Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]([CH3:22])=[N:10][N:9]=2)=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH:38](O)=[O:39]>ClCCl>[CH:38]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]([CH3:22])=[N:10][N:9]=2)=[CH:4][CH:3]=1)=[O:39]
Reactant: O=CO
Reactant: CC1=NN=C(c2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC1=NN=C(c2ccc(NC=O)cc2)c2cc3c(cc2C1)OCO3
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
3.0 g (10.2 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine were dissolved in 160 ml of dichloromethane and first 2.75 g (13.3 mmol) of dicyclohexylcarbodiimide, then 0.51 ml (13.3 mmol) of 100% formic acid were added and the reaction mixture was stirred for 2 hours at room temperature. The precipitated N,N'-dicyclohexylurea was filtered, the filtrate was extracted with 2×30 ml of 10% aqueous sodium carbonate solution, then with 2×30 ml of distilled water, the organic layer was dried and evaporated at reduced pressure. The residue was dissolved in ethyl acetate, filtered and evaporated under reduced pressure. The resulting raw product was recrystallized from 20 ml of 50% ethanol to yield 2.93 g (89.3%) of the aimed product, m.p. 152°-154° C. (slight decomp.).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[NH2:23]>>[O:11]([C:9]1[CH:8]=[CH:7][N:6]=[C:5]([NH:23][C:22]2[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:20]([O:19][CH3:18])[CH:21]=2)[N:10]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)c1nccc(Oc2ccccc2)n1
Reactant: COc1cc(N)cc(OC)c1OC
Product: COc1cc(Nc2nccc(Oc3ccccc3)n2)cc(OC)c1OC
Yield: 1.7 %

Procedure:
2-Methylsulphonyl-4-phenoxypyrimidine (0.76 g, 3.04 mmol) and 3,4,5-trimethoxyaniline (0.56 g, 4.0 mmol) were heated as a melt at 140° for 2 h. On cooling the residue was partitioned between ethyl acetate (50 ml) and 2M hydrochloric acid (50 ml), and the organic layer was washed with water (50 ml), dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to column chromatography [silica 20% ethyl acetate-hexane] to give the title compound (18 mg) as a white solid m.p. 149° after recrystallisation from ethyl acetate. δH (CDCl3) 8.26 (1H, d, J 5.6 Hz), 7.39 (2H, m), 7.26 (1H,m), 7.18-7.15 (2H, m), 6.73 (2H, s), 6.31 (1H, d, J 5.6 Hz), 3.77 (3H, s) and 3.64 (6H, s). MS m/z 354 (M+H)+.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:14][CH2:15][C@@H:16]1[O:21][CH2:20][C@@:19]([NH:30][C:31]([NH:33][C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[S:32])([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])[C@H:18]([CH2:42]O)[CH2:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.O>ClCCl>[CH2:7]([O:14][CH2:15][C@@H:16]1[O:21][CH2:20][C@:19]2([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])[N:30]=[C:31]([NH:33][C:34](=[O:41])[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[S:32][CH2:42][C@@H:18]2[CH2:17]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(NC(=S)N[C@@]1(c2ccc(F)cc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](COCc3ccccc3)C[C@H]2CS1)c1ccccc1
Temperature: -55 °C

Procedure:
Pyridine (11.0 mL, 137 mmol) was added to a solution of C7 (19.00 g, 36.08 mmol) in dichloromethane (150 mL), and the resulting solution was cooled to −50 to −60° C. Trifluoromethanesulfonic anhydride (12.1 mL, 71.9 mmol) in dichloromethane (50 mL) was added drop-wise, and the reaction mixture was gradually warmed to −5° C. over 3 hours. Water was added, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 20% to 40% ethyl acetate in heptane) provided the product as a yellow foam. Yield: 15.51 g, 30.50 mmol, 85%. LCMS m/z 509.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.23 (br d, J=7 Hz, 2H), 7.37-7.57 (br m, 4H), 7.24-7.36 (m, 5H), 6.85-6.97 (m, 2H), 4.58 (AB quartet, upfield signals are slightly broadened, JAB=11.9 Hz, ΔνAB=23.5 Hz, 2H), 4.17 (br d, J=12 Hz, 1H), 3.90-3.97 (m, 1H), 3.83 (br d, J=12 Hz, 1H), 3.64 (dd, half of ABX pattern, J=10.1, 6.4 Hz, 1H), 3.50 (dd, half of ABX pattern, J=10.2, 4.4 Hz, 1H), 3.11-3.21 (br m, 1H), 3.02 (dd, J=12.9, 4.1 Hz, 1H), 2.64 (br d, J=13 Hz, 1H), 1.92-2.05 (br m, 1H), 1.71 (br d, J=13 Hz, 1H).
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[CH2:6]([O:8][C:9](=[O:17])[C:10](=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:7]>[I-].[Zn+2].[I-]>[CH3:5][C:3]1[CH2:4][C:10]([C:9]([O:8][CH2:6][CH3:7])=[O:17])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:16][CH2:1][CH:2]=1
Reactant: C=CC(=C)C
Reactant: CCOC(=O)C(=O)C(=O)OCC
Agent: [I-]
Agent: [Zn+2]
Product: CCOC(=O)C1(C(=O)OCC)CC(C)=CCO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 3.5 %

