Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1](O)(=O)(=O)=O.[S:6]1[CH:10]=[CH:9][N:8]2[CH2:11][CH:12]([C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[NH:17]C(=O)C)[N:13]=[C:7]12.[ClH:24]>>[ClH:1].[ClH:24].[NH2:17][C:16]1[CH:15]=[C:14]([CH:12]2[CH2:11][N:8]3[C:7]([S:6][CH:10]=[CH:9]3)=[N:13]2)[CH:23]=[CH:22][CH:21]=1
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: CC(=O)Nc1cccc(C2CN3C=CSC3=N2)c1
Agent: Cl
Product: Nc1cccc(C2CN3C=CSC3=N2)c1

Procedure:
A 2.80 g. (0.0078 mole) portion of 3'-(5,6-dihydroimidazo[2,1-b]thiazol-6-yl)acetanilide perchlorate (Example 7) is converted to the free base and then dissolved in 15 ml. of 6N hydrochloric acid. The solution is stirred at reflux for 1.6 hours and then evaporated at reduced pressure. The residue is azeotroped with 2-propanol and crystallized from 95% ethanol/-2-propanol to give 1.69 g. (75%) of crystalline product, melting point 242°-244°C. Anal. Calcd. for C11H13Cl2N3S: C, 45.54; H, 4.52; Cl, 24.43; N, 14.48; S, 11.05. Found: C, 45.39; H, 4.66; Cl, 24.26; N, 12.27; S, 10.83.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]=3[C:26]([F:29])([F:28])[F:27])[O:12][N:11]=2)=[CH:6][CH:5]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH:31]1[CH2:36][C:37]([O:39]CC)=[O:38]>C(O)C>[OH:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]=3[C:26]([F:28])([F:27])[F:29])[O:12][N:11]=2)=[CH:8][CH:9]=1)[CH2:3][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH:31]1[CH2:36][C:37]([OH:39])=[O:38]
Reactant: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc(-c2ccc(C3CO3)cc2)no1
Reactant: CCOC(=O)CC1COCCN1
Solvent: CCO
Product: O=C(O)CC1COCCN1CC(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Temperature: 80 °C

Procedure:
To a mixture of 3-(4-(oxiran-2-yl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole, Preparation 28C (30 mg, 0.075 mmol) in ethanol (2 mL) was added ethyl 2-(morpholin-3-yl)acetate (52.1 mg, 0.301 mmol). The resulting mixture was heated at 80° C. overnight. Solvent was removed in vacuo. The residue was treated with 6N HCl/MeCN at 50° C. overnight. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 18 mg of 2-(4-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)morpholin-3-yl)acetic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 8.23 (2H, d, J=7.91 Hz), 7.72 (2H, dd, J=8.35, 2.20 Hz), 7.68 (2H, d, J=7.03 Hz), 7.53-7.65 (3H, m), 5.22-5.30 (1H, m), 3.61-4.21 (7H, m), 3.35-3.55 (2H, m), 2.88-3.10 (2H, m). MS (m+1)=545. HPLC Peak RT=3.23 minutes (Analytical Method A). Purity=93%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:21](=[S:23])[NH2:22])[NH:6]2.Br[CH2:25][CH:26](OCC)OCC.CN(C)C(=O)C>C(OCC)(=O)C>[CH3:20][N:11]([C:8]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]2[C:7]=1[NH:6][C:5]([C:21]1[S:23][CH:25]=[CH:26][N:22]=1)=[CH:4]2)[S:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)(=[O:14])=[O:13]
Reactant: CCOC(CBr)OCC
Reactant: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(N)=S)cc12
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(-c3nccs3)cc12
Yield: 43 %

Procedure:
A mixed solution of 4-methyl-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (0.20 g), 1-bromo-2,2-diethoxyethane (0.23 mL) and N,N-dimethylacetamide (10 ml) was stirred at 100° C. for 6 hr. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=25:75-35:65), and the obtained oil was crystallized from ethyl acetate-hexane to give the title compound (92 mg, yield 43%) as pale-yellow prism crystals. melting point 159-160° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:4][C:3]=1[Cl:25].[C:26]([O-:29])(=[O:28])C.[Na+].[C]=O.[CH3:33]O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:33][O:29][C:26](=[O:28])[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)([C:13]([F:14])([F:15])[F:16])[O:10][N:9]=2)=[CH:4][C:3]=1[Cl:25]
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(Br)c(Cl)c2)=NO1
Reactant: CC(=O)[O-]
Reactant: CO
Agent: [Pd+2]
Agent: [C]=O
Agent: [Na+]
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 100 °C
Reaction time: 16 h
Yield: 58 %

