Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[C:15]([O:16]C)=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[N:11])=[O:2].[I-].[Mg+2].[I-].Cl>O1CCCC1.CCOCC>[CH:1]([C:3]1[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[N:11])=[O:2]
Reactant: COc1cccc(OCCCCC#N)c1C=O
Agent: Cl
Agent: [I-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CCCCCOc1cccc(O)c1C=O

Procedure:
To a stirred solution of 5-(2-formyl-3-methoxyphenoxy)pentanonitrile (2.33 g, 0.01 M) in dry tetrahydrofuran (28 ml) was added dropwise a solution of magnesium iodide (4.17 g, 0.015 M) in dry ether (55 ml). The mixture was then stirred under reflux (51/2 hr). The cooled mixture was poured into 10% hydrochloric acid (50 ml). The organic layer was separated and the aqueous phase extracted with ethyl acetate. The combined organic solutions were washed with water and extracted quickly with 2 N sodium hydroxide solution (1×25 ml). The separated aqueous phase was immediately acidified with concentrated hydrochloric acid with cooling and the solid produced filtered off and washed with water to give 5-(2-formyl-3-hydroxyphenoxy)pentanonitrile, m.p. 66°-67° C. from benzene/petrol.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[C:17]([O:20][C:21](=O)[CH3:22])(=O)[CH3:18]>CCOC(OCC)(OCC)C1C=CC=CC=1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:17]([O:20][CH2:21][CH3:22])[C:18]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: CC(=O)OC(C)=O
Agent: CCOC(OCC)(OCC)c1ccccc1
Product: CCOC(=C1C(=O)N(C(C)=O)c2ccc(C(C)=O)cc21)c1ccccc1
Reaction time: 24 h

Procedure:
32.6 g (150 mmol) 1,5-diacetyl-2-indolinone are suspended in 100 ml triethyl orthobenzoate and stirred overnight with 150 ml acetic anhydride at 110° C. Then a further 50 ml triethyl orthobenzoate are added and the mixture is stirred for a further 24 h. Then it is evaporated down and the resulting precipitate is suction filtered, washed and dried.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:24][O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:12][C@H:11]1[N:34]1[CH:42]=[N:41][C:40]2[C:35]1=[N:36][C:37]([Cl:44])=[N:38][C:39]=2Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:46]1([CH2:52][O:53][NH2:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:24][O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:12][C@H:11]1[N:34]1[C:35]2[N:36]=[C:37]([Cl:44])[N:38]=[C:39]([NH:54][O:53][CH2:52][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]=2[N:41]=[CH:42]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NOCc1ccccc1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(OC[C@H]1O[C@@H](n2cnc3c(NOCc4ccccc4)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Yield: 43.4 %

Procedure:
(This example was also prepared by general method A). 9-(2,3,5-Tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.0 g, 3.2 mmol), O-(phenylmethyl)hydroxylamine hydrochloride (0.77 g, 4.8 mmol) and diisopropylethylamine (1.03 g, 8.0 mmol) were dissolved in dioxan (50 ml). The reaction mixture was heated at reflux for 20 h, filtered and evaporated in vacuo. The crude product was coevaporated with dichloromethane and crystallised from a mixture of dichioromethane and methanol to provide the title compound (1.0 g, 43%), as white crystals, mp 115°-119° C., 1H NMR (CDCl3)γ 3.52-3.70 (2H, m, H-5'a and H-5'b) 3.95 (1H, d, H-4'), 4.15 (1H, dd, H-3'), 4.52 (1H, dd, H-2'), 5.00 (2H, s, CH2), 5.88 (1H, d, H-1'), 8.52 (1H, s, H-8).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([NH2:23])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.[OH:24]OS([O-])=O.[K+]>O1CCCC1.O>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([NH2:23])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:24]
Reactant: O=S([O-])OO
Reactant: CSc1ccc(-c2coc3ccc(-c4nnc(N)o4)cc23)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)c1ccc(-c2coc3ccc(-c4nnc(N)o4)cc23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 5.8 %

