Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH:12]=[O:13])[CH2:8][CH2:9][C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20]([Mg]Br)=[CH2:21].O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH:12]([OH:13])[CH:20]=[CH2:21])[CH2:8][CH2:9][C:10]#[N:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C[Mg]Br
Reactant: N#CCCC(C=O)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)C(CCC#N)(c1ccccc1)c1ccccc1

Procedure:
Under argon gas, 4,4-diphenyl-4-formylbutanenitrile (5.0 g) was dissolved in dry tetrahydrofuran (200 ml). Then, 1M vinylmagnesium bromide-tetrahydrofuran (30 ml) was added dropwise -40° C. After completion of addition, the reaction temperature was allowed to rise gradually to 0° C. (over 3 hours). After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction mixture and the insoluble matter was filtered off. The filtrate was extracted with ethyl acetate, washed, dried, and concentrated and the group was purified by silica gel column chromatography. The active fraction was concentrated to provide the title compound as oil (5.4 g).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.[CH:21]([NH:24][CH2:25][CH2:26][NH:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29])([CH3:23])[CH3:22]>C(N(CC)CC)C>[C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([N:24]([CH2:25][CH2:26][NH:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29])[CH:21]([CH3:22])[CH3:23])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)NCCNC(C)C)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NCCN(C(=O)c2ccccc2C(=O)c2ccccc2)C(C)C)cc1

Procedure:
A solution of 37 grams of ψ-acid chloride of 0-benzoyl benzoic acid in 60 ml. of dichloromethane was added dropwise to a stirred solution of 38.5 grams of N-[2-(isopropylamino) ethyl]-p-toluenesulfonamide, 200 ml. of dichloromethane and 25 ml. of triethylamine. The mixture was refluxed for 3.5 hours. After cooling, the solution was extracted successively with water, 10% hydrochloric acid, and saturated sodium carbonate solution. The dichloromethane solution was dried over magnesium sulfate and the solvent evaporated in vacuo to a solid residue. On recrystallization from ethyl acetate there was obtained 2-benzoyl-N-[2-(p-toluenesulfonamido)ethyl]-N-isopropylbenzamide, m.p. 135°-137°C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O.O>[S:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[NH:25][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1nc2ccccc2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1nc2ccccc2s1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 1, 0.133 g, 0.465 mmol) in methylene chloride (2.5 mL) cooled to 0° C. was treated with a 2M solution of oxalyl chloride in methylene chloride (0.3 mL, 1.0 mmol) and N,N-dimethylformamide (1 drop). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of 2-aminobenzothiazole (0.087 g, 0.58 mmol) in methylene chloride (2.5 mL) followed by N,N-diisopropylethylamine (0.2 mL, 2.14 mmol). The reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was then diluted with water (10 mL) and extracted with methylene chloride (3×10 mL). The combined organic layers were sequentially washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), a 1N aqueous hydrochloric acid solution (1×10 mL), and a saturated aqueous sodium chloride solution (1×10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded the N-benzothiazol-2-yl-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide (0.082 g, 42%) as a white solid: mp 104-105° C.; EI-HRMS m/e calcd for C21H20Cl2N2OS (M+) 418.0673, found 418.0674.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].P(Br)(Br)([Br:30])=O.CC#N.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:30])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(O)c2cc(Oc3ccc(F)cc3)ccc2c1O
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CCCCOC(=O)c1nc(Br)c2cc(Oc3ccc(F)cc3)ccc2c1O
Yield: 68 %

