Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.[C:2]1([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:11][C:10]([S:19][CH3:20])=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30]>CN(C)C1C=CN=CC=1.ClCCl>[C:32]1([O:31][C:29]([N:9]2[C@H:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@H:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:11]=[C:10]2[S:19][CH3:20])=[O:30])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1
Agent: CN(C)c1ccncc1
Agent: I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of 2-(methylthio)-cis-4,5-diphenyl-4,5-dihydro-1H-imidazole hydroiodide (42) (1.00 mg, 2.52 mmol), triethylamine (0.528 mL, 0.379 mmol), 4-dimethylamino-pyridine (10 mg) in dichloromethane (20 mL) is added phenyl chloroformate (0.379 mL, 3.02 mmol), and the mixture is stirred at rt overnight. The reaction mixture is diluted with dichloromethane and washed with water, brine, and the organic layer is dried (MgSO4), filtered, and evaporated. The residue is purified by chromatography on silica gel; gradient elution with heptane:EtOAc (70:30-60:40) gives 0.58 g of the product 548. 1H NMR (CDCl3) δ 7.25-6.95 (m, 11H), 6.95-6.80 (m, 2H), 6.80-6.70 (m, 2H), 5.80-5.65 (m, 2H), 2.62 (s, 3H). MS: m/z 389 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)[S:7][C:6]=2[CH:17]=1.N1C=CC=CC=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>CN(C)C1C=CN=CC=1.O>[CH3:24][S:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:12][CH:11]=3)[S:7][C:6]=2[CH:17]=1)(=[O:27])=[O:26]
Reactant: Oc1ccc(-c2cc3ccc(O)cc3s2)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Oc1ccc(-c2cc3ccc(OS(C)(=O)=O)cc3s2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Twenty g. of 6-hydroxy-2-(4-hydroxyphenyl)-benzo[b]thiophene was dissolved in 400 ml. of pyridine, together with 23.4 g. of methanesulfonyl chloride and 50 mg. of 4-dimethylaminopyridine. The mixture was stirred under a nitrogen blanket overnight at ambient temperature, and was then poured into 2 liters of water and stirred vigorously. The solids were collected by filtration, and washed successively with water, methanol and diethyl ether. The washed solids were then vacuum dried at 60° C. to obtain 32.5 g. of the desired intermediate product, m.p. 195°-197° C.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=[CH:9][C@H:10]([C@H:12]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])[OH:11].[Sb](Cl)(Cl)(Cl)(Cl)Cl>ClCCl>[CH2:4]1[CH2:5][CH2:6][C:1]2([O:11][C@@H:10]([C@H:12]3[O:13][C@@H:18]4[O:19][C:1]5([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[O:17][C@H:16]4[C@H:14]3[OH:15])[CH2:9][O:7]2)[CH2:2][CH2:3]1
Reactant: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C1CCCCC1
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: O[C@@H]1[C@@H]2OC3(CCCCC3)O[C@H]2O[C@@H]1[C@H]1COC2(CCCCC2)O1
Temperature: 68 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a mixed solution consisting of 100 ml of cyclohexanone and 100 ml of dichloromethane were added 10.0 g of D-mannose and 89.7 mg of antimony pentachloride, and the mixture was refluxed with stirring in a water bath of 68° C. for 8 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the condenser. The reaction mixture was diluted with benzene, washed with aqueous sodium bicarbonate and water, and dried over anhydrous magnesium sulfate. The solvents including cyclohexanone were distilled off under reduced pressure to give 16.49 g (87.3%) of 2,3:5,6-di-O-cyclohexylidene-α-D-mannofuranose as a residue. The compound, when recrystallized from cyclohexane, showed m.p. 122°-124° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O.O.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[Na+]>[Cu]I.CS(C)=O>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: O=S([O-])c1ccc(Br)cc1
Reactant: COC(=O)c1ccccc1Br
Agent: [Cu]I
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccccc1S(=O)(=O)c1ccc(Br)cc1

Procedure:
Methyl 2-[(4-bromophenyl)sulfonyl]benzoate was prepared according to the method of Example 135, Step 2 using methyl 2-bromobenzoate (2.8 mL, 20 mmol) in place of (S)-1-(2-iodophenyl)ethanol and sodium 4-bromophenylsulfinate dihydrate (5.6 g, 20 mmol) in place of Intermediate 1, together with CuI (19 g, 100 mmol) and DMSO (40 mL), affording product as a white solid (3.8 g).
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Br:20][C:21]1[CH:29]=[C:28]([Br:30])[CH:27]=[C:26]([Br:31])[C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[Br:20][C:21]1[CH:29]=[C:28]([Br:30])[CH:27]=[C:26]([Br:31])[C:22]=1[C:23]([N:7]1[C:8](=[O:9])[CH:3]2[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]1=[O:6])=[O:24]
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Reactant: O=C(Cl)c1c(Br)cc(Br)cc1Br
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(c1c(Br)cc(Br)cc1Br)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,4,6-Tribromobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered ans stripped of solvent under reduced pressure to yield the desired product N-(2,4,6-tribromobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:5]=[N:4][N:3]=1.[OH-].[Na+].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>CO>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][S:1][C:2]2[N:6]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:5]=[N:4][N:3]=2)=[CH:17][CH:16]=1
Reactant: CCCCn1cnnc1S
Reactant: COc1ccc(CCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCn1cnnc1SCc1ccc(OC)cc1

