Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].O.[CH2:4]([O:6][C:7]1[CH:8]=[C:9]([C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([O:30]CC)=[O:29])[N:22]=3)[N:20]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH3:5].Cl>C(O)C>[CH2:4]([O:6][C:7]1[CH:8]=[C:9]([C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([OH:30])=[O:29])[N:22]=3)[N:20]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH3:5]
Reactant: CCOC(=O)c1nc(-c2csc(-c3ccc(OCC)c(OCC)c3)n2)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1ccc(-c2nc(-c3ccc(O)c(C(=O)O)n3)cs2)cc1OCC
Yield: 47.7 %

Procedure:
A solution of 0.32 g of sodium hydroxide dissolved in 20 ml of ethanol and 20 ml of water was added to 0.54 g of 2-(3,4-diethoxyphenyl)-4-(5-hydroxy-6-ethoxycarbonyl-2-pyridyl)thiazole. The mixture was refluxed for 2.5 hours. To the reaction mixture was added 100 ml of water. The mixture was made acidic with concentrated hydrochloric acid and subjected to extraction four times with 70 ml of ethyl acetate. The solvent in the extract was removed and the resulting residue was recrystallized from ethyl acetate-diethyl ether to obtain 0.24 g of 2-(3,4-diethoxyphenyl)-4-(5-hydroxy-6-carboxy-2-pyridyl)thiazole. m.p.: 161.4°-162° C.
Reaction SMILES: [CH2:1]([C:7]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]=1[OH:18])[CH2:2][CH:3]=[CH:4][CH2:5][CH3:6]>FC(F)(F)C(O)=O>[Cl:17][C:15]1[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]2[O:18][C@@H:2]3[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]3[C:7]=2[CH:16]=1
Reactant: CCC=CCCc1cc(Cl)cc(C(=O)OC)c1O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Cl)cc2c1O[C@@H]1CCCC[C@@H]21
Temperature: 70 °C

Procedure:
A mixture of 9 g of methyl 3-(3-hexenyl)-5-chlorosalicylate and 20 ml trifluoroacetic acid is heated at 70° C. overnight. The cooled reaction mixture is diluted with hexanes, washed three times with water, dried and evaporated to dryness. The residue is purified with flash chromatography using 10% ethylacetate/hexane to give four fractions
Reaction SMILES: [H-].[K+].[CH2:3]([N:6]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)=[O:8])[CH:4]=[CH2:5].[CH2:37](Br)[CH:38]=[CH2:39]>C1COCC1.ClCCl>[CH2:39]([N:9]([C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][CH:15]=1)[C:7]([N:6]([CH2:3][CH:4]=[CH2:5])[C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:27][CH:28]=1)=[O:8])[CH:38]=[CH2:37]
Reactant: C=CCN(C(=O)Nc1ccc(Oc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1
Reactant: C=CCBr
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCN(C(=O)N(CC=C)c1ccc(Oc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
Potassium hydride (30% in oil, 40 mg) was added to a solution of 1-allyl-1-(4-benzyloxyphenyl)-3-(4-phenoxyphenyl)urea (133 mg) in THF (3 mL) at −78° C. After 30 minutes, allyl bromide (30 μL) was added. After 14 hours at room temperature, the solution was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was dried and concentrated. The product with the molecular weight of 490.61 (C32H30N2O3); MS (ESI): 491 ([M+H]+), was obtained in this way.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH:19]=C)[CH:15]=[CH:14][C:13]=2[C:12]2[N:21]([S:24]([N:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])[N:22]=[CH:23][C:11]=2[N:10]=1.O.C([OH:35])CCC.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.CC(O)(C)C.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([CH:19]=[O:35])[CH:15]=[CH:14][C:13]=2[C:12]2[N:21]([S:24]([N:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])[N:22]=[CH:23][C:11]=2[N:10]=1
Reactant: C=Cc1ccc2c(c1)c(-c1c(F)cccc1F)nc1cnn(S(=O)(=O)N(C)C)c12
Reactant: CCCCO
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)(C)O