Procedure:
To 50 g (0.70 mol) isoprene was added 25 g (0.14 mol) diethylketomalonate and 0.78 g (2.4 mmol) zinc iodide. The reaction mixture was stirred at room temperature for 48 hours. The excess isoprene was removed under vacuum. Flash chromatography in 20:1 hexanes:ethyl acetate yielded 1.2 g of oil.
Reaction SMILES: [C:1]([C:5]1[O:9][CH:8]=[N:7][C:6]=1[CH:10]=[C:11]([OH:15])[C:12]([OH:14])=O)([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:40][C@H:41]([C:49]([NH2:51])=[O:50])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([C:5]1[O:9][CH:8]=[N:7][C:6]=1[CH:10]=[C:11]([OH:15])[C:12]([NH:40][C@H:41]([C:49](=[O:50])[NH2:51])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ocnc1C=C(O)C(=O)O
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ocnc1C=C(O)C(=O)N[C@@H](Cc1ccccc1)C(N)=O

Procedure:
To a solution of compound 3 (2.6 g, 12.3 mmol) in DMF was added HOBt.H2O (2.26 g, 14.76 mmol), EDC.HCl (2.80 g, 14.76 mmol), HCl.H-Phe-NH2 (3.16 g, 14.76 mmol), triethylamine (1.72 mL, 12.3 mmol) sequentially at 0° C. and the mixture was stirred for 14 h at room temperature. After the solvent was removed in vacuo, the residue was dissolved in AcOEt and washed with 5% citric acid, 5% NaHCO3 and saturated NaCl for three times, respectively. Then, the organic layer was dried over Na2SO4 and evaporated in vacuo. The resultant crude product was purified by silica-gel column chromatography (CHCl3:MeOH=100:1 to 10:1) to obtain the desired compound 4; yield 1.9 g (43.4%); m.p. 49-53° C.; 1H NMR (300 MHz, CDCl3) δ 11.04 (s, 1H), 7.82 (s, 1H), 7.34-7.22 (m, 5H), 6.24 (s, 1H), 5.96 (br s, 1H), 5.45 (br s, 1H), 4.78-4.71 (m, 1H), 3.24-3.11 (m, 2H), 1.38 (s, 9H); HRMS (EI): m/z 357.1689 (M+) (calced for C19H23N3O4: 357.1688).
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: O=C1C=CC(O)OC1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
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: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][N+:8]([O-:10])=[O:9].[CH3:16][N:17]([CH3:21])[C:18](=[S:20])[S-:19].C[NH2+]C>C(=S)=S>[CH3:16][N:17]([CH3:21])[C:18](=[S:19])[S:20][CH:6]([CH2:7][N+:8]([O-:10])=[O:9])[C:5]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CN(C)C(=S)[S-]
Reactant: COc1ccc(C=C[N+](=O)[O-])cc1OC
Agent: C[NH2+]C
Solvent: S=C=S
Product: COc1ccc(C(C[N+](=O)[O-])SC(=S)N(C)C)cc1OC

Procedure:
As in Example 17, reaction of 3,4-dimethoxy-β-nitrostyrene with dimethylammonium dimethyldithiocarbamate in the presence of carbon disulfide gave 3,4-dimethoxy-α-(nitromethyl)-benzyl dimethyldithiocarbamate melting at 108° C.-110° C. after recrystallization without heating from acetone-methanol solution.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:6]3[N:7]([C:11]([C:21]4[CH:26]=[CH:25][N:24]=[C:23](SC)[N:22]=4)=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=4)[N:13]=3)[CH:8]=[CH:9][N:10]=2)[CH2:3][CH2:2]1.O[O:30][S:31]([O-:33])=O.[K+].[C:35]([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CO.O>[CH:1]1([CH2:4][C:5]2[C:6]3[N:7]([C:11]([C:21]4[CH:26]=[CH:25][N:24]=[C:23]([S:31]([CH3:35])(=[O:33])=[O:30])[N:22]=4)=[C:12]([C:14]4[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=4)[N:13]=3)[CH:8]=[CH:9][N:10]=2)[CH2:2][CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: CSc1nccc(-c2c(-c3ccc(F)cc3)nc3c(CC4CC4)nccn23)n1
Reactant: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)nc3c(CC4CC4)nccn23)n1
Reaction time: 4 h
Yield: 85 %

