaporated to give the subtitle compound as a beige foam. Yield 1.1 g.
Reaction SMILES: [Na].[SH:2][C:3]1[NH:4][C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.[CH2:18](I)[CH2:19][CH3:20]>CO>[CH2:18]([S:2][C:3]1[NH:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:4]=1)[CH2:19][CH3:20]
Reactant: CCCI
Reactant: CCOC(=O)c1nc(S)[nH]c1C(=O)OCC
Agent: [Na]
Solvent: CO
Product: CCCSc1nc(C(=O)OCC)c(C(=O)OCC)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium (0.253 g, 11 mmol) was dissolved in anhydrous methanol (150 mL) with ice-bath cooling. The ice-bath was removed after all the sodium had reacted and diethyl 2-mercapto-4,5-imidazoledicarboxylate prepared in accord with the second paragraph of Example XI (2.44 g, 10 mmol) was added. The appropriate n-propyl iodide (11 mmol) was added and the reaction mixture was stirred at ambient temperature under a nitrogen atmosphere for 1 hour. A second aliquot of n-propyliodide (3.52 mmol) was added and the solution was stirred for an additional 3 hours. The reaction mixture was concentrated to dryness in vacuo. The residue was partitioned between dichloromethane-water (5:1). The organic layer was separated, dried (sodium sulfate), filtered and concentrated to dryness in vacuo to give the captioned product as an oil.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](=O)[CH3:18])=[CH:12][CH:11]=1.C1(C)C=CC=CC=1>O>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[NH:1][N:2]=[C:17]([CH3:18])[CH2:16][C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1
Reactant: NNc1ccccn1
Reactant: CC(=O)Cc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(Cc1ccc(F)cc1)=NNc1ccccn1

Procedure:
In a vessel fitted with a condenser under nitrogen, 21.8 g (0.2M) of 2-hydrazinopyridine and 30.4 g (0.2M) of (4-fluorophenyl)acetone are heated at 80°-90° for about 30 to 60 mins. Toluene is then added and the mixture refluxed until all water is azeotropically distilled off. The mixture is then evaporated to dryness yielding crude product of this step as a yellow gum. The gum is distilled under reduced pressure (150°-160° at about 50 microns) to obtain the product of this step (as a yellow gum).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].[SH:31][CH2:32][CH2:33][OH:34]>CN(C=O)C.C(OCC)(=O)C>[OH:34][CH2:33][CH2:32][S:31][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc([N+](=O)[O-])ccc2Cl)CC1
Reactant: OCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc([N+](=O)[O-])ccc2SCCO)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a stirred solution of tert-butyl 4-(2-chloro-5-nitrophenylamino)piperidine-1-carboxylate (1.25 g, 3.51 mmol) in DMF (10 mL) were added sequentially potassium carbonate (0.971 g, 7.03 mmol) and 2-mercaptoethanol (0.493 mL, 7.03 mmol). The resulting mixture was stirred at 60° C. for 1 hour, after which TLC analysis (2:3 ethyl acetate:hexanes) showed that the reaction was complete. The mixture was then diluted with ethyl acetate and washed sequentially with water and saturated sodium carbonate (3×). The organic phase was dried, filtered, concentrated, and then chromatographed in 2:3 ethyl acetate:hexanes, giving the desired product (1.202 g, 86%) as an orange foam. 1H NMR (DMSO-d6) δ 7.51 (d, J=8.4 Hz, 1H), 7.43-7.37 (m, 2H), 5.40 (d, J=8.1 Hz, 1H), 5.06 (t, J=5.4 Hz, 1H), 3.95-3.86 (m, 2H), 3.75-3.60 (m, 1H), 3.59-3.50 (m, 2H), 3.01-2.85 (m, 4H), 1.94-1.83 (m, 2H), 1.49-1.29 (m, 11H); ESI-MS (m/z, %): 420 (M+Na, 22), 342 (100).