Procedure:
To a solution of 5-[3-[4-(methylthio)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazol-2-amine (0.25 g, 0.77 mmol) in tetrahydrofuran (10 mL) was added a solution of oxone (registered trade mark, 0.24 g, 0.77 mmol) in water (3 mL) at 0° C., and the mixture was stirred at 0° C. for 30 min and at room temperature for 1 hr. Water was added to the reaction mixture, and the precipitate was collected by filtration and purified by preparative HPLC to give the title compound (15.2 mg, yield 6%) as colorless crystals.
Reaction SMILES: [C:1]1([S:7]([O-:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH2:12][P+:13]([CH2:18]O)([CH2:16]O)[CH2:14]O.[CH3:20][NH:21][C:22]([NH:24][CH3:25])=[O:23]>C1(C)C=CC=CC=1>[C:1]1([S:7]([O-:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:23]=[C:22]1[N:24]([CH3:25])[CH2:16][P+:13]2([CH2:12][N:24]([CH3:25])[C:22](=[O:23])[N:21]([CH3:20])[CH2:14]2)[CH2:18][N:21]1[CH3:20]
Reactant: OC[P+](CO)(CO)CO
Reactant: CNC(=O)NC
Agent: O=S(=O)([O-])c1ccccc1
Solvent: Cc1ccccc1
Product: CN1C[P+]2(CN(C)C1=O)CN(C)C(=O)N(C)C2
Yield: 111.2 %

Procedure:
Reaction of tetrakis(hydroxymethyl)phosphonium benzenesulfonate (31.23 g, 0.1 mol) with 1,3-dimethylurea (17.62 g, 0.2 mol) in toluene (100 ml), following Example 19, gave 46.30 g of 3,9-dioxo-2,4,8,10-tetramethyl-2,4,8,10-tetraaza-6-phosphoniaspiro [5.5]undecane benzenesulfonate (II, R=R'=CH3, X=SO3C6H5) as a caramel-colored, low-melting solid.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3](=[S:16])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:6]=1[C:12]([O:14][CH3:15])=[O:13].[H-].[Na+].I[CH3:21].O>CN(C)C=O>[CH3:17][N:2]([CH3:1])[C:3](=[S:16])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:21])[C:6]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1c(O)cccc1OC(=S)N(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(OC)cccc1OC(=S)N(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of O-2-carbomethoxy-3-hydroxyphenyl dimethylthiocarbamate (1.0 g, 3.9 mmol) in N,N-dimethylformamide (10 ml) was added dropwise with stirring to a suspension of sodium hydride (0.19 g, 3.9 mmol) in N,N-dimethylformamide (15 ml) cooled to 0° C. in an ice bath. The reaction mixture was stirred for 1 hour at room temperature. Iodomethane (0.26 ml, 4.3 mmol) was added, and stirring was continued for an additional 3 hours, at which time the mixture was poured into water. Extraction with diethyl ether followed by washing of the extracts with water (3×), saturated aqueous sodium chloride solution, drying (sodium sulfate), and evaporation gave a syrup that was triturated with methanol to afford O-2-carbomethoxy-3-methoxyphenyl dimethylthiocarbamate as a white crystalline solid; yield 0.80 g (76%). NMR (CDCl3, 60 MHz: δ3.30 (d, NME2) p.p.m.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][C:23]([CH3:25])=[CH2:24])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([OH:19])=O)=[CH:13][CH:12]=1)[CH2:9][CH3:10].[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][S:34]([NH2:37])(=[O:36])=[O:35])[CH2:28][CH2:27]1>>[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][S:34]([NH:37][C:17]([C:14]2[N:15]=[N:16][C:11]([N:8]([CH2:7][C:6]3[CH:20]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:21][CH2:22][C:23]([CH3:25])=[CH2:24])[CH2:9][CH3:10])=[CH:12][CH:13]=2)=[O:19])(=[O:36])=[O:35])[CH2:28][CH2:27]1
Reactant: C=C(C)COc1ccc(Cl)cc1CN(CC)c1ccc(C(=O)O)nn1
Reactant: NS(=O)(=O)CCN1CCOCC1
Product: C=C(C)COc1ccc(Cl)cc1CN(CC)c1ccc(C(=O)NS(=O)(=O)CCN2CCOCC2)nn1

