Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7]([CH3:10])[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].C([Li])CCC.Br[CH2:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28].[Cl-].[NH4+]>O1CCCC1>[CH:1]1([C:5]2[N:6]=[C:7]([CH2:10][CH2:23][C:24]3[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=3)[C:27]#[N:28])[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc(C2CCC2)cs1
Reactant: N#Cc1cccc(CBr)c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1cccc(CCc2nc(C3CCC3)cs2)c1
Reaction time: 0.67 h
Yield: 65.3 %

Procedure:
766 mg (5 mmol) of 4-cyclobutyl-2-methylthiazole was dissolved in 15 ml of anhydrous tetrahydrofuran and mixed with 561 mg (5 mmol) of potassium tert-butoxide, and 3 ml (5 mmol) of n-butyllithium (1.68M hexane solution) was added dropwise at −78° C. After 3 hours of stirring at the same temperature, 1270 mg (6 mmol) of 3-bromomethylbenzonitrile in 3 ml anhydrous tetrahydrofuran was added dropwise, and the reaction solution was stirred for one hour and 40 minutes. After addition of saturated aqueous ammonium chloride, the reaction solution was extracted with diethyl ether twice, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo for removal of the solvent. The residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=4:1) to give 876 mg of the title compound as a yellow oily substance in a yield of 64%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2(O)[CH2:14][N:13]([CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CS([Cl:33])(=O)=O>ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([Cl:33])[CH2:14][N:13]([CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C2(O)CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C2(Cl)CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reaction time: 18 h

Procedure:
To a stirred solution of compound (9) (6.23 g) and N,Ndiisopropylethylamine (3.5 mL) in dichloromethane (100 mL) at 0° C. was added, dropwise, methanesulfonyl chloride (1.4 mL). The mixture was stired at 0° C. for 18 hrs, then washed (water, brine), dried (Na2SO4) and concentrated in vacuo. The crude product was recrystallised from hexane to give 3-(4-tert-butylphenyl)-3-chloro-1-(diphenylmethyl)azetidine (10) (4.73 g) m.p. 145° C. (hexane). Found: C, 80.30; H, 7.05; N, 3.64. C26H28CIN requires C, 80.08; H. 7.24; N, 3.59%.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:34]=[CH:35][C:36]=1[Cl:37])[CH2:14][N:15]([CH3:33])[C:16]([C:18]1[CH2:19][N:20]([CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[C:21](=[O:24])[C:22]=1[OH:23])=[O:17]>ClCCl.N1C=CC=CC=1.ClCCl>[Cl:10][C:11]1[CH:12]=[C:13]([CH:34]=[CH:35][C:36]=1[Cl:37])[CH2:14][N:15]([CH3:33])[C:16]([C:18]1[CH2:19][N:20]([CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][N:30]([C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:31][CH2:32]2)[C:21](=[O:24])[C:22]=1[OH:23])=[O:17]
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCNCC2)C1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCN(C(=O)c3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.2 %

Procedure:
To a solution of benzoyl chloride (0.023 mL, 0.23 mmol) in dichloromethane (1 mL) cooled to 0° C. was added dropwise a solution of 4-hydroxy-5-oxo-1-(2-piperazin-1-yl-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide (0.10 g, 0.20 mmol) in pyridine/dichloromethane (4 mL, 1:1). The resulting mixture was stirred at room temp 18 h and quenched with 1N HCl. The organic phase was washed with 1N HCl (3 times). The aqueous washings were combined and purified by preparative HPLC (C18, ODS-A, S-75 μm, 30% acetonitrile/water/0.5% TFA) to give the title compound as a white powder (0.0215 g, 20% yield). HRMS (M+H) calcd for C26H29N4Cl2O4: 531.1566; found: 531.1563.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5](C#N)[CH:6]([C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)C.C(O)(=O)C.S(=O)(=O)(O)O>O>[Br:20][C:17]1[CH:16]=[CH:15][C:14]([CH:6]([C:7]2[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[CH2:5][C:4]([OH:23])=[O:3])=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(C#N)C(c1ccc(Cl)cc1)c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CC(c1ccc(Cl)cc1)c1ccc(Br)cc1
Yield: 49.6 %