Procedure:
A mixture of 3-(4-Bromo-3-chloro-phenyl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (4.00 g), palladium bis(diphenylphosphine) dichloride CH2Cl2-complex (0.69 g), palladium acetate (0.14 g), sodium acetate (1.03 g), and methanol (50 mL) was placed in an autoclave, charged with 5 bar of carbon monoxide and stirred at 100° C. for 16 h. After cooling, the autoclave was opened and the reaction mixture was filtered. The filtrate was concentrated in vacuum and the residue was purified by flash chromatography on silica gel to obtain the title compound (2.2 g, 58%).
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:18]=[C:17]([CH3:19])[N:16]=[C:15](Cl)[N:14]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Br:22][C:23]1[CH:29]=[C:28]([CH:30]([CH3:32])[CH3:31])[CH:27]=[CH:26][C:24]=1[NH2:25].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(O)CO>[Br:22][C:23]1[CH:29]=[C:28]([CH:30]([CH3:31])[CH3:32])[CH:27]=[CH:26][C:24]=1[NH:25][C:15]1[N:14]=[C:13]([N:10]2[CH2:11][CH:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)[CH:18]=[C:17]([CH3:19])[N:16]=1
Reactant: CC(C)c1ccc(N)c(Br)c1
Reactant: Cc1cc(N2CC=C(c3ccccc3)CC2)nc(Cl)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N2CC=C(c3ccccc3)CC2)nc(Nc2ccc(C(C)C)cc2Br)n1
Yield: 60.7 %

Procedure:
4-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)-2-chloro-6-methylpyrimidine (466 mg), 408 mg of 2-bromo-4-isopropylaniline hydrochloride and 232 mg of diisopropylethylamine were heated in 5 ml of ethylene glycol under reflux for 1 hour. The reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The desiccant was filtered off, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=6/1) to give 458 mg of 2-[N-(2-bromo-4-isopropylphenyl)amino]-4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)-6-methylpyrimidine as an amorphous substance.
Reaction SMILES: [S:1]([C:5]1[S:13][C:8]2=[CH:9][N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>C(#N)C.C(Cl)(Cl)Cl>[CH3:16][N:17]([CH3:19])[CH:18]=[N:2][S:1]([C:5]1[S:13][C:8]2=[CH:9][N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1)(=[O:3])=[O:4]
Reactant: NS(=O)(=O)c1cc2ccncc2s1
Reactant: COC(OC)N(C)C
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CN(C)C=NS(=O)(=O)c1cc2ccncc2s1
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a partial suspension of 2-sulfamoylthieno[2,3-c]pyridine (1.81 g, 8.5 mmol) in acetonitrile (20 ml), under a nitrogen atmosphere, was added dropwise dimethylformamide dimethyl acetal (1.3 ml, 9.7 mmol). After 2 hours, the mixture was diluted with chloroform, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to give 2.2 g of product. This material was recrystallized from ethyl acetate to give 2.05 g (90% yield); m.p. 169°-171° C. Analysis calculated for C10H11N3O2S2 : N, 15.60; C, 44.59, H, 4.12. Found: N, 15.79; C, 44.95; H, 4.08.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>CCO.C(OCC)C.O>[C:8]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1ccccn1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: c1ccc(-c2ccccn2)cc1
Temperature: 25 °C