Procedure:
To a mixture of 10 g. (0.064 mole) of 3-mercapto-4-n-butyl-1,2,4-triazole and 2.6 g. (0.064 mole) of sodium hydroxide in 200 ml. of methanol was added 9.9 g. (0.064 mole) of p-methoxybenzyl chloride. The reaction mixture was heated at reflux about 20 hours. The solvent was evaporated off, the residue washed with water, dried and distilled. There was obtained 17.8 g. of yellow liquid distilling at 190°-205° C. at 0.03 mm. Nuclear magnetic resonance and ultraviolet spectra indicated this to be approximately an equal mixture of 3-(4-methoxybenzylmercapto)-4-n-butyl-1,2,4-triazole and 4-n-butyl-2-(4-methoxybenzyl)-1,2,4-triazoline-3-thione.
Reaction SMILES: C(=O)([O-])N.C(OC([N:12]1[CH2:16][CH2:15][C:14]2([CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[C:32]([O:37][CH2:38][CH:39]6[CH2:41][CH2:40]6)[CH:33]=5)[C:28]4=[O:42])=[CH:23][C:22]=3[F:43])[CH2:17]2)[CH2:13]1)=O)(C)(C)C>>[CH:39]1([CH2:38][O:37][C:32]2[CH:33]=[C:34]3[C:29](=[CH:30][CH:31]=2)[C:28](=[O:42])[N:27]([C:24]2[CH:25]=[CH:26][C:21]([N:18]4[CH2:19][CH2:20][C:14]5([CH2:15][CH2:16][NH:12][CH2:13]5)[CH2:17]4)=[C:22]([F:43])[CH:23]=2)[CH:36]=[CH:35]3)[CH2:41][CH2:40]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccc(-n4ccc5cc(OCC6CC6)ccc5c4=O)cc3F)C2)C1
Agent: NC(=O)[O-]
Product: O=c1c2ccc(OCC3CC3)cc2ccn1-c1ccc(N2CCC3(CCNC3)C2)c(F)c1

Procedure:
According to Method H, the carbamate was cleaved to 7-[4-(6-cyclopropylmethoxy-1-oxo-1H-isoquinolin-2-yl)-2-fluorophenyl]-2,7-diaza-spiro[4.4]nonane-2-carboxylic acid tert-butyl ester. In this way the product was obtained with molecular weight 433.53 (C26H28FN3O2); MS (ESI): 434 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]3[CH2:12][CH2:13][CH2:14][NH:15][C:10]3=[N:9][N:8]=2)=[CH:3][CH:2]=1.Cl[CH2:17][C:18]1[O:22][C:21]([C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=2)[C:26]#[N:27])=[N:20][N:19]=1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]3[CH2:12][CH2:13][CH2:14][N:15]([CH2:17][C:18]4[O:22][C:21]([C:23]5[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=5)[C:26]#[N:27])=[N:20][N:19]=4)[C:10]3=[N:9][N:8]=2)=[CH:3][CH:2]=1
Reactant: c1cc(-c2nnc3n2CCCN3)ccn1
Reactant: N#Cc1cccc(-c2nnc(CCl)o2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N#Cc1cccc(-c2nnc(CN3CCCn4c(-c5ccncc5)nnc43)o2)c1
Yield: 16.3 %

Procedure:
3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine (172 mg, 0.85 mmol) and 3-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]benzonitrile (94 mg, 0.43 mmol) were dissolved in butanone (5 ml) and K2CO3 (118 mg, 0.85 mmol) and KI (35 mg, 0.21 mmol) were added. The reaction mixture was refluxed for 1 h and the solvent was evaporated. The residue was dissolved in K2CO3 (aq., 1M, 25 ml) and was extracted with DCM. The combined organic layers were dried (Na2SO4) and purified with prep. HPLC to give the title compound (27 mg, 16%). 1H NMR: 8.75 (d, 2H), 8.30 (m, 2H), 7.79 (d, 1H), 7.63 (m, 1H), 7.53 (dd, 2H), 5.57 (d, 2H), 4.06 (t, 2H), 3.58 (t, 2H), 1.99 (m, 2H).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].[Na+].[C:11]1([CH2:17][C:18]#[N:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN(C)C=O>>[C:18]([CH:17]([CH:2]([CH2:3][C:4]([OH:6])=[O:5])[C:1]([O:8][CH3:9])=[O:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)#[N:19]
Reactant: N#CCc1ccccc1
Reactant: COC(=O)/C=C\C(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CC(=O)O)C(C#N)c1ccccc1
Yield: 87.9 %

