Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=O)[CH:3]=1.[OH-:13].[K+].[O-]Cl.[Na+]>C(O)C.O>[Br:1][C:2]1[C:8]([F:9])=[CH:7][C:5]2=[N+:6]([O-:13])[O:12][N:10]=[C:4]2[CH:3]=1
Reactant: [OH-]
Reactant: Nc1cc(F)c(Br)cc1[N+](=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CCO
Product: [O-][n+]1onc2cc(Br)c(F)cc21
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 41.7 %

Procedure:
4-Bromo-5-fluoro-2-nitroaniline (8.5 g, 36 mmol) was stirred in 200 mL ethanol and treated with 45% KOH solution (4.5 g, 36 mmol) to produce a dark solution. This solution was cooled to 0-5° C. and treated dropwise with 6% NaOCl solution (84 g, 68 mmol) over 20 min while maintaining the temperature below 10° C. After 90 min, the mixture was diluted with 300 mL water and extracted twice with 200 mL portions of ethyl acetate. The combined extracts were washed with 30 mL saturated NaCl, dried (Na2SO4) and evaporated. The crude material was chromatographed on silica gel with a 0-30% ethyl acetate-hexane gradient to give the title compound as pale yellow solid (3.5 g, 42%): mp 87-89° C.; 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.23 (s, 1H); 19F NMR (376 MHz, CDCl3) δ −96.03; EIMS m/z 232.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:36]4[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccc(F)cc4)cc3)oc2C)cc1

Procedure:
To a 25 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.410 mmoles, 200 mg), 4-fluorophenyl boronic acid (0.451 moles), toluene (5 mL), ethanol (5 mL), and sodium carbonate (0.819 mmoles, 0.410 mL of a 2M solution). This mixture was vacuum degassed and nitrogen was added in at a positive pressure. Pd(PPh3)4 (catalytic, spatula tip) was added and the reaction was heated to reflux for 3 h. Distilled water was added to the mixture. Subsequently, this was extracted with ethyl acetate and washed with brine. The organic layer was collected, filtered over a thin pad of silica gel, and concentrated in-vacuo. The crude mixture was then purified by chromatography on silica gel affording 2-(4-{2-[2-(4′-fluorobiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([CH3:7])(=[O:6])=[O:5].[CH3:8][N:9]([CH3:28])[C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([N:25]([CH3:27])[CH3:26])[C:19]=1[N:20]([CH3:24])[C:21](=[O:23])[CH3:22])[C:13](OC)=[O:14]>CS(C)=O>[CH3:27][N:25]([CH3:26])[C:18]1[CH:17]=[C:12]([C:13](=[O:14])[CH2:3][S:4]([CH3:7])(=[O:6])=[O:5])[CH:11]=[C:10]([N:9]([CH3:28])[CH3:8])[C:19]=1[N:20]([CH3:24])[C:21](=[O:23])[CH3:22]
Reactant: CS(C)(=O)=O
Reactant: COC(=O)c1cc(N(C)C)c(N(C)C(C)=O)c(N(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)N(C)c1c(N(C)C)cc(C(=O)CS(C)(=O)=O)cc1N(C)C
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A suspension of 0.77 g. of sodium hydride (50% suspension in oil) and 2.28 g. of dimethylsulfone in 28 ml. of dimethylsulfoxide was stirred with the exclusion of moisture and under nitrogen for 2 hours at 50° C. 2 G. of methyl 3,5-bis(dimethylamino)-4-(N-methylacetamido)benzoate were then added, the mixture heated to 70° C. for a short time and stirred for a further 2 hours without heating. The solution was diluted with 100 ml. of ice water, washed with 100 ml. of low-boiling petroleum ether, the product extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulfate and evaporated. After purification of the residue over aluminum oxide with benzene and recrystallization from ethyl acetate/petroleum ether, there was obtained 2'.6'-bis(dimethylamino)-N-methyl-4'-[(methylsulfonyl)acetyl]acetanilide having a melting point of 130° C.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[N:3]=1.FC(F)(F)C(O)=O.[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23]([NH:30][C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[O:32])=[N:22]1.C(N(CC)CC)C.O>CN(C)C=O>[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23]([NH:30][C:31]([N:33]2[CH2:38][CH2:37][N:36]([C:2]3[S:6][N:5]=[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=4)[N:3]=3)[CH2:35][CH2:34]2)=[O:32])=[N:22]1
Reactant: Fc1cccc(-c2nsc(Cl)n2)c1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(Nc1noc2ccccc12)N1CCN(c2nc(-c3cccc(F)c3)ns2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of 5-chloro-3-(3-fluorophenyl)-1,2,4-thiadiazole (119 mg, 0.555 mmol) and N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) in N,N-dimethylformamide (2 ml) was added triethylamine (0.389 ml, 2.78 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured to water, and the precipitated solid was separated by filtration, which was recrystallized from a mixed solvent of ethyl acetate and tetrahydrofuran to give 132 mg (56.2%) of the desired product.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]2[C:17]([C:38](=[O:40])[NH2:39])=[C:18]([NH:20][C:21](=[O:37])[NH:22][C:23]3[CH:28]=[CH:27][C:26](C(=O)C4C=CC=CC=4)=[CH:25][CH:24]=3)[S:19][C:13]=2[CH2:12]1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:50]>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]2[C:17]([C:38]([NH2:39])=[O:40])=[C:18]([NH:20][C:21](=[O:37])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:50])=[CH:25][CH:24]=3)[S:19][C:13]=2[CH2:12]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)NCCCN1CCc2c(sc(NC(=O)Nc3ccc(C(=O)c4ccccc4)cc3)c2C(N)=O)C1
Solvent: O=C(O)C(F)(F)F
Product: NCCCN1CCc2c(sc(NC(=O)Nc3ccc(Cl)cc3)c2C(N)=O)C1