Procedure:
A 30 mL of reactor equipped with magnetic stir bar was charged with 15.8 mg (0.022 mmol) of [(t-Bu)2P(Cl)PdC2]2, 0.50 g (4.4 mmol) of 2-chloropyridine, 0.65 g (5.33 mmol) of PhB(OH)2 and 0.92 g (6.67 mmol) of K2CO3 in 3 mL of EtOH. The reaction mixture was refluxed for 5 hours. The reaction mixture was cooled to room temperature, transferred to a separatory funnel, and diluted with 100 mL of diethyl ether and 20 mL of H2O. The layers were separated, and organic layer was washed with H2O (50 mL), brine (30 mL), and dried over MgSO4, filtered, and solvents removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel. The eluate was concentrated by rotary evaporation followed by high vacuum to give 2-phenylpyridine. LC-MS Found: 156.2 (M++1).
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([CH2:18][CH3:19])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O>[C:31]([C:30]1[CH:33]=[CH:34][C:27]([CH:24]2[CH2:25][CH2:26][N:21]([C:9]([C:8]3[C:7]([CH2:18][CH3:19])=[CH:6][C:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)=[C:13]([CH:12]=3)[C:14]([O:16][CH3:17])=[O:15])=[O:10])[CH2:22][CH2:23]2)=[CH:28][CH:29]=1)#[N:32]
Reactant: CCc1cc(C2CCC2)c(C(=O)OC)cc1C(=O)O
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(C2CCC2)c(C(=O)OC)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a round-bottom flask were added a solution of 4-cyclobutyl-2-ethyl-5-(methoxycarbonyl)benzoic acid (compound 215.4, 1.15 g, 4.38 mmol, 1.00 equiv), 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 1.07 g, 4.80 mmol, 1.10 equiv), HBTU (2.50 g, 6.59 mmol, 1.50 equiv), and DIEA (1.07 g, 8.28 mmol, 3.00 equiv) in N,N-dimethylformamide (10 mL). The resulting solution was stirred for 1 h at 25° C. The reaction was then quenched by the addition of 20 mL of water. The resulting mixture was extracted with 2×50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:3) to yield 1.80 g (95%) of methyl 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-ethylbenzoate as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([OH:9])=[C:4]([CH2:10][CH3:11])[N:3]=1.O.[OH-].[Li+].S(O[CH2:20][CH2:21][CH2:22][O:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1)(=O)(=O)C>CN(C=O)C.ClCCl>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:20][CH2:21][CH2:22][O:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=[CH:26][CH:25]=2)=[C:4]([CH2:10][CH3:11])[N:3]=1
Reactant: CS(=O)(=O)OCCCOc1ccnc2ccccc12
Reactant: CCc1nc(N)nc(N)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1nc(N)nc(N)c1OCCCOc1ccnc2ccccc12
Reaction time: 1 h
Yield: 100.6 %

Procedure:
2,4-diamino-6-ethyl-5-hydroxypyrimidine (0.3963 g, 2.6 mmol) was added to a stirred solution of lithium hydroxide monohydrate (497.2 mg, 11.8 mmol) in DMF (2 mL) and the reaction mixture was stirred for 1 hour. A solution of 3-(quinolin-4-yloxy)-propyl mesylate (0.3868 g, 1.37 mmol) in DMF (1 mL) was slowly added and the reaction mixture was left stirring at 25° C. overnight. The reaction was diluted with dichloromethane and extracted with water. The dichloromethane layer was evaporated followed by crystallization of the residue from aqueous methanol. The product was obtained as a slightly yellow solid (0.4677 g, 53%). 1H NMR (400 MHz, DMSO-d6): 0.87 (3H, t, J=7.0 Hz), 2.24 (2H, q, J=7.0 Hz), 2.30 (2H, m), 3.85 (2H, t, J=5.5 Hz), 4.43 (2H, t, J=5.5 Hz), 5.53 (2H, s), 6.11 (2H, s), 7.06 (1H, d, J=5.2 Hz), 7.54 (1H, t, J=8.0 Hz), 7.72 (1H, ddd, J=1.4, 6.9, 8.3 Hz), 7.93 (1H, d, J=8.3 Hz), 8.15 (1H, d, J=8.5 Hz), 8.72 (1H, d, J=5.2 Hz).
Reaction SMILES: Cl[C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:5]=1)=[O:3].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]([C@H:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][C@@H:33]([CH3:41])[CH2:32]2)[C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:17][O:16][C:14](=[O:15])[C:13]([CH3:19])([CH3:18])[CH2:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([N:34]2[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:31]([N:27]([C:28](=[O:30])[CH3:29])[C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=3)[CH2:32][C@@H:33]2[CH3:41])=[O:3])=[CH:5][CH:6]=1
Reactant: COC(=O)C(C)(C)CCCc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)Nc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(C)(C)CCCc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.1 %

