Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:20]([CH2:22]N)[OH:21]>C(Cl)Cl.O.O.C([O-])(=O)C.[Cd+2].C([O-])(=O)C>[CH2:2]([C:1]1[O:21][CH2:20][CH2:22][N:19]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC#N
Reactant: NCCO
Agent: CC(=O)[O-]
Agent: [Cd+2]
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCCCCCCC1=NCCO1
Temperature: 115 °C
Reaction time: 88 h
Yield: 99.6 %

Procedure:
A stirred mixture of about 50.0 grams (0.19 mole) stearonitrile, about 11.7 grams (0.19 mole) ethanolamine, and about 1.2 grams (0.0048 mole) cadmium acetate dihydrate is heated at about 115 degrees C. to about 125 degrees C. under nitrogen for about 88 hours. The mixture is cooled and then dissolved in about 450 ml of methylene chloride and dried over magnesium sulfate. The mixture is then filtered. Residual solvent is removed from the filtrate by vacuum. About 58.6 grams of light yellow solid is obtained. The solid is recrystallized from about 300 ml of hexane. The recrystallized material is collected, washed, and dried, yielding about 4.7 grams with a melting point of about 77 degrees C. to about 90 degrees C. The resulting filtrate, rinses, material removed in the initial filtration step and about 200 ml additional hexane are combined, heated, and filtered using gravity. The product is stored in a refrigerator for several days. The formed crystals are collected, rinsed, and dried at 50 degrees C. under vacuum, yielding about 36.3 grams of white solid with a melting point of about 50 degrees C. to about 54 degrees C.
Reaction SMILES: [O:1]1CC[O:3][CH:2]1[CH2:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([CH3:17])[CH:11]=1)[OH:9].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:8](=[O:9])[CH2:7][CH2:6][C:2]([OH:3])=[O:1])=[CH:11][C:12]=1[CH3:17]
Reactant: Cc1cc(C(O)CCC2OCCO2)ccc1F
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(C(=O)CCC(=O)O)ccc1F
Reaction time: 0.5 h

Procedure:
To a solution of 3-(1,3-dioxolan-2-yl)-1-(4-fluoro-3-methylphenyl)propan-1-ol (1.6 g, 6.7 mmol) in 15 ml acetone was added Jones reagent (1.5 mL) dropwise at room temperature. The mixture was stirred for 30 min. and then 50 mL of water was added before extracting with DCM (3×40 mL). The combined DCM layers were washed with water (2×20 mL) and dried over Na2SO4. The solvent was evaporated under reduce pressure and the crude product used for the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([CH2:23][CH2:24][CH3:25])=[CH:16][C:17]([C:20]([OH:22])=[O:21])=[N:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[C:32](O)=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:28]=1[F:37].C1(N=C=NC2CCCCC2)CCCCC1.O>C(OCC)(=O)C>[F:26][C:27]1[C:28]([F:37])=[C:29]([F:36])[C:30]([F:35])=[C:31]([F:34])[C:32]=1[O:21][C:20]([C:17]1[N:18]=[CH:19][C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]2)=[C:15]([CH2:23][CH2:24][CH3:25])[CH:16]=1)=[O:22]
Reactant: CCCc1cc(C(=O)O)ncc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1cc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)ncc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 119.4 %

Procedure:
5-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-4-propyl picolinic acid (134 mg, 0.307 mmol) was dissolved in ethyl acetate (6.2 mL). At room temperature, pentafluorophenol (68 mg, 0.368 mmol) and N,N′-dicyclohexylcarbodiimide (76 mg, 0.368 mmol) were added sequentially, and the mixture was stirred at room temperature overnight. The reaction solution was added water under ice-cold conditions, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (189 mg (yield >99%)) was obtained as a yellow brown crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=1.Cl.[CH:32]12[CH2:37][CH:36]1[CH2:35][NH:34][CH2:33]2>C1COCC1.C(N(CC)CC)C>[CH:32]12[CH2:37][CH:36]1[CH2:35][N:34]([C:9]1[N:8]=[C:7]([NH:6][CH2:5][C:4]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:13]([NH:15][CH2:16][C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[O:14])=[CH:11][N:10]=1)[CH2:33]2
Reactant: C1NCC2CC12
Reactant: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)NCc2ncccn2)cc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCc2ncccn2)cc1Cl
Yield: 39 %

