Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19](=[CH2:22])[CH2:20]Br>CN(C=O)C.O>[C:1]1([C:7]([CH2:20][C:19]([CH3:22])=[CH2:18])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=C(C)CBr
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)CC(C(=O)OCC)(C(=O)OCC)c1ccccc1
Reaction time: 0.25 h
Yield: 95 %

Procedure:
NaH (440 mg of a 60% dispersion in mineral oil, 11 mmole) was washed free of mineral oil, and suspended in 20 mL of DMF. This was treated with a solution of diethyl phenylmalonate (2.36 g, 10 mmole) in 10 mL of DMF, and the reaction was stirred for 15 minutes, at which time the solution was clear. 2-Methylallyl bromide (2.0 mL) was added, and stirring continued for 1 hour. The reaction was diluted with H2O and extracted with Et2O. The extracts were washed with H2O, dried and the solvent removed and gave the titled compound, 2.85 g (95% yield). MS (ESI) 291 (MH+)
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH:12]([C:21]1[C:25]([CH:26]2[CH2:28][CH2:27]2)=[C:24]([CH:29]2[CH2:32][CH:31]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:30]2)[O:23][N:22]=1)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])C1C=CC=CC=1.CO>[Pd].O1CCCC1>[CH:26]1([C:25]2[C:21]([CH:12]([CH2:11][CH2:10][CH2:9][OH:8])[CH2:13][C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[N:22][O:23][C:24]=2[CH:29]2[CH2:30][CH:31]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:32]2)[CH2:27][CH2:28]1
Reactant: CC(C)(C)CC1CC(c2onc(C(CCCOCc3ccccc3)CC(=O)OC(C)(C)C)c2C2CC2)C1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)CC1CC(c2onc(C(CCCO)CC(=O)OC(C)(C)C)c2C2CC2)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
tert-Butyl 6-benzyloxy-3-{4-cyclopropyl-5-[3-(2,2-dimethylpropyl)cyclobutyl]isoxazol-3-yl]hexanoate (980 mg), methanol (10 mL) and tetrahydrofuran (3 mL) were mixed. To the mixture was added 7.5 w/w % palladium on activated carbon (200 mg). The mixture was stirred at RT under hydrogen atmosphere (1 atm) for 5 hr. The catalyst was freshened up, and the mixture was stirred at RT under hydrogen atmosphere (1 atm) overnight. The 7.5 w/w % palladium on activated carbon was filtered off and the filtrate was concentrated in vacuo.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:17]([C:16]2[CH:20]=[CH:21][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[O:18])=[CH:7][CH:6]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: ClCCOc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(OCCCl)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
To a stirred solution of 1-(2-chloroethoxy)benzene (48 g, 1.0 eq) in 400 mL CH2Cl2 at 0° C. was added dropwise a solution of 4-methoxybenzoyl chloride (62 g, 1.2 eq) and AlCl3 (49 g, 1.2 eq) in 400 mL CH2Cl2 while maintaining the temperature at 0° C. After the addition, the reaction was stirred at rt for 1 h. Then added ice water to quench the reaction and extracted with CH2Cl2. The extract was washed with brine, dried and evaporated in vacuo. Hexane (500 mL) was added to the residue, cooled to 0° C. and stirred for 30 min, then filtered and washed with cold hexane and dried to give the product as a white solid (85 g, 96%). 1H NMR (400 MHz, CDCl3) δ7.79 (dd, J=6.8 Hz, 2.0 Hz, 4H), 6.97 (dd, J=8.8 Hz, 2.0 Hz, 4H), 4.32 (t, J=6.0 Hz, 2H), 3.89 (s, 3H), 3.86 (t, J=6.0 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:18])[C:11]([OH:17])([CH3:16])[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].Cl[C:22](OCC)=[O:23]>C1COCC1.[Na].C(C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:10](=[O:18])[C:11]([CH3:16])([C:12]([F:14])([F:15])[F:13])[O:17][C:22]2=[O:23])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)Cl
Reactant: CC(O)(C(=O)Nc1ccc(Cl)c(Cl)c1)C(F)(F)F
Agent: O=C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C(F)(F)F)OC(=O)N(c2ccc(Cl)c(Cl)c2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
3 g of N-(3,4-dichlorophenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropionamide were dissolved in 50 ml of THF distilled beforehand over sodium/benzophenone. 1 g of sodium hydride (NaH), at 60% in oil, was added. The reaction mixture was stirred for 30 min and then cooled to 0-5°. 2.3 g of ethyl chloroformate, in solution in 10 ml of THF, were added without exceeding 5° C. After maintaining overnight at room temperature, the reaction mixture was poured onto 100 ml of ice-cold water and then extracted with 4×50 ml of dichloromethane. The organic phase was washed with 20% sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was purified by silica chromatography (eluent: 1/1 heptane/dichloromethane). 1.25 g of 3-(3,4-dichlorophenyl)-5-methyl-5-(trifluoromethyl)oxazolidine-2,4-dione was obtained, for a yield 38%.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][C:29]1[O:33][N:32]=[C:31]([C:34]2[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=2)[C:37](O)=[O:38])[N:30]=1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:37](=[O:38])[C:36]5[CH:40]=[CH:41][CH:42]=[C:34]([C:31]6[N:30]=[C:29]([CH3:28])[O:33][N:32]=6)[CH:35]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: Cc1nc(-c2cccc(C(=O)O)c2)no1
Agent: Cl
Product: Cc1nc(-c2cccc(C(=O)N[C@H]3CC[C@H](CCN4CCN(c5nccc6c5CCO6)CC4)CC3)c2)no1

