Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:5])[OH:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][CH3:38])=[O:36]>CC(=O)CC>[CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=[O:4])[O:5][CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH3:2]
Reactant: CCP(=O)(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCP(=O)(OCC(=O)OC)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic acid (500 mg), potassium carbonate (300 mg) and methyl bromoacetate (400 mg) in 2-butanone (10 ml) is heated under reflux for 1 hour. The reaction is filtered and concentrated, and the crude product is purified by prep. TLC to yield methoxycarbonylmethyl P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[OH:23]>>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[O:23][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1F
Reactant: Oc1c(F)cccc1F
Product: COC(=O)c1cc([N+](=O)[O-])ccc1Oc1c(F)cccc1F

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 67 from methyl 2-fluoro-5-nitrobenzoate (J. Org. Chem. 1990, 55, 2034.) and 2,6-difluorophenol: 1H-NMR (CDCl3) δ 8.83 (1H, d, J=2.8 Hz), 8.25 (1H, dd, J=9.2, 2.8 Hz), 7.32–7.20 (1H, m), 7.12–7.02 (2H, m), 6.82 (1H, d, J=9.2 Hz), 3.98 (3H, s); MS (ESI) m/z 310 (M+H)+.
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]4[CH2:28][NH:27][CH2:26][CH2:25][CH2:24][C:23]=4[CH:29]=3)[N:15]=2)=[CH:10][C:7]=1[C:8]#[N:9])[CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].CCOC(C)=O>CN(C=O)C>[C:8]([C:7]1[CH:10]=[C:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]4[CH2:28][N:27]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:26][CH2:25][CH2:24][C:23]=4[CH:29]=3)[N:15]=2)[CH:12]=[CH:13][C:6]=1[O:5][CH:3]([CH3:2])[CH3:4])#[N:9]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCCNC4)no2)cc1C#N
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCCN(CC(=O)OC(C)(C)C)C4)no2)cc1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.3 %

Procedure:
2-[(1-Methylethyl)oxy]-5-[3-(2,3,4,5-tetrahydro-1H-2-benzazepin-7-yl)-1,2,4-oxadiazol-5-yl]benzonitrile hydrochloride (Example 3) (70 mg, 0.170 mmol) and caesium carbonate (167 mg, 0.511 mmol) in dry DMF (5 ml) were treated with tert-butyl bromoacetate (0.038 ml, 0.256 mmol) and stirred at RT for 3 hours to give a single product. EtOAc (40 ml) was added and the mixture washed with water (2×50 ml), dried over anhydrous MgSO4 and evaporated to yield the title compound (85 mg) as a clear, colourless oil. MS (ES) C28H32N4O4 requires 488; found 489 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=2)[C:10]2[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:10]3[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)c(Cl)c23)cc1Cl
Product: COc1ccc(CNc2nc(-n3cncn3)nc3sc(C)c(Cl)c23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2,5-dichloro-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5-chloro-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[CH2:20][CH:21]([CH3:23])[CH3:22].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>>[CH2:14]([N:11]1[CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([O:1][CH2:30][C:29]3[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)=[C:3]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:4]=2)[CH2:13][CH2:12]1)[CH:15]([CH3:17])[CH3:16]
Reactant: COc1ccc(CBr)cc1
Reactant: CC(C)Cc1cc(C(=O)N2CCN(CC(C)C)CC2)ccc1O
Product: COc1ccc(COc2ccc(C(=O)N3CCN(CC(C)C)CC3)cc2CC(C)C)cc1
Yield: 82.4 %

Procedure:
As in the case of Example 18, 1-(4-hydroxy-3-isobutylbenzoyl)-4-isobutylpiperazine (1.59 g) was benzylated with 4-methoxybenzyl bromide (0.94 g), thereby yielding 1.69 g of the aimed compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:23][N+:24]([O-])=O)[CH2:10][P:11]([CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])(=[O:15])[O:12][CH2:13][CH3:14])=[CH:5][CH:4]=1.N.[H][H]>C(O)C.[Ni]>[NH2:24][CH2:23][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH2:10][P:11]([CH:16]([O:17][CH2:18][CH3:19])[O:20][CH2:21][CH3:22])(=[O:15])[O:12][CH2:13][CH3:14]
Reactant: [H][H]
Reactant: CCOC(OCC)P(=O)(CC(C[N+](=O)[O-])c1ccc(OC)cc1)OCC
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(CC(CN)c1ccc(OC)cc1)OCC