Procedure:
Into a 200 ml, one-neck flask is placed 35 grams of sodium methyl maleate (0.23 moles), 85 grams (0.73 moles) of phenyl acetonitrile and 80 g(1.1 moles) dimethyl formamide. The reaction mixture is heated to 135°-140° C. for 5 hours and then distilled in vacuo. The residue is extracted three times with 300 ml ether. The solid (56 grams) is then dissolved in water and acidified with 23 grams conc. HCl in 50 mls water. The liquid that separates out is dissolved in ether and washed with water to remove unreacted starting materials. The ether is distilled off to give a residue of 50 grams of product (yield: 88%). The structure is verified by NMR (in CDCl3):
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:3]=1[C:4](=[O:13])[NH:5][S:6]2(=[O:8])=[O:7].[C:14]1([S:20][CH2:21]Cl)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:14]1([S:20][CH2:21][N:5]2[C:4](=[O:13])[C:3]3[C:9](=[CH:10][CH:11]=[CH:12][C:2]=3[CH3:1])[S:6]2(=[O:8])=[O:7])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cccc2c1C(=O)NS2(=O)=O
Reactant: ClCSc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cccc2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Yield: 46.3 %

Procedure:
A mixture of 1.0 g (0.005 mol) of 4-methylsaccharin, 0.33 g (0.001 mol) of TBAB and 1.2 g (0.0075 mol) of chloromethyl phenyl sulfide in 25 ml of toluene was heated under reflux for about sixteen hours and then cooled, diluted with ethyl acetate and the solution washed with aqueous bicarbonate and water. The organic layer was dried and taken to dryness to give 0.74 g of 2-phenylthiomethyl-4-methylsaccharin.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[C:21]([CH3:25])=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:26]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:28]=[CH:29][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:41])C(=O)C1>ClCCl.C(#N)C>[Br:41][C:22]1[CH:23]=[CH:24][C:19]2[NH:18][C:17]3[N:26]=[C:27]([C:30]([F:32])([F:33])[F:31])[CH:28]=[CH:29][C:16]=3[CH2:15][N:14]([S:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=3)(=[O:12])=[O:13])[C:20]=2[C:21]=1[CH3:25]
Reactant: Cc1cccc2c1N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CC#N
Product: Cc1c(Br)ccc2c1N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Temperature: 5 °C
Reaction time: 12 h

Procedure:
To a solution of the product of Step C (0.95 g, 2 mmol mol) in dichloromethane (5 ml) and acetonitrile (50 ml) was added NBS (0.35 g, 2 mmol mol) in portions at 0° C. After stirring at 5° C. for 12 h, the reaction mixture was concentrated, and the residue was partitioned between dichloromethane and water. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=7.2 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.13 (m, 5H), 6.52 (m, 2H), 5.20 (d, J=16.8 Hz, 1H), 4.34 (d, J=16.8 Hz, 1H), 2.65 (s, 3H), 1.24 (s, 9H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][SH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]>>[CH2:8]([S:9][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCCCBr
Reactant: SCCc1ccccc1
Product: OCCCCCCCSCCc1ccccc1

Procedure:
2-Phenylethanethiol was alkylated with 7-bromo-1-heptanol in analogy with example 18, step 1, affording 7-phenethylsulfanyl-heptan-1-ol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[N:14][N:13]([CH2:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH2:25]O)=[CH:21][CH:20]=3)=[O:18])[C:12](=[O:27])[CH:11]=2)=[N:6][CH:7]=1.S(Cl)([Cl:30])=O>C(Cl)Cl.C(OC)(C)(C)C>[Cl:30][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:17](=[O:18])[CH2:16][N:13]2[C:12](=[O:27])[CH:11]=[C:10]([O:9][CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)[CH:15]=[N:14]2)=[CH:20][CH:21]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(Cn1ncc(OCc2ccc(F)cn2)cc1=O)c1ccc(CO)cc1
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: O=C(Cn1ncc(OCc2ccc(F)cn2)cc1=O)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 400 mg (1.08 mmol) 5-(5-fluoro-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one (preparation 19c) in 10 mL DCM is added 0.12 mL (1.62 mmol) thionylchloride at 0° C. The reaction mixture is stirred 2 h at RT and diluted with tert-butylmethylether. The precipitate is collected and dried.
Reaction SMILES: C(O)(C)C.[Cl:5][C:6]1[CH:12]=[C:11]([N+:13]([O-])=O)[C:10]([CH3:16])=[CH:9][C:7]=1[NH2:8].[OH-].[K+]>C1(=O)C=CC=CC1=O.O>[Cl:5][C:6]1[CH:12]=[C:11]([NH2:13])[C:10]([CH3:16])=[CH:9][C:7]=1[NH2:8]
Reactant: Cc1cc(N)c(Cl)cc1[N+](=O)[O-]
Agent: O=C1C=CC=CC1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1cc(N)c(Cl)cc1N
Yield: 91.4 %