Procedure:
The title compound, white solid (125 mg, 97%), MS (ISP) m/z=517.4 [(M+H)+], mp 218° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 3-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzoic acid.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:13])[C:11]#[N:12])=[CH:6][C:5]=1[O:14][CH:15]1[CH2:19][CH2:18][O:17][CH2:16]1>CO.N.[Ni]>[F:20][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:13])[CH2:11][NH2:12])=[CH:6][C:5]=1[O:14][CH:15]1[CH2:19][CH2:18][O:17][CH2:16]1
Reactant: CC(C#N)c1ccc(OC(F)F)c(OC2CCOC2)c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CC(CN)c1ccc(OC(F)F)c(OC2CCOC2)c1
Yield: 98.8 %

Procedure:
A mixture of intermediate 9 (0.0129 mol) in CH3OH/NH3 (100 ml) was hydrogenated at RT with Raney Nickel (3 g) as a catalyst. After uptake of H2, the catalyst was filtered off and the filtrate was evaporated, yielding 3.66 g (98%) of (±)-4-(difluoromethoxy)-β-methyl-3-[(tetrahydro-3-furanyl)oxy]benzeneethanamine (intermediate 10).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([OH:20])=O)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:21]([N:23](CC)[CH2:24][CH3:25])[CH3:22].ClC(OCC)=O.C(NCC)C>C(Cl)(Cl)Cl>[CH2:21]([N:23]([CH2:24][CH3:25])[C:18]([C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:17]2[C:12]([CH:11]=1)=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:20])[CH3:22]
Reactant: O=C(O)c1cc2ccccc2c(-c2cccc(Cl)c2)n1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCNCC
Product: CCN(CC)C(=O)c1cc2ccccc2c(-c2cccc(Cl)c2)n1
Yield: 71.4 %

Procedure:
Operations are carried out as for Example 7, starting with 1.7 g of 1-(3-chlorophenyl) isoquinoline 3-carboxylic acid, 0.69 g of triethylamine, 0.74 g of ethyl chloroformate and 0.56 g of diethylamine in 60 ml of chloroform. 1.45 g of N,N-diethyl 1-(3-chlorophenyl) isoquinoline 3-carboxamide melting at 116° C., are obtained.
Reaction SMILES: [OH2:1].[OH-].[Na+].[CH:4]([C:6]1[CH2:12][C:11]2[CH:13]=[C:14]3[O:19][CH2:18][O:17][C:15]3=[CH:16][C:10]=2[C:9]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([CH3:29])[CH:21]=2)=[N:8][N:7]=1)=[O:5]>O1CCCC1.[N+]([O-])([O-])=O.[Ag+]>[CH3:29][C:22]1[CH:21]=[C:20]([C:9]2[C:10]3[CH:16]=[C:15]4[O:17][CH2:18][O:19][C:14]4=[CH:13][C:11]=3[CH2:12][C:6]([C:4]([OH:1])=[O:5])=[N:7][N:8]=2)[CH:25]=[CH:24][C:23]=1[N+:26]([O-:28])=[O:27]
Reactant: O
Reactant: Cc1cc(C2=NN=C(C=O)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C2=NN=C(C(=O)O)Cc3cc4c(cc32)OCO4)ccc1[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 71 %