Procedure:
A mixture of 3-(4-bromo-phenyl)-3-(4-chloro-phenyl)-2-cyano-propionic acid ethyl ester (1.91, 4.87 mmol), acetic acid (10 ml), concentrated sulfuric acid (5 ml) and water (5 ml) were refluxed for 2 hours. Reaction mixture was poured into iced water and extracted with ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and concentrated, the crude product was purified over flash silica chromatography eluting with ethyl acetate/petroleum ether (1:1) to afford the desired product (0.82 g, 50% yield). LC/MS: (PS-A2) Rt 3.39 [M+H]− 338.86.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.CO[CH:17]1[CH2:21][CH2:20][CH:19](OC)O1>C(O)(=O)C>[N:1]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][CH:3]=2)[CH:17]=[CH:21][CH:20]=[CH:19]1
Reactant: Nc1ccc(-c2ccc(=O)[nH]n2)cc1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: O=C1CCC(c2ccc(-n3cccc3)cc2)=NN1
Yield: 25.5 %

Procedure:
A mixture of 6-(4-aminophenyl)-3(2H)-pyridazinone (3.7 g) and 2,5-dimethoxytetrahydrofuran (2.6 g) in glacial acetic acid (37 ml) is heated under reflux for four hours. The reaction mixture is cooled, filtered and the solid is washed with ethanol, and finally crystallized from methanol to give 1.2 g of the product, 4,5-dihydro-6-[4-(1H)-pyrrol-1-yl)phenyl]-3(2H)-pyridazinone, mp 222°-223° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH:15]2[CH2:18][CH2:17][CH2:16]2)=[CH:6][C:7]([CH3:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:29](Cl)(=[O:32])[CH2:30][CH3:31]>O1CCCC1>[CH:15]1([C:5]2[C:4]([C:1](=[O:3])[CH2:2][C:29](=[O:32])[CH2:30][CH3:31])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:14])[CH:6]=2)[CH2:16][CH2:17][CH2:18]1
Reactant: COC(=O)c1cc(C(C)=O)c(C2CCC2)cc1C
Reactant: CCC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(=O)CC(=O)c1cc(C(=O)OC)c(C)cc1C1CCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 5-acetyl-4-cyclobutyl-2-methylbenzoate (compound 238.1, 500 mg, 2.03 mmol, 1.00 equiv) in tetrahydrofuran (15 mL) at 0° C. was added dropwise a solution of LiHMDS (680 mg, 4.06 mmol, 2.00 equiv) in tetrahydrofuran (5 mL). After 30 min of stirring at 0° C., a solution of propanoyl chloride (280 mg, 3.03 mmol, 1.50 equiv) in tetrahydrofuran (5 mL) was added dropwise. The resulting mixture was stirred for 3 h at 15° C., and then concentrated under reduced pressure. The residue was diluted with 40 mL of ethyl acetate, washed with of brine (3×40 mL), dried (Na2SO4), and concentrated under reduced pressure. This resulted in 500 mg (crude) of the title compound as a brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[N:17][C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].CC1(C)COB([C:29]2[CH:30]=[N:31][CH:32]=[C:33]([CH3:35])[CH:34]=2)OC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[N:17][C:12]3=[N:11][CH:10]=2)=[CH:3][C:2]=1[C:29]1[CH:30]=[N:31][CH:32]=[C:33]([CH3:35])[CH:34]=1
Reactant: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)cc1Br
Reactant: Cc1cncc(B2OCC(C)(C)CO2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cncc(-c2cc(-c3cnc4nc(C(F)(F)F)ccn34)ccc2F)c1
Temperature: 70 °C
Yield: 35 %

Procedure:
To a mixture of 3-(3-bromo-4-fluorophenyl)-7-trifluoromethylimidazo[1,2-α]pyrimidine (150 mg, 0.42 mmol) and 3-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-5-methylpyridine in 1,4-dioxane (5 ml) was added a solution of caesium carbonate (340 mg, 1.04 mmol) in water (0.5 ml). The reaction was degassed with nitrogen and tetrakis(triphenylphosphine)palladium(0) (48 mg, 0.04 mmol) was added and the mixture heated at 70° C. for 1 h. The solvent was evaporated in vacuo and the residue was partitioned between dichloromethane and water. The aqueous phase was re-extracted with dichloromethane and the combined organic layers dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was purified using a short silica gel column eluting with 2% diethyl ether in dichloromethane followed by 15% diethyl ether in dichloromethane to give a yellow solid. This was purified further by loading as a solution in methanol onto a cartridge of strong cation-exchange resin, eluting with methanol then with 2M ammonia in methanol. The basic fractions were concentrated in vacuo to give a dark cream solid. The solid was triturated with diethyl ether to give 3-[4-fluoro-3-(5-methylpyridin-3-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a cream solid (55 mg, 35%): δH (360 MHz, d6-DMSO) 2.39 (3H, s), 7.51 (1H, d, J 7), 7.60 (1H, dd, J 11 and 9), 7.85 (1H, ddd, J 9, 5 and 2), 7.91-7.94 (1H, m), 8.00 (1H, dd, J 7 and 2), 8.33 (1H, s), 8.49 (2H, d, J 2), 8.68-8.71 (1H, m), 9.36 (1H, d, J 7); m/z (ES+) 373 (M++H).
Reaction SMILES: C[O:2][C:3]1[C:8]2[O:9][C:10]([C:12]3[O:13][C:14]([CH3:17])=[N:15][N:16]=3)=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[C:8]2[O:9][C:10]([C:12]3[O:13][C:14]([CH3:17])=[N:15][N:16]=3)=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2cc(-c3nnc(C)o3)oc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1nnc(-c2cc3cccc(O)c3o2)o1
Temperature: -8 °C
Yield: 79.9 %