Product: CN(C)S(=O)(=O)n1ncc2nc(-c3c(F)cccc3F)c3cc(C=O)ccc3c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 250 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 2.36 g of 5-(2,6-difluorophenyl)-7-ethenyl-N,N-dimethyl-1H-pyrazolo[4,3-c]isoquinoline-1-sulphonamide in 30 ml of THF and then 23 ml of water, 30 ml of tort-butanol, 2.14 ml of a solution of osmium tetroxide at 2.5% in 2-methyl-2-propanol, and 5.04 g of sodium periodate are added. The mixture is stirred at RT for 4 h and then poured into 100 ml of water and extracted with AcOEt. The organic phase is washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. The crude product is purified by chromatography on silica gel (15-40 μm), eluting with DCM, to give 1.92 g of 5-(2,6-difluorophenyl)-7-formyl-N,N-dimethyl-1H-pyrazolo[4,3-c]isoquinoline-1-sulphonamide (beige solid). LC-MS-DAD-ELSD: 417 (+)=(M+H)(+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]([OH:28])[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH:21]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23](=[O:28])[CH2:22]4)=[O:19])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(NC1CCCCC(O)C1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C1CCCCC(NC(=O)N2CCN(c3ccnc4cc(Cl)ccc34)CC2)C1
Reaction time: 3 h

Procedure:
To a stirred solution of 4-(7-chloro-4-quinolinyl)-N-(3-hydroxycycloheptyl)-1-piperazinecarboxamide (300 mg, 0.744 mmol) in CH2Cl2 (20 mL), the Dess-Martin reagent (348 mg, 0.82 mmol) was added at rt. After 3 h, the reaction mixture was quenched with 1 g of Na2S2O3 and 5 mL of NaHCO3 (sat.). The reaction mixture was extracted with CH2Cl2, washed with brine, and dried over Na2SO4. Concentration in vacuo followed by flash chromatography afforded the title product. LC-MS: 401 (M++1). 1H NMR (CDCl3) δ 8.78 (d, 1H), 8.05 (s, 1H), 7.95 (d, 1H), 7.45 (d, 1H), 6.85 (d, 1H), 4.70 (m, 1H), 4.25 (m, 1H), 3.60 (m, 4H), 3.25 (m, 4H), 3.00 (m, 1H), 2.45–2.65 (m, 3H), 1.70–1.90 (m, 6H).
Reaction SMILES: C([O:5][C:6](=[O:12])[C@@H:7]([CH3:11])[C@@H:8]([NH2:10])[CH3:9])(C)(C)C.C[O:14][C:15]([C:17]1[N:18]=[C:19]([C:35]#[N:36])[C:20]2[C:25]([C:26]=1[OH:27])=[CH:24][CH:23]=[C:22]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:21]=2)=O.C(N(CC)CC)C>CCO>[C:35]([C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[C:22]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:21]=2)[C:26]([OH:27])=[C:17]([C:15]([NH:10][C@@H:8]([CH3:9])[C@H:7]([CH3:11])[C:6]([OH:5])=[O:12])=[O:14])[N:18]=1)#[N:36]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: C[C@H](N)[C@H](C)C(=O)OC(C)(C)C
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)[C@H](C)C(=O)O
Temperature: 140 °C
Yield: 35.1 %

Procedure:
A mixture of (2S,3S)-3-amino-2-methyl-butyric acid tert-butyl ester (20 mg, 0.12 mmol), 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (25 mg, 0.078 mmol), and triethylamine (0.050 mL) in EtOH (2 mL) was heated in a microwave reactor at 140° C. for 6 h. The resulting mixture was concentrated to dryness, and the residue was re-dissolved in CH2Cl2 and passed through a plug of silica gel. After evaporating the solvent, the residue was dissolved in CH2Cl2 (3 mL) and treated with trifluoroacetic acid (2 mL) for 2 h. The mixture was concentrated in vacuo, and the resulting residue was taken up in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH ˜2 and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 11.1 mg of the title compound as a white solid. MS: (−) m/z 404.32 (M−1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[C:12]([O:33][CH3:34])=[C:13]([CH:19]2[CH2:22][N:21](C(OCC3C=CC=CC=3)=O)[CH2:20]2)[C:14]([CH3:18])=[C:15]([Cl:17])[CH:16]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.O>[Pd].CO>[NH:21]1[CH2:22][CH:19]([C:13]2[C:12]([O:33][CH3:34])=[C:11]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:10])[CH:16]=[C:15]([Cl:17])[C:14]=2[CH3:18])[CH2:20]1
Reactant: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C1CNC1
Reaction time: 1 h
Yield: 75.1 %

Procedure:
Benzyl 3-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylate (720 mg, 1.5 mmol) (second peak from chiral separation of previous step) and 5% palladium on carbon (100 mg) were combined in methanol (40 mL), to which was added 0.25 M HCl in water (11 mL, 2.8 mmol). The suspension was hydrogenated under balloon pressure of H2 at room temperature for 1 hour. The suspension was then filtered, neutralized with sat. NaHCO3 solution, concentrated, and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product (0.4 g). LCMS calculated for C18H28ClN2O3 (M+H)+: m/z=355.2. found: 355.1.