Procedure:
To a solution of 3.40 g (20.0 millimoles) of silver(I)nitrate and 25 ml of water a solution of 1.60 g (4.0 millimoles) of sodium hydroxide and 25 ml of water is added. The mixture is stirred for 10 minutes, diluted with 50 ml of tetrahydrofurane and 3.51 g (10.0 millimoles) of 8-formyl-5-(3-methyl-4-nitro-phenyl)-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepine are added under cooling with icecold water. The reaction mixture is stirred at room temperature for 5 hours, filtered on a coal-bed and washed with cold water. The pH of the solution is adjusted to 2 with 6 N hydrochloric acid. After cooling the precipitated product is filtered and washed with 10 ml of cold water. Thus 2.61 g of the desired compound are obtained, yield 71%, mp.: 185–186° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C:5]2[CH:7]=[C:8]3[O:12][C:11]([CH3:14])([CH3:13])[O:10][C:9]3=[CH:15][C:4]=2[O:3]1.C([Li])CCC.C[Mg]Br.C([O:27]CC)C>>[OH:27][C:7]1[C:5]2[O:6][C:2]([CH3:16])([CH3:1])[O:3][C:4]=2[CH:15]=[C:9]2[C:8]=1[O:12][C:11]([CH3:14])([CH3:13])[O:10]2
Reactant: CCOCC
Reactant: CC1(C)Oc2cc3c(cc2O1)OC(C)(C)O3
Agent: C[Mg]Br
Agent: [Li]CCCC
Product: CC1(C)Oc2cc3c(c(O)c2O1)OC(C)(C)O3
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
2,2,6,6-Tetramethylbenzo[1,2-d:4,5-d']-(1,3)dioxole (5.00 g, 22.5 mmol (Example 5)) was dissolved in diethyl ether (150 mL, sodium benzophenone ketyl) under argon. n-Butyl lithium (10.0 mL, 25 mmol, 2.5M in toluene) was added at room temperature followed by methyl magnesium bromide (4.25 mL, 13 mmol, 3.0M in diethyl ether, Aldrich). the resulting mixture was stirred at room temperature for 1 h. Oxygen was bubbled through the solution over a period of 2 hours, while cooling with a cold water bath. The reaction mixture was poured into a solution of NaOH (50 mL, 1M) and extracted with diethyl ether (100 mL). The aqueous phase was acidified with conc. HCl to pH 2 while stirring. The product was isolated by extracting with diethyl ether (3×50 mL). The ether was dried (Na2SO4) and evaporated yielding 1.50 g (6.3 mmol, 28%) of 8-hydroxy-2,2,6,6-tetramethyl-benzo[1,2-d:4,5-d']bis(1,3)dioxole.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1)(=[O:4])=[O:3].[OH-].[Na+]>C(O)C>[CH3:1][S:2]([CH2:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[NH2:12])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)Cc1cccc(N)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
1-Methylsulfonylmethyl-3-nitrobenzene (4.70 g, 21.8 mmol) was added ethanol (70 mL) and the mixture was heated to reflux. At reflux the mixture was added SnCl2 dihydrate (24.6 g, 109 mmol) and heating at reflux was continued for 1 hour. After cooling, the mixture was poured into ice/water (200 mL) and neutralised (to pH 7) with 1 N sodium hydroxide. The mixture was filtered through celite, and the filter cake was washed with ethyl acetate. The phases from the combined filtrate and washings were separated, and the aqueous phase was extracted with ethyl acetate (2×150 mL). The combined organic phases were dried (MgSO4) and evaporated in vacuo to afford 2.23 g (55%) 3-(methylsulfonylmethyl)aniline.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23](C)(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH:7]=1.C(B(CC)CC)C.C([O-])(=O)C.[Na+].[NH2:39]OS(O)(=O)=O>C1COCC1.O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:39])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH:5]=[N:4][CH:3]=1
Reactant: Cc1cncc(-c2nc(C(F)(F)F)cn2-c2ccc(S(C)(=O)=O)cc2)c1
Reactant: NOS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: CCB(CC)CC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cncc(-c2nc(C(F)(F)F)cn2-c2ccc(S(N)(=O)=O)cc2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 9.6 %