Procedure:
A solution of 6.6 g of ethyl 2-(4-methoxyphenyl)-3-nitropropyl-(diethoxymethyl)phosphinate in 50 ml of ethanol is added to 52 g of an 8% solution of ammonia in ethanol. To this are added 8 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered and the filtrate is concentrated under reduced pressure to give ethyl 3-amino-2-(4-methoxyphenyl)propyl-(diethoxymethyl)phosphinate as a viscous oil, 31P=+44.5 ppm (CDCl3).
Reaction SMILES: [S:1]([C:5]1[O:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[OH:14]O.O>C(O)(=O)C>[S:1]([C:5]1[O:13][C:12]2[C:7](=[N+:8]([O-:14])[CH:9]=[CH:10][CH:11]=2)[CH:6]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: OO
Reactant: NS(=O)(=O)c1cc2ncccc2o1
Solvent: CC(=O)O
Solvent: O
Product: NS(=O)(=O)c1cc2c(ccc[n+]2[O-])o1
Temperature: 60 °C
Yield: 63.5 %

Procedure:
To a suspension of 2-sulfamoylfuro[3,2-b]pyridine (647 mg, 3.27 mmol) in glacial acetic acid (8 mL) was added 30% hydrogen peroxide (0.6 mL). This suspension was warmed at 60° C. for four hours to give a clear solution. Upon cooling the reaction mixture and adding water the product crystallized out. This pure product (444 mg, 63.5% yield) was collected by filtration, washed with water, ethanol and diethyl ether, mp: 236°-237° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH:7]=1)[O:8][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: COc1ccc(Cl)cc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-chloro-2-methoxyphenol (488 mg) in acetone (15 ml) were added cesium carbonate (1.20 g) and ethyl bromoacetate (375 μl), and the mixture was stirred for 1 hour at room temperature. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=6/1) gave ethyl 2-(5-chloro-2-methoxyphenoxy)acetate (572 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[C:4]([Cl:9])[CH:3]=1
Reactant: CC(C)=CCBr
Reactant: Oc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCOc1ccc(Br)cc1Cl
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-bromo-2-chlorophenol (1.00 g, 4.82 mmol) and cesium carbonate (3.14 g, 9.64 mmol) in DMF (6.89 mL) at room temperature was added 4-bromo-2-methyl-2-butene (0.68 mL, 5.78 mmol) dropwise via a syringe. The reaction mixture was stirred at 85° C. for 1 hour before it was allowed to cool to room temperature. Water (30.0 mL) was then added and the mixture was extracted with hexane (75.0 mL, 2×). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The crude mixture was purified by silica gel chromatography eluting with 0-5% EtOAc/hexanes to afford the product as a colorless oil.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][NH2:8].C(N(CC)CC)C.S=[C:17]1[CH2:21][S:20][C:19](=[O:22])[NH:18]1>C(O)C>[O:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][NH:8][C:17]1[CH2:21][S:20][C:19](=[O:22])[N:18]=1
Reactant: NCc1ncco1
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1N=C(NCc2ncco2)CS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
To a solution of 1-(1,3-oxazol-2-yl)methanamine hydrochloride (500 mg) in ethanol (10 mL) were added triethylamine (0.99 mL) and 4-thioxothiazolidin-2-one (495 mg) at room temperature. The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (357 mg).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([O:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[C:29]([NH2:37])[CH:28]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(#N)C>[C:10]([O:14][C:15](=[O:16])[NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22](=[O:24])[NH:37][C:29]2[CH:28]=[N:27][C:36]3[C:31]([CH:30]=2)=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:25][CH:26]=1)([CH3:11])([CH3:12])[CH3:13]
Reactant: Nc1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc(C(=O)Nc2cnc3ccccc3c2)cc1
Temperature: 25 °C