Procedure:
To a solution of 8-cyclopropylmethyl-2-(4-fluorophenyl)-3-(2-methylsulfanylpyrimidin-4-yl)imidazo[1,2-a]pyrazine (5.16 g, 13.2 mmol) in DCM (50 mL) and MeOH (50 mL) was added a solution of Oxone® (16.2 g, 26.4 mmol) in water (50 mL). After about 4 h of rapid stirring, the mixture was neutralized with saturated Na2CO3 solution and extracted with DCM. The combined organic phase was dried over Na2SO4 and concentrated. The crude material was purified by silica gel chromatography with heptane/EtOAc (gradient 50-100% EtOAc). After concentration, the residue was three times re-dissolved in DCM and re-concentrated to give 4.77 g (85%) of the title compound as a yellowish solid: LC/MS (Table 1, Method g) Rt=2.68 min; MS m/z: 424.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:19][O:20][C:21]([C:23]1[CH:40]=[CH:39][CH:38]=[CH:37][C:24]=1[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1)=[O:22].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[CH2:12]([N:11]([CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[C:34](=[O:35])[CH2:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][CH2:25][C:24]2[CH:37]=[CH:38][CH:39]=[CH:40][C:23]=2[C:21]([O:20][CH3:19])=[O:22])=[CH:28][CH:29]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCNCCc1ccccc1OC
Reactant: COC(=O)c1ccccc1COc1ccc(CC(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCN(CCc1ccccc1OC)C(=O)Cc1ccc(OCc2ccccc2C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
N-[2-(2-Methoxyphenyl)ethyl]heptan-1-amine (0.091 g, 0.366 mmol) was dissolved in DMF (5 ml), (4-{[2-(methoxycarbonyl)benzyl]oxy}phenyl)acetic acid (0.100 g, 0.333 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-Benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.118 g, 0.366 mmol) and N-ethyl-N,N-diisopropylamine (0.090 g, 0.699 mmol) were added. The solution was stirred overnight at room temperature. EtOAc (20 ml) was added and the organic phase was washed with two portions of water (2×20 ml). The organic layer was dried (MgSO4) and the solvent was removed by evaporation. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4) and the solvent was removed by evaporation to give 0.094 g of methyl 2-{[4-(2-{heptyl[2-(2-methoxyphenyl)ethyl]amino}-2-oxoethyl)phenoxy]methyl}benzoate (yield 53.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH:9]2[CH:14]([OH:15])[C:13]([CH3:17])([CH3:16])[O:12][C:11]3[CH:18]=[CH:19][S:20][C:10]2=3)=[O:7])=[CH:4][CH:3]=1.[N+:23]([O-])([OH:25])=[O:24].[K+].[Br-]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]2[CH:14]([OH:15])[C:13]([CH3:17])([CH3:16])[O:12][C:11]3[CH:18]=[C:19]([N+:23]([O-:25])=[O:24])[S:20][C:10]2=3)=[O:7])=[CH:21][CH:22]=1
Reactant: O=[N+]([O-])O
Reactant: CC1(C)Oc2ccsc2C(NC(=O)c2ccc(Cl)cc2)C1O
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC1(C)Oc2cc([N+](=O)[O-])sc2C(NC(=O)c2ccc(Cl)cc2)C1O