Procedure:
To a solution of 3-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine (Example 41) (1.9 mmol) in 25 mL of dry THF was added n-Bu4MgCl (3.8 mL of 2.0M THF solution, 7.5 mmol) slowly at 0° C. After stirring for additional 15 minutes, the solution was stirred at room temperature for 2 hours. The reaction mixture was re-cooled to 0° C. and triethylborane (9.5 mL of 1.0M THF solution, 9.5 mmol) was added. After stirring at for 2 hours, the mixture was heated to reflux for 72 hours. The reaction mixture was cooled to room temperature and treated with a solution of sodium acetate (2.3 g) in 10 mL of water. After stirring for 5 minutes, hydroxylamine-O-sulfonic acid (2.3 g) was added and the mixture was stirred for 20 hours. The reaction mixture was extracted with ether (2×100 mL). The ethereal layer was dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (isopropanol/toluene, 5:95) to give 0.07 g of 4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl) -1H-imidazol-1-yl]benzenesulfonamide as a colorless solid (8%): mp 242°-243° C. Anal. Calc'd. For C16H13F3N4O2S: C, 50.26, H, 3.43, N, 14.65, S, 8.39. Found: C, 50.02, H, 3.63, N, 14.26, S, 8.41.
Reaction SMILES: Br[C:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2S[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:20]([Cu])#[N:21].CN(C)C=O.[NH4+].[OH-]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[O:9]=[C:8]1[C:2]([C:20]#[N:21])=[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]2[C:6](=[CH:5][CH:13]=[CH:12][CH:11]=2)[NH:7]1
Reactant: N#C[Cu]
Reactant: O=C1Nc2ccccc2SC(c2ccccc2)=C1Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: N#Cc1c(-c2ccccc2)c2ccccc2[nH]c1=O
Temperature: 0 °C
Yield: 29.8 %

Procedure:
A stirred mixture of 10 g (0.030 mole) of 3-bromo-2-phenyl-1,5-benzothiazepin-4(5H)-one from part A, 10 g (0.11 mole) of CuCN, and 75 ml of dimethylformamide is treated with 1 ml of pyridine, heated, and the resulting dark solution refluxed for 2 hours. After cooling, the reaction mixture is poured into a vigorously stirred mixture of 600 ml of ice-water, 600 ml of concentrated NH4OH, and 300 ml of CHCl3. Stirring is continued until essentially 2 clear layers are obtained. The layers are separated and the blue aqueous NH4OH layer is extracted with additional CHCl3 (4×150 ml). The combined organic layers are washed with 10% NH4OH (2×150 ml), then with 150 ml of H2O, dried (MgSO4), and the solvent evaporated (finally at 1 mm. pressure to remove dimethylformamide) to give 5.9 g of a reddish, partly solid residue. The latter is crystallized from 60 ml of MeCN to give 2.2 g (30%) of a pale yellow solid, m.p. 263°-265°(dec.).
Reaction SMILES: C(OP([N:9]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)[C:10]([CH3:12])=[O:11])(OCC)=O)C.[H-].[Na+].[CH:25]([C:28]1[CH:29]=[C:30]([O:33][C:34]=1[CH:35]([CH3:37])[CH3:36])[CH:31]=O)([CH3:27])[CH3:26].[Cl-].[NH4+]>O1CCCC1>[CH:25]([C:28]1[CH:29]=[C:30]([CH:31]=[CH:12][C:10]([NH:9][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)=[O:11])[O:33][C:34]=1[CH:35]([CH3:37])[CH3:36])([CH3:27])[CH3:26]
Reactant: CC(C)c1cc(C=O)oc1C(C)C
Reactant: CCOP(=O)(OCC)N(C(C)=O)c1ccc(C(=O)OC)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)C=Cc2cc(C(C)C)c(C(C)C)o2)cc1
Reaction time: 0.08 h
Yield: 98 %

