Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8](=[O:27])[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[C:10]([CH2:17][CH3:18])[NH:11]2.C(=O)([O-])[O-].[K+].[K+].Cl[C:36](OC(=O)C)([F:38])[F:37]>O>[CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:27][CH:36]([F:38])[F:37])=[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(F)cc1
Reactant: CC(=O)OC(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(F)cc1
Temperature: 70 °C
Reaction time: 96 h

Procedure:
A mixture of [2-ethyl-8-fluoro-3-(4-fluorobenzyl)-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (1.5 g), N/N-dimethylformamide (30 mL), potassium carbonate (5.2 g) and acetic acid chlorodifluoromethyl ester (5.5 mL) was stirred at 70° C. for 4 days. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (3:1 by volume) to afford title compounds, 0.50 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[N:17]=[CH:16][C:15](=[O:19])[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[N:31]=[C:32]=[O:33]>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[NH:31][C:32]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[N:17]=[CH:16][C:15](=[O:19])[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1)=[O:33]
Reactant: Nc1ccc(Sc2ccnc3[nH]c(=O)cnc23)cc1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Product: O=C(Nc1ccc(Sc2ccnc3[nH]c(=O)cnc23)cc1)Nc1cc(C(F)(F)F)ccc1F

Procedure:
Method F2 was used with 8-(4-aminophenylthio)pyrido[2,3-b]pyrazin-3(4H)-one (36.7 mg, 136 μmol) and 2-fluoro-5-trifluoromethyl-phenylisocyanate (22.5 μL, 156 136 μmol) to afford the title compound. Yield: 53 mg (82%).
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[S:20]([CH3:23])(=[O:22])=[O:21])[C:9]2[C:8](=[O:24])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:42][CH2:43][O:44][C:45](=[O:47])[CH3:46]>CN(C=O)C>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([CH:10]2[C:9]3[C:8](=[O:24])[CH2:7][CH2:6][CH2:5][C:4]=3[N:3]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=3)[C:2](=[O:1])[N:11]2[CH2:42][CH2:43][O:44][C:45](=[O:47])[CH3:46])=[C:13]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:14]=1)#[N:17]
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)OCCN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1S(C)(=O)=O
Temperature: 60 °C
Reaction time: 72 h

Procedure:
To a solution of 4-[2,5-dioxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4,5,6,7,8-octahydro-quinazolin-4-yl]-3-methanesulfonyl-benzonitrile (INTERMEDIATE 18, 200 mg, 0.41 mmol) in DMF (4 mL) is added cesium carbonate (266 mg, 0.82 mmol) and 2-bromoethylacetate (91.0 μL, 0.82 mmol) and the mixture is stirred at 60° C. for 3 days. The mixture is purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 60.0 mg; ESI mass spectrum [M+H]+=576; Retention time HPLC: 1.07 min (Z018_S04).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH2:10][CH2:11][C:12](=[O:14])[CH3:13].S([O-])([O-])(=O)=O.[Na+].[Na+].[NH2:22][CH2:23][CH2:24][CH2:25]O>CO>[CH3:13][C:12]1([CH2:11][CH2:10][C:3]2[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH2:7][C:2]=2[CH3:1])[NH:22][CH2:23][CH2:24][CH2:25][O:14]1
Reactant: CC(=O)CCC1=C(C)CCCC1(C)C
Reactant: NCCCO
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC1=C(CCC2(C)NCCCO2)C(C)(C)CCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 0° C. stirred solution of 4-(2,6,6-trimethyl-cyclohex-1-enyl)-butan-2-one (25.2 g, 0.13 mol) and sodium sulfate (20 g) in 80 mL of methanol is added 3-amino-1-propanol (10 g, 0.13 mol). The reaction is allowed to warm to room temperature. After stirring for 24 h the mixture is cooled to 0° C. and the solids are removed via vacuum filtration through Celite. Evaporation of the solvent gives a clear yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=O)=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[N+:22]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)([O-:24])=[O:23]>CO.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[N:15][C:14]([O:17][CH2:18][C:19](=[O:21])[NH:29][C:28]3[CH:30]=[CH:31][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=3)=[N:13][CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: CO
Solvent: ClCCl
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)Nc1ccc([N+](=O)[O-])cc1
Yield: 23 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 4-nitroaniline (25 mg, 0.18 mmol) as the coupling partner. Chromatography (5% methanol/dichloromethane) through SiO2 yielded 13 mg (23%) of the titled compound. ESI-MS m/z 412 (MH+), 410 (M−H−).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].C([O-])([O-])=O.[Na+].[Na+]>[Pd]>[Cl:11][C:12]1[CH:13]=[C:14]([C:2]2[C:3]([CH:4]=[O:5])=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: COc1ccc(B(O)O)cc1Cl
Reactant: O=Cc1cc(O)ccc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(-c2ccc(O)cc2C=O)cc1Cl
Yield: 93 %

Procedure:
2-bromo-5-hydroxybenzaldehyde (1 mmol), 3-chloro-4-methoxyphenylboronic acid (1 mmol) and Na2CO3 (2 mmol) were dissolved in AcN/H2O (7:3). Then, palladium tetrakistriphenylphosfine (0.03 mmol) was added and the resulting mixture was refluxed until completion. After concentrating the mixture in vacuo the residue was taken up in water and extracted with AcOEt. The combined organic fractions were dried over Na2SO4, filtered, and evaporated. The crude reaction product was purified by means of flash chromatography on silica gel (hexane/AcOEt 5:1) to yield 3′-chloro-4-hydroxy-4′-methoxybiphenyl-2-carbaldehyde as a white solid (93%); m.p.: 168-170° C.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[N:16]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C[Si](C)(C)[O:41][NH2:42].CO>ClCCl>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[N:16]=2)[CH2:11][C:12]([NH:42][OH:41])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(Cc2cccnc2)no1
Reactant: C[Si](C)(C)ON
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CO
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(Cc2cccnc2)no1)NO
Reaction time: 1 h
Yield: 33 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-[3-(3-pyridinylmethyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 109) (410 mg, 1.04 mmol) in dichloromethane (10 ml) was treated with 1,1′-carbonyldiimidazole (169 mg, 1.04 mmol) and stirred under a nitrogen atmosphere for 1 hour. O-(Trimethylsilyl)hydroxylamine (418 μl, 3.12 mmol) was added and the reation mixture was stirred for 18 hours. The reaction mixture was then treated with methanol (5 ml) and stirred at room temperature for 3 hours. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water (3×30 ml) and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a solvent gradient of 100:0 (dichloromethane:methanol) gradually changing to 95:5 (dichloromethane:methanol) to afford a white waxy solid. The solid was recrystallised from ethyl acetate to afford the title compound as a white solid (128 mg).
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[CH3:10]OS(OC)(=O)=O.CI>>[OH:9][C:8]1[CH:7]=[C:5]([OH:6])[N:4]=[C:2]([S:3][CH3:10])[N:1]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C1CC(=O)NC(=S)N1
Solvent: CI
Product: CSc1nc(O)cc(O)n1

Procedure:
Another method described by Wheeler and Jamieson, Am. Chem. J. 32, p. 345 (1904) initiates the synthesis with 2-thiobarbituric acid which is methylated. Either dimethylsulfate or methyl iodide is used to obtain 4,6-dihydroxy-2-methylthiopyrimidine. Dichlorination at 4- and 6- positions is accomplished with phosphorus oxychloride in the presence of dimethylaniline, and the 4,6-dichloro-2-(methylthio)pyrimidine thus obtained is reacted with aqueous alcoholic ammonia to produce the desired 4-amino-6-chloro-2-(methylthio)pyrimidine.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]=[S:27]1(=[O:35])[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:32]([CH:29]5[CH2:30][CH2:31][S:27](=[O:35])(=[O:26])[CH2:28]5)=[O:33])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)C1CCS(=O)(=O)C1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)C1CCS(=O)(=O)C1

Procedure:
The title compound, white solid (21.1 mg, 54.1%), MS (ISP) m/z=477.2 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and 1,1-Dioxo-tetrahydro-thiophene-3-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH:26]=[CH:27][CH:28]=2)[C:19]([F:34])=[CH:18][N:17]=1>C(O)CCC>[C:30]([NH:29][C:25]1[CH:24]=[C:23]([NH:22][C:20]2[C:19]([F:34])=[CH:18][N:17]=[C:16]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=3)[N:21]=2)[CH:28]=[CH:27][CH:26]=1)(=[O:33])[CH:31]=[CH2:32]
Reactant: CCOC(=O)COc1ccc(N)cc1
Reactant: C=CC(=O)Nc1cccc(Nc2nc(Cl)ncc2F)c1
Solvent: CCCCO
Product: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(OCC(=O)OCC)cc3)ncc2F)c1
Yield: 19.5 %

Procedure:
A solution of ethyl 2-(4-aminophenoxy)acetate (0.801 g) and N-(3-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)acrylamide (1.0 g) in 1-butanol (10 mL) was heated to 135° C. for 2 hr. The reaction was monitored on TLC using hexanes:ethyl acetate (3:7) as mobile phase. After completion of the reaction, butanol was removed under reduced pressure and water was added. The mixture was extracted with ethyl acetate and the organic layer was dried over sodium sulfate and solvent was removed under reduced pressure. Crude material was purified by Combiflash chromatography and eluted with 29% ethyl acetate in hexane to give 0.30 g of ethyl 2-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[CH2:6][NH:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17](O)=[O:18])=[C:12]2[N:11]=[CH:10][C:9]=1[C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21].[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][CH:36]=1)[CH2:6][NH:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:18])=[C:12]2[N:11]=[CH:10][C:9]=1[C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1)=[O:21]
Reactant: COc1cccc(CNc2c(C(=O)N3CCC(c4ccccc4)CC3)cnc3c(C(=O)O)cnn23)c1
Reactant: CS(N)(=O)=O
Product: COc1cccc(CNc2c(C(=O)N3CCC(c4ccccc4)CC3)cnc3c(C(=O)NS(C)(=O)=O)cnn23)c1
Yield: 88.9 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(3-methoxybenzylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.06 g, 0.12 mmol) obtained in step 2 and methanesulfonamide (0.06 g, 0.62 mmol), the title compound (0.06 g, 69%) was obtained.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.Cl[C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1.C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][N:12]1[CH2:13][CH2:14][N:15]([C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH2:16][CH2:17]1
Reactant: c1ccc2c(c1)OCC(CN1CCNCC1)O2
Reactant: Clc1cnccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: c1ccc2c(c1)OCC(CN1CCN(c3cnccn3)CC1)O2
Temperature: 100 °C
Yield: 27.2 %

Procedure:
1-(2,3-Dihydro-1,4-benzodioxin-2-ylmethyl)piperazine (2.35 g, 10 mmole), 2-chloropyrazine (1.15 g, 10 mmole) and diisopropylethylamine (1.3 g, 10 mmole) were combined in 100 ml of 1-methyl-2-pyrrolidinone and heated under N2 at 100° C. for 24 hours. Upon cooling, the solvent was removed in vacuum and the residue filtered through 75 g of silica gel using chloroform as the eluent. The product-containing fractions were combined, the solvent evaporated and the residue was crystallized from methanol with addition of 4N isopropanolic HCl. A second recrystallization from methanol gave 850 mg of title compound, as the dihydrochloride salt, m.p. 248°-253° C.(d).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.C([Li])CCC.[CH2:23]([CH:25]([CH2:28][CH3:29])[CH:26]=[O:27])[CH3:24].[NH4+].[Cl-]>C1COCC1>[S:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([CH:26]([CH:25]([CH2:28][CH3:29])[CH2:23][CH3:24])[OH:27])=[CH:3][CH:4]=1
Reactant: CCC(C=O)CC
Reactant: Brc1ccc(Nc2nc3ccccc3s2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CC)C(O)c1ccc(Nc2nc3ccccc3s2)cc1
Temperature: -70 °C
Yield: 67.9 %

Procedure:
The following reaction was performed under a N2 atmosphere. A mixture of N-(4-bromophenyl)-2-benzothiazolamine (0.492 mol) in THF (2700 ml) was stirred at −70° C. Butyllithium (0.984 mol; 2.5 M in hexane) was added dropwise at −65° C. The mixture was stirred for one hour. A solution of 2-ethyl-butanal (0.492 mol) in THF (300 ml) was added dropwise at −75° C. The mixture was allowed to warm to RT overnight. A 10% aqueous NH4Cl solution (3000 ml) was added and the mixture was stirred for 15 minutes The separated aqueous phase was extracted with EtOAc (1000 ml). The separated organic layer was dried, filtered and the solvent evaporated. The residue was crystallized from methyl isobutyl keton. The precipitate was filtered off and dried, yielding 109 g (68%) of (±)-4-(2-benzothiazolylamino)-α-(1-ethyl-propyl)benzenemethanol (interm 28).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[CH2:16]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25](Br)[N:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([C:23]1[N:24]=[C:25]([CH:14]([C:9]2[C:10]([CH3:13])=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[OH:15])[CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Brc1cccc(Cc2ccccc2)n1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cccc(Cc2ccccc2)n1