Procedure:
7-Methoxy-2-(5-methyl-1,3,4-oxadiazol-2-yl)benzo(b)furan (2 g) was dissolved in dichloromethane (50 ml) and boron tribromide (2 ml) was added dropwise with stirring at −8° C. The mixture was then stirred for 1 hr under ice-cooling and the reaction mixture was poured into ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give red crystals (1.5 g) of 7-hydroxy-2-(5-methyl-1,3,4-oxadiazol-2-yl)benzo(b)furan. This compound and (S)-glycidyl nosylate (2 g) were dissolved in DMF (100 ml) and potassium carbonate (11 g) was added. The mixture was stirred at 50° C. for 2 hr. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oily product (2 g). The oily product and 4-(naphthalen-1-yl)piperidine were dissolved in methanol (20 ml) and the mixture was refluxed under heating for 1 hr. After cooling, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol) to give the title compound (1.0 g) as a pale-yellow oil.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:21]=2[O:29][CH2:30][CH2:31][OH:32])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[C:21]=2[O:29][CH2:30][CH2:31][O:32][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccc([N+](=O)[O-])c3OCCO)[nH]c2c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccc([N+](=O)[O-])c3OCCOS(C)(=O)=O)[nH]c2c1
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
To a solution of methyl 3-cyclohexyl-2-[2-(2-hydroxyethoxy)-3-nitrophenyl]-1H-indole-6-carboxylate (11.00 g, 25.1 mmol) and triethylamine (5.25 ml, 37.7 mmol) in chloroform (77 ml) was added dropwise methanesulfonyl chloride (2.33 ml, 30.1 mmol) under ice-cooling, and the mixture was stirred for 30 min. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give methyl 3-cyclohexyl-2-[2-(2-methanesulfonyloxyethoxy)-3-nitrophenyl]1H-indole-6-carboxylate (12.60 g, yield 97%).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:11])[CH2:4][S:5][CH2:6][CH:7]([OH:10])[CH2:8]Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[O:10]1[CH2:8][CH:7]1[CH2:6][S:5][CH2:4][CH:3]1[O:11][CH2:2]1
Reactant: OC(CCl)CSCC(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C1OC1CSCC1CO1
Temperature: 5 °C
Yield: 95 %

Procedure:
Next, bis(3-chloro-2-hydroxypropyl)sulfide described above was dripped into a reaction vessel containing a mixed solvent consisting of 410 g of toluene and 260 g of 32% aqueous solution of sodium hydroxide with the temperature of the solution in the reaction vessel being maintained at 0 to 10° C. At the point of the completion, no scum-like insoluble matter was generated. The aqueous layer was removed, and the organic layer was washed with 180 g of water three times. After that, no scum-like insoluble matter was generated. After that, the solvent was distilled away, thereby obtaining 138 g (total yield: 95%) of bis(β-epoxypropyl)sulfide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH3:11])(=[O:10])=[O:9].[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[CH3:11][S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccccc1Br
Reactant: C1CNCCN1
Product: CS(=O)(=O)c1ccccc1N1CCNCC1
Temperature: 110 °C
Yield: 31.9 %

Procedure:
A mixture of 2-bromo(methylsulfonyl)benzene (1.10 g, 4.7 mmol) and anhydrous piperazine (2.02 g, 23.5 mmol) was heated at 110° C. overnight. Then, the mixture was cooled and partitioned between 2 N NaOH and CH2Cl2. The separated organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude residue was chromatographed (CHCl3/CH3OH, 9:1, as eluent) to give 8 as a white semisolid (0.36 g, 34% yield). 1H NMR: δ 2.58 (s, 1H, NH, D2O exchanged), 2.84 (s, 4H, piperazinic), 3.14 (s, 3H, CH3), 7.10-7.83 (m, 4H, aromatic).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[CH:10]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:11]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][CH2:13][CH2:14]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[N-:50]=[N+:51]=[N-:52].[Na+]>N1C=CC=CC=1.CCOCC.CN(C=O)C.O.[Cl-].[Na+].O>[CH2:1]([O:8][C:9](=[O:27])[CH:10]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:11]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][CH2:13][CH2:14][N:50]=[N+:51]=[N-:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)C(C(=O)OCc1ccccc1)N(CCCO)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Cl-]
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)C(C(=O)OCc1ccccc1)N(CCCN=[N+]=[N-])C(C)(C)C
Temperature: 0 °C
Reaction time: 16 h

Procedure:
BOC-(2-isobutyl)-3-hydroxypropyl glycine benzyl ester (0.17 g, 0.45 mmol) is dissolved in pyridine (2 ml), cooled to 0° C., and p-toluenesulfonyl chloride (0.25 g, 1.31 mmol) is added. The mixture is then stirred at room temperature for 16 hours, diluted with ether, and the organic layer washed with 1N HCl, 10% copper sulfate solution, brine. The organic layer is dried over magnesium sulfate, filtered, concentrated in vacuo to give the tosylated product. The primary tosylate (0.23 g, 0.43 mmol) is dissolved in DMF/water (10:1) (2 ml) and sodium azide (0.29 g, 4.46 mmol) is added. The mixture is heated at 90° C. for four hours, cooled, diluted with ether and poured into brine. The organic layer is washed with water, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product is purified by flash chromatography, eluting with 10% ethyl aceate in hexanes to give BOC-(2-isobutyl)-3-azidopropyl glycine benzyl ester.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:11]([NH:13][C:14](/[C:16]/1=[CH:17]\[CH2:18][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:15])=[O:12])([OH:3])=[O:2].C(=O)(O)[O-].[Na+].[BH4-].[Na+].Cl>O>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:11]([NH:13][C:14](/[C:16]/1=[CH:17]\[CH2:18][CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:15])=[O:12])([OH:3])=[O:2]
Reactant: CCCCCC(=O)C/C=C1\C(=O)NC(=O)N1CCCCCCC(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: O
Product: CCCCCC(O)C/C=C1\C(=O)NC(=O)N1CCCCCCC(=O)O
Reaction time: 1 h

Procedure:
A stirred solution of 1-(6-carboxyhexyl)-5-((E)-3-oxooctylidene)hydantoin (20 mg) in H2O (1.5 ml) containing a slight excess of sodium bicarbonate was treated with sodium borohydride (5 mg). After 60 minutes, the solution was acidified to Congo Red with N-aqueous hydrochloric acid, the liberated carboxylic acid was extracted into ethyl acetate, and the ethyl acetate solution was thrice washed with water and dried (MgSO4). Evaporation of the ethyl acetate left a pale yellow gum (14 mg) which was identified by 'H n.m.r. spectroscopy (characteristic signal at δ5.61 (1H, triplet =CH--, J 7.1 Hz) in deuterochloroform) as 1-(6-carboxyhexyl)-5-((E)-3-hydroxyoctylidene)hydantoin.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12](SC)=[NH:13])[CH2:2][CH2:3][CH2:4][CH3:5].[N:16]1[CH:21]=[CH:20][C:19]([C:22]([NH:24][NH2:25])=O)=[N:18][CH:17]=1>C(O)C>[CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]1[NH:25][N:24]=[C:22]([C:19]2[CH:20]=[CH:21][N:16]=[CH:17][N:18]=2)[N:13]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNc1nc[nH]c1C(=N)SC
Reactant: NNC(=O)c1ccncn1
Solvent: CCO
Product: CCCCCNc1nc[nH]c1-c1nc(-c2ccncn2)n[nH]1

Procedure:
The mixture of methyl 4-(pentylamino)-1H-imidazole-5-carbimidothioate (1.5 g, 6.6 mmol) and pyrimidine-4-carbohydrazide (1.2 g, 8.7 mmol) in ethanol (10 mL) was refluxed overnight. The reaction mixture was concentrated under reduced pressure to yield the desired product as light green viscous oil. LCMS calculated for C14H19N8 (M+H): 299.2. found: 299.1.
Reaction SMILES: [CH3:1][Si:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[N:17]=[N:16][C:15]([NH:18][NH2:19])=[CH:14][CH:13]=2)[CH:9]=[N:8]1.C([O-])([O-])=O.[K+].[K+].[C:28](=S)=[S:29]>C(O)C.O>[CH3:1][Si:2]([CH3:21])([CH3:20])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:28]([SH:29])=[N:19][N:18]=3)[N:17]=2)[CH:9]=[N:8]1
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccc(NN)nn2)cn1
Reactant: S=C=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCOCn1cc(-c2ccc3nnc(S)n3n2)cn1
Temperature: 80 °C