Procedure:
The title compound was prepared as described in Example 9 starting with 7-(4-chlorobenzamido)-5,6-dihydro-6-hydroxy-5,5-dimethyl-7H-thieno[3,2-b]pyran (1.23 g, 3.64 mmol) and 90% nitric acid (1.5 mL) in acetic acid (20 mL) to give the product, 0.384 g (28%), as a yellow solid: mp 226°-229° C. dec; IR (KBr): 3315, 1655, 1535 and 1503 cm-1;MS: m/z 383 (MH+); 1H NMR (DMSO-d6): δ 1.25 (s, 3H), 1.44 (s, 3H), 3.90 (m, 1H, simplifies to d, J=8.9 Hz with D2O), 4.95 (m, 1H, simplifies to d, J=8.9 Hz, with D2O), 5.94 (d, J=6.0 Hz, 1H exchanges with D2O), 7.60 (d, J=8.6 Hz, 2H), 7.72 (s, 1H), 7.94 (d, J=8.6 Hz, 2H) and 9.11 (d, J=7.6 Hz, 1H, exchanges with D2O).
Reaction SMILES: [C:1]1([C@H:7]2[C:12]3[NH:13][C:14]4[C:19]([C:11]=3[CH2:10][C@H:9]([C:20](OC)=[O:21])[NH:8]2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:24]1([N:30]=[C:31]=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([N:30]2[C:20](=[O:21])[C@H:9]3[N:8]([C@@H:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:12]4[NH:13][C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=5[C:11]=4[CH2:10]3)[C:31]2=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C=NC1CCCCC1
Reactant: COC(=O)[C@H]1Cc2c([nH]c3ccccc23)[C@H](c2ccccc2)N1
Product: O=C1[C@@H]2Cc3c([nH]c4ccccc34)[C@H](c3ccccc3)N2C(=O)N1C1CCCCC1

Procedure:
The same method as employed in the preparation of Example 1 but starting from trans methyl 1,2,3,4-tetrahydro-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxylate and cyclohexyl isocyanate gave after recrystallisation from methanol, the title compound as white crystals m.p.:248-250° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C1C(=O)N([Br:18])C(=O)C1>CN(C=O)C.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][C:3]=1[Br:18]
Reactant: Nc1ccc(CCO)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(CCO)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
To a solution of 2-(4-amino-phenyl)-ethanol (5.10 g, 37.2 mmol) in 37 mL of DMF was added NBS (6.60 g, 37.1 mmol) and the mixture stirred overnight at RT. The reaction was diluted with 100 mL of water and extracted with EtOAc (3×100 mL). The organic layer was washed with brine (200 mL) and dried over Na2SO4. The title compound was purified by silica gel flash chromatography eluting with 50% EtOAc/hexanes to give 5.10 g (64%) of a white solid. Mass spectrum (ESI, m/z): Calcd. for C8H10BrNO, 216.0 (M+H), found 216.1.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C@H:10]([NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@@H:14]1[C:19](OC)=[O:20])=[O:12].C[Al](C)C.C1(C)C=CC=CC=1>C(Cl)CCl>[O:20]=[C:19]1[NH:8][CH2:9][C@H:10]([NH:23][C:24](=[O:25])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:11](=[O:12])[N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]12
Reactant: COC(=O)[C@H]1CCCCN1C(=O)[C@H](CN)NC(=O)OCc1ccccc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: O=C(N[C@H]1CNC(=O)[C@H]2CCCCN2C1=O)OCc1ccccc1
Temperature: 75 °C
Reaction time: 72 h
Yield: 16.7 %

Procedure:
To a solution of (R)-methyl 1-((S)-3-amino-2-(benzyloxycarbonylamino)propanoyl)piperidine-2-carboxylate trifluoroacetate (601 mg, 1.26 mmol) in ClCH2CH2Cl (10 mL) at rt was added trimethylaluminum in toluene (1.89 mL, 3.78 mmol). The reaction was stirred in a sealed bottle at 75° C. for 3 days. After cooling to rt, the reaction was quenched with water and then aqueous 1 N HCl solution until the solution became clear. The aqueous solution was extracted with DCM (2×30 mL). The combined organic layers were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 50-100% EtOAc/Hex to give benzyl (4S,10aR)-1,5-dioxodecahydropyrido[1,2-a][1,4]diazepin-4-ylcarbamate (71 mg, 0.21 mmol, 17% yield) as a white solid. Anal. Calcd. for C17H21N3O4 m/z 331.4. found: 332.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.65-7.02 (m, 5H), 6.20 (d, J=5.5 Hz, 1H), 5.59 (s, 1H), 5.35-4.96 (m, 2H), 4.58 (s, 1H), 4.15 (d, J=13.3 Hz, 1H), 3.99-3.70 (m, 1H), 3.26-2.82 (m, 2H), 2.46-2.14 (m, 1H), 1.93-1.37 (m, 6H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[C:13]3[C:14]([O:18][C@@H:19]4[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]4)=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][N:10]=2)[CH2:3][CH2:2]1.[CH:26]([C:28]1([C:34]([O:36][CH3:37])=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=O.C(C1(C(OC)=O)CCC1)=O>>[OH:25][C@@H:22]1[CH2:23][CH2:24][C@H:19]([O:18][C:14]2[C:13]3[C:9]([O:8][CH2:7][CH:4]4[CH2:5][CH2:6][N:1]([CH2:26][C:28]5([C:34]([O:36][CH3:37])=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH2:2][CH2:3]4)=[N:10][O:11][C:12]=3[CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21]1
Reactant: O[C@H]1CC[C@@H](Oc2cccc3onc(OCC4CCNCC4)c23)CC1
Reactant: COC(=O)C1(C=O)CCOCC1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(O[C@H]5CC[C@@H](O)CC5)c34)CC2)CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using cis-4-{[3-(piperidin-4-ylmethoxy)-1,2-benzisoxazol-4-yl]oxy}cyclohexanol (EXAMPLE 43, Step 2) and methyl 4-formyltetrahydro-2H-pyran-4-carboxylate (EXAMPLE 18, Step 1) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1.[NH2:20][NH2:21]>CO>[O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([NH:20][NH2:21])=[O:15])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:3][CH2:2]1
Reactant: NN
Reactant: COC(=O)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Solvent: CO
Product: NNC(=O)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Temperature: 65 °C
Yield: 74 %