Procedure:
A reaction vessel was charged with 60 g of isopropyl alcohol, 50 g of water, 37.3 g of 2-chloro-5-methyl-p-nitroaniline, 5 g of potassium hydroxide and 0.6 g of 1,2-benzoquinone, and then the same procedure as in Example 1 was followed, to obtain 28.6 g of 2-chloro-5-methyl-p-phenylenediamine.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([CH:5]1[NH:20][C:19](=[O:21])[C@H:18]([CH3:22])[N:17]([CH3:23])[C:16](=[O:24])[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][CH2:8][C@@H:7]([CH3:25])[CH2:6]1)[OH:4]>CCO.[Pd]>[Cl:1][CH2:2][CH:3]([CH:5]1[NH:20][C:19](=[O:21])[C@H:18]([CH3:22])[N:17]([CH3:23])[C:16](=[O:24])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]([CH3:25])[CH2:6]1)[OH:4]
Reactant: C[C@@H]1CCC=CCCCCC(=O)N(C)[C@@H](C)C(=O)NC(C(O)CCl)C1
Agent: [Pd]
Agent: C[C@@H]1CC/C=C/CCCCC(=O)N(C)[C@@H](C)C(=O)NC(C(O)CCl)C1
Solvent: CCO
Product: C[C@@H]1CCCCCCCCC(=O)N(C)[C@@H](C)C(=O)NC(C(O)CCl)C1
Reaction time: 4 h

Procedure:
A solution of 1.24 g (3.32 mmol) of (E)-(3S,14R)-16-(2-chloro-1-hydroxy-ethyl)-3,4,14-trimethyl-1,4diaza-cyclohexadec-10-ene-2,5-dione in 33 ml EtOH is stirred at rt in the presence of 332 mg 10% Pd/C under a hydrogen atmosphere for 1 h. More catalyst is added (332 mg) and the hydrogenation is continued for 4 h. The catalyst is filtered off and the filtrate evaporated. The residue is purified by chromatography on silica gel (DCM/methanol 95/5) and gives the title compound as a brownish foam (mixture of diastereomers).
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.[CH2:10]([N:18]1[C:26]2[C:21](=[C:22]([CH3:41])[C:23]([CH2:35][C:36]([O:38]CC)=[O:37])=[C:24]([CH3:34])[C:25]=2[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[CH:20]=[CH:19]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[OH-].[Na+]>CCO.O>[CH2:10]([N:18]1[C:26]2[C:21](=[C:22]([CH3:41])[C:23]([CH2:35][C:36]([OH:38])=[O:37])=[C:24]([CH3:34])[C:25]=2[NH:27][C:28](=[O:33])[C:29]([CH3:30])([CH3:31])[CH3:32])[CH:20]=[CH:19]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCn1ccc2c(C)c(CC(=O)OCC)c(C)c(NC(=O)C(C)(C)C)c21
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc2[nH]ccc2c1
Solvent: CCO
Solvent: O
Product: CCCCCCCCn1ccc2c(C)c(CC(=O)O)c(C)c(NC(=O)C(C)(C)C)c21
Temperature: 60 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
0.70·1.10 (3H, br-t, —(CH2)7CH3), 1.10- 1.70 (15H, m, —CH2 CH3, —(CH2)6CH3), 1.38 (9H, s, —C(CH3)3), 2.21 (3H, s, —CH3), 2.47 (3H, s, —CH3), 3.79 (2H, m, —CH2 CO2—), 3.90·4.30 (4H, m, —CH2 CH3, >NCH2—), 6.42 (1H, t, J=3.5 Hz, Indole C3—H), 6.91 (1H, t, J=3.5 Hz, Indole C2—H), 7.12 (1H, br, —CONH—). (3) N-(1-Octyl-5-ethoxycarbonylmethyl-4,6-dimethylindol-7-yl)-2,2-dimethylpropanamide (3.5 g) was dissolved in EtOH (50 ml), and a solution of NaOH (1.6 g) in water (20 ml) was added, which was followed by stirring at 60° C. for 1 hr. EtOH was evaporated under reduced pressure, and the residue was dissolved in water (20 ml), and washed with AcOEt (10 ml). The aqueous layer was neutralized with 2N HCl and extracted with AcOEt (50 ml). The AcOEt layer was washed successively with saturated brine and dried over anhydrous sodium sulfate. AcOEt was evaporated under reduced pