Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1F.[NH2:13][C@H:14]([C:18]([O-:20])=[O:19])[CH:15]([CH3:17])[CH3:16].[K+].S1(CCCC1)(=O)=O.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[NH:13][CH:14]([CH:15]([CH3:17])[CH3:16])[C:18]([OH:20])=[O:19]
Reactant: CC(C)[C@H](N)C(=O)[O-]
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Temperature: 125 °C
Yield: 96 %

Procedure:
A mixture of 10 parts of 3-chloro-4-fluorobenzotrifluoride, 10 parts of potassium valinate and 50 parts of sulfolane was heated and maintained at about 125° C. for about 17 hours, with mixing. The mixture was then cooled to room temperature, diluted with water and acidified with hydrochloric acid to a pH of 1.0. The aqueous layer was extracted with diethyl ether. The ether layers were washed with water, then dried and concentrated by evaporation to yield 9.6 parts of 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid (96% purity); a yield of about 65% based on the 3-chloro-4-fluorobenzotrifluoride starting material.
Reaction SMILES: [Mg].BrCCBr.[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[CH:9][CH:8]=1.[O:15]=[C:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.[Cl-].[NH4+]>C(OCC)C>[Br:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][C:16]2([OH:15])[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:20][CH2:21]2)=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: BrCc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: BrCCBr
Product: CC(C)(C)OC(=O)N1CCC(O)(Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40.4 %

Procedure:
To a suspension of magnesium (2.9 g) in diethyl ether (50 mL) was added dropwise 1,2-dibromoethane (0.90 mL) at room temperature, and the reaction mixture was vigorously stirred at room temperature for 20 min. To the reaction mixture was added dropwise a solution of 4-bromobenzyl bromide (25 g) in diethyl ether (150 mL) over 30 min or more at 0° C., and then added dropwise a solution of tert-butyl 4-oxopiperidine-1-carboxylate (16 g) in diethyl ether (200 mL) over 30 min or more 0° C. The reaction mixture was allowed to warm to room temperature, and stirred at room temperature for 3 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution (200 mL), and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (12 g).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:13])[NH:4][C:5](=[O:12])[N:6]2[CH2:11][CH2:10][CH2:9][S:8][C:7]=12.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][Cl:25]>CN(C)C=O>[Cl:25][CH2:24][CH2:23][CH2:22][CH2:21][N:4]1[C:3](=[O:13])[C:2]([CH3:1])=[C:7]2[S:8][CH2:9][CH2:10][CH2:11][N:6]2[C:5]1=[O:12]
Reactant: ClCCCCBr
Reactant: Cc1c2n(c(=O)[nH]c1=O)CCCS2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c2n(c(=O)n(CCCCCl)c1=O)CCCS2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a suspension of 3.28 g (16.5 mmol) of 9-methyl-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione and 3.81 g (28.8 mmol) of potassium carbonate in 70 ml of N,N-dimethylformamide, 2.07 ml (36 mmol) of 1-bromo-4-chlorobutane was added at room temperature, followed by stirring at 60° C. for 2 hours and then at 100° C. for 3 hours. After cooling, the reaction mixture was concentrated to dryness. The residue was dissolved in dichloromethane-water; the organic layer was washed with water and dried. The oily substance obtained by distilling off the solvent was purified by column chromatography (eluent, n-hexane/ethyl acetate=5/1-2/1) to yield 3.24 g (67.9%, light yellow oily substance) of the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:25](I)[CH:26]([CH3:28])[CH3:27]>>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:13]2[CH2:25][CH:26]([CH3:28])[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2[nH]1
Reactant: CC(C)CI
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2n1CC(C)C

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 9 using ethyl 4-benzyloxy-1H-indole-2-carboxylate (10.0 g), sodium hydride (1.6 g) and isobutyl iodide (3.3 ml), the title compound (6.0 g) was obtained as a brown oil.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=O)=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2].Cl.CN(C)CCCN=C=NCC.Cl.[CH3:28][NH:29][O:30][CH3:31].CN(C)C=O>CN(C)C1C=CN=CC=1.C(Cl)Cl.O>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([N:29]([O:30][CH3:31])[CH3:28])=[O:14])=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2]
Reactant: CCc1n[nH]c2cc(C(=O)O)ccc12
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCc1n[nH]c2cc(C(=O)N(C)OC)ccc12
Yield: 34.3 %