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][C:8]=1Cl)(=[O:3])[CH3:2].[BH4-].[Na+].[OH:12]C(C1OC=CC=1Cl)C.BrBr>CO.O>[CH3:8][C:4]1[O:5][CH:6]=[CH:7][C:2](=[O:12])[C:1]=1[OH:3]
Reactant: CC(=O)c1occc1Cl
Reactant: CC(O)c1occc1Cl
Agent: BrBr
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1occc(=O)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Acetyl-3-chloro-furan (1.0 g, 7 mmoles) in 30 ml methanol was cooled to 10° C. and 0.065 g, (1.7 mmoles) of NaBH4 added in one portion. After stirring for 30 minutes at 25° C., the solution was treated with 15 ml of water and cooled to 5° C. To the formed 2-(1-hydroxyethyl)-3-chloro-furan was then added 1.1 g (7 mmoles) of bromine, dropwise and with cooling. After the addition was complete the reaction was heated to 95° C. for 2 hours, distilling off a portion of the methanol. The reaction was then cooled and maltol isolated by the method of Example 1.
Reaction SMILES: O.[S-2:2].[Na+].[Na+].S.Cl[CH:7]1[NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[O:9][C:8]1=[O:17]>O.O1CCCC1>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[NH:12][C:7](=[S:2])[C:8]1=[O:17]
Reactant: O=C1Oc2ccccc2NC1Cl
Reactant: [S-2]
Agent: S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1oc2ccccc2[nH]c1=S

Procedure:
A solution of 3.6 g of sodium sulfide hydrate in 15 ml of water saturated with hydrogen sulfide was added dropwise to a solution of 5.45 g of 3-chloro-4H-1,4-benzoxazin-2-one in 30 ml of tetrahydrofuran at -150° C. The mixture was stirred one hour to 0° C. The tetrahydrofuran was evaporated and the precipitated filtered and recrystallized from toluene to provide the solid product 4H-1,4-benzoxazin-2-one-3-thione, m.p. 215°-220° C.
Reaction SMILES: [ClH:1].C([NH:5][C:6]1[C:15](=[O:16])[C:14]2[N:13]=[C:12]([CH3:17])[CH:11]=[CH:10][C:9]=2[C:8](=[O:18])[CH:7]=1)(=O)C.C(=O)(O)[O-].[Na+]>CO>[NH2:5][C:6]1[C:15](=[O:16])[C:14]2[N:13]=[C:12]([CH3:17])[CH:11]=[CH:10][C:9]=2[C:8](=[O:18])[C:7]=1[Cl:1]
Reactant: CC(=O)NC1=CC(=O)c2ccc(C)nc2C1=O
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1ccc2c(n1)C(=O)C(N)=C(Cl)C2=O

Procedure:
A slow stream of hydrogen chloride gas was passed through a solution of 7-acetamido-2-methylquinoline-5,8-dione (6, 230 mg, 1 mmol) in dry methanol (15 ml) at 60° C. for 48 h. (See Equation 11 below) The resulting acidic solution was neutralized with 2% sodium bicarbonate (10 ml), extracted with CH2Cl2 (5×30 ml) and dried over sodium sulfate (2.0 g, 20 min). Evaporation of the solvent in vacuo afforded 98 mg (42%) of pure (59) as red crystals: mp 270° C. (Dec., MeOH); 1H NMR (CDCl3) δ 8.31 (1H, d, J=8.0 Hz, H-4), 7.47 (1H, d, J=8.0 Hz, H-3), 5.70 (2H, brs, NH2), 2.68 (3H, s, CH3); IR (KBr) vmax 3471, 3329, 3191, 3085, 2960, 2924, 1649, 1605, 1587, 1573, 1382, 1370, 1326, 1273, 1259, 1164, 737 cm−1; EIMS, m/e (relative intensity) 223 (M+1, 100), 189 (4.1), 133 (0.4), 81 (0.8), 69 (1.2); EIMS, m/e (relative intensity) 224 (M+2, 27.3), 222 (M+, 97.2), 195 (7.4), 187 (M-CI, 100), 166 (5.3), 131 (10.4), 104 (12.1), 77 (14.9), 64 (10.5); HRMS, m/e for C10H7ClN2O2 calcd 222.0196, found 222.0194.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22](OCC)=[O:23])[N:21]=2)[CH:18]=1>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22]([NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=3)=[O:23])[N:21]=2)[CH:18]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: Nc1cccc(C(F)(F)F)c1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using 3-(trifluoromethyl)aniline and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C.C(=O)(O)[O-].[NH4+].[N:34]1C=CC=CC=1>C(#N)C.O>[C:4]([O:3][C:1](=[O:2])[NH:8][CH:9]([C:11](=[O:13])[NH2:34])[CH3:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: c1ccncc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CC(NC(=O)OC(C)(C)C)C(N)=O