Procedure:
Prepared according to the procedure described in Example 58, Step, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 2-benzyl-6-bromo-pyridine.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]1[O:22][CH2:23][C:24]([CH3:26])=[CH2:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34].C1COCC1>O>[CH2:1]([N:8]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][C@H:10]1[O:22][CH2:23][C:24]([CH3:26])=[CH2:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NCc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N(Cc1ccccc1)C(=O)OCc1ccccc1
Yield: 90.5 %

Procedure:
The same operation as in Example (103a) was performed using tert-butyl cis(±)-4-(benzylamino)-3-[(2-methyl-2-propen-1-yl)oxy]piperidine-1-carboxylate obtained in Example (117c) (4.4 g, 12.2 mmol), sodium bicarbonate, benzyl chloroformate (2.81 g, 16 mmol), THF (15 mL) and water (15 mL). The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 1/1) to obtain 5.46 g of the title compound as a colorless oily substance (99%).
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][CH:6]([OH:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[CH:11][CH:10]=1)[CH3:3]>C(#N)C.C(O)(=O)C>[CH3:3][CH:2]([NH:4][CH2:5][C@H:6]([OH:19])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[CH:13][CH:14]=1)[CH3:1]
Reactant: CC(C)NCC(O)COc1ccc(CC(N)=O)cc1
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(C)NC[C@H](O)COc1ccc(CC(N)=O)cc1

Procedure:
20 μg (R,S)-atenolol is injected in 20 μl of the eluant acetonitrile/acetic acid (v/v, 93/7). k'R =1.18 k'S =2.34 α=2.0 RS =0.5
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][CH3:11])[CH:6]=[CH:7][CH:8]=1.BrBr.S([O-])([O-])(=O)=S.[Na+].[Na+].[NH2:24][C:25](=[S:37])[CH2:26][N:27]1[CH:31]=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:29]=[N:28]1>C(OCC)C>[CH3:11][C:10]1[S:37][C:25]([CH2:26][N:27]2[CH:31]=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:29]=[N:28]2)=[N:24][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=1
Reactant: CCOC(=O)c1cnn(CC(N)=S)c1
Reactant: CCC(=O)c1cccc(C(F)(F)F)c1
Agent: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)c1cnn(Cc2nc(-c3cccc(C(F)(F)F)c3)c(C)s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
Under a nitrogen atmosphere, to a solution (10 mL) of 1-[3-(trifluoromethyl)phenyl]propan-1-one (1.0 g, 4.95 mmol) in diethyl ether was added bromine (0.15 mL, 5.94 mmol) at 0° C., and the mixture was stirred at room temperature overnight. An aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (4 mL), the compound (175 mg, 0.82 mmol) obtained in Example 1b was added and the mixture was heated under reflux for 3 hr. The reaction mixture was allowed to cool and the solvent was evaporated under reduced pressure. The obtained crude product was purified by recrystallization (ethyl acetate-hexane) to give the title compound (112 mg, 35%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:8])([CH3:7])[CH2:4][CH2:5][OH:6].[N+:9]([C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([N+]([O-])=O)[C:13]=1[C:14]#[N:15])([O-:11])=[O:10]>>[CH3:1][O:2][C:3]([CH3:8])([CH3:7])[CH2:4][CH2:5][O:6][C:16]1[CH:17]=[CH:18][CH:19]=[C:12]([N+:9]([O-:11])=[O:10])[C:13]=1[C:14]#[N:15]
Reactant: COC(C)(C)CCO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: COC(C)(C)CCOc1cccc([N+](=O)[O-])c1C#N
Yield: 52 %

Procedure:
Prepared as in Example 215c from 3-methoxy-3-methylbutan-1-ol and 2,6-dinitrobenzonitrile in 52% yield. MS 265 (MH+).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.O.[CH2:14]([NH2:16])[CH3:15]>CO>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:16][CH2:14][CH3:15])=[O:4]
Reactant: CCN
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CO
Solvent: O
Product: CCNC(=O)c1ccccc1N
Reaction time: 1 h
Yield: 93.4 %