Reaction SMILES: [CH3:1][C:2]1[C:6](=[O:7])[O:5][CH2:4][C:3]=1[N:8]1[CH:12]=[C:11](OS(C(F)(F)F)(=O)=O)[C:10]2([CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[C:9]1=[O:33].[CH3:34][Al](C)C>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:34][C:11]1[C:10]2([CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:24][CH2:25]2)[C:9](=[O:33])[N:8]([C:3]2[CH2:4][O:5][C:6](=[O:7])[C:2]=2[CH3:1])[CH:12]=1
Reactant: CC1=C(N2C=C(OS(=O)(=O)C(F)(F)F)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Reactant: C[Al](C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1=CN(C2=C(C)C(=O)OC2)C(=O)C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl 2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-2,8-diazaspiro[4.5]dec-3-ene-8-carboxylate (180 mg, 0.363 mmol) was dissolved in THF (3.6 mL), and Pd(Ph3P)4 (209 mg, 0.181 mmol) was added, followed by trimethylaluminum (3.6 mL, 7.25 mmol) at 0° C. This reaction was stirred at rt for 2 h before it was quenched with saturated aqueous NaHCO3 solution at 0° C. (highly exothermic). This mixture was diluted with EtOAc, dried over Mg2SO4 and concentrated under reduced pressure. The crude material was purified by column chromatography (0-10% MeOH/DCM) to afford the title compound. LC/MS: [(M+1)]+=363
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[C:11]1([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:10][C:4]1[N:3]=[C:2]([N:20]2[CH2:19][CH2:18][CH:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:22][CH2:21]2)[CH:7]=[C:6]([NH:8][CH3:9])[N:5]=1
Reactant: CNc1cc(Cl)nc(C)n1
Reactant: c1ccc(C2CCNCC2)cc1
Product: CNc1cc(N2CCC(c3ccccc3)CC2)nc(C)n1
Yield: 74.4 %

Procedure:
A mixture of 4-chloro-2-methyl-6-methylaminopyrimidine (525 mg, 3.3 mM; described in J. Pharm. Soc. (Japan) 1966, 86, p. 952) and 4-phenylpiperidine (1.08 g, 6.6 mM) was heated as a melt at 135°-140° C. for 1 hour. The residue, obtained after cooling, was triturated with ether and the mixture separated by filtration. The solid was suspended in a mixture of 50% w/v potassium hydroxide solution (50 ml) and isopropanol (50 ml). The mixture was heated under reflux for 2 hours and cooled. The organic layer was separated and the solvent removed in vacuo. The residue was dissolved in methylene chloride (50 ml), washed with water (2×25 ml), dried (MgSO4) and the solvent evaporated. The residue was purified by flash chromatography on silica (Merck Art. 9385, 100 g), using a mixture of methanol and methylene chloride (1:9 v/v) as eluant, to give 2-methyl-6-methylamino-4-(4-phenylpiperidino)-pyrimidine (700 mg, 75% yield), m.p. 186°-188° C.; microanalysis, found: C, 71.6; H,7.5; N,19.3%; C17H22N4.1/4H2O requires C,71.2; H,7.8; N,19.5%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1)[O:7][CH:8]1[CH2:12][CH2:11][O:10][CH2:9]1)([O-])=O>CO.[Pd]>[O:10]1[CH2:11][CH2:12][CH:8]([O:7][C:6]2[CH:5]=[C:4]([NH2:1])[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=2)[CH2:9]1
Reactant: O=[N+]([O-])c1cc(OC2CCOC2)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(OC2CCOC2)cc(C(F)(F)F)c1
Reaction time: 4 h

Procedure:
The nitrobenzotrifluoride (Step B, 6.026 g, 21.7 mmol, 1 eq) was dissolved in MeOH (210 mL). 10% Pd/C (600 mg (10 wt %)) was carefully added to the reaction. The suspension was sparged with H2 and stirred under a H2 atm for 4 h. The mixture was filtered through a Celite® pad and the solvent removed in vacuo to yield the desired amine which was used without further purification.