Procedure:
The title compound was prepared by reacting 6-[N-(5-chloro-2-(2-methylprop-2-enyloxy)benzyl)-N-ethylamino]pyridazine-3-carboxylic acid (example 19) and 2-(morpholino)ethanesulphonamide using a similar method to that described in example 20 (yield 43%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:26][C:27]1[C:35]([CH3:36])=[CH:34][C:30]2[N:31]=[CH:32][NH:33][C:29]=2[CH:28]=1.C(N(CC)CC)C>CC([O-])=O.CC([O-])=O.[Cu+2].C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:13])[O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N:31]3[C:30]4[CH:34]=[C:35]([CH3:36])[C:27]([CH3:26])=[CH:28][C:29]=4[N:33]=[CH:32]3)=[CH:19][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(B(O)O)cc2)cc1
Reactant: Cc1cc2nc[nH]c2cc1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(-n3cnc4cc(C)c(C)cc43)cc2)cc1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
A mixture of 4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)oxy]ethyl}phenylboronic acid (100 mg, 0.28 mmol), 5,6-dimethylbenzimidazole (40 mg, 0.28 mmol), Cu(OAc)2 (60 mg, 0.33 mmol), triethylamine (115 μl, 0.83 mmol), MS4A (100 mg), and CH2Cl2 (4 ml) was stirred at room temperature for 1 week. After filtration through a bed of celite, the filtrate was diluted with CH2Cl2, and washed with water. The organic fraction was dried over MgSO4 and filtered. After concentration under reduced pressure, the residue was purified by preparative TLC (CH2Cl2/MeOH=10/1) to afford 28 mg (22%) of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:29][CH3:30])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[NH:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:15]1)=[O:4].Cl[C:32]1[N:40]=[CH:39][N:38]=[C:37]2[C:33]=1[N:34]=[CH:35][N:36]2[CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][O:42]1.CCN(C(C)C)C(C)C>C(O)CCC>[F:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][C:32]2[N:40]=[CH:39][N:38]=[C:37]3[C:33]=2[N:34]=[CH:35][N:36]3[CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)[CH2:29][CH3:30])=[C:7]([NH:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][CH2:21][O:22][C:23](=[O:28])[C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:15]2)[CH:8]=1
Reactant: CC[C@H](N)C(=O)Nc1ccc(F)cc1N[C@@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC[C@H](Nc1ncnc2c1ncn2C1CCCCO1)C(=O)Nc1ccc(F)cc1N[C@@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Temperature: 100 °C
Reaction time: 16 h
Yield: 59.4 %

Procedure:
A mixture of 2,2-dimethylpropionic acid 2-{(R)-3-[2-((S)-2-aminobutyrylamino)-5-fluorophenylamino]piperidin-1-yl}ethyl ester (0.588 g, 1.39 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.333 g, 1.39 mmol), and DIPEA (0.71 mL, 4.15 mmol) in n-butanol (6 mL) was stirred in a sealed vial at 100° C. for 16 h. After cooling to RT, volatiles were removed in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 2-10% 2M NH3/MeOH in DCM) affording the title compound as a light brown gum (0.516 g, 59%). LCMS (Method B): RT 2.47 min [M+H]+ 625.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[C:41]([C:43]1[CH:44]=[C:45]([S:49](Cl)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1)#[N:42]>O1CCCC1.O>[C:41]([C:43]1[CH:44]=[C:45]([S:49]([N:7]2[C:8]([C:9]3[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=3)=[C:4]([F:3])[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6]2)(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1)#[N:42]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2cccc(C#N)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 17 h
Yield: 91.4 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added dropwise a solution (5 mL) of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (323 mg) in tetrahydrofuran, 15-crown-5 (330 mg) and 3-cyanobenzenesulfonyl chloride (302 mg) under ice-cooling and the mixture was stirred for 17 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→2:1) to give the title compound as a pale-yellow oil (yield 446 mg, 91%).
Reaction SMILES: [OH:1][CH:2]1[O:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.[C:9](Cl)(=[O:12])[O:10][CH3:11].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][O:10][C:9]([O:1][CH:2]1[O:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1)=[O:12]
Reactant: COC(=O)Cl
Reactant: O=C1C=CC(O)OC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)OC1C=CC(=O)CO1
Temperature: 0 °C
Reaction time: 3 h
Yield: 60.2 %

Procedure:
12 g of 6-hydroxy-2H-pyran-3(6H)-one was dissolved in 100 ml of methylene chloride, and the solution was cooled to 0° C. Then, 9.4 g of methyl chlorocarbonate was added thereto, and a solution comprising 10.6 g of triethylamine and 20 ml of methylene chloride was dropwise added thereto. The mixture was stirred for 3 hours, and the reaction mixture was poured into ice water and extracted with methylene chloride. The solvent was distilled off under reduced pressure, and the residue was subjected to distillation under reduced pressure to obtain 10.3 g (yield: 60%) of the above-identified compound.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:10][CH:9]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7].[O:36]1[CH2:38][CH:37]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CO>[F:35][C:2]([F:34])([F:1])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:15][CH2:16][N:17]([CH2:38][CH:37]([OH:36])[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:18][CH2:19]2)[CH2:10][C@@H:9]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(N2CCNCC2)CC1Cc1ccccc1
Reactant: c1ccc(C2CO2)cc1
Solvent: CO
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(CC(O)c3ccccc3)CC2)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.4 %