Procedure:
A solution of methyl 4-[(diethoxyphosphoryl)acetamino]benzoate (165 mg, 0.501 mmol) in anhydrous tetrahydrofuran (3 ml) was cooled on an ice bath, and added with sodium hydride (60% mineral oil dispersion, 20 mg, 0.50 mmol) under an argon atmosphere, and the mixture was stirred for 5 minutes. The reaction mixture was added dropwise with a solution of 4,5-diisopropylfurfural (60 mg, 0.33 mmol) in anhydrous tetrahydrofuran (2 ml), and the mixture was further stirred at 0° C. for 50 minutes. The reaction mixture was added with saturated aqueous ammonium chloride, and the mixture was extracted with chloroform. The reaction mixture was treated in a conventional manner, and then the resultant was purified by silica gel chromatography (2% methanol-chloroform) to obtain methyl 4-[[3-(4,5-diisopropyl-2-furanyl)acryloyl]amino]benzoate (115 mg, 97%) as colorless syrup-like substance.
Reaction SMILES: [Br:1]Br.[C:3]([CH:6]([CH2:18][CH2:19][CH2:20][CH:21]([O:27][C:28](=[O:30])[CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:5])[CH3:4]>C(Cl)(Cl)(Cl)Cl>[C:3]([C:6]([Br:1])([CH2:18][CH2:19][CH2:20][CH:21]([O:27][C:28](=[O:30])[CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:5])[CH3:4]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(C)=O)OC(C)=O
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCC(CCCC(Br)(CCCCCCC(=O)OCC)C(C)=O)OC(C)=O

Procedure:
Bromine (16.7 g., 0.104 mole) dissolved in carbon tetrachloride (100 ml.) is added dropwise to a stirred solution of ethyl 8-acetyl-12-acetoxyheptadecanoate (Example 1, Step C) (37.4 g., 0.094 mole) in carbon tetrachloride (200 ml.) during one hour. The solvent is distilled in vacuo. The residual oil is dissolved in ether and washed with dilute sodium bicarbonate, water and brine and dried over sodium sulfate. Evaporation of the ether leaves the crude bromo ester as a yellow oil weighing 43 g. It is purified by column chromatography on silica gel with benzene as the eluant. This procedure serves to separate the desired bromo ester from a small amount of a by-product, ethyl 8-bromoacetyl-8-bromo-12-acetoxyheptadecanoate. Ethyl 8-acetyl-8-bromo-12-acetoxyheptadecanoate is thus obtained as a pale yellow oil weighing 12.7 g. (28%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[N:13]=[N:12][NH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:16]1([S:22][CH2:23][CH2:24]O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[N:13]([CH2:24][CH2:23][S:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[N:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=c1nn[nH]n1-c1ccc([N+](=O)[O-])cc1
Reactant: OCCSc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1n(CCSc2ccccc2)nnn1-c1ccc([N+](=O)[O-])cc1
Yield: 90.5 %

Procedure:
1-(4-Nitrophenyl)-5-tetrazolone (Example 8) (153 mg, 0.74 mmol), 2-hydroxyethyl phenyl sulfide (0.1 mL, 0.74 mmol), and triphenylphosphine (194 mg, 0.74 mmol) were suspended in tetrahydrofuran (2.5 mL). Diethyl azodicarboxylate (0.12 mL, 0.74 mmol) was added dropwise. After 12 hours the mixture was concentrated in vacuo to an oil. Silica gel chromatography (9:1 hexane/ethyl acetate) afforded a solid (230 mg, 90%). 1H NMR (CDCl3, 300 MHz) δ 8.30 (d, 9.2 Hz, 2H), 8.13 (d, 9.2 Hz, 2H), 7.37 (d, 7.0 Hz, 2H), 7.20 (d, 7.0 Hz, 2H), 7.12 (m, 1H), 4.19 (t, 6.6 Hz, 2H), 3.32 (t, 6.6 Hz, 2H); MS (CI) m/z 344 (MH+).
Reaction SMILES: [F:1][C:2]([F:19])([CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([OH:5])=O.Br.[NH2:21][CH2:22][CH2:23][C:24]1[C:32]2[S:31][C:30](=[O:33])[NH:29][C:28]=2[C:27]([OH:34])=[CH:26][CH:25]=1>>[F:19][C:2]([F:1])([CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([NH:21][CH2:22][CH2:23][C:24]1[C:32]2[S:31][C:30](=[O:33])[NH:29][C:28]=2[C:27]([OH:34])=[CH:26][CH:25]=1)=[O:5]
Reactant: O=C(O)C(F)(F)CCCCOCCc1ccccc1
Reactant: NCCc1ccc(O)c2[nH]c(=O)sc12
Agent: Br
Product: O=C(NCCc1ccc(O)c2[nH]c(=O)sc12)C(F)(F)CCCCOCCc1ccccc1