Procedure:
To the prepared methyl 5-[4-(chlorocarbonyl)phenyl]-2,2-dimethylpentanoate (2.9 mmol, 1.0 eq.) was added a solution of N-(4-chlorophenyl)-N-((2S,4R)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)acetamide (754 mg, 2.4 mmol, 0.83 eq.) in methylene chloride (8 ml) followed by diisopropylethylamine (505 ul, 2.9 mmol, 1.0 eq.) and reaction mixture was stirred at room temperature for 20 h. The mixture was concentrated and the residue dissolved in ethyl acetate and washed with water, brine, and then dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (ethyl acetate/hexane: ⅓ to ½ gradient) to afford 5-(4-{(2S,4R)-4-[acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-2,2-dimethyl-pentanoic acid methyl ester (675 mg, 50%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])[CH:4]=1.[OH:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:16][C:15]1[O:14][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:12][C:11]=1[CH2:10][O:9][C:5]1[CH:4]=[C:3]([CH2:2][O:23][C:24]2[CH:25]=[C:26]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH:8]=[CH:7][N:6]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(CCl)ccn1
Reactant: COC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(OCc2ccnc(OCc3nc(-c4ccccc4)oc3C)c2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
A mixture of 4-(chloromethyl)-2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]pyridine (0.472 g), methyl 2-(3-hydroxyphenyl)acetate (0.249 g), anhydrous potassium carbonate (0.415 g) and N,N-dimethylformamide (10 mL) was stirred at 60° C. for 3 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give methyl 2-[3-[2-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]-4-pyridylmethoxy]phenyl]acetate as a colorless oil (0.597 g, 90%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8]([Br:10])[N:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=1[O:15][CH3:16])=[N+]=[N-].[BH4-].[Na+].C(OCC)(=O)C.O>CO>[NH2:1][C:4]1[CH:9]=[C:8]([Br:10])[N:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=1[O:15][CH3:16]
Reactant: COC(=O)c1nc(Br)cc(N=[N+]=[N-])c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1nc(Br)cc(N)c1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
To methyl 4-azido-6-bromo-3-methoxypyridine-2-carboxylate (0.500 g, 1.74 mmol) in 10 mL of methanol was added NaBH4 (0.046 g, 1.22 mmol). The reaction mixture was stirred at room temperature for 10 min. Ethyl acetate and water were added and the phases were separated. The organic phase was washed with H2O, dried (MgSO4) and concentrated to dryness in vacuo. The residue was purified by chromatography (silica gel). Elution with 100% ethyl acetate gave 0.300 g of a white solid. 1H NMR(CDCl3): δ 3.90 (s, 1H); 3.95 (s, 1H); 4.60 (s, 2H); 6.85 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH:26]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH2:28][C@H:29]([C:31]([O:33]C)=[O:32])[CH3:30].[BH-](OC(C)=O)(OC(C)=O)O[C:37](C)=O.[Na+].C=O>C(Cl)Cl.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][N:28]([CH3:37])[C@H:29]([C:31]([OH:33])=[O:32])[CH3:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: COC(=O)[C@H](C)N
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)c[nH]c34)no2)cc1Cl
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CN(C)[C@@H](C)C(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 7.1 %

Procedure:
To a stirred solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole-3-carbaldehyde (D71) (150 mg), methyl L-alaninate (81 mg) and acetic acid (24 mg) in DCM (10 mL) was added NaBH(OAc)3 (167 mg). The mixture was stirred at 40° C. for 2 h, followed by addition of formaldehyde (120 mg). This mixture was stirred at 40° C. overnight. After concentration, the residue was dissolved in THF (5 mL), followed by addition of aqueous NaOH (2 M, 2 mL). The mixture was stirred at 60° C. overnight, and then acidified with aqueous HCl (2 M) to pH 4-5, partitioned between ethyl acetate (25 mL) and water (25 mL). The organic phase was washed with water (25 mL) and brine (25 mL), dried over anhydrous sodium sulphate, and evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}-N-methyl-L-alanine (E54) (13 mg). δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 1.56 (3H, d), 2.75 (3H, s), 4.17 (1H, q), 4.54 (2H, q), 4.90 (1H, m), 7.35 (1H, t), 7.46 (1H, d), 7.75 (1H, d), 8.03 (1H, d), 8.10 (1H, d), 8.21 (1H, dd), 8.39 (1H, d), 11.46 (1H, br s). MS (ES): C24H26ClN4O4 requires 468; found 366.1 (M—C4H8NO2+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]([O:28]CC)=O)[C:5]2[C:6](=O)[CH:7]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:8]([C:12]3[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=3)[NH:9][C:10]=2[CH:11]=1.O.[NH2:32][NH2:33]>CO>[F:1][C:2]1[CH:11]=[C:10]2[NH:9][CH:8]([C:12]3[N:13]([CH3:17])[CH:14]=[CH:15][N:16]=3)[CH:7]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:6]3=[N:32][NH:33][C:26](=[O:28])[C:4]([CH:3]=1)=[C:5]23
Reactant: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ccc(F)cc1)C(c1nccn1C)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: Cn1ccnc1C1Nc2cc(F)cc3c(=O)[nH]nc(c23)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 14 %