Reaction SMILES: C([O:5][C:6](=[O:45])[C:7]([N:31]=C(C1C=CC=CC=1)C1C=CC=CC=1)([CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[CH2:8][CH2:9][CH2:10][CH2:11][B:12]1[O:16]C(C)(C)C(C)(C)[O:13]1)(C)(C)C>Cl.O>[ClH:30].[NH2:31][C:7]([CH2:21][CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1)([CH2:8][CH2:9][CH2:10][CH2:11][B:12]([OH:13])[OH:16])[C:6]([OH:45])=[O:5]
Reactant: CC(C)(C)OC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)(CCOc1ccc(Cl)cc1)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Product: NC(CCCCB(O)O)(CCOc1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-(benzhydrylidene-amino)-2-[2-(4-chlorophenoxy)-ethyl]-6-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-hexanoic acid tert-butyl ester (486 mg) in 6 N HCl (6 ml) was warmed to 60° C. and stirred overnight. After cooling to room temperature, the reaction mixture was transferred to a separatory funnel, diluted with deionized water (6 ml) and washed with dichloromethane (3×). The aqueous layer was frozen in liquid nitrogen and lyophilized to give 2-amino-6-borono-2-(2-(4-chlorophenoxy)ethyl)hexanoic acid hydrochloride, as a colorless foam (125 mg, 85%); 1H NMR (D4-MeOH, 300 MHz) δH 7.24 (2H, d, J=7 Hz, 2H), 6.94 (d, J=7 Hz, 2H), 4.18 (m, 2H), 2.52 (m, 1H), 2.46 (m, 1H), 1.92 (m, 2H), 1.22-1.52 (m, 4H) and 0.82 (t, J=7 Hz, 2H,); MS (+CI): m/z for C14H21BClNO5: expected 329.1. found 330.2 (M+H)+, 312.2 (M+H−H2O)+, 659.4 (2 M+H)+, 641.4 (2 M+H−H2O)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl>[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:11][CH2:10]1
Reactant: CN1CCC(=O)CC1
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCC(Nc2ccccc2)CC1
Reaction time: 16 h
Yield: 97.9 %

Procedure:
A solution of aniline (2.0 g, 1.95 mL, 21.475 mmol), N-methyl-4-piperidone (2.64 mL, 21.475 mmol) and AcOH (1.21 mL, 21.475 mmol) in dry 1,2-dichloroethane (20 mL) was treated with NaBH(OAc)3 (6.82 g, 32.213 mmol) at 0° C. The reaction was brought to room temperature and stirred for over night (16 h). The reaction was basified with 1 N NaOH solution (40 mL) and product was extracted into CH2Cl2 (2×25 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) to obtain compound 1-methyl-N-phenylpiperidin-4-amine (4.0 g, 98%) as a solid. 1H NMR (DMSO-d6) δ: 1.29-1.42 (m, 2H), 1.82-1.88 (m, 2H), 1.93-2.02 (m, 2H), 2.15 (s, 3H), 2.68-2.74 (m, 2H), 3.08-3.18 (m, 1H), 5.36 (d, 1H, J=8.1 Hz), 6.47 (t, 1H, J=7.2 Hz), 6.54 (d, 2H, J=7.8 Hz), 7.03 (t, 2H, J=7.2 Hz); ESI-MS (m/z, %) 191 (MH+, 100).