Procedure:
In absolute anhydrous THF (10 mL) was dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylsulphinyl)-N-(pyrimidin-2-ylmethyl) pyrimidine-5-formamide (100 mg, 0.22 mmol). Several drops of triethylamine were added, then 3-azabicyclo[3.1.0]hexan hydrochloride salt (42 mg, 0.35 mmol) was added. The reaction mixture was heated to reflux overnight. The solvent was removed by rotary evaporation, and water was added, followed by extraction with DCM. The organic phase was dried over sodium sulfate and purified by silica gel column chromatography (DCM/methanol=20/1 to 10/1). 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide as a white solid was obtained (40 mg, 39% yield).
Reaction SMILES: FC1C=C(F)C=C(F)C=1C(N[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[O:14])[N:8]=1)=O.C(N(CC)C(C1CCN(C)CC1)=O)C.[Br:42]C1C=CC=C(Br)N=1.Br>>[Br:42][C:7]1[N:8]=[C:9]([C:13]([CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[O:14])[CH:10]=[CH:11][CH:12]=1
Reactant: CN1CCC(C(=O)c2cccc(NC(=O)c3c(F)cc(F)cc3F)n2)CC1
Reactant: Brc1cccc(Br)n1
Agent: Br
Agent: CCN(CC)C(=O)C1CCN(C)CC1
Product: CN1CCC(C(=O)c2cccc(Br)n2)CC1

Procedure:
The present invention is directed to a process for preparing 2,4,6-trifluoro-N-[6-(1-methyl-piperidine-4-carbonyl)-pyridin-2-yl]-benzamide or a pharmaceutically acceptable salt thereof e.g., the hemi-succinate salt comprising the step of: reacting N,N-diethyl-1-methylpiperidine-4-carboxamide (III) with a solution of 2,6-dibromopyridine and Grignard reagent followed by the addition of hydrobromic acid to yield (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone (IV) hydrobromide.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:16][CH2:17]CC1CCC(=O)CC1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(P(N(C)C)(N(C)C)=[O:30])C.C(C(OC)=O)#N>C1COCC1>[CH3:17][O:16][C:9]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:30]
Reactant: O=C1CCC(CCOCc2ccccc2)CC1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: CC(C)[N-]C(C)C
Agent: COC(=O)C#N
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1CCCCC1

Procedure:
A solution of LDA (33 ml, 1.5 M in Et2O) in THF (50 mL) at −78 EC was treated with 4-(2-benzyloxy-ethyl)-cyclohexanone (9.5 g, 40.2 mmol). The mixture was warmed to 0 EC over 30 min. before re-cooling to −78 EC and adding HMPA (7 mL). Methyl cyanoformate (CNCO2Me, 4.1 mL, 85 mmol) was added and the mixture was stirred for 15 m before aqueous quench and work-up. The product was purified by chromatography on SiO2 with 10% EtOAc:Hx. 5-(2-Benzyloxy-ethyl)-2-oxo-) cyclohexanecarboxylic acid methyl ester was isolated, 5.8 g (49%).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Sn](CCCC)(CCCC)CCCC)[N:18]=1>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([CH3:16])[N:18]=2)[C:11]=1[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(C)n1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1cccc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)n1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.2 g, 0.806 mmol) in toluene (1.60 mL) was added 2-methyl-6-(tributylstannyl)pyridine (0.34 g, 0.89 mmol), and palladium tetrakistriphenylphosphine (0.093 g, 0.081 mmol). The reaction was stirred at 100° C. and stirring continued for 18 h. The reaction mixture was cooled to rt and concentrated in vacuo. The crude material was purified by column chromatography on silica gel, eluting with (0-50% EtOAc in hexanes) to provide 4-chloro-5,7-difluoro-3-methyl-2-(6-methylpyridin-2-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=305.0 (M+1).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][N:14]([CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH:15]=O.[C:24](#[N:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[CH3:13][N:14]1[C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:31]=[CH:15]1
Reactant: CN(C=O)Cc1ccncc1
Reactant: N#Cc1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cn1cnc(-c2ccccc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of di-iso-propyl-amine (11.2 mL, 79.9 mmol ) in 150 mL of THF at −78° C. was added n-butyllithium (31.9 mL of 2.5 M solution, 79.9 mmol). To the resulting mixture was added a solution of N-methyl-N-[4-picolyl]formamide (10 g, 66.5 mmol) in THF. The resulting orange-brown solution was stirred at −78° C. for 20 min, at which time benzonitrile (13.6 mL, 133 mmol) was added. The resulting dark brown mixture was allowed to warm to rt and stirred for 1 h, heated to reflux for 4 h, and then cooled to rt and partitioned between CH2Cl2 and H2O. The organic extract was washed with aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 50:1 CH2Cl2/MeOH. The title compound was obtained as a light tan solid (5.83 g, 37%): mp 158-159° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C@H:8]2[CH2:12][CH2:11][C@@:10]3([CH2:16][CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[NH:9]2)[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CC#N.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:21]=1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C@H:8]2[CH2:12][CH2:11][C@@:10]3([CH2:16][CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[NH:9]2)[CH:3]=1
Reactant: OB(O)c1cc(O)ccc1F
Reactant: CN1CC[C@@]2(CC[C@H](c3cc(Br)ccn3)N2)C1=O
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CN1CC[C@@]2(CC[C@H](c3cc(-c4cc(O)ccc4F)ccn3)N2)C1=O
Temperature: 100 °C
Yield: 77.9 %

