Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=[NH:9])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:11][C:12]([C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)=O.C(=O)(O)[O-].[Na+].O>C1COCC1>[C:1]1([C:7]2[NH:9][CH:11]=[C:12]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N=C(N)c1ccccc1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(-c2c[nH]c(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzenecarboximidamide (2.9 g, 24 mmol), 4-bromoacetylbenzonitrile (5 g, 22 mmol), and sodium bicarbonate (1.8 g, 22 mmol) were suspended in 70 mL of THF and 10 mL of water and heated at reflux overnight. The reaction mixture was cooled rt, and partially concentrated. An additional 10 mL of water was added, and the resulting suspension was stirred at 50-60° C. for 30 min. The mixture was cooled with an ice-water bath and the precipitate was collected by filtration, rinsed with two 10-mL portions of water, and air-dried. The solid material was stirred with 15 mL of EtOAc and 15 mL of hexanes, and was again collected by filtration, and dried to give 4-(2-phenyl-1H-imidazol-4-yl)benzonitrile. LCMS: min [M+1]=246.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[NH:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O.N1CCCCC1>CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:17]/[C:13]3[NH:12][CH:16]=[CH:15][CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Br)cc2N1
Reactant: O=Cc1ccc[nH]1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(Br)ccc2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Yield: 47.8 %

Procedure:
A solution of 6-bromo-1,3-dihydro-2H-indol-2-one (100 mg, 0.47 mmol), 1H-pyrrole-2-carbaldehyde (49.2 mg, 0.52 mmol), and piperidine (0.02 mL, 0.2 mmol) in methanol (3 mL) was stirred at 65° C. for 2 hours, cooled to room temperature, and filtered. The filter cake was washed with hexanes to provide the desired product (65 mg, 48%). MS (DCI/NH3) m/z 290 (M+H)+.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([I:18])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[OH:17][C:15]1[C:14]([I:18])=[CH:13][C:9]2[CH:10]([CH3:12])[CH2:11][NH:5][CH2:6][CH2:7][C:8]=2[CH:16]=1
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)c(I)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1CNCCc2cc(O)c(I)cc21
Reaction time: 8 h
Yield: 68.1 %

Procedure:
A solution of N-trifluoroacetyl-7-hydroxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (25 mg, 0.063 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and stirred overnight at 20 C. The product mixture was diluted with water (5 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (5 mL), dried with Na2SO4 and concentrated to give 13 mg of a white solid. 1H NMR (400 MHz, CD3OD) d 7.46 (s, 1H), 6.64 (s, 1H), 3.16 (m, 3H), 2.94 (m, 3H), 2.81 (m, 1H), 1.35 (d, J=7 Hz, 3H). MS calculated for C11H14INO+H: 304, observed: 304.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH:37]=[CH:38][C:39]=1[F:40])[NH:17][C:18]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:19]=1[C:20]([NH:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21]>>[Cl:13][C:14]1[CH:15]=[C:16]([N:17]2[C:18]3[C:19](=[CH:31][C:32]([F:36])=[C:33]([F:35])[CH:34]=3)[C:20](=[O:21])[N:22]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:1]2=[O:2])[CH:37]=[CH:38][C:39]=1[F:40]
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1ccc(F)c(Cl)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: O=c1c2cc(F)c(F)cc2n(-c2ccc(F)c(Cl)c2)c(=O)n1OCc1ccccc1
Yield: 19.6 %

Procedure:
Using General Method 3, the reaction of carbonyldiimidazole (4.9 g, 30 mmol) and crude 2-(3-chloro-4-fluoro-anilino)-N-benzyloxy-4,5-difluoro-benzamide (Example W, 6.1 g, 15 mmol) provided 1.27 g of the title compound as a solid, mp 184-186° C.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1>[Rh]>[NH2:7][CH2:6][CH:5]1[CH2:8][CH2:9][CH:2]([CH2:1][NH2:10])[CH2:3][CH2:4]1
Reactant: N#Cc1ccc(C#N)cc1
Agent: [Rh]
Product: NCC1CCC(CN)CC1
Reaction time: 1 h