Procedure:
N,N-diisopropylethyl amine (12.1 mL, 69.4 mmol) was added to a solution of 4-tert-butoxycarbonylamino-benzoic acid (9.05 g, 38.1 mmol), quinolin-3-ylamine (5.0 g, 34.7 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophospate (HBTU) (14.5 g, 38.1 mmol) in acetonitrile (200 mL) and was stirred at ambient temperature for ten minutes. The solution was heated at reflux for approximately 18 hours. Upon cooling to room temperature, the product crystallized and was collected by filtration, to give a colorless solid, 7.9 g (63%). MS: m/z 364 (MH+). 1H NMR (DMSO-d6): δ 1.51 (s, 9 H), 7.57-7.70 (m, 4 H), 7.75-8.00 (m, 4 H), 8.83 (d, J=2 Hz, 1 H), 9.15 (d, J=2 Hz, 1 H), 9.75 (br s, 1 H) and 10.54 (br s, 1 H).
Reaction SMILES: [S:1]([C:4]1[CH:22]=[CH:21][C:7]2[N:8]=[C:9]([NH:11][C:12](=[O:20])OC3C=CC=CC=3)[S:10][C:6]=2[CH:5]=1)[C:2]#[N:3].[CH3:23][C@H:24]1[O:29][C@@H:28]([CH3:30])[CH2:27][N:26]([CH2:31][CH2:32][NH2:33])[CH2:25]1>>[CH3:30][C@H:28]1[O:29][C@@H:24]([CH3:23])[CH2:25][N:26]([CH2:31][CH2:32][NH:33][C:12]([NH:11][C:9]2[S:10][C:6]3[CH:5]=[C:4]([S:1][C:2]#[N:3])[CH:22]=[CH:21][C:7]=3[N:8]=2)=[O:20])[CH2:27]1
Reactant: N#CSc1ccc2nc(NC(=O)Oc3ccccc3)sc2c1
Reactant: C[C@@H]1CN(CCN)C[C@H](C)O1
Product: C[C@@H]1CN(CCNC(=O)Nc2nc3ccc(SC#N)cc3s2)C[C@H](C)O1

Procedure:
The 2-[({2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethyl}carbamoyl)amino]-1,3-benzothiazol-6-yl thiocyanate was prepared according to the method described in Example 9c, but using 654 mg of phenyl (6-thiocyanato-1,3-benzothiazol-2-yl)carbamate and 0.35 cm3 of 2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethanamine. 783 mg of 2-[({2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethyl}carbamoyl)amino]-1,3-benzothiazol-6-yl thiocyanate are thus obtained in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[OH:10].[CH3:11][N:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13](Cl)=[O:14]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:13](=[O:14])[N:12]([CH3:11])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1nc2ccccc2s1
Product: CN(C(=O)Oc1nc2ccccc2s1)c1ccccc1

Procedure:
The title product was prepared from 2-benzothiazolol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (70%, white crystals). HPLC-MS: m/z=307.1 (M+1); Rt: 4.24 min, purity 85%.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:20])=[C:5]([CH3:19])[C:6]=1[C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1.[Cl:21][CH2:22][C:23]#[N:24].[Cl-].[Al+3].[Cl-].[Cl-]>>[Cl:21][CH2:22][C:23]1[N:24]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)[C:6]2[C:5]([CH3:19])=[C:4]([CH3:20])[S:3][C:2]=2[N:1]=1
Reactant: N#CCCl
Reactant: COc1ccc(C(=O)c2c(N)sc(C)c2C)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(-c2nc(CCl)nc3sc(C)c(C)c23)cc1OC
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 44 %

Procedure:
To a mixture of 2-amino-3-(3,4-dimethoxybenzoyl)-4,5-dimethylthiophene (3.0 g) and chloroacetonitrile (11 g) was added, in limited amounts, powdered aluminum chloride (2.75 g). The mixture was stirred for 2.5 hours at 100° C. The reaction mixture was poured into ice-water, which was subjected to extraction with chloroform. The chloroform layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and water, which was dried (MgSO4). Chloroform was distilled off, and the residue was subjected to column chromatography on silica gel. From the fraction eluted with dichloromethane, 2-chloromethyl-4-(3,4-dimethoxyphenyl)-5,6-dimethylthieno[2,3-d]pyrimidine (1.58 g, 44%) was obtained. Recrystallization from ethyl acetate-hexane gave colorless prisms, m.p.117°-118° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:36]=[C:37]([CH:40]=[C:41]([F:44])[C:42]=1F)[C:38]#[N:39].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[C:38]([C:37]1[CH:36]=[C:35]([F:34])[C:42]([N:11]2[CH2:12][CH2:13][CH:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:9]([CH2:8][N:7]([C@@H:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH3:22])[C:6](=[O:33])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]2)=[C:41]([F:44])[CH:40]=1)#[N:39]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: N#Cc1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(c2c(F)cc(C#N)cc2F)CCC1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 73 %