Procedure:
A mixture of 7-(4-Fluoro-phenoxy)-1,4-dihydroxy-isoquinoline-3-carboxylic acid butyl ester (14.33 g, 38.6 mmol), POBr3 (44.7 g, 154.4 mmol) and anhydrous methyl cyanide (290 ml) was refluxed gently with stirring for 75 min before NaHCO3 (100.8 g, 1.2 mol) was added in small portions with stirring. Subsequently, water (200 ml) was added slowly with stirring and the mixture was stirred vigorously for 1 h at ambient temperature before it was concentrated in vacuo to ca. ½ of its volume. Then water (200 ml) was added and the mixture was extracted with EtOAc (1×400 ml, 1×200 ml). The combined organic phases were dried over MgSO4 and evaporated in vacuo to give a tan solid. The tan solid was dissolved in CH2Cl2 and purified by filtration through a plug of silica gel. In vacuo concentration of the resulting CH2Cl2 solution yielded the title compound (11.4 g); 1H NMR (CDCl3) δ=11.89 (s, 1H), 8.36 (d, 1H), 7.57 (d, 1H), 7.44 to 7.50 (m, 1H), 7.08 to 7.16 (m, 4H), 4.47 (t, 2H), 1.78 to 1.93 (m, 2H), 1.38 to 1.58 (m, 2H), 0.99 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:22])[NH:5][C:6](=[O:21])[C:7]=1[NH:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][C:11]=1[O:18][CH3:19].[OH-].[Na+]>C(O)C>[CH3:19][O:18][C:11]1[CH:12]=[C:13]([S:16][CH3:17])[CH:14]=[CH:15][C:10]=1[C:9]1[N:8]=[C:7]2[C:2](=[N:3][C:4](=[O:22])[NH:5][C:6]2=[O:21])[N:1]=1
Reactant: COc1cc(SC)ccc1C(=O)Nc1c(N)[nH]c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(SC)ccc1C1=NC2=NC(=O)NC(=O)C2=N1
Reaction time: 0.25 h

Procedure:
Two grams of 4-amino-5-(2-methoxy-4-methylmercapto-benzoylamino)-pyrimidin-2,6-dione are refluxed for 21 hours with 50 ml of ethanol and 50 ml of 2N sodium hydroxide solution. After about 15 minutes, a solution is formed. After cooling, the solution is suction filtered with glacial acetic acid, washed with water, and dried at 70° C. in a circulating air drier. The crude product thus obtained is purified by chromatography on silica gel [eluant: methylene chloride/ethanol (19:1, 9:1, 4:1 and ethanol)].
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[NH:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[O:4].Br[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([O:26][CH3:27])[CH:20]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([CH:5]1[N:10]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([O:26][CH3:27])[CH:20]=2)[CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[O:4]
Reactant: COc1cc(Br)ccc1Cl
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CCOC(C)=O
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Cl)c(OC)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 15.4 %

Procedure:
To a vial containing piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (907 mg, 4.04 mmol), was added 4-bromo-1-chloro-2-methoxybenzene (913 mg, 4.12 mmol), palladium acetate (33 mg, 0.14 mmol) and 2-(di-tert-butylphosphino)biphenyl (88 mg, 0.29 mmol). The vial was evacuated and back-filled with nitrogen and to it was added toluene (2 mL). The reaction mixture was heated to 80° C. for 5 min to give a homogeneous solution. Upon cooling to room temperature, sodium tert-butoxide (557 mg, 5.80 mmol) was added to the reaction solution. The resultant mixture was again heated to 80° C. After 4 h, the reaction mixture was cooled to room temperature, then diluted with EtOAc (10 mL) and hexanes (10 mL). The resultant solution was filtered through celite, and the filtrate concentrated in vacuo and purified by silica gel flash chromatography (30 g) (20% EtOAc/Hexanes) to afford 4-(4-chloro-3-methoxyphenyl)piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (63) (239 mg, 15% yield): HPLC retention time=2.72 minutes. MS (ES) [M+H]+ expected 385.2, found 385.1.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:27]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:17]2)=[C:8]([NH2:29])[N:7]=1)[CH2:2][CH2:3][CH3:4].[ClH:30]>CO.O1CCOCC1>[ClH:30].[NH2:29][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:27])[N:12]2[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26]2)[CH2:17]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCCN(C4CCCC4)C3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCCN(C4CCCC4)C3)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(butyloxy)-9-[(1-cyclopentyl-3-piperidinyl)methyl]-8-(methyloxy)-9H-purin-6-amine (37.2 mg, 0.092 mmol) in methanol (3 ml) at room temperature was added 4.0 M HCl in 1,4-dioxane (0.578 ml). The reaction mixture was stirred at ambient temperature overnight. The reaction solution was evaporated under N2 in a Radleys blow down unit to give the title compound as an off-white solid (39 mg).
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.I[CH:11]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.I[C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1>C1COCC1.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:18]([O:17][C:15]([N:13]1[CH2:14][CH:11]([C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=2)[CH2:12]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
1,2-Dibromoethane (0.146 mL, 1.69 mmol) was added to a vigorously stirred suspension of zinc dust (0.901 g, 13.8 mmol) in THF (3.5 mL) under a nitrogen atmosphere and the resulting suspension heated at 80° C. for 10 minutes. Trimethylsilyl chloride (0.202 mL, 1.59 mmol) in THF (1.75 mL) was added at room temperature and after stirring for 4 minutes a solution of tert-butyl 3-iodoazetidine-1-carboxylate (3.00 g, 10.6 mmol) in THF (3.5 mL) was added dropwise over a period of 15 minutes. The resulting mixture was stirred at room temperature for 2 hours then Pd2(dba)3 (0.155 g, 0.170 mmol) and tri-2-furylphosphine (0.143 g, 0.615 mmol) were added followed by 1-iodo-4-nitrobenzene (2.90 g, 11.7 mmol) in THF (18 mL). The resulting mixture was heated at 55° C. for 3 hours then quenched at room temperature with a saturated aqueous sodium chloride solution (15 mL). The aqueous phase was extracted with DCM (2×15 mL) then the combined organic fractions were dried (magnesium sulfate), filtered and evaporated in vacuo. The residue was purified using silica gel column chromatography (CombiFlash Rf, 40 g SiO2 Cartridge, 10-40% EtOAc in cyclohexane) to give the title compound I6 as an orange oil (2.14 g, 72%); 1H NMR (300 MHz, CDCl3) δ 8.24 (dd, J=6.8, 1.9 Hz, 2H), 7.51 (d, J=8.6 Hz, 2H), 4.41 (t, J=8.7 Hz, 2H), 3.98 (dd, J=8.5, 5.7 Hz, 2H), 3.89-3.81 (s, 1H), 1.49 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8](F)=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:4]2[CH:3]=[CH:2][C:11]3[C:6](=[CH:7][C:8]([NH:22][CH2:21][CH2:20][C:17]4[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=4)=[CH:9][CH:10]=3)[N:5]=2)=[CH:16][CH:15]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: Fc1ccc2c(Cl)ccnc2c1
Product: Clc1ccc(CCNc2ccc3ccc(NCCc4ccc(Cl)cc4)nc3c2)cc1