Procedure:
The subtitled compound was prepared by the method outlined in Example 15a) using the material from step c) and 7-[2-aminoethyl]-4-hydroxy-1,3-benzothiazol-2(3H)-one hydrobromide.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][C@@H:16]([C:20]4[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][C:21]=4[O:28][CH3:29])[CH2:15]3)[N:11]([CH3:30])[C:10](=[O:31])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH:32](CCO)[CH2:33]CO>CNC=O>[C:26]([C:24]1[CH:23]=[CH:22][C:21]([O:28][CH3:29])=[C:20]([C@@H:16]2[O:17][CH2:18][CH2:19][N:14]([C:12]3[N:11]([CH3:30])[C:10](=[O:31])[CH:9]=[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:32][CH3:33])[CH:7]=4)[N:13]=3)[CH2:15]2)[CH:25]=1)#[N:27]
Reactant: COc1ccc(C#N)cc1[C@H]1CN(c2nc(-c3ccnc(Cl)c3)cc(=O)n2C)CCO1
Reactant: OCCNCCO
Solvent: CNC=O
Product: CNc1cc(-c2cc(=O)n(C)c(N3CCO[C@@H](c4cc(C#N)ccc4OC)C3)n2)ccn1
Temperature: 150 °C
Yield: 4.6 %

Procedure:
A suspension of 6-(2-chloropyridin-4-yl)-2-((2S)-2-(5-cyano-2-methoxyphenyl) morpholin-4-yl)-3-methyl-3H-pyrimidin-4-one obtained in Example 10-1 (0.80 g, 1.83 mmol), and diethanolamine (1.0 g, 9.51 mmol) in N-methylformamide (8 ml) was heated at 150° C. for 48 hours. The resulting suspension was partitioned between chloroform and brine and the aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish 2-((2S)-2-(5-cyano-2-methoxyphenyl)-morpholin-4-yl)-3-methyl-6-(2-methylaminopyridin-4-yl)-3H-pyrimidin-4-one (0.036 g, 0.084 mmol, 5.0%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)=[O:4].[CH3:13][O:14][C:15]1[CH:23]=[C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:20][C:16]=1[C:17](O)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]2[N:11]=[C:17]([C:16]3[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:15]=3[O:14][CH3:13])[NH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: COc1cc(NS(C)(=O)=O)ccc1C(=O)O
Reactant: COC(=O)c1ccc(N)c(N)c1
Product: COC(=O)c1ccc2nc(-c3ccc(NS(C)(=O)=O)cc3OC)[nH]c2c1

Procedure:
Prepared analogously to Example 14 from 4-methoxycarbonyl-1,2-phenylenediamine and 2-methoxy-4-methanesulfonylamino-benzoic acid.
Reaction SMILES: [CH3:1][C:2]([NH:4][CH2:5][CH2:6][C:7]1[C:11]2[CH:12]=[C:13]([O:16]C)[CH:14]=[CH:15][C:10]=2[NH:9][CH:8]=1)=[O:3].B(Br)(Br)Br>C(Cl)Cl.CC(C)=O>[OH:16][C:13]1[CH:12]=[C:11]2[C:10](=[CH:15][CH:14]=1)[NH:9][CH:8]=[C:7]2[CH2:6][CH2:5][NH:4][C:2](=[O:3])[CH3:1]
Reactant: COc1ccc2[nH]cc(CCNC(C)=O)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CC(C)=O
Product: CC(=O)NCCc1c[nH]c2ccc(O)cc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In round bottom flask, melatonin (48 mg, 0.21 mmol) was taken in dry CH2Cl2 (3 ml). The reaction mixture was cooled to −78° C. by keeping in acetone bath with liquid nitrogen. To this chilled reaction mixture boron tribromide (0.12 ml, 12 mmol) was added dropwise and stirring continued at this temperature for another 1 h. Then the reaction mixture was stirred overnight at room temperature for overnight. Completion of reaction was monitored by TLC; the reaction mixture was quenched by addition of water, and 10% Hcl and extracted with ethyl acetate. The combined organic phases were washed with water (20 mL) and brine (10 mL) and dried over sodium sulfate. The organic layer was removed under reduced pressure. The crude product was purified by silica gel column chromatography to give N-(2-(5-hydroxy-1H-indol-3-yl)ethyl) acetamide (5a). Isolated as reddish colored semi solid (20 mg, 45%), by elution with 6% methanol in chloroform.