Procedure:
3-ethyl-1H-indazole-6-carboxylic acid (3.9 g, 0.020 mol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (4.3 g, 0.022 mol) and 4-dimethylaminopyridine (3.11 g, 0.0254 mol), N,O-dimethylhydroxylamin hydrochloride (2.8 g, 0.028 mol) were dissolved in methylene chloride (200 mL) and N,N-dimethylformamide (20 mid) and the solution stirred at room temperature for one hour. The resulting mixture was poured in iced water. The aqueous layer was removed, and extracted with ethyl acetate (2×50 mL). The combined organics were washed with 1 N HCl, 2N NaOH, water, and brine, then dried. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel eluting with a gradient of 50% ethyl acetate in hexanes to 100% ethyl acetate over 30 minutes to give 1.6 g (33%) of 3-ethyl-N-methoxy-N-methyl-1H-indazole-6-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]=[C:40]=[O:41]>CO.CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH:30][C:40]([NH:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[O:32][CH3:31])=[O:41])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: COc1ccccc1N=C=O
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Solvent: CC#N
Solvent: CO
Product: COc1ccccc1NC(=O)Nc1nc2nc(NCCCN3CCN(C)CC3)ncc2cc1-c1c(Cl)cccc1Cl
Yield: 69.2 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (1.0 g) from Example 36 was reacted with 0.334 g of 2-methoxyphenyl isocyanate according to the general procedure of Example 37 to give 0.9232 g of 1-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido[2,3-d]pyrimidin-7-yl}-3-(2-methoxy-phenyl)-urea, ESMS (20/80 MeOH/CH3CN+0.1% AcOH): M+ +H=595; mp 152.5°-154° C.
Reaction SMILES: ClC1C=CC(B(O)O)=CC=1.BrC1N=CNC=1.Br[C:18]1[N:19]=[CH:20][N:21]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:22]=1.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([N:21]2[CH:22]=[C:18]([C:31]3[S:30][CH:34]=[CH:33][CH:32]=3)[N:19]=[CH:20]2)=[CH:24][CH:25]=1
Reactant: Clc1ccc(-n2cnc(Br)c2)cc1
Reactant: OB(O)c1cccs1
Agent: [Pd]
Agent: Brc1c[nH]cn1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: Clc1ccc(-n2cnc(-c3cccs3)c2)cc1
Temperature: 90 °C
Yield: 10 %

Procedure:
The procedure described above for Formula Ic-iii in Example 16 was followed, starting from 4-chloro-phenylboronic acid and 4-bromo-1H-imidazole, to prepare 4-bromo-1-(4-chlorophenyl)-1H-imidazole. 4-Bromo-1-(4-chlorophenyl)-1H-imidazole (150 mg, 0.0.583 mmol), thiophen-2-ylboronic acid (149 mg, 1.66 mmol), Pd2(dba)3 (27 mg, 0.029 mmol), 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos) (28 mg, 0.058 mmol) and Cs2CO3 (475 mg. 1.459 mmol) were then combined in dioxane (5 ml). The reaction mixture was heated under microwave at 90° C. for 16 hours. It was then filtered and washed with ethyl acetate, and the filtrate was concentrated. The crude material was column purified using 15-20% ethyl acetate/hexanes to yield the desired 1-(4-chlorophenyl)-4-(thiophen-2-yl)-1H-imidazole (16 mg, 0.061 mmol, yield 10%) as a reddish solid. The HPLC purity of the final product was 99.35%. LC-MS [M+H] 261 (C13H9ClN2S+H expected 261.02). The 1H-NMR spectra was in accordance with the chemical structure
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([CH3:42])([CH3:41])[CH2:11][N:12]1[C:17](=[O:18])[C:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:22][CH:21]=2)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]2[N:37]=[C:38]([CH3:40])[N:39]=[C:13]12)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][CH2:9][C:10]([CH3:41])([CH3:42])[CH2:11][N:12]1[C:17](=[O:18])[C:16]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:24][CH:25]=2)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]2[N:37]=[C:38]([CH3:40])[N:39]=[C:13]12
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)c2nc(C)nn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(C)(C)CO)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
A mixture of 4′-{[4-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.5 g), tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 4 mL) and tetrahydrofuran (30 mL) was stirred at room temperature for 3 hr. The reaction mixture was extracted with ethyl acetate and water, and the organic layer was washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.98 g, 79%).
Reaction SMILES: C([NH:4][C:5]1[C:6](=[O:16])[O:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])(=O)C.S(=O)(=O)(O)O.C([O-])(O)=O.[Na+].O>>[NH2:4][C:5]1[C:6](=[O:16])[O:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[F:15]
Reactant: CC(=O)Nc1cc2cccc(F)c2oc1=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Nc1cc2cccc(F)c2oc1=O
Temperature: 0 °C