Procedure:
A mixture of 2.0 g of 4-chloro-7-fluoroquinoline and 3.5 g of 2-(4-chlorophenyl)ethyl amine was heated neat until fuming began. The mixture was then cooled. The product was extracted into a CHClz/ammonium hydroxide solution, which was then washed with water. Solvent was removed by reducing pressure. The residue was placed on a silica gel column with acetone, then flushed with ethanol. Solvent was removed by reducing pressure, giving the title product as a yellow-brown foam. Yield 1.1 g. M.P. 55°-60° C.
Reaction SMILES: [B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.[F:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:33][CH2:32][CH2:31][C@H:30]2[C:34]2[CH:35]=[C:36]([C:51]([OH:53])=O)[CH:37]=[C:38]3[C:43]=2[O:42][C:41]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[CH:40][C:39]3=[O:50])[CH:25]=[C:26]([F:28])[CH:27]=1.CCN(C(C)C)C(C)C.[NH:63]1[CH2:68][CH2:67][O:66][CH2:65][CH2:64]1>>[F:28][C:26]1[CH:25]=[C:24]([N:29]2[CH2:33][CH2:32][CH2:31][C@H:30]2[C:34]2[CH:35]=[C:36]([C:51]([N:63]3[CH2:68][CH2:67][O:66][CH2:65][CH2:64]3)=[O:53])[CH:37]=[C:38]3[C:43]=2[O:42][C:41]([N:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)=[CH:40][C:39]3=[O:50])[CH:23]=[C:22]([F:21])[CH:27]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1cc([C@@H]2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc([C@@H]2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57 %

Procedure:
TSTU (75.0 mg, 0.23 mmol) was added in one portion to a stirred solution of 8-[(2S)-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)]-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (102 mg, 0.21 mmol, >98% enantiomeric purity, made from the first eluting ester enantiomer from chiral separation of tert-butyl 2-(6-(methoxycarbonyl)-2-morpholino-4-oxo-4H-chromen-8-yl)pyrrolidine-1-carboxylate—see below) and DIPEA (0.041 mL, 0.23 mmol) at room temperature The resulting mixture was stirred at room temperature for 1.5 h. Morpholine (0.037 mL, 0.42 mmol) was then added to the reaction mixture and stirring was continued over the week-end. The reaction mixture was purified by preparative HPLC. The fractions were evaporated to dryness, the residue was dissolved in DCM, dried over MgSO4 and concentrated. The remaining solid was triturated with diethyl ether, filtered, washed with diethyl ether and dried under vacuum at 50° C. to afford 8-[(2S)-1-(3,5-difluorophenyl)pyrrolidin-2-yl]-6-(morpholine-4-carbonyl)-2-morpholino-4H-chromen-4-one (64 mg, 57%) as a pale yellow solid.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:12])([F:11])[CH2:9][OH:10].F[C:14]1[C:15]([C:20]([OH:22])=[O:21])=[N:16][CH:17]=[CH:18][CH:19]=1>O>[F:7][C:8]([F:12])([F:11])[CH2:9][O:10][C:14]1[C:15]([C:20]([OH:22])=[O:21])=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: OCC(F)(F)F
Reactant: O=C(O)c1ncccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1ncccc1OCC(F)(F)F
Reaction time: 4 h
Yield: 49 %