Procedure:
A solution of 200 mg of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(4-phenylpiperidin-3-yl)methyl]carbamate, 212 mg of 3,4,5-trifluorobenzonitrile, and 187 mg of potassium carbonate in 4.0 mL of DMSO was heated at 110° C. for 2 hours. The reaction mixture was cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 191 mg of tert-butyl {[1-(4-cyano-2,6-difluorophenyl)-4-phenylpiperidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate as a colorless foamy substance. ESI+: 582
Reaction SMILES: CO.[CH2:3]([O:10][C:11]1[CH:28]=[CH:27][C:14]([CH:15]=[C:16]([C:22]([O:24]CC)=[O:23])C(OCC)=O)=[C:13]([O:29][CH3:30])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C-:31]#[N:32].[K+]>O>[CH2:3]([O:10][C:11]1[CH:28]=[CH:27][C:14]([CH:15]([C:31]#[N:32])[CH2:16][C:22]([OH:24])=[O:23])=[C:13]([O:29][CH3:30])[CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(=Cc1ccc(OCc2ccccc2)cc1OC)C(=O)OCC
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc(OCc2ccccc2)ccc1C(C#N)CC(=O)O
Temperature: 70 °C
Yield: 100 %

Procedure:
To a 25 mL RB flask fitted with magnetic stirrer was charged with methanol (20 mL) and water (5 mL). To the stirred solvent was added diethyl [4-(benzyloxy)-2-methoxybenzylidene]propanedioate (0.775 g, 2.02 mmol), followed by potassium cyanide (0.262 g, 4.04 mmol). The RM was heated at 70° C. for 2 h. The RM was concentrated, diluted with saturated NaHCO3 solution (50 mL) and washed with ethyl acetate (50 mL×2). The aqueous layer was acidified to pH 3 with 1N hydrochloric acid and extracted with ethyl acetate (50 mL×2). The organic layer was washed with water (50 mL) and saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as brown liquid. (0.62 g, yield: 100.0%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[O:11][CH:12]=[C:13]([CH2:15]Cl)[N:14]=2)=[C:4]([F:17])[CH:3]=1.[CH3:18][S:19]([CH2:22][C:23]1[N:24]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=2)[CH:25]=[CH:26][N:27]=1)(=[O:21])=[O:20].[H-].[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[O:11][CH:12]=[C:13]([CH2:15][O:38][C:35]3[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][N:24]4[CH:25]=[CH:26][N:27]=[C:23]4[CH2:22][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:37][CH:36]=3)[N:14]=2)=[C:4]([F:17])[CH:3]=1
Reactant: CS(=O)(=O)Cc1nccn1CCCCc1ccc(O)cc1
Reactant: Fc1cc(Br)ccc1/C=C/c1nc(CCl)co1
Agent: [H-]
Agent: [Na+]
Product: CS(=O)(=O)Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(Br)cc3F)n2)cc1
Yield: 65.6 %

Procedure:
Using 2-[(E)-2-(4-bromo-2-fluorophenyl)ethenyl]-4-(chloromethyl)-1,3-oxazole (282 mg), 4-[4-[2-[(methylsulfonyl)methyl]-1H-imidazol-1-yl]butyl]phenol (250 mg) and 65% sodium hydride (32.9 mg), the same reaction as Example 11-(i) was carried out to yield the titled compound (313 mg) as a colorless crystal powder.
Reaction SMILES: O[CH2:2][C@H:3]1[C:11]2[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[N:9][CH:8]=[N:7][C:6]=2[CH2:5][CH2:4]1.[F:25]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.F.F.F.C(N(CC)CC)C.C(N(CC)CC)C>O1CCCC1>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][N:12]([C:10]2[C:11]3[C@H:3]([CH2:2][F:25])[CH2:4][CH2:5][C:6]=3[N:7]=[CH:8][N:9]=2)[CH2:13][CH2:14]1)=[O:19])([CH3:23])([CH3:22])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2[C@H](CO)CC3)CC1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2[C@H](CF)CC3)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.8 %