Procedure:
To a solution of (2R,5S)-2-(4-bromo-2-pyridyl)-7-methyl-1,7-diazaspiro[4.4]nonan-6-one (which may be prepared as described in Description 4) (140 mg, 0.4513 mmol) in MeCN (1.5 mL) and water (0.3000 mL) in a Smith microwave vessel was added (2-fluoro-5-hydroxy-phenyl)boronic acid (0.0774 g, 0.4965 mmol), bis(triphenylphosphine)palladium (II) dichloride (0.0095 g, 0.0135 mmol) and sodium carbonate (0.0957 g, 0.9027 mmol). The reaction vessel was sealed and purged with nitrogen. The reaction mixture was heated by microwave at 100° C. for 40 min. The reaction mixture was treated with water and was extracted with DCM twice and the organic layers were collected by passing down a PhaseSep cartridge. Evaporation of solvents gave an amber oil, It was further purified by silica gel chromatography (11 g KPNH silica cartridge) eluting with ethyl acetate in iso-hexane (20-100%) followed by methanol in ethyl acetate (0-18%) to give the desired product (2R,5S)-2-[4-(2-fluoro-5-hydroxy-phenyl)-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]nonan-6-one (D134) (0.1200 g, 0.3515 mmol, 77.9% yield) as cream solid;
Reaction SMILES: [H-].[Na+].CCCC(C)C.[Br:9][C:10]1[CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:13][CH:14]=1.Br[CH2:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[N+:29]([O-:31])=[O:30]>CN(C)C(=O)C>[Br:9][C:10]1[CH:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]([CH2:21][C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[N+:29]([O-:31])=[O:30])[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CBr
Reactant: CCOC(=O)c1cc(Br)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCCC(C)C
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc(Br)cn1Cc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Wash 60% mineral oil suspended sodium hydride (1.2 equiv; 1.1 g, 27.52 mmoles) with a small amount of iso-hexane (×2). Suspend in N,N-dimethylacetamide (15 mL) and chill in an ice-bath. Add ethyl 4-bromo-1H-pyrrole-2-carboxylate (5.0 g, 22.93 mmoles) portionwise over 15 minutes allowing gas evolution to subside between additions. Stir at room temperature for 15 minutes to give a brown solution. Add 2-(bromomethyl)-4-chloro-1-nitro-benzene (1.15 equiv; 6.61 g, 26.37 mmoles) in portions over 15 minutes and stir the resulting purple solution at room temperature for 2.5 h. Cool in an ice-bath and quench with water (10 mL). Partition between 1M hydrochloric acid (100 mL) and EtOAc (300 mL). Wash the organic layer with water (2×100 mL) then brine. Dry over Na2SO4 and decolorize with activated charcoal. Filter through celite and evaporate to give ethyl 4-bromo-1-(5-chloro-2-nitrobenzyl)-1H-pyrrole-2-carboxylate as a an orange oil (9.1 g, quantitative). 1H-NMR (CDCl3) δ: 8.12 (1H, d), 7.40 (1H, dd), 7.07 (1H, d), 6.92 (1H, d), 6.53 (1H, d), 5.87 (2H, s), 4.17 (2H, q), 1.25 (3H, t).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([N:7]1[C:15]([NH2:16])=[C:10]2[CH2:11][NH:12][CH2:13][CH2:14][C:9]2=[N:8]1)=[O:6])[CH3:3].C(N(CC)C(C)C)(C)C.[F:26][C:27]1[CH:28]=[C:29]([S:34](Cl)(=[O:36])=[O:35])[CH:30]=[C:31]([F:33])[CH:32]=1>ClCCl>[CH2:2]([O:4][C:5]([N:7]1[C:15]([NH2:16])=[C:10]2[CH2:11][N:12]([S:34]([C:29]3[CH:28]=[C:27]([F:26])[CH:32]=[C:31]([F:33])[CH:30]=3)(=[O:36])=[O:35])[CH2:13][CH2:14][C:9]2=[N:8]1)=[O:6])[CH3:3]
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: CCOC(=O)n1nc2c(c1N)CNCC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)n1nc2c(c1N)CN(S(=O)(=O)c1cc(F)cc(F)c1)CC2
Reaction time: 1 h
Yield: 92.1 %