Reaction SMILES: [CH:1]1([C:4]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[C:33](=[O:34])[N:32]([CH3:35])[N:31]=[N:30]3)[C:5]=2[CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C:18]([CH3:19])=[C:17]([CH:20]=[N:21]O)[C:16]([CH3:23])=[N:15]3)=[CH:10][C:9]=2[CH3:24])[CH2:3][CH2:2]1.CN(C)C=O.ClC1N=C(Cl)N=C(Cl)N=1>O>[CH:1]1([C:4]2[C:5]([CH2:6][O:7][C:8]3[CH:13]=[CH:12][C:11]([N:14]4[C:18]([CH3:19])=[C:17]([C:20]#[N:21])[C:16]([CH3:23])=[N:15]4)=[CH:10][C:9]=3[CH3:24])=[C:25]([N:29]3[C:33](=[O:34])[N:32]([CH3:35])[N:31]=[N:30]3)[CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(-n2nc(C)c(C=NO)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-n2nc(C)c(C#N)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
At room temperature, to the mixture of 1-{4-[2-Cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-3,5-dimethyl-1H-pyrazole-4-carbaldehyde oxime (described in Reference Preparation example 118) 1.5 g and N,N-dimethylformamide was added 2,4,6-trichloro-[1,3,5]triazine 0.6 g and the resulting mixture was stirred at room temperature for three hours. To the resulting mixture was added water 100 ml and the precipitates were filtrated. The precipitates were washed with water and dried under reduced pressure to give 1-{3-cyclopropyl-2-[2-methyl-4-(4-cyano-3,5-dimethyl-pyrazol-1-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (hereinafter, referred to as “Present compound 52”) 1.0 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:42])[C:10]([NH:12][CH:13]([CH:39]([CH3:41])[CH3:40])[C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][C:22]1[C:26]2[CH:27]=[C:28](OS(C(F)(F)F)(=O)=O)[CH:29]=[CH:30][C:25]=2[O:24][CH:23]=1)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[N:49]1[CH:54]=[CH:53][CH:52]=[C:51](B(O)O)[CH:50]=1>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:10](=[O:11])[NH:12][CH:13]([C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][C:22]1[C:26]2[CH:27]=[C:28]([C:51]3[CH:50]=[N:49][CH:54]=[CH:53][CH:52]=3)[CH:29]=[CH:30][C:25]=2[O:24][CH:23]=1)=[O:15])[CH:39]([CH3:40])[CH3:41])[CH3:42])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cccnc1
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)NC(C(=O)N1CCCC1Cc1coc2ccc(OS(=O)(=O)C(F)(F)F)cc12)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(NC(=O)OC(C)(C)C)C(=O)NC(C(=O)N1CCCC1Cc1coc2ccc(-c3cccnc3)cc12)C(C)C
Temperature: 100 °C
Yield: 72.9 %

Procedure:
A mixture of 35 (0.063 g, 0.10 mmol), K2CO3 (70 mg, 0.50 mmol), 3-pyridineboronic acid (0.015 g, 0.12 mmol), and (Ph3P)4Pd (5 mg, 3 mol %) in anhydrous toluene (5 mL) was heated at 100° C. in a sealed tube for 1 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash silica gel chromatography (EtOAc) to afford 40 mg (72%) of 36 as an oil. 1H NMR (CDCl3, 300 MHz) δ8.94 (d, 1H); 8.59 (d, 1H); 8.01-7.95 (m, 1H); 7.74-7.64 (m, 1H); 7.58-7.37 (m, 4H); 6.94 (d, 1H); 4.61 (t, 1H); 4.50-4.47 (m, 1H); 4.30 (t, 1H0; 4.21 (br, 1H); 3.79-3.71 (m, 1H); 3.66-3.59 (m, 1H); 2.42-3.36 (m, 1H); 2.58-2.50 (m, 1H); 2.13-2.09 (m, 1H); 2.01-1.71 (m, 4H); 1.45 (m, 9H); 1.37 (d, 3H); 1.03-0.94 (m, 6H) ppm.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH2:28])=[O:27])=[CH:21][CH:20]=1>CN1C(=O)CCC1.O>[CH:13]1([O:12][C:4]2[N:3]=[C:2]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][C:26]([NH2:28])=[O:27])=[CH:23][CH:24]=3)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: FC(F)(F)c1cc(Cl)nc(OC2CCCC2)n1