Reaction time: 12 h
Yield: 89.7 %

Procedure:
DL-N-Boc-alanine (5.0 g, 26.4 mmol), di-tert-butylpyrocarbonate (7.9 mL, 34 mmol), and ammonium bicarbonate (2.5 g, 32 mmol) were stirred together in acetonitrile (101 mL). Pyridine (1.3 mL, 16 mmol) was added. The mixture stirred for 12 hours. Water was added and then the acetonitrile was removed in vacuo. The resulting slurry was filtered. The solid was collected, dissolved in methylene chloride and methanol (90:10), dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (2.7 g, 55%): 1H NMR (400 MHz, d6-DMSO): 7.20 (br s, 1H), 6.90 (br s, 1H), 6.77 (d, 1H), 3.86 (quintet, 1H), 1.37 (s, 9H), 1.15 (d, 3H).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[C:23]([NH:27][C:28]1[N:29]=[C:30]([N:37]2[CH2:41][CH2:40][C:39]([F:43])([F:42])[CH2:38]2)[C:31]2[N:36]=[N:35][NH:34][C:32]=2[N:33]=1)([CH3:26])([CH3:25])[CH3:24].Br[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[S:52]([CH3:55])(=[O:54])=[O:53]>>[C:23]([NH:27][C:28]1[N:29]=[C:30]([N:37]2[CH2:41][CH2:40][C:39]([F:42])([F:43])[CH2:38]2)[C:31]2[C:32](=[N:34][N:35]([CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[S:52]([CH3:55])(=[O:54])=[O:53])[N:36]=2)[N:33]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CS(=O)(=O)c1ccccc1CBr
Reactant: CC(C)(C)Nc1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: CC(C)(C)Nc1nc(N2CCC(F)(F)C2)c2nn(Cc3ccccc3S(C)(=O)=O)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from tert-Butyl-[7-(3,3-difluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]-amine and 1-(bromomethyl)-2-(methylsulfonyl)benzene. MS (m/e): 466.4 (MH+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1[CH2:8]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1[CH2:8][N:34]1[C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]2[C:30]1=[O:40]
Reactant: OCc1c(Br)cncc1Br
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1c(Br)cncc1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of benzylic alcohol 18 (300 mg, 1.13 mmol), triphenylphosphine (357 mg, 1.36 mmol) and phthalimide (200 mg, 1.36 mmol) in dry THF (10 mL) was added DIAD (0.26 mL, 1.36 mmol) under an N2 atmosphere. The resulting mixture was stirred at 25° C. for 24 hours after which solvents were evaporated under reduced pressure. The crude product mixture was purified by chromatography on silica gel to give the title compound 19 as a white (300 mg, 0.762 mmol, 67%). 1H NMR (400 MHz, CDCl3) δ 8.68 (bs, 2H), 7.88-7.83 (m, 2H), 7.78-7.75 (m, 2H), 5.13 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 168.1, 151.8, 142.7, 135.1, 132.4, 124.4, 43.3; MS (ESI) Calculated for C14H9N2O2Br2[M+H]+: 397.04. Found: 396.90.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)[CH3:5].[CH:23](NC(C)C)(C)C.[Li].CI>C1COCC1>[CH3:1][O:2][C:3](=[O:22])[C:4]([CH3:23])([N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][N:13]=2)[CH2:10][CH2:11]1)[CH3:5]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)C(C)N1CCN(c2ccc(C(F)(F)F)cn2)CC1