Procedure:
A solution of 3-acetylamino-8-fluorocoumarin (3.00 g, 0.014 mole) in concentrated sulfuric acid (2.65 g, 0.027 mole) was heated at 75°-80° C. for 1 hour. The cooled solution was poured onto an ice-water mixture and it was alkalized with a saturated NaHCO3 water solution up to pH=6 and subsequently left to precipitate at +4° C. The obtained 3-amino-8-fluorocoumarin was recrystallized from 50% ethanol (1.63 g, 67%). M.p.: 173°-174° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[CH2:5][CH2:4]1)[CH3:2].[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[C:24]1[C:33]2[N:32]=[CH:31][CH:30]=[N:29][C:28]=2[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.CC1C=CC=C(C)C=1B(O)O>>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:10]=[C:11]([NH:12][C:34]([C:27]3[C:28]4[N:29]=[CH:30][CH:31]=[N:32][C:33]=4[C:24]([C:18]4[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=4[CH3:16])=[CH:25][CH:26]=3)=[O:35])[CH:13]=[CH:14][CH:15]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2cccc(N)c2)CC1
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)c2nccnc12
Agent: Cc1cccc(C)c1B(O)O
Product: CCN1CCN(c2cccc(NC(=O)c3ccc(-c4c(C)cccc4C)c4nccnc34)c2)CC1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 3-(4-ethylpiperazin-1-yl)-aniline (Step 2.1) and 8-(2,6-dimethyl-phenyl)-quinoxaline-5-carboxylic acid. The carboxylic acid was synthesized as described in Steps 1.2-1.7 but using 2,6-dimethylphenylboronic acid and Pd(PPh3)-4 in Step 1.4. Title compound: ESI-MS: 466.2 [M+H]+; tR=3.74 min (System 3).
Reaction SMILES: C([O:4][C@H:5]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:32])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:23])[CH2:16][CH2:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH2:6]1)(=O)C.[OH-].[K+].O>CO.C1C=CC=CC=1>[OH:4][C@H:5]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:32])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:23])[CH2:16][CH2:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH2:6]1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)C(C)C)[C@@]4(C)CC[C@@H]32)C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: c1ccccc1
Product: CC(C)C(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 90 %