Procedure:
A stirred suspension of tert-butyl-N-[3-(2-{[(4-benzoylphenyl)carbamoyl]amino}-3-carbamoyl-4H,5H,6H,7H-thieno[2,3-c]pyridin-6-yl)propyl]carbamate (70 mg, 0.14 mmol) in 4 mL of DCM at rt was treated with 2 mL of TFA. The resultant solution was stirred at rt for 40 min whereupon it was concentrated in a rotary evaporator. The product was taken up in MeOH and the solution concentrated in vacuo (×2) to afford the title compound as a light tan solid in quantitative yield. LRMS [M+H]408.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[NH:4][C:5](=[O:9])[CH2:6][C:7]#[N:8].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[NH:4][C:5](=[O:9])[C:6]([C:7]#[N:8])=[CH:17][N:18]([CH3:19])[CH3:20]
Reactant: COC(OC)N(C)C
Reactant: N#CCC(=O)Nc1ccc(F)cc1Cl
Product: CN(C)C=C(C#N)C(=O)Nc1ccc(F)cc1Cl

Procedure:
As for Example 1, 2'-chloro-2-cyano-4'-fluoroacetanilide as colorless needles, m.p. 138°-139° C. (prepared by the procedure described in U.S. Pat. No. 3,116,312), is heated with N,N-dimethylformamide dimethylacetal to give 2'-chloro-2-cyano-3-dimethylamino-4'-fluoroacrylanilide as colorless needles, m.p. 155.5°-156.5° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([O:10][CH3:11])=[O:9])[C:4](=[O:12])[N:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C(=O)N([Br:26])C(=O)C1>C(Cl)(Cl)Cl>[Br:26][CH2:7][C:6]1[N:2]([CH3:1])[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4](=[O:12])[C:5]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1c(C)n(C)n(-c2ccccc2)c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(CBr)n(C)n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32.7 %

Procedure:
Methyl 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate (7.82 g, 31.8 mmol) was dissolved in CHCl3 (150 ml) and n-bromosuccimide (6.91 g, 38.8 mmol) was added. The reaction was stirred at room temperature, and after 1.5 hours, more NBS (6.23 g, 35.2 mmol) was added. After another hour of stirring, the reaction was filtered, and the solid was washed with chloroform. The filtrate was concentrated, treated with dichlormethane, and refiltered. The filtrate was again concentrated, and filtered through silica gel (˜3 inches, dichlormethane/MeOH). The fractions with product collected, concentrated, and purified on silica gel (dichlormethane/MeOH) to give the desired methyl 5-(bromomethyl)-1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate (4.11 g, 82% purity, 10.4 mmol, 33% yield). MS (ESI pos. ion) m/z: 325, 327 (MH+). Calc'd exact mass for C13H13Br79.0N2O3: 324. Calc'd exact mass for C13H13Br81.0N2O3: 326.
Reaction SMILES: C(S([NH:7][CH:8]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:9]1[C:13]([C:14]#[N:15])=[C:12]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[S:11][C:10]=1[C:22]([OH:24])=[O:23])=O)(C)(C)C.Cl>C(Cl)Cl>[ClH:31].[NH2:7][CH:8]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:9]1[C:13]([C:14]#[N:15])=[C:12]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[S:11][C:10]=1[C:22]([OH:24])=[O:23]
Reactant: CC(C)(C)S(=O)NC(c1ccc(Cl)cc1)c1c(C(=O)O)sc(N2CCOCC2)c1C#N
Agent: Cl
Solvent: ClCCl
Product: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1C(N)c1ccc(Cl)cc1
Yield: 175.3 %