Procedure:
Following the details of the above Example I, when terephthalonitrile was reduced over a 60 minute period using 6.0 g. of the supported rhodium catalyst, 1,4-bisaminomethlycyclohexane was obtained and 100% conversion of terephthalonitrile had occurred.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]([N:15]1[CH2:20][CH2:19][CH:18]([F:21])[CH2:17][CH2:16]1)=[O:14])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:21][CH:18]1[CH2:17][CH2:16][N:15]([C:13]([C@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:14])[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)N1CCC(F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C([C@H]1CCCN1)N1CCC(F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A mixture of (R)-2-(4-fluoro-piperidine-1-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.5 g, 5 mmol) and TFA (3 mL) in DCM (4 mL) was stirred at rt for one hour to give 1 g of (4-fluoro-piperidin-1-yl)-(R)-pyrrolidin-2-yl-methanone.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[C:33]1([CH:39]([NH2:42])[CH2:40][CH3:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[C:33]1([CH:39]([NH:42][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:32])[F:31])=[CH:4][CH:5]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:29])[CH2:40][CH3:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCC(N)c1ccccc1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with 1-phenylpropylamine (31 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was concentrated under vacuum, the residue was suspended in water, and the solid was collected by vacuum filtration. This material was purified by preparative thin-layer-chromatography on silica eluting with a 3:1 ethyl acetate-hexanes mixture. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 66 mg of the title compound as a colorless solid.
Reaction SMILES: [OH-:1].[Na+:2].C([O:13][C:14]1[C:27]2=[C:28]3[C:29]4[C:24]([CH:25]=[CH:26]2)=[C:23]([S:30]([O-:33])(=[O:32])=[O:31])[CH:22]=[C:21]([S:34]([O-:37])(=[O:36])=[O:35])[C:20]=4[CH:19]=[CH:18][C:17]3=[C:16](S([O-])(=O)=O)[CH:15]=1)CCCCCCCCC.Cl>O>[Na+:2].[Na+:2].[CH2:26]([O:1][C:16]1[C:17]2=[C:28]3[C:29]4[C:20]([CH:19]=[CH:18]2)=[C:21]([S:34]([O-:37])(=[O:35])=[O:36])[CH:22]=[C:23]([S:30]([O-:33])(=[O:32])=[O:31])[C:24]=4[CH:25]=[CH:26][C:27]3=[C:14]([OH:13])[CH:15]=1)[CH2:27][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:29]
Reactant: [OH-]
Reactant: CCCCCCCCCCOc1cc(S(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c4ccc1c2c43
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCOc1cc(O)c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c4ccc1c2c34

Procedure:
14.5 g Sodium hydroxide and 9.0 g water are heated to ca. 130° C. and 8.53 g 1-decyloxypyrene-3,6,8-trisulfonate (structure IV, R=decyl, M=Na) are added to the melt in small portions under stirring. The temperature is raised within 30 min to 190° C. The mixture is cooled, cautiously acidified with concentrated hydrochloric acid, and the resulting precipitate is filtered and recrystallized from a saturated aqueous salt solution. For further purification it is recrystallized from aqueous ethanol. Yield is 2.6 g of yellow crystals that decompose at above 232° C. and which have a green fluorescence that is strongly pH-dependent in the pH 6-8 range.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[NH:22][CH2:21][CH2:20][CH2:19]4)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]([C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:21][CH2:20][CH2:19]4)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2nc(-c3ccc4c(c3)CCCN4)cs2)cc1OC
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(-c2nc(-c3ccc4c(c3)CCCN4C(=O)c3ccccc3)cs2)cc1OC
Reaction time: 5 h
Yield: 54 %

Procedure:
In 10 ml of pyridine was dissolved 1 g of 2-(3,4-dimethoxyphenyl)-4-(1,2,3,4-tetrahydroquinolin-6-yl)thiazole. Thereto was added 0.44 g of benzoyl chloride at 0° C., and the mixture was stirred for 5 hours. The solution was concentrated and mixed with ethanol and water in this order. The resulting crystals were collected by filtration and recrystallized from ethanol to obtain 0.7 g of 2-(3,4-dimethoxyphenyl)-4-(1-benzoyl-1,2,3,4-tetrahydroquinolin-6-yl)thiazole as a light yellow powder.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:19][C:20]1[S:21][CH:22]=[C:23]([C:25]([O:27]CC)=[O:26])[N:24]=1.O>CN(C)C=O>[C:3]1([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:19][C:20]3[S:21][CH:22]=[C:23]([C:25]([OH:27])=[O:26])[N:24]=3)[N:10]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(-c2n[nH]c3ccccc23)cc1
Reactant: CCOC(=O)c1csc(CBr)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1csc(Cn2nc(-c3ccccc3)c3ccccc32)n1
Reaction time: 0.08 h
Yield: 10.5 %