Procedure:
Specifically, the crude 3β-acetoxy-24-oxocholest-5-ene was dissolved in 100 ml of a mixture of methanol and benzene (1:1). To the solution was added dropwise a 10% methanol solution of potassium hydroxide at room temperature with stirring. After the addition, the mixture was stirred at 70° C. for 4 hours. After the reaction, 100 mg of water was added to separate the reaction mixture into layers. The resulting aqueous layer was extracted twice with benzene. The benzene extracts were combined with the organic layer. The mixture was washed successively with dilute hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to form 3.6 g (yield: 90% based on 3β-acetoxychol-5-enic acid) of 3β-hydroxy-24-oxocholest-5-ene as a white solid. The properties of the product were as follows:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C@H:8]([CH2:10][NH:11][C:12]([CH3:24])([CH3:23])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[OH:9])=[CH:4][CH:3]=1.C(OC(=O)C)(=[O:27])C>N1C=CC=CC=1>[NH2:1][C:2]1[N+:7]([O-:27])=[CH:6][C:5]([C@H:8]([CH2:10][NH:11][C:12]([CH3:24])([CH3:23])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[OH:9])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(Cc1c[nH]c2ccccc12)NC[C@H](O)c1ccc(N)nc1
Solvent: c1ccncc1
Product: CC(C)(Cc1c[nH]c2ccccc12)NC[C@H](O)c1ccc(N)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.5 g of (R)-6-Amino-α-[[(1,1-dimethyl-2-(1H-indol-3-yl)ethyl)amino]methyl]-3-pyridinemethanol in 20 ml of pyridine under nitrogen, acetic anhydride (10 ml) is added and the reaction mixture stirred at ambient temperature overnight. The mixture is then concentrated under reduced pressure. The crude acetylated product is treated with 0.9 g of m-chloroperbenzoic acid in 20 ml of CH2Cl2 for 4 hours at room temperature. The reaction mixture is concentrated once again and redissolved in 10 ml of methanol and treated with excess methanolic KOH solution at room temperature for 6 hours. The mixture is partially concentrated and then diluted with water and extracted repeatedly with CH2Cl2. The combined extracts is backwashed with saturated sodium chloride solution and dried with anhydrous magnesium sulfate. The solution is concentrated and the residue chromatographed on silica gel to give the (R)-6-Amino-α-[[(1,1-dimethyl-2-(1H-indol-3-yl)ethyl)amino]methyl]-3-pyridinemethanol-1-oxide.
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12](#[N:14])[CH3:13].[Cl:15][C:16]1[CH:17]=[C:18]([C:23](=[O:27])[CH2:24][O:25][CH3:26])[CH:19]=[CH:20][C:21]=1[Cl:22]>C1COCC1>[Cl:15][C:16]1[CH:17]=[C:18]([C:23]([OH:27])([CH2:24][O:25][CH3:26])[CH2:13][C:12]#[N:14])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: COCC(=O)c1ccc(Cl)c(Cl)c1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCC(O)(CC#N)c1ccc(Cl)c(Cl)c1
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
To a solution of 1.6 M n-butyllithium/hexane solution (20 ml) in THF (50 mL) was added dropwise a solution of acetonitrile (1.23 g) in THF (5 mL) at −78° C., and the mixture was stirred for 15 min, and at −40° C. for 15 min. A solution of 1-(3,4-dichlorophenyl)-2-methoxyethanone (5.00 g) in THF (30 mL) was added dropwise at −78° C., and the mixture was gradually warmed with stirring to room temperature, and stirred for 20 min. The reaction mixture was quenched with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (0%-100%)) to give the title compound (5.63 g).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11](Br)=[N:10][N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[OH:21])[C:8]2=[O:22])=[CH:4][CH:3]=1.[CH3:25][O-:26].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([O:26][CH3:25])=[N:10][N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[OH:21])[C:8]2=[O:22])=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: O=c1c(Br)nn(-c2ccccc2O)c(=O)n1Cc1ccc(Cl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nn(-c2ccccc2O)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.1 %