Reactant: NC(=O)Cc1ccc(N)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: NC(=O)Cc1ccc(Nc2cc(C(F)(F)F)nc(OC3CCCC3)n2)cc1
Temperature: 120 °C
Yield: 51.8 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-(cyclopentyloxy)-6-(trifluoromethyl)pyrimidine (0.090 g, 0.34 mmol) and (4-aminophenyl)acetamide (0.076 g, 0.51 mmol) in NMP (3 mL). The resulting mixture was heated at 120° C. under microwave irradiation for 1 h. The reaction mixture was cooled, diluted with water (50 mL) affording a solid. The solid was isolated by filtration and chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent to afford the title compound (0.067 g, 52%) as a white solid. MW=380.36. M.p. 208-210° C. 1H NMR (DMSO-d6, 500 MHz) δ 10.05 (s, 1H), 7.58 (br d, J=7.5 Hz, 2H), 7.42 (s, 1H), 7.25 (d, J=7.5 Hz, 2H), 6.85 (s, 1H), 6.74 (s, 1H), 5.31 (septet, J=3.0 Hz, 1H), 2.01-1.90 (m, 2H), 1.80-1.66 (m, 4H), 1.65-1.55 (m, 2H); APCI MS m/z 381 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10]C)=[O:9])[CH:3]=1.Cl.[NH2:13][C:14]1[CH:15]=[C:16]2[C:29](=[CH:30][CH:31]=1)[CH2:28][C:18]1([C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]1=[O:27])[CH2:17]2>CC(O)C>[O:27]=[C:19]1[NH:20][C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:26]2[C:18]21[CH2:17][C:16]1[C:29](=[CH:30][CH:31]=[C:14]([NH:13][C:2]3[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=[O:9])[CH:3]=3)[CH:15]=1)[CH2:28]2
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: COC(=O)c1cc(Br)ccn1
Agent: Cl
Solvent: CC(C)O
Product: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.17 g (0.79 mmol) methyl 4-bromo-pyridine-2-carboxylate and 17 μL (70 μmol) of a 4M aqueous hydrochloric acid solution were added to 0.20 g (0.78 mmol) 5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one in 5.0 mL of 2-propanol. The reaction mixture was refluxed for 2 h, then cooled to RT and evaporated down. The residue was taken up in THF and mixed with 0.50 mL (2.0 mmol) of a 4M aqueous NaOH solution and stirred overnight at RT. The reaction mixture was diluted with water, combined with 0.5 mL conc. HCl and the solvent was eliminated. The precipitated product was suction filtered and dried.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>CC(=O)CC.O>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:6][CH:7]=2)=[CH:24][CH:23]=1
Reactant: CCC(=O)c1ccc(O)cc1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCC(=O)c1ccc(OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Yield: 96.7 %

Procedure:
4′-Hydroxypropiophenone (50.0 g, 0.33 mol), potassium carbonate (69.0 g, 0.50 mol), and sodium iodide (25.0 g, 0.17 mol) were suspended in 2-butanone (500 mL), and with stirring at room temperature, 4-methoxybenzyl chloride (57.4 g, 0.37 mol) was added at room temperature. The reaction solution was stirred at 60° C. for 12 hours. The reaction solution was poured into water, extracted with ethyl acetate, the organic layer was washed with saturated saline, and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting pale yellow solid was washed with hexane to obtain the entitled compound (86.3 g, 96%) as a milky white solid.