Agent: [Li]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)N1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-propionic acid methyl ester (1.23 g, 3.9 mmoles) from Example 14A in dry THF (3 mL) was added dropwise to a −65° C. solution of 1.8 N lithium diisopropylamine (LDA) in dry THF (2.4 mL) and stirred at this temperature for 1 hour. Methyl iodide (0.49 mL, 7.88 mmoles) was added and the mixture was allowed to slowly warm to room temperature and stir for 2 hours at room temperature. The mixture was quenched with ice/water and partitioned with ethyl acetate. The aqueous layer was extracted with ethyl acetate (3×) and the combined organic extracts washed with water, dried (MgSO4), filtered and the filtrate concentrated under reduced pressure. The residue was purified (silica gel, 10-30% acetone in hexane) to provide the title compound as a yellowish solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](/[C:11](=[CH:15]\[C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)/[C:12]([OH:14])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[Cl:46][C:47]1[S:51][C:50]([NH2:52])=[N:49][CH:48]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:46][C:47]1[S:51][C:50]([NH:52][C:12](=[O:14])/[C:11](/[C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=2)=[CH:15]/[C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[N:49][CH:48]=1
Reactant: CS(=O)(=O)c1ccc(/C(=C\c2cccs2)C(=O)O)cc1
Reactant: Nc1ncc(Cl)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(/C(=C\c2cccs2)C(=O)Nc2ncc(Cl)s2)cc1
Temperature: 60 °C
Reaction time: 0.03 h

Procedure:
A solution of (E)-2-(4-methanesulfonylphenyl)-3-thiophen-2-ylacrylic acid (Preparation 2, 309 mg, 1.0 mmol), HATU (813 mg, 2.1 mmol), 5-chlorothiazol-2-ylamine hydrochloride (258 mg, 1.5 mmol), and DIPEA (0.71 mL, 4.0 mmol) in anhydrous DMF (5 mL) was heated under microwave irradiation with stirring at 60° C. for 2 min. The solvents were evaporated off under reduced pressure, then the remainder was partitioned between CH2Cl2 (60 mL) and 1M HCl (60 mL). The organic layer was separated and washed with 1M HCl (60 mL), H2O (60 mL), saturated aqueous Na2CO3 (2×60 mL), H2O (60 mL), and brine (60 mL), before being dried (Na2SO4). Filtration, solvent evaporation, and flash chromatography (IH-EtOAc, 4:1 to 2:3) gave the title compound: RTA=3.77 min; m/z (ES+)=466.1 [M+MeCN+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br)[CH:11]=[CH:10][C:9]=2[N:8]=1)[CH3:2].[OH:32][C:33]1[CH:43]=[CH:42][C:36]2[C:37](=[O:41])[CH2:38][CH2:39][O:40][C:35]=2[C:34]=1[CH2:44][CH2:45][CH3:46].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:32][C:33]3[CH:43]=[CH:42][C:36]4[C:37](=[O:41])[CH2:38][CH2:39][O:40][C:35]=4[C:34]=3[CH2:44][CH2:45][CH3:46])[CH:11]=[CH:10][C:9]=2[N:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc2c(CCC(=O)OCC)c(OCCCCCBr)ccc2n1
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCCOc2ccc3nc(CCC(=O)OCC)ccc3c2CCC(=O)OCC)ccc2c1OCCC2=O
Temperature: 90 °C
Reaction time: 18 h
Yield: 54.8 %

Procedure:
A mixture of 0.96 g of the partially purified 6-[(5-bromopentyl)oxy]-2,5-quinolinedipropanoic acid diethyl ester from the preceding example, 0.402 g (1.95 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, 1.08 g (7.8 mmol) of anhydrous granular potassium carbonate and 25 mL of 2-butanone was stirred at 90° C. for 18 hr. A second portion of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one (0.117 g, 0.57 mmol) was added and the reaction was continued for another 22.5 hr. The mixture was cooled and filtered through anhydrous magnesium sulfate and the solids were washed with ethyl acetate. The filtrate and washes were combined and concentrated under reduced pressure. The crude product was purified by flash chromatography on 110 g of silica gel, eluting with hexane-ethyl acetate (5:2) to give 0.66 g (54.8%) of the title compound as a white solid, mp 59°-61° C.