Procedure:
(R)-tert-Butyl 4-(5-(hydroxymethyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (30.0 mg, 0.0897 mmol) was dissolved in tetrahydrofuran (0.080 mL). Perfluoro-1-butanesulfonylfluoride (0.0644 mL, 0.359 mmol) and triethylamine trishydrofluoride (0.0584 mL, 0.359 mmol) were added to this solution, followed by triethylamine (0.150 mL, 0.726 mmol). The reaction mixture was allowed to stir for 12 hours at room temperature. The reaction was concentrated, and the material was subjected to chromatography on SiO2 and eluted with 10% MeOH/DCM. The desired 4-((R)-5-fluoromethyl-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (25.0 mg, 83%) was isolated. LC/MS (APCI)+ m/z 337.2.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[Br:14][C:15]1[S:19][C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:14][C:15]1[S:19][C:18]([N:20]2[CH2:21][CH2:22][N:23]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=3)[CH2:24][CH2:25]2)=[N:17][CH:16]=1
Reactant: Brc1cnc(N2CCNCC2)s1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NCc1ccc(CN2CCN(c3ncc(Br)s3)CC2)cc1
Yield: 82.7 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (0.9 g), 1-(5-bromothiazol-2-yl)piperazine (1.1 g) and potassium carbonate (0.9 g) in dimethylformamide (10 ml) was stirred at 70° C. for 9 hr. Water (100 ml) was poured into the reaction mixture to allow precipitation of crystals. The crystals were collected by filtration and washed with water to give the title compound (1.5 g) as yellow crystals, m.p.=160-163° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][CH:9]([NH:18][CH:19]([C:28]([O:30]CC2C=CC=CC=2)=[O:29])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:8]1=[O:38])=[O:5])[CH3:2].CCOCC>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][CH:9]([NH:18][CH:19]([C:28]([OH:30])=[O:29])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:8]1=[O:38])=[O:5])[CH3:2]
Reactant: CCOC(=O)CN1C(=O)C(NC(CCc2ccccc2)C(=O)OCc2ccccc2)CCc2ccccc21
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)CN1C(=O)C(NC(CCc2ccccc2)C(=O)O)CCc2ccccc21

Procedure:
1-Ethoxycarbonylmethyl-3-(1-benzyloxycarbonyl-3-phenylpropylamino-2,3,4,5-tetrahydro-1H-[1]-benzazepine-2-one (isomer B of Example 20, 1.1 g) in ethanol (150 ml) was hydrogenated at room temperature and atmospheric pressure using palladium on charcoal (0.5 g) as catalyst. After uptake of hydrogen had terminated, the catalyst was filtered off, and the solvent removed under reduced pressure to give a semi-solid. Trituration with ether (30 ml) yielded isomer B of the title compound, m.p. 175°-177° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:14]O)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[NH2:16][C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1>CO>[C:18]1([CH3:23])[C:17]([NH:16][CH:14]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(=CO)c1ccccc1Br
Reactant: Cc1ccccc1N
Solvent: CO
Product: CCOC(=O)C(=CNc1ccccc1C)c1ccccc1Br
Reaction time: 18 h
Yield: 94.9 %

Procedure:
To a solution of ethyl 2-(2-bromophenyl)-3-hydroxyacrylate (1 g, 3.88 mmol) in methanol (10 mL) was added o-toluidine (0.416 g, 3.88 mmol) via syringe at room temperature. After being stirred for 18 hours at the same temperature, solvent was removed under reduced pressure to give the crude product of ethyl 3-(o-toluidino)-2-(2-bromophenyl)acrylate (1.326 g, 95%), which was used in the next step without further purification. LRMS (M+H) m/z: calcd 359.05. found 359.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N[C:6]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:7]=1[CH:8]=O>O>[OH:3][C:2]1[N:4]=[CH:8][C:7]2[C:10](=[CH:11][C:12]([Cl:14])=[CH:13][CH:6]=2)[N:1]=1
Reactant: Nc1cc(Cl)ccc1C=O
Reactant: NC(N)=O
Solvent: O
Product: Oc1ncc2ccc(Cl)cc2n1
Temperature: 160 °C
Reaction time: 0.25 h

Procedure:
Urea (115 g, 1915 mmol) was melted in a 500 mL 3 neck flask under nitrogen and heated at 160° C. The crude aminobenzaldehyde from step 1 (8.4 g) was added, one of the necks of the flask was opened to the atmosphere and the temperature of the oil bath raised to 190° C. When the bath temperature reached 175° C., a white precipitate was observed. The mixture was cooled and water (400 mL) was added. It was stirred for 15 minutes then filtered through a sintered glass frit. The collected solids were dried by azeotroping with toluene at reduced pressure (3×300 mL) then further dried under high vacuum at 70° C. The crude material was used without further purification.