Procedure:
A round-bottomed flask was charged with isatoic anhydride (5.0 g, 0.030 mol), 200 mL water, and 5 mL of methanol. Ethylamine (2N in methanol, 18.4 mL, 0.036 mol) was added slowly to the reaction mixture. After 1 h, the reaction mixture was concentrated to 20 mL. The reaction mixture was acidified with 1N HCl and extracted with EtOAc. The aqueous layer was basified with 6N NaOH and extracted with EtOAc. The EtOAc layer was dried over Na2SO4, filtered, and concentrated to dryness to afford 2-amino-N-ethylbenzamide (4.6 g, 91%): Mass (M+H)+=165.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@@H:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[C@@H:3]1[C:9]([O-:11])=[O:10].[K+].[F:14][C:15]1[C:20]([CH2:21]Cl)=[C:19]([F:23])[C:18]([F:24])=[C:17]([F:25])[C:16]=1[F:26]>C(#N)C>[F:14][C:15]1[C:20]([CH2:21][O:10][C:9]([C@H:3]2[C@H:4]([CH:5]=[C:6]([Cl:8])[Cl:7])[C:2]2([CH3:12])[CH3:1])=[O:11])=[C:19]([F:23])[C:18]([F:24])=[C:17]([F:25])[C:16]=1[F:26]
Reactant: Fc1c(F)c(F)c(CCl)c(F)c1F
Reactant: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)OCc1c(F)c(F)c(F)c(F)c1F

Procedure:
0.1 mole of potassium (±) trans-2,2-dimethyl-3-dichlorovinyl-cyclopropanecarboxylate and 0.1 mole of pentafluorobenzyl chloride were heated in acetonitrile until the reaction was complete. After concentrating, taking up in water/petroleum ether and concentrating the organic phase, a colorless oil was obtained, in the NMR spectrum of which the doublet mentioned in Example 2 for the vinyl proton of the cis-ester was lacking.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([CH2:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[S:14]([NH2:17])(=[O:16])=[O:15]>O1CCOCC1>[Br:1][CH:10]([C:8]1[CH:7]=[CH:6][C:5]([S:14]([NH2:17])(=[O:16])=[O:15])=[C:4]([Cl:3])[CH:9]=1)[C:11](=[O:13])[CH3:12]
Reactant: CC(=O)Cc1ccc(S(N)(=O)=O)c(Cl)c1
Reactant: BrBr
Solvent: C1COCCO1
Product: CC(=O)C(Br)c1ccc(S(N)(=O)=O)c(Cl)c1
Yield: 145.8 %

Procedure:
Bromine 0.022 ml, 0.42 mmol) is added to a stirred solution of ketone (23c) (0.15 g, 6.1 mmol) in dioxan (15 ml). After 30 minutes the solvent is removed to give a brown oil (0.2 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:12]=[C:13]([CH2:17][NH2:18])[CH:14]=[N:15][CH:16]=1.[F:19][C:20]([F:27])([F:26])[CH2:21][S:22](Cl)(=[O:24])=[O:23]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:12]=[C:13]([CH2:17][NH:18][S:22]([CH2:21][C:20]([F:27])([F:26])[F:19])(=[O:24])=[O:23])[CH:14]=[N:15][CH:16]=1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: Cn1c(-c2cncc(CN)c2)cc2ccccc21
Product: Cn1c(-c2cncc(CNS(=O)(=O)CC(F)(F)F)c2)cc2ccccc21

Procedure:
C-[5-(1-Methyl-1H-indol-2-yl)-pyridin-3-yl]-methylamine (Example 200b) and 2,2,2-trifluoro-ethanesulfonyl chloride are processed according to the method described in Example 186f to give 2,2,2-trifluoro-ethanesulfonic acid [5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide. 1H NMR (400 MHz, MeOD) δ ppm 3.78 (s, 3H), 4.23 (q, J=9.6 Hz, 2H), 4.44 (s, 2H), 6.66 (d, J=0.5 Hz, 1H), 7.06-7.12 (m, 1H), 7.23 (ddd, J=7.7, 1.1 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 8.04 (t, J=2.0 Hz, 1H), 8.56 (d, J=2.0 Hz, 1H), 8.68 (d, J=1.9 Hz, 1H). HRMS (ESI) m/z 384.0999 [(M+H)+ Calcd for C17H17F3N3O2S: 384.0994].