Procedure:
To a suspension of 3-amino-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-2-carboxylic acid ethyl ester hydrochloride (36.2 g, 127.8 mmol) in anhydrous dichloromethane (1 L), at 0°-5° C., N,N-diisopropylethylamine (111.3 mL, 639 mmol) was added. To the resulting solution, 3,5-difluorobenzenesulfonyl chloride (27.17 g, 127.8 mmol) was added portionwise. The mixture was stirred at 0°-5° C. for 1 hour then at room temperature for 3 hours. The organic phase was washed with NaHCO3 saturated solution, water and brine, dried over sodium sulfate filtered and evaporated. The crude, was triturated with diethylether (500 mL) to obtain the title compound as yellowish solid (45.48 g, 92%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:17]O.S(=O)(=O)(O)O>O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([O:14][CH3:17])=[O:13])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of 4-(4-hydroxyphenyl)benzoic acid (5 g), methanol (120 mL), and concentrated sulfuric acid (0.5 mL) was heated at 70° C. for 15 hours. The solution was cooled to ambient temperature, water (120 mL) was added, and the precipitated white solid was filtered. The filtered solid was washed with water and methanol and dried to yield 5.2 g (97%) of the methyl 4-(4-hydroxyphenyl)benzoate.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4S[C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:29][N:30]=4)=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5].NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=[O:55])=CC=2)=CC=1.C1(C2OC(C(OCC)=O)=NC=2)C=CC=CC=1>>[CH3:1][CH:2]([CH3:38])[C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[O:55][C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:29][N:30]=4)=[O:25])=[CH:19][CH:18]=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)s4)cc3)cc2C1=O
Agent: CCOC(=O)c1ncc(-c2ccccc2)o1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)o4)cc3)cc2C1=O

Procedure:
The compound of example 613 was prepared analogous to the compound of example 611 by reaction of compound of example 6 with ethyl 5-phenyloxazole-2-carboxylate.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[C:17]1([CH3:28])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1/[CH:23]=[CH:24]/[C:25](O)=[O:26]>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH:16][C:25](=[O:26])/[CH:24]=[CH:23]/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH3:28])=[N:12]1
Reactant: Cc1ccccc1/C=C/C(=O)O
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Product: CC(=O)CCCCn1ccc(NC(=O)/C=C/c2ccccc2C)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and (E)-3-o-tolyl-acrylic acid.
Reaction SMILES: C(OC(N(C)[C@H](C(O)=O)C)=O)(C)(C)C.C(O[C:20](=O)[N:21]([C@H:23]([C:25](=[O:45])[NH:26][CH2:27][CH2:28][CH2:29][CH:30]([C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[CH3:24])C)(C)(C)C>CO.C(Cl)Cl>[F:37][C:34]1[CH:33]=[CH:32][C:31]([CH:30]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[CH2:29][CH2:28][CH2:27][NH:26][C:25](=[O:45])[C@H:23]([NH:21][CH3:20])[CH3:24])=[CH:36][CH:35]=1
Reactant: C[C@@H](C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1)N(C)C(=O)OC(C)(C)C
Agent: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Solvent: CO
Solvent: ClCCl
Product: CN[C@H](C)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
(R)-N-[4,4-Bis-(4-fluoro-phenyl)-butyl]-2-methylamino-propionamide was prepared in accordance with the methods of Example 12, except that: N-tert-butoxycarbonyl-N-methyl-L-alanine was used instead of N-tert-butoxycarbonyl-N-methyl-L-leucine in Step A, and (S){1-[4,4-Bis-(4-fluoro-phenyl)-butylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester was used instead of (S){1-[4,4-bis-(4-fluoro-phenyl)-butylcarbamoyl]-3-methyl-butyl}-methyl-carbamic acid tert-butyl ester in Step B. MS: 347 (M+1 for C20H24N2F2O1); an oil; Rf 0.3 (5% MeOH/CH2Cl2).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2].[C:19]1([CH3:26])[C:24]([OH:25])=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:25][C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:26])=[N:8][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: Cc1ccccc1O
Reactant: CCOC(=O)c1cnc(-c2ccncc2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cnc(-c2ccncc2)nc1Oc1ccccc1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 7.9 %