Procedure:
Potassium tert-butoxide (954 mg, 8.51 mmol) was charged to a sealed tube with 2,2,2-trifluoroethanol (4 mL) and 3-fluoropyridine-2-carboxylic acid (400 mg, 2.84 mmol) and the mixture was heated to 130 C for 26 h, then to 150 C for 4 h, and then to 120 C for approximately 18 h. The mixture was diluted with water (6 mL) and washed with DCM (2×4 mL), which was then discarded. 1M HCl was added to bring the solution to pH 7 and the aqueous was extracted with DCM (2×4 mL). The extraction process was repeated as above at pH 5, 4 and 3. The combined organic extractions were dried over sodium sulfate and evaporated under vacuum to afford the title compound as a white solid (305 mg, 49%). Method B HPLC-MS: MH+ requires m/z=222. Found: m/z=222, Rt=0.73 min (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[N:16]2[CH:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH:19]=[CH:20][C:15]2=[N:14][N:13]=1.[Cl:29][Sn]Cl.C([O-])([O-])=O.[Na+].[Na+].Cl>C(OCC)(=O)C.O>[ClH:29].[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([C:12]2[N:16]3[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=4)[CH:19]=[CH:20][C:15]3=[N:14][N:13]=2)=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1ccc(-c2ccc3nnc(-c4ccc([N+](=O)[O-])cc4OC)n3c2)cc1
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc3nnc(-c4ccc(N)cc4OC)n3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.1 %

Procedure:
A mixture of 3-(2-methoxy-4-nitrophenyl)-6-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine (50 mg, 0.13 mmol) and SnCl2 (120 mg, 0.65 mmol) in ethyl acetate (25 mL) was heated to reflux for 6 h under Argon. The reaction mixture was cooled to room temperature and basified to pH=10 with saturated aqueous Na2CO3. The biphasic solution was separated and the aqueous layer was extracted with ethyl acetate (40 mL). The combined organic layers were washed with brine and concentrated. The residue was purified by flash column chromatography (petroleum ether:ethyl acetate=2:1 to 0:1) to give crude product as yellow oil. The oil was stirred in a solution of HCl in ethyl acetate (2M, 20 mL) at room temperature, and then was mixed with water (30 mL). The aqueous phase was washed with ethyl acetate (30 mL), basified with saturated aqueous Na2CO3 to pH>10 and extracted with ethyl acetate (30 mL). The organic phase was stirred with a solution of HCl in ethyl acetate (2M, 10 mL) at room temperature for 2 h and concentrated in vacuo to give the title compound as yellow solids (16 mg, 30% yield). 1H NMR (DMSO-d6): 8.32 (s, 1H), 8.19 (dd, J=9.6 and 1.2 Hz, 1H), 8.09 (d, J=9.6 Hz, 1H), 7.72 (d, J=8.7 Hz, 2H), 7.36 (d, J=8.4 Hz, 1H), 7.08 (d, J=8.7 Hz, 2H), 6.61 (d, J=1.5 Hz, 1H), 6.52 (dd, J=8.4 and 1.5 Hz, 1H), 3.82 (s, 3H), 3.79 (s, 3H). MS: m/z 347.1 [M+H+].
Reaction SMILES: CC1C=CC(C2C=NN(C)C=2)=C(C=1)C(O)=O.[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([C:28]2[CH:33]=[N:32][CH:31]=[CH:30][N:29]=2)=[C:22]([CH:27]=1)[C:23]([O:25]C)=[O:24]>>[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([C:28]2[CH:33]=[N:32][CH:31]=[CH:30][N:29]=2)=[C:22]([CH:27]=1)[C:23]([OH:25])=[O:24]
Reactant: COC(=O)c1cc(C)ccc1-c1cnccn1
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)O)c1
Product: Cc1ccc(-c2cnccn2)c(C(=O)O)c1