Procedure:
A mixture of compound 15 (0.005 mol) and 1,2-epoxyethylbenzene (0.006 mol) in methanol (50 ml) was stirred at RT for 1 hour. The mixture was stirred and refluxed for 3 hours. The solvent was evaporated and the residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0, 99/1 and 98/2). The pure fractions were collected and the solvent was evaporated. The residue was purified by HPLC over silica gel (eluent: CH2Cl2/CH3OH 98/2 to 95/5). Two pure fractions were collected and their solvents were evaporated. Each residue was dried, yielding 0.7 g (23%) of (±)-cis-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(2-hydroxy-2-phenylethyl)-1piperazinyl]-2-(phenylmethyl)piperidine (compound 60) and 0.23 g (7%) of (±)-cis-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(2-hydroxy-2-phenylethyl)-1piperazinyl]-2-(phenylmethyl)piperidine (compound 61).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[C:16](F)[CH:15]=[C:14]([Br:19])[CH:13]=1.O>C1COCC1>[CH2:1]([O:8][C:16]1[CH:17]=[C:12]([Br:11])[CH:13]=[C:14]([Br:19])[CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Fc1cc(Br)cc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1cc(Br)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 104 %

Procedure:
Benzylalcohol (9.7 ml, 94 mmol) was added dropwise to a suspension of NaH (4.0 g of a 60% suspension in mineral oil, 100 mmol) in THF (150 ml) at room temperature and the mixture was stirred at room temperature for 1 h before 1,3-dibromo-5-fluorobenzene (15.9 g, 62.5 mmol) was added. The reaction was stirred at room temperature for 12 h. Water was added carefully and the THF was evaporated under reduced pressure. The residue was extracted with iso-hexane (×3) and the combined organic extracts were washed with NaOH solution (1M aq). water, brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc:petroleum ether) to give 1-benzyloxy-3,5-dibromobenzene (14.7 g, 65 mmol) as a colourless liquid in 69% yield. 1H NMR (CDCl3) δ 7.45-7.33 (m, 5H), 7.30-7.28 (m, 1H), 7.10-7.08 (m, 2H), 5.02 (s, 2H).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([O:16][CH:17]1[C:23]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=2[N:21]([C:29](=[O:48])[C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:45])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[CH3:44])=[CH:32][C:31]=2[O:46][CH3:47])[CH2:20][CH2:19][CH2:18]1)=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=O)(C)(C)C.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[NH2:8][C@H:9]([C:14]([O:16][CH:17]1[C:23]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=2[N:21]([C:29](=[O:48])[C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:45])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[CH3:44])=[CH:32][C:31]=2[O:46][CH3:47])[CH2:20][CH2:19][CH2:18]1)=[O:15])[CH2:10][CH2:11][S:12][CH3:13]
Reactant: COc1cc(NC(=O)c2ccccc2C)ccc1C(=O)N1CCCC(OC(=O)[C@H](CCSC)NC(=O)OC(C)(C)C)c2cc(Cl)ccc21
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(NC(=O)c2ccccc2C)ccc1C(=O)N1CCCC(OC(=O)[C@@H](N)CCSC)c2cc(Cl)ccc21
Yield: 32.2 %

Procedure:
A uniform solution of 5-(N-tert-butoxycarbonyl-L-methionyloxy)-7-chloro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.27 g), trifluoroacetic acid (2.5 ml) and anisole (0.6 ml) is stirred at room temperature for 2 hours. The trifluoroacetic acid is almost distilled off under reduced pressure, and the residue is acidified with an 0.2 N aqueous sodium hydroxide solution, and the mixture is extracted with dichloromethane. The dichloromethane layer is washed with water, dried over magnesium sulfate and concentrated. The resulting residue is purified by silica gel column chromatography (eluent; ethyl acetate) to give Isomer A (0.34 g) and Isomer B (0.35 g) of 5-(L-methionyloxy)-7-chloro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine.
Reaction SMILES: [C:1]1([C:7]2[CH:35]=[CH:34][CH:33]=[CH:32][C:8]=2[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[C:24](=O)[CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][C:44]([NH2:46])=[S:45]>>[N:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][C:44]1[S:45][C:23]2[CH2:22][CH2:21][N:20]([C:18]([C:15]3[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[C:8]4[CH:32]=[CH:33][CH:34]=[CH:35][C:7]=4[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:13][CH:14]=3)=[O:19])[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[C:24]=2[N:46]=1
Reactant: O=C(Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1)c1ccccc1-c1ccccc1
Reactant: NC(=S)Cc1ccccn1
Agent: Cl
Product: O=C(Nc1ccc(C(=O)N2CCc3sc(Cc4ccccn4)nc3-c3ccccc32)cc1)c1ccccc1-c1ccccc1
Yield: 58.3 %