Procedure:
A suspension of 0.6 g (2 28 mmol) 4-chloro-2-pyridin-4-yl-pyrimidine-5-carboxylic acid ethyl ester, 0.27 g (2 50 mmol) o-cresol and 2.97 g (9.10 mmol) Cs2CO3 in 15 ml acetonitrile was stirred for 17 h at RT. The suspension was poured into 150 ml H2O and extracted three times with 90 ml ethyl acetate. The combined organic phases were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, ethyl acetate/MeOH 100:1) to give 0.74 g (97%) 2-pyridin-4-yl-4-o-tolyloxy-pyrimidine-5-carboxylic acid ethyl ester as a yellow solid, MS (EI): 335.1 (M+).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:18][CH2:17][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][C:9]=3[C:5]=2[CH2:4]1.[NH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([NH:20][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[O:7][C:6]4[CH2:17][CH2:18][CH:3]([N:2]([CH3:1])[CH3:19])[CH2:4][C:5]=4[C:9]=3[CH:10]=2)=[O:16])[CH:22]=1
Reactant: Nc1cccnc1
Reactant: CN(C)C1CCc2oc3ccc(C(=O)O)cc3c2C1
Product: CN(C)C1CCc2oc3ccc(C(=O)Nc4cccnc4)cc3c2C1
Yield: 43.4 %

Procedure:
Beginning with 0.17 gm (0.57 mMol) N,N-dimethyl-8- carboxy-1,2,3,4-tetrahydro-2-dibenzofuranamine and 0.06 gm (0.63 mMol) 3-aminopyridine, 0.083 gm (44%) of the title compound were recovered as an off-white foam by the procedure described in Example 25.
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[CH:17]1[C:22]([CH:23]=O)=[CH:21][C:20]2[O:25][CH2:26][O:27][C:19]=2[CH:18]=1>>[CH:1]([N:4]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:23]([C:22]2[CH:17]=[CH:18][C:19]3[O:27][CH2:26][O:25][C:20]=3[CH:21]=2)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N(C(N)=O)c1ccc2c(c1)OCO2
Reactant: O=Cc1ccc2c(c1)OCO2
Product: CC(C)N1C(=O)NC(c2ccc3c(c2)OCO3)c2cc3c(cc21)OCO3
Yield: 41 %

Procedure:
The title compound was synthesized from N-isopropyl-N-[3.4-(methylenedioxy)phenyl]urea and piperonal by the procedure described in example 10 in 41% yield, mp: 87-89° C. 1H NMR (CDCl3,): 6.77 (s, 3H), 6.68 (s, 1H), 6.28 (s, 1H), 5.96 (s, 2H), 5.92-5.90 (m, 2H), 5.22 (d, J=1.8, 1H), 4.98 (br s, 1H), 4.44 (m, 2H), 1.58-1.54 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:3]=1[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[C:15](OC(=O)C)(=[O:17])[CH3:16].C(=S)=S.[Cl-].[Al+3].[Cl-].[Cl-]>O>[C:15]([C:12]1[CH:11]=[C:10]([CH3:14])[C:3]([O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])=[C:2]([CH3:1])[CH:13]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)COc1c(C)cccc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: S=C=S
Product: COC(=O)COc1c(C)cc(C(C)=O)cc1C

Procedure:
7 Grams of methyl 2,6-dimethylphenoxyacetate, 3.4 ml of acetic anhydride and 100 ml of carbon disulfide were mixed at 0° C., and to the mixture was added 17.9 g of aluminum chloride, and the resulting mixture was heated until gas was evolved. After the gas-evolution was ceased, the reaction mixture was refluxed for 30 minutes under heating. Then water was added to the solution. The resulting mixture was extracted with di-isopropyl ether, washed with water, dried over anhydrous magnesium sulfate. The oily solution was concentrated to obtain an oily substance. The oily substance was chromatographed on silica gel to obtain 6.1 g of methyl 4-acetyl-2,6-dimethylphenoxyacetate, nD21.6 1.5165.
Reaction SMILES: [CH2:1]([N:5]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]([C:8]1[C:12](Cl)=[C:11]([CH3:14])[NH:10][N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[O:25][CH2:26]CC1NN=C(C(OCC)=O)C=1>>[CH2:1]([N:5]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]([C:8]1[CH:12]=[C:11]([CH2:14][CH2:26][O:25][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][O:19]2)[NH:10][N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)c1cc(CCOC2CCCCO2)[nH]n1
Reactant: CCCCN(CCCC)C(=O)c1n[nH]c(C)c1Cl
Product: CCCCN(CCCC)C(=O)c1cc(CCOC2CCCCO2)[nH]n1
Yield: 83 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1B, ethyl 5-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazole-3-carboxylate (2.15 g, 8.01 mmol) was converted to the title compound (2.35 g, 83%). MS(ESI+) m/z 352.4 (M+H)+.