Procedure:
The title compound was synthesized following the same general protocol as described for 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoic acid in Example A1, using methyl 5-methyl-2-(pyrazin-2-yl)benzoate. ESI-MS (m/z): 215 [M+1]+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19]C#N)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].SC[C@@H]([C@@H](CS)O)O.Cl[CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19][CH2:37][CH2:38][N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)=[CH:17][N:18]=2)=[O:12])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(N(C(=O)Nc2ncc(SC#N)s2)C2CCCCC2)CC1
Reactant: ClCCN1CCCC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: CC(=O)N1CCC(N(C(=O)Nc2ncc(SCCN3CCCC3)s2)C2CCCCC2)CC1

Procedure:
Prepared as described in general procedures (H) and (I) using 1-(1-acetyl-piperidin-4-yl)-1-cyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and N-(2-chloroethyl)pyrrolidine.
Reaction SMILES: Br.Cl[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH:16][CH3:17])[S:14][CH:15]=2)=[CH:7][CH:6]=1.[C:18]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(Cl)Cl.CC(CC(C)C)=O>[C:18]1([N:28]2[CH2:33][CH2:32][N:31]([CH2:3][CH2:4][C:5]3[CH:10]=[CH:9][C:8]([C:11]4[N:12]=[C:13]([NH:16][CH3:17])[S:14][CH:15]=4)=[CH:7][CH:6]=3)[CH2:30][CH2:29]2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CNc1nc(-c2ccc(CCCl)cc2)cs1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)CC(C)C
Product: CNc1nc(-c2ccc(CCN3CCN(c4cccc5ccccc45)CC3)cc2)cs1

Procedure:
To a 125 ml round-bottomed flask equipped with condenser and N2 inlet were added 2.50 g (7.5 mmol) of 4-(4-(2-chloroethyl)phenyl)-2-methylaminothiazole hydrobromide, 1.59 g (7.5 mmol) of N-(1-naphthyl)piperazine, 1.31 ml (7.5 mmol) of diisopropylethylamine, 1.59 g (15 mmol) of sodium carbonate, 5 mg of sodium iodide, and 50 ml of methylisobutylketone. The reaction was heated at reflux for 4 days, cooled, and the precipitate filtered, and the filtrate evaporated. The residue was taken up in methylene chloride and chromatographed on silica gel using methylene chloride/ethyl acetate as eluent to give an oil. The oil was taken up in methylene chloride, precipitated by addition of methylene chloride saturated with hydrochloride, and the precipitate filtered, washed with ether, and dried to give a white solid, m.p. 272°-273° C., 2.37 g (63%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:29][C:30]2[C:31]([CH2:36][CH3:37])=[N:32][CH:33]=[CH:34][CH:35]=2)[C:5]([NH:8][C:9]2[S:13][N:12]=[C:11]([CH:14]3[CH2:20][CH:19]4[N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[N:10]=2)=[N:6][CH:7]=1.[SH:38][CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42]>>[CH2:36]([C:31]1[C:30]([O:29][C:4]2[C:5]([NH:8][C:9]3[S:13][N:12]=[C:11]([CH:14]4[CH2:20][CH:19]5[N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:16]([CH2:17][CH2:18]5)[CH2:15]4)[N:10]=3)=[N:6][CH:7]=[C:2]([S:38][CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42])[CH:3]=2)=[CH:35][CH:34]=[CH:33][N:32]=1)[CH3:37]
Reactant: CCc1ncccc1Oc1cc(Br)cnc1Nc1nc(C2CC3CCC(C2)N3C(=O)OC(C)(C)C)ns1
Reactant: COC(=O)CCS
Product: CCc1ncccc1Oc1cc(SCCC(=O)OC)cnc1Nc1nc(C2CC3CCC(C2)N3C(=O)OC(C)(C)C)ns1
Yield: 89.6 %

Procedure:
Following the procedure in Example 52, tert-butyl 3-(5-(5-bromo-3-(2-ethylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (120 mg, 0.2042 mmol) and methyl 3-mercaptopropanoate (24.34 μL, 0.2247 mmol) afforded tert-butyl 3-(5-(3-(2-ethylpyridin-3-yloxy)-5-(3-methoxy-3-oxopropylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (115 mg, 0.183 mmol, 89.8% yield).