Procedure:
A mixture of ethyl 7-fluoro-3-(4-fluorophenyl)-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (200 mg, 0.486 mmol) in 85% hydrazine monohydrate (1 mL) and methanol (5 mL) was stirred at room temperature for 4 h. The resulting mixture was filtered and washed by water (20 mL) and methanol (5 mL) to obtain a white solid, which was then dried in vacuum at 50° C. to obtain the title compound (25.4 mg, yield 14%). LC-MS (ESI) m/z: 380 (M+1)+; 1H-NMR (400 MHz, DMSO-d) δ (ppm): 3.56 (s, 3H), 4.52-4.53 (d, J=6.8 Hz, 1H), 5.02-5.04 (m, 1H), 6.73 (s, 1H), 6.82-6.85 (m, 1H), 6.99-7.09 (m, 4H), 7.18-7.22 (m, 2H), 7.69 (s, 1H), 12.34 (s, 1H).
Reaction SMILES: CS(O[CH2:6][C:7]([CH3:17])([N:9]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[N:10]1)[CH3:8])(=O)=O.[I-:18].[Na+].O>CN(C)C=O>[I:18][CH2:6][C:7]([N:9]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[N:10]1)([CH3:17])[CH3:8]
Reactant: [I-]
Reactant: CC(C)(COS(C)(=O)=O)n1cc([N+](=O)[O-])cn1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(CI)n1cc([N+](=O)[O-])cn1
Temperature: 130 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
To a solution of the crude 2-methyl-2-(4-nitro-1H-pyrazol-1-yl)propyl methanesulfonate (18 g) obtained in Step A of Example 115 in N,N-dimethylformamide (150 mL) was added sodium iodide (20 g), and the mixture was stirred overnight at 130° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (14 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:22]=[CH:21][NH:20][N:19]=1.O=[C:24]([CH2:31][CH2:32][CH3:33])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]1[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:24]([CH2:31][CH2:32][CH3:33])[NH:17][C:18]2=[N:19][NH:20][CH:21]=[C:22]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc[nH]n1
Reactant: CCCC(=O)CC(=O)OCC
Reactant: O=Cc1ccccc1OCc1ccccc1
Product: CCCC1=C(C(=O)OCC)C(c2ccccc2OCc2ccccc2)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2-benzyloxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:26][CH3:27])=[CH:4][C:5]([CH3:25])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](OS(C(F)(F)F)(=O)=O)[C:9]=2[N+:22]([O-:24])=[O:23])[CH:7]=1.[CH3:28][O:29][CH2:30][CH:31]([NH2:34])[CH2:32][CH3:33]>>[Cl:1][C:2]1[C:3]([O:26][CH3:27])=[CH:4][C:5]([CH3:25])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:34][CH:31]([CH2:30][O:29][CH3:28])[CH2:32][CH3:33])[C:9]=2[N+:22]([O-:24])=[O:23])[CH:7]=1
Reactant: CCC(N)COC
Reactant: COc1cc(C)c(-c2ccnc(OS(=O)(=O)C(F)(F)F)c2[N+](=O)[O-])cc1Cl
Product: CCC(COC)Nc1nccc(-c2cc(Cl)c(OC)cc2C)c1[N+](=O)[O-]
Yield: 38.5 %

Procedure:
Trifluoro-methanesulfonic acid 4-(5-chloro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl ester (0.38 g, 0.89 mmol) and 1-methoxymethyl-propylamine (0.23 g, 2.23 mmol) were treated substantially as described in Part C of Example 19a to produce 0.13 g (40%) of crude [4-(5-chloro-4-methoxy-2-methyl-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine: MS (EI) m/z 380.19 [(M+H)+, 100].