Procedure:
Sodium hydride (added with 40% mineral oil, 9 mg, manufactured by Kanto Chemical Co., Inc.) was added to a solution of 3-phenyl-1H-indazole (40 mg), which had been synthesized according to the literature (T. Edward, C., et al., Tetrahedron, 1991, 47, 9599-9620), in N,N-dimethylformamide (1 mL, manufactured by Kanto Chemical Co., Inc.) under ice cooling, and the mixture was stirred for 5 minutes at the same temperature. Subsequently, ethyl 2-bromomethylthiazole-4-carboxylate (51 mg) synthesized according to the method of the literature (K. Benno, et al., Leibigs. Ann. Chem., 1981, 4, 623-632) was added thereto, and the mixture was stirred overnight at room temperature. Water (1 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×2 mL), washed with brine (10 mL), and dried (MgSO4). The solvent was then evaporated. The resulting residue was purified by PTLC (hexane:ethyl acetate=2:1), to give 7.2 mg of the title compound. LC-MS: HPLC retention time 4.08 minutes, m/z 336 (M+H), condition A-1.
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]([NH:6][C:7]1[NH:8][C:9]2[C:14]([C:15]=1[C:16]([NH2:18])=[O:17])=[CH:13][CH:12]=[C:11]([C:19]1[O:20][C:21]([CH:24]=O)=[CH:22][CH:23]=1)[CH:10]=2)=[O:5].[BH4-].[Na+]>CO>[NH2:3][C:4]([NH:6][C:7]1[NH:8][C:9]2[C:14]([C:15]=1[C:16]([NH2:18])=[O:17])=[CH:13][CH:12]=[C:11]([C:19]1[O:20][C:21]([CH2:24][NH:2][CH3:1])=[CH:22][CH:23]=1)[CH:10]=2)=[O:5]
Reactant: CN
Reactant: NC(=O)Nc1[nH]c2cc(-c3ccc(C=O)o3)ccc2c1C(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1ccc(-c2ccc3c(C(N)=O)c(NC(N)=O)[nH]c3c2)o1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
A solution of 40% methylamine in methanol (49 μL, 0.48 mmol) was added to a solution of 2-aminocarbonylamino-6-(5-formylfuran-2-yl)indole-3-carboxamide (Compound 4-74, 0.10 g, 0.32 mmol) in anhydrous methanol (2 mL), and the mixture was stirred at 60° C. for 6 hours in a sealed tube. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a solution mixture of methanol and tetrahydrofuran (methanol/tetrahydrofuran=1/2, 3 mL). Sodium borohydride (0.024 g, 0.64 mmol) was added to the solution mixture under ice-cooling, and the mixture was stirred at room temperature overnight. After the reaction mixture was concentrated under reduced pressure, the precipitated solid was washed with H2O (5 mL) and dried under reduced pressure to give the title compound (0.077 g) as a slightly brown solid (yield 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:27])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=2[CH:26]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:28][O:29][C:30]([C:32]1[CH:33]=[N:34][C:35](Cl)=[N:36][CH:37]=1)=[O:31]>>[CH3:28][O:29][C:30]([C:32]1[CH:33]=[N:34][C:35]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:27])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=4[CH:26]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:36][CH:37]=1)=[O:31]
Reactant: COC(=O)c1cnc(Cl)nc1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)nc1

Procedure:
The title compound was prepared in analogy to Example 196 from 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (obtained in Example 172) by alkylation with methyl-2-chloropyrimidine-5-carboxylate [CAS Reg. No. 287714-35-6]. MS (m/e)=538.2 [M+H+].
Reaction SMILES: [CH:1](/[Sn](CCCC)(CCCC)CCCC)=[CH:2]/[CH3:3].[O:17]([CH2:24][C:25]([NH:27][CH:28]1[C:56](=[O:57])[N:30]2[C:31]([C:40]([O:42][CH:43]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])=[C:32](OS(F)(=O)=O)[CH2:33][S:34][C@H:29]12)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:17]([CH2:24][C:25]([NH:27][CH:28]1[C:56](=[O:57])[N:30]2[C:31]([C:40]([O:42][CH:43]([C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])=[C:32](/[CH:1]=[CH:2]\[CH3:3])[CH2:33][S:34][C@H:29]12)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C/C=C\[Sn](CCCC)(CCCC)CCCC
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OS(=O)(=O)F)CS[C@H]12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: C/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Reaction time: 0.05 h
Yield: 92.9 %