Procedure:
Using 400 mg of 2-phenyl-4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]benzanilide and 370 mg of 2-pyridylthioacetamide hydrochloride, the procedure of Example 5 was repeated, and the resulting free base was recrystallized from chloroform-diethyl ether to obtain 300 mg of 4'-[[2-(2-pyridylmethyl)-5,6-dihydro-4H-thiazolo[5,4-d][1]benzazepin-6-yl)carbonyl]-2-phenylbenzanilide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH:11]2[CH2:13][O:12]2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[OH:14][CH2:15][C@H:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1>CCO>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([CH:11]([OH:12])[CH2:13][N:21]2[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:17][C@H:16]2[CH2:15][OH:14])=[CH:10][C:3]=1[O:2][CH3:1])#[N:6]
Reactant: COc1cc(C2CO2)ccc1C#N
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Solvent: CCO
Product: COc1cc(C(O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)ccc1C#N
Temperature: 25 °C

Procedure:
A Pyrex vessel was charged with magnetic stirring bar, (0.350 g, 2.00 mmol) of 2-methoxy-4-(oxiran-2-yl)benzonitrile, (0.457 g, 2.20 mmol) of tert-butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate, and 6 mL of EtOH. Then it was introduced in the microwave reactor and irradiated at 150° C. for 3 h. Then the mixture was cooled to RT and the solvent was evaporated and the resulting residue was purified by column chromatography (silica gel, 1-20% dichloromethane/MeOH) which afforded the title compound as a mixture of two diastereomers (1:1). LC/MS: (IE, m/z) [(M+1)-t-Bu]+=336.1.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[CH3:13][C:14]([O:17][C:18](=[O:27])[NH:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]#[N:26])([CH3:16])[CH3:15]>C(O)C>[CH3:16][C:14]([O:17][C:18](=[O:27])[NH:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:24][C:25]#[N:26])[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])([CH3:13])[CH3:15]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: CC(C)(C)OC(=O)NCCCNCC#N
Solvent: CCO
Product: CCOc1c(N(CC#N)CCCNC(=O)OC(C)(C)C)c(=O)c1=O
Yield: 90.2 %

Procedure:
A solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (2.6 mL, 18 mmol) in absolute ethanol (90 mL) was treated with [3-(cyanomethylamino)propyl]carbamic acid 1,1-dimethylethyl ester (3.90 g, 18 mmol) in ethanol (30 mL) over 90 min. After 40 hours the reaction mixture was evaporated, dissolved in dichloromethane, preadsorbed onto silica gel, and purified by flash chromatography (7 cm diameter, gradient elution with 0-5% methanol in dichloromethane) to yield [3-[(cyanomethyl)-(2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)amino]propyl]carbamic acid 1,1-dimethylethyl ester as a yellow oil (5.48 g, 90%); IR (neat, cm-1): 3360, 1800; MS (+FAB): 282 (76), 238 (98), 158 (100); 1H NMR (CDCl3, 400 MHz): δ 4.81 (q, J=7 Hz, 2H), 4.75 (br s, NH), 4.45, 3.66 (s, 2H), 3.84, 3.60 (br m, 2H), 3.26-3.15 (m, 2H), 1.91 (p, J=6.5 Hz, 2H), 1.50 (t, J=7 Hz, 3H), 1.45 (s, 9H).
Reaction SMILES: [CH:1]1[C:7]([F:8])=[C:6]([NH2:9])[NH:5][C:3](=[O:4])[N:2]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[C:15](Cl)=[O:16].O>N1C=CC=CC=1>[F:8][C:7]1[C:6]([NH:9][C:15](=[O:16])[C:14]2[CH:13]=[C:12]([O:11][CH3:10])[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=2)=[N:5][C:3](=[O:4])[NH:2][CH:1]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: Nc1[nH]c(=O)ncc1F
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(C(=O)Nc2nc(=O)[nH]cc2F)cc(OC)c1OC
Yield: 90.4 %

Procedure:
To a suspension of 12.9 g of fluorocytosine in 78 ml of pyridine was added 23.1 g of 3,4,5-trimethoxybenzoyl chloride, and the mixture was reacted at 100° C. for 5 hours. After the completion of reaction, the reaction mixture was poured into 300 ml of water at room temperature with stirring. After stirring the resulting mixture for additional 3 hours, the precipitated crystals were collected by filtration, washed with water and then dried to obtain 29.2 g of 5-fluoro-N4 -(3,4,5-trimethoxybenzoyl)cytosine.