Procedure:
To a solution of 3-{[(tert-butylsulfinyl)amino](4-chlorophenyl)methyl}-4-cyano-5-(morpholin-4-yl)thiophene-2-carboxylic acid (1.46 g, 3.03 mmol) in methylene chloride (25.0 mL) was slowly added hydrochloric acid (4M in 1,4-dioxane, 15.0 mL), and the resultant suspension was stirred at room temperature for 1 hour. The suspension was filtered through a fine frit funnel. The collected solid was washed with DCM and dried in vacuo to afford 3-[amino(4-chlorophenyl)methyl]-4-cyano-5-(morpholin-4-yl)thiophene-2-carboxylic acid hydrochloride (113) (1.10 g, yield 86.5%) as a white powder. LCMS: (FA) ES+ 378; ES− 376; 1H NMR (400 MHz, CD3OD) δ 7.44-7.90 (m, 4H), 5.84 (s, 1H), 3.81-3.84 (m, 4H), 3.64-3.67 (m, 4H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1.[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)C)=O)=O)(C)C>O1CCCC1>[CH3:13][C:5]1[CH:4]=[C:3]([CH2:2][O:1][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(CO)cc1C
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(COc2ccccc2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
A mixture of methyl 4-(hydroxymethyl)-2-methylbenzoate (126 mg, 0.7 mmol), phenol (66 mg, 0.7 mmol), triphenylphosphine (275 mg, 1.0 mmol) and tetrahydrofuran (15 mL) was stirred at room temperature for half hour. And then azodicarboxylic acid diisopropyl ester (212 mg, 1.0 mmol) was added. The mixture was stirred at room temperature for 12 hours. The resultant mixture was washed with water (20 mL×2). The organic phase was separated, dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give methyl 2-methyl-4-(phenoxymethyl)benzoate as a colorless oil (66 mg, 37%). 1H NMR (300 MHz, CDCl3): δ 7.92 (d, J=8.4 Hz, 1H), 7.30-7.24 (m, 4H), 6.97-6.94 (m, 3H), 5.06 (s, 2H), 3.88 (s, 3H), 2.61 (s, 3H).
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([CH:26]=[CH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:14][N:15]3COCC[Si](C)(C)C)=[CH:11][CH:10]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)(O)[O-].[Na+]>C1COCC1>[C:1]1([C:7]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([CH:26]=[CH:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[CH2:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C(c1ccccc1)c1ccc2c(C=Cc3ccccc3)nn(COCC[Si](C)(C)C)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: C=C(c1ccccc1)c1ccc2c(C=Cc3ccccc3)n[nH]c2c1
Temperature: 60 °C
Yield: 39.9 %

Procedure:
6-(1-Phenyl-vinyl)-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole (16.2 mg, 0.0358 mmol) was dissolved in THF (0.6 mL) and was treated with tetrabutylammonium fluoride (TBAF, 1M in THF, 0.6 mL). The mixture was heated to 60° C. under argon for 4 h. The mix was cooled, neutralized with excess saturated sodium bicarbonate and the organic material was extracted into ethyl acetate and concentrated. This mix of 3 compounds (by TLC visualization) was treated with THF-water-TFA (1:1:2, 4 mL) for 30 min. The mix was diluted with toluene (20 mL), concentrated, neutralized with excess saturated sodium bicarbonate, and the organic material was extracted into ethyl acetate. The organic material was dried over sodium sulfate, decanted and concentrated. Purification by silica gel chromatography (2:8 ethyl acetate-hexane) gave 6-(1-Phenyl-vinyl)-3-styryl-1H-indazole (4.6 mg, 40%): Rf sm 0.62, p 0.24 (ethyl acetate-hexane 3:7); 1H NMR (300 MHz, CDCl3) δ 7.99 (d, 1H, J=8.5 Hz), 7.60-7.25 (m, 14H), 5.58 (d, 1H, J=1.1 Hz), 5.56 (d, 1H, J=1.1 Hz); HRMS (FAB) [m+H]/z Calc'd 323.1548, Found 323.1545.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([CH2:9]O)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.S([O-])(=O)(=O)C.CS(Cl)(=O)=O.[C-:21]#[N:22].[Na+]>C(Cl)(Cl)Cl.CN(C)C=O.C(N(CC)CC)C>[N:1]12[CH2:8][CH2:7][C:4]([CH2:9][C:21]#[N:22])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: [C-]#N
Reactant: OCC12CCN(CC1)CC2
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: N#CCC12CCN(CC1)CC2
Yield: 71.3 %