Procedure:
A solution of palladium (II) acetate (3.6 mg, 0.016 mmole, 0.1 eq.) in dichloromethane (2 mL) was treated with Z-1-propenyl tri-n-butylstannane (66.2 mg, 0.2 mmole, 1.2 eq.) under an inert atmosphere and allowed to stir for 3 minutes. The resulting dark suspension was then treated with diphenylmethyl 7-phenoxyacetamido-3-[(fluorosulfonyl) oxy]-3-cephem-4-carboxylate (100.0 mg, 0.16 mmole, 1.0 eq.) in one portion and the reaction mixture was allowed to stir for 10 minutes. The reaction mixture was diluted with additional dichloromethane and washed with water (1×10 mL). The organic fraction was dried over magnesium sulfate and purified by flash filtration through a pad of silica gel (W. R. Grace, 951W) first with dichloromethane (50 mL) to remove the residual stannane and then with 10% ethyl acetate in dichloromethane (50 mL) which upon concentration furnished 80.4 mg (89%) of the title compound as a pale yellow solid. The product was then recrystallized from isopropyl alcohol to afford 62.3 mg (69%) of a white solid, mp. 103°-104° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>ClCCl>[Cl:24][CH2:25][C:26]([N:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)=[O:27]
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a mixture of 1-[4-(trifluoromethyl)phenyl]piperazine (600 mg, 2.61 mmol) and triethylamine (660 mg, 6.52 mmol) in dichloromethane (20 ml) was added 2-chloroacetyl chloride (380 mg, 3.36 mmol) dropwise at 0° C. The resulting solution was stirred for 1 hour at room temperature. The reaction mixture was then quenched by water (80 ml) and extracted with dichloromethane (3×30 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography using 1%-10% ethyl acetate in petroleum ether to afford 2-chloro-1-[4-[4-(trifluoromethyl)phenyl]piperazin-1-yl]ethan-1-one as a white solid (479 mg, 60%). (ES, m/z): [M+H]+ 307.1; 1H NMR (300 MHz, CDCl3): δ 7.52 (d, J=8.4 Hz, 2H), 6.97 (d, J=8.7 Hz, 2H), 4.12 (s, 1H), 3.81 (t, J=5.1 Hz, 2H), 3.72 (t, J=5.1 Hz, 2H), 3.36 (t, J=5.1 Hz, 2H), 3.30 (t, J=5.1 Hz, 2H).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][C:3](Cl)=[O:4].[CH3:8][O:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20]>ClC1C=CC=CC=1Cl>[CH3:8][O:9][CH2:10][CH2:11][CH2:12][N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][C:3](=[O:4])[CH2:2][C:1]1=[O:6]
Reactant: COCCCNc1ccccc1N
Reactant: O=C(Cl)CC(=O)Cl
Solvent: Clc1ccccc1Cl
Product: COCCCN1C(=O)CC(=O)Nc2ccccc21
Temperature: 130 °C
Reaction time: 1.6 h

Procedure:
To a stirred mixture of 8 ml of malonyl dichloride and 90 ml of o-dichlorobenzene at 60° C., a solution containing 12.7 g of N-(3-methoxypropyl)-o-phenylenediamine in 10 ml of o-dichlorobenzene is added for 32 minutes in several times. The resulting mixture is stirred at 130° C. for 1.6 hours and then subjected to filtration during hot. The filtrate is concentrated and purified by silica gel column chromatography (ethyl acetate). n-hexane is added and precipitated crystals are separated by filtration and dried to obtain 9.8 g of (208).
Reaction SMILES: [C:1]12([CH2:11][NH2:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Br:13][C:14]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:15]=1[C:16](O)=[O:17]>>[Br:13][C:14]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:15]=1[C:16]([NH:12][CH2:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)=[O:17]
Reactant: O=C(O)c1cc(F)ccc1Br
Reactant: NCC12CC3CC(CC(C3)C1)C2
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(F)ccc1Br