Procedure:
To a solution of {6-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-yl]-pyridazin-3-yl}-hydrazine (490 mg, 1.6 mmol) in ethanol (6.5 mL) and water (1.8 mL) was added K2CO3 (359 mg, 2.6 mmol), followed by CS2 (0.212 mL, 3.5 mmol). The mixture was stirred and heated at 80° C. for 3 h under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated to 50% volume in vacuo and acidified to pH 1 with 1 N aqueous HCl. The resulting precipitate was collected, washed with water, and dried in vacuo to provide title compound as a dark red solid (quantitative yield): 1H NMR (DMSO-d6) δ 0.01 (9H, s), 0.90 (2H, t), 3.63 (2H, t), 5.56 (2H, s), 7.82 (1H, d), 8.24 (1H, d), 8.27 (1H, s), 8.80 (1H, s), 15.23 (1H, bs); MS (m/z) 349 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:14][CH2:13][C@@:12]34[C:15]5[C:21]6[CH2:22][C@@H:6]2[C@@:7]23[CH2:25][CH2:24][C@:10]([O:26][CH3:27])([C@@H:11]4[O:17][C:16]=5[C:18]([OH:23])=[CH:19][CH:20]=6)[C@@H:9]([CH2:28][O:29][CH2:30][C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:34]=[CH:35][CH:36]=3)[CH2:8]2)[CH2:3][CH2:2]1.BrC1C=C(C=CC=1)CBr.NC1C=CC=CC=1.C([Cl:70])(=O)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>>[CH:1]1([CH2:4][N:5]2[CH2:14][CH2:13][C@@:12]34[C:15]5[C:21]6[CH2:22][C@@H:6]2[C@@:7]23[CH2:25][CH2:24][C@:10]([O:26][CH3:27])([C@@H:11]4[O:17][C:16]=5[C:18]([OH:23])=[CH:19][CH:20]=6)[C@@H:9]([CH2:28][O:29][CH2:30][C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:34]=[CH:35][CH:36]=3)[CH2:8]2)[CH2:3][CH2:2]1.[ClH:70]
Reactant: O=C(Cl)c1ccccc1
Agent: BrCc1cccc(Br)c1
Agent: CO[C@]12CC[C@@]3(C[C@@H]1COCc1cccc(NC(=O)c4ccccc4)c1)[C@H]1Cc4ccc(O)c5c4[C@@]3(CCN1CC1CC1)[C@H]2O5
Solvent: O=C(O)C(F)(F)F
Solvent: Nc1ccccc1
Product: Cl

Procedure:
In a similar manner N-(3-((((4R,4aS,6R,7R,7aR,12bS)-3-(cyclopropylmethyl)-9-hydroxy-7-methoxy-1,2,3,4,5,6,7,7a-octahydro-4a,7-ethano-4,12-methanobenzofuro[3,2-e]isoquinolin-6-yl)methoxy)methyl)phenyl)benzamide (Compound 74) was prepared from C using 3-bromobenzyl bromide, followed by conversion of the aryl bromide to the aniline, subsequent reaction of the aniline with benzoyl chloride and final cleavage of the p-methoxybenzyl group by TFA. Purification by flash column chromatography (silica gel, 0-10% MeOH/DCM) followed by HCl salt formation gave Compound 74 HCl salt as a white solid.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:8][CH2:9][N:10]([CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[OH:28])[C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.[C:42]([O:46][CH3:47])(=[O:45])[CH2:43][CH3:44]>CC#N.CCOC(C)=O>[C:11]([N:10]([CH2:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28]/[CH:44]=[CH:43]/[C:42]([O:46][CH3:47])=[O:45])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCC(=O)OC
Reactant: O=C(c1ccccc1)N(CCCc1ccccc1O)CCC(c1ccccc1)c1ccccc1
Solvent: CN1CCOCC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/Oc1ccccc1CCCN(CCC(c1ccccc1)c1ccccc1)C(=O)c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of N-(3,3-diphenylpropyl)-N-[3-(2-hydroxyphenyl)propyl]benzamide (100 mg) in MeCN (2 mL) was added NMM (2.3 mg) and methyl propionate (22.4 mg) at ambient temperature. The reaction mixture was stirred for 2 hours at the same temperature. The resulting mixture was diluted with EtOAc (15 mL) and washed successively with water and brine. The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=80:20-70:30) to give a methyl (2E)-3-(2-{3-[benzoyl(3,3-diphenylpropyl)amino]propyl}phenoxy)acrylate.