Procedure:
Quinuclidin-4-ylmethanol (1.94 g, 0.014 moles) was converted to the corresponding mesylate by treatment with methane sulphonyl chloride and triethylamine in chloroform. The mesylate was dissolved in dimethylformamide (50 ml) and treated with sodium cyanide (1.4 g, 0.028 moles) at 120° C. for 18 hours. The mixture was cooled and concentrated in vacuo. The residue was partitioned between saturated potassium carbonate and chloroform. The organic layer was separated and dried (Na2SO4), filtered and evaporated to dryness. Chromatography on silica gel eluting with 0-10% methanol/chloroform gave the title compound 1.5 g (72%). M.S. (+ve electrospray) m/z 151 (MH+, 100%).
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:23])[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1.[CH3:24][N:25]([O:29][CH3:30])[C:26](Cl)=[O:27]>O1CCCC1>[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:23])[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([NH:22][C:26]([N:25]([CH3:24])[O:29][CH3:30])=[O:27])=[CH:20][CH:21]=2)=[CH:9][CH:8]=1
Reactant: Cc1ccc(C(=O)CCc2ccc(N)cc2)cc1
Reactant: CON(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CON(C)C(=O)Nc1ccc(CCC(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
15.3 g of sodium bicarbonate were added to a solution, in 250 ml of tetrahydrofuran, of 36 g of the 1-(4-methylphenyl)-3-(4-aminophenyl)-n-propan-1-one prepared as described in Example A, and 18.5 g of N-methyl-N-methoxycarbamyl chloride were added dropwise at 10°-15° C., while cooling with ice. The mixture was stirred for 6 hours at 25° C., after which it was filtered and the filtrate was evaporated down under reduced pressure. The oil obtained crystallized after trituration with diisopropyl ether, and 38.5 g (79% of theory) of product of melting point 73°-74° C. were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16](=[O:32])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=2)[N:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Sn]Cl>CCO.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:32])[NH:17][C:18]1[S:19][CH:20]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=2)[N:22]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1)C1CCCN1C(=O)OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cccc(-c2csc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)n2)c1
Temperature: 25 °C