Procedure:
Prepared according to the method of Example 41 from 1-adamantanemethylamine (0.1 ml) and 2-bromo-5-fluorobenzoic acid (0.123 g) to give the title compound as a white solid (0.140 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Li+].CC([N-]C(C)C)C.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH:29]=[O:30])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH:29]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[Br:1])[OH:30])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccncc2Br)CC1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 70.2 %

Procedure:
To a cold (−90° C.) solution of 3-bromo pyridine (741 mg, 4.7 mmol) in freshly distilled THF (18 ml) was added LDA (2.0M, 2.6 mL, 5.2 mmol). The mixture was stirred under N2 for 20 min. A solution of 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 2.34 mmol) was added slowly to maintain the bath temperature below −80° C. The reaction was continued at below −80° C. for 30 min, warmed to −20° C. within 30 min and quenched with saturated aqueous NH4Cl (10 mL). Work-up and purification gave 4-[(3-bromo-pyridin-4-yl)-hydroxy-methyl]-piperidine-1-carboxylic acid tert-butyl ester (610 mg, 70%) as colourless oil.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1.Cl.[F:29][C:30]([F:41])([F:40])[O:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38]N)=[CH:34][CH:33]=1>>[CH3:25][CH:24]([CH3:26])[C:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH:13]2[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH2:7][C:6]3[C:36]4[C:35](=[CH:34][CH:33]=[C:32]([O:31][C:30]([F:41])([F:40])[F:29])[CH:37]=4)[NH:38][CH:2]=3)[CH2:15][CH2:14]2)[CH:17]=1)=[O:27]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC3OCCO3)CC2)c1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure H and Scheme S using N-(3-{1-[4-(1,3-dioxolan-2-yl)butyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-[4-(trifluoromethoxy)phenyl]hydrazine hydrochloride: ESMS m/e: 488.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C@@H:19]([OH:20])[C@@H:18]([CH2:21][OH:22])[O:17][C@@H:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C@@H:6]1[OH:23])[CH:2]=[CH2:3].[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(Cl)(Cl)Cl>CN(C=O)C>[CH2:1]([O:4][C@H:5]1[C@@H:19]([O:20][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:18]([CH2:21][O:22][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:17][C@@H:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[C@@H:6]1[O:23][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@H]1[C@@H](O)[C@@H](CO)O[C@@H](Oc2ccc(OC)cc2)[C@@H]1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: C=CCO[C@H]1[C@@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](Oc2ccc(OC)cc2)[C@@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
To a solution of compound 8 (1.21 g, 3.71 mmol) in anhydrous DMF (15 mL), under nitrogen and cooled at 0° C., was added NaH (116 mg, 4.83 mmol). The reaction mixture was stirred 15 minutes at 0° C. and treated with benzyl bromide (0.66 mL, 5.57 mmol). After 12 hours at room temperature, the reaction mixture was cooled at 0° C., quenched by slow addition of water and extracted with chloroform. The combined organic layers were washed with H2O, dried over anhydrous Na2SO4, filtered and the solvents were evaporated. Purification by chromatography on silica gel (ethyl acetate-petroleum ether, v/v 1:3) afforded 91% as white crystals in 91% yield (2.01 g). mp=59-61° C.; [αD]24=−23° (c 1, CHCl3); 1H NMR (500 MHz, CDCl3): δ3.48 (dd, 1H, J2,3 9.6 Hz, J3,4 2.8 Hz, H-3), 3.63 (bs, 3H, H-5, H-6a and H-6b), 3.75 (s, 3H, OMe), 3.90 (d, 1H, J4,5<1.5 Hz, H-4), 4.01 (dd, 1H, J1,2 7.8 Hz, H-2), 4.22 (m, 2H, OCH2), 4.40, 4.45, 4.64, 4.84, 4.96 and 4.97 (6 d, 1H each, JA,B 11.7 Hz, CH2Ph), 4.83 (d, 1H, H-1), 5.19 and 5.33 (2 dd, 1H each, CH═CH2), 5.95 (m, 1H, CH═CH2), 6.78 and 7.02 (2 d, 2H each, C6H4), 7.22-7.40 (m, 15H, 3C6H5). Anal. Calcd for C37H40O7 (596.7): C 74.48, H 6.76; found: C 74.32, H 6.75.