Procedure:
Methyl 4-(morpholinosulfonyl)benzoate (135 mg, 0.473 mmol) was added to the hydrazine (30.3 mg, 0.946 mmol) in methanol and refluxed for 8 h at 65° C. Following cooling, reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by flash chromatography (3% methanol/DCM) to yield the 4-(morpholinosulfonyl)benzohydrazide (102 mg, 0.350 mmol, 74.0% yield) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 7.94 (m, 2H), 7.79 (m, 2H), 3.72 (m, 4H), 2.99 (m, 4H). Mass [M+H]+:286.0
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B2OCCO2)=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].Br[C:18]([C:20]([F:23])([F:22])[F:21])=[CH2:19].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]([C:20]([F:23])([F:22])[F:21])=[CH2:19])=[CH:4][C:3]=1[C:13]([F:14])([F:15])[F:16]
Reactant: Fc1ccc(B2OCCO2)cc1C(F)(F)F
Reactant: C=C(Br)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1ccc(F)c(C(F)(F)F)c1)C(F)(F)F
Temperature: 70 °C
Yield: 23.2 %

Procedure:
The mixture of 2-(4-fluoro-3-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (2.34 g, 10 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (2.10 g, 12 mmol), Pd(Ph3P)2Cl2 (0.281 g, 0.4 mmol) and K2CO3 (2.76 g, 20 mmol) in THF (30 mL) and H2O (15 mL) was heated at 70° C. overnight. Then the reaction mixture was cooled down to rt, added water and extracted with ethyl acetate, washed with brine, dried with Na2SO4, concentrated to dryness to afford the crude product. It was further purified by column chromatography eluted with PE to afford the desired product (0.6 g, yield 23.3%) as light yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.69-7.62 (m, 2H), 7.27-7.21 (t, 1H), 6.05 (d, 1H), 5.80 (d, 1H) ppm.
Reaction SMILES: Br[CH:2]([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][F:6].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>C(#N)C>[ClH:17].[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[O:10][CH:2]([N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][F:6]
Reactant: CC(C)(CF)C(=O)C(Br)Oc1ccc(Cl)cc1Cl
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: CC(C)(CF)C(=O)C(Oc1ccc(Cl)cc1Cl)n1ccnc1
Product: Cl
Yield: 78.6 %

Procedure:
157.5 g (0.44 mol) of 1-bromo-1-(2,4-dichlorophenoxy)-3,3-dimethyl-4-fluoro-2-butanone were dissolved in 500 ml of acetonitrile and the solution was added dropwise to a solution of 109 g (1.6 mol) of imidazole in 600 ml of acetonitrile. The mixture was heated under reflux for 10 hours. Thereafter, the solvent was distilled off under a waterpump vacuum, the residue was taken up in 1,000 ml of methylene chloride and the methylene chloride mixture was washed three times with 500 ml of water each time. The organic phase was dried over sodium sulphate and filtered and the filtrate was concentrated under a waterpump vacuum by distilling off the solvent. The residue was dissolved in 500 ml of ethanol, 40 ml of concentrated hydrochloric acid were added and the solvent was distilled off under a waterpump vacuum. The residue was stirred with 50 ml of ether, whereupon it crystallized. 66 g (39.3% of theory) of 1-(2,4-dichlorophenoxy)-3,3-dimethyl-4-fluoro-1-(imidazol-1-yl)-2-butanone hydrochloride of melting point 91°-110° C. were obtained. ##STR84##