Procedure:
500 mg (1.1 mmol) of 2-[4-(3-Nitro-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester was dissolved in 30 mL of 1:1 mixture of EtOH/EtOAc. To this solution was added SnCl2 (0.87 g, 3.9 mmol). Reaction mixture was heated under reflux for 5 hours. After 5 hours reaction mixture was cooled to room temperature and evaporated. It was redissolved in EtOAc (150 mL) and washed using sat. K2CO3. Organic phase was isolated, washed using brine and water and evaporated to dryness to give Compound 5001. MS: 422.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=1)[C:10]([OH:12])=O)[CH3:5].[CH3:24][N:25]1[C:29]([CH3:30])=[CH:28][C:27]([NH2:31])=[N:26]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:24][N:25]1[C:29]([CH3:30])=[CH:28][C:27]([NH:31][C:10](=[O:12])[C:9]2[CH:13]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[C:7]([O:6][C@@H:4]([CH3:5])[CH2:3][O:2][CH3:1])[CH:8]=2)=[N:26]1
Reactant: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: Cc1cc(N)nn1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2cc(C)n(C)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
A solution of 3-[(1S)-2-methoxy-(1-methylethyl)oxy]-5-{[phenylmethyl]oxy}benzoic acid (4.11 mmol) in DMF (10 mL) was treated with the 1,5-dimethyl-1H-pyrazol-3-ylamine (4.52 mmol), DIPEA (5.93 mmol) and HATU (3.85 mmol) and stirred at RT overnight, under an argon atmosphere. The mixture was poured onto water (100 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was washed with brine (20 mL) and evaporated in vacuo before chromatography on silica, eluting with 20-80% ethyl acetate in isohexane, to afford the desired compound as a yellow oil (1.05 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][C:12]([C:14]([CH3:20])([CH3:19])[C:15](OC)=[O:16])=[N:11][C:10]=1[C:21]1[N:26]=[C:25]2[O:27][C:28]([NH:30][C@@H:31]([CH3:36])[CH2:32][CH2:33][O:34][CH3:35])=[N:29][C:24]2=[CH:23][CH:22]=1.[BH4-].[Li+].Cl>C(OCC)C.C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][C:12]([C:14]([CH3:20])([CH3:19])[CH2:15][OH:16])=[N:11][C:10]=1[C:21]1[N:26]=[C:25]2[O:27][C:28]([NH:30][C@@H:31]([CH3:36])[CH2:32][CH2:33][O:34][CH3:35])=[N:29][C:24]2=[CH:23][CH:22]=1
Reactant: COCC[C@H](C)Nc1nc2ccc(-c3nc(C(C)(C)C(=O)OC)[nH]c3-c3ccc(F)cc3F)nc2o1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCC[C@H](C)Nc1nc2ccc(-c3nc(C(C)(C)CO)[nH]c3-c3ccc(F)cc3F)nc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
Methyl 2-[5-(2,4-difluorophenyl)-4-[2-[[(1S)-3-methoxy-1-methyl-propyl]amino]oxazolo[5,4-b]pyridin-5-yl]-1H-imidazol-2-yl]-2-methyl-propanoate (50 g, 100.1 mmol) is dissolved in a mixture of diethyl ether (1 L) and THF (500 mL). The mixture is cooled to 0° C. and lithium borohydride (4.36 g, 200.19 mmol) is added. The reaction mixture is stirred at RT under a nitrogen atmosphere for 2 h. 1 M HCl (600 mL) is slowly added (gas evolution) and the resulting mixture is stirred for 1.5 h at RT. The layers are separated and the aqueous phase is extracted with methyl tert-butyl ether. The aqueous layer is basified (pH=8) by the addition of 2 M NaOH (200 mL) and is extracted with dichloromethane (3×400 mL). The combined organic layers are dried over Na2SO4, filtered, and concentrated under reduced pressure to a brown foam. The crude is eluted through a silica gel column (eluent: dichloromethane/3N NH3 in methanol 95:5) to obtain the desired product as a violet colored foam (35 g). The solid is suspended in a mixture of 2:1 heptane/methyl tert-butyl ether and sonicated. The suspension is stirred at RT overnight. The solid is filtered and dried under a vacuum to afford the title compound as a crystalline off-white solid (30 g, 64%). MS (m/z): 472 (M+1).
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:18][CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1>>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:18][C:19]([C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1
Reactant: NCc1ccc2ccccc2c1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(C)cc1
Product: CCOC(=O)c1nc(-c2ccc3ccccc3c2)[nH]c1-c1ccc(C)cc1

Procedure:
Ethyl 2-hydroxyimino-3-(4-methylphenyl)-3-oxopropionate(12.8 g) and 2-aminomethylnaphthalene (10.3 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-methylphenyl)-2-(2-naphthyl)imidazole-4-carboxylate (4.8 9g). 0.5 g therefrom was dissolved in ethyl alcohol (10 ml), and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-methylphenyl)-2-(2-naphthyl)imidazole-4-carboxylic acid (0.26 g), melting point 227° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[C:22](O)=[O:23]>>[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23]
Reactant: Cc1cc(C)cc(C(=O)O)c1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: Cc1cc(C)cc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3c2)c1
Yield: 94.3 %

Procedure:
Beginning with 10.0 mg (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 19.6 mg (0.131 mMol) 3,5-dimethylbenzoic acid, 15.0 mg (95%) of the title compound were recovered.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[F:9][C:10]1([F:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.O>CC(N(C)C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:14][CH2:15][C:10]([F:16])([F:9])[CH2:11][CH2:12]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: FC1(F)CCNCC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: FC1(F)CCN(c2ccc(Br)cn2)CC1
Reaction time: 8 h
Yield: 46 %

Procedure:
2,5-Dibromopyridine (1.30 g) was heated with 4,4-difluoropiperidine (2 g) in dimethylacetamide (4 ml) at 120° C. for 24 h, then at 150° C. for 8 h. The solution was allowed to cool, then poured into water (30 ml). The aqueous phase was extracted with ether (×3) and the combined extracts washed with water, dried over magnesium sulfate, filtered and evaporated. Purification by column chromatography gave the product as a colourless oil (0.70 g).