Procedure:
According to Scheme 9 Step 2: To a solution of 4-(4-chlorobenzyl)-6-bromo-2-(2-hydroxyphenyl)-1,2,4-triazine-3,5(2H,4H)-dione (0.130 g, 0.32 mmol) in DMF (3 ml) was added, dropwise, at 0° C. a solution 2M of sodium methoxide (0.32 mmol, 0.160 ml). The mixture was stirred 1 h at 0° C. 1 more equivalent of a solution 2M of sodium methoxide was necessary to complete the conversion. Then the reaction mixture was quenched with water. The aqueous layers was neutralised till pH=7 and extracted with ethyl acetate (×3). The organic layer were combined and successively washed with water then, brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography, 10 g prepacked column, DCM/MeOH 98/2 to afford (30 mg, Yield=26%) 30 mg (Yield=26%) of 4-(4-chlorobenzyl)-2-(2-hydroxyphenyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione 4.143 were recovered as a white solid.
Reaction SMILES: [CH3:1][C:2]([S:22]([CH3:25])(=[O:24])=[O:23])([CH2:6][CH2:7][N:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:10]([CH3:20])[C:9]1=[O:21])[C:3](O)=[O:4].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[O:56]1[CH2:61][CH2:60][CH2:59][CH2:58][CH:57]1[O:62][NH2:63]>C(Cl)Cl>[CH3:1][C:2]([S:22]([CH3:25])(=[O:23])=[O:24])([CH2:6][CH2:7][N:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:10]([CH3:20])[C:9]1=[O:21])[C:3]([NH:63][O:62][CH:57]1[CH2:58][CH2:59][CH2:60][CH2:61][O:56]1)=[O:4]
Reactant: NOC1CCCCO1
Reactant: Cc1c(-c2ccccc2)ccn(CCC(C)(C(=O)O)S(C)(=O)=O)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)ccn(CCC(C)(C(=O)NOC2CCCCO2)S(C)(=O)=O)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-methyl-4-(3-methyl-2-oxo-4-phenylpyridin-1(2H)-yl)-2-(methylsulfonyl)butanoic acid (109.4 mg, 0.301 mmol) in methylene chloride (3 mL) at ambient temperature was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80.7 mg, 0.421 mmol), 1-hydroxy benzotriazole monohydrate (83 mg, 0.542 mmol), triethyl amine (75 uL, 0.542 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (53 mg, 0.452 mmol). The resulting mixture was stirred at ambient temperature overnight. The mixture was diluted with methylene chloride and washed successively with sat. aqueous sodium bicarbonate, aqueous HCl (1 N) and water. The organic extracts were dried over magnesium sulfate, filtered and concentrated to a crude residue. The crude residue was purified via silica gel chromatography eluting with methylene chloride and methanol. The fractions containing the desired product were combined and concentrated to afford 2-methyl-4-(3-methyl-2-oxo-4-phenylpyridin-1(2H)-yl)-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide as a solid. 137.3 mg
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:29][CH:26]2[CH2:28][CH2:27]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: NC1CC1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNC2CC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 5, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and cyclopropylamine.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH2:5]([O:7][C:8](=[O:25])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:6].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:5]([O:7][C:8](=[O:25])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:3][CH:2]=[CH2:1])=[CH:13][C:12]=1[O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:6]
Reactant: CCOC(=O)COc1ccc(O)cc1OCC(=O)OCC
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(OCC(=O)OCC)c(OCC(=O)OCC)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Allyl bromide (25.53 ml; 302 mmol) was added slowly to a mixture of the compound of example 65b (75 g; 251.4 mmol), K2CO3 (52.04 g; 377 mmol) and KI (˜1 g) in DMF (150 ml) under vigorous stirring for 15 min at room temperature. The reaction mixture was stirred overnight (˜16 h), treated with water (1 lit.), and extracted with EtOAc. The EtOAc layer was washed with water, brine, dried (Na2SO4), concentrated and purified using flash chromatography (silica gel, 3% CH3CN in chloroform) to obtain the title compound as an oil. Yield, 76 g (89.7%); MS (EI): 337 (M+), 136.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=O)[C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][C:22]#[N:23]>>[S:1]1[CH:5]=[C:4](/[CH:6]=[C:21](/[C:13]2[S:12][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=2)\[C:22]#[N:23])[C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: O=Cc1csc2ccccc12
Reactant: N#CCc1nc2ccccc2s1
Product: N#C/C(=C\c1csc2ccccc12)c1nc2ccccc2s1
Yield: 69.8 %

Procedure:
Benzo[b]thiophene-3-carboxaldehyde (81 mg) was condensed with 2-benzothiazoleacetonitrile (87 mg) through Method B (production step 3), to thereby yield the target product (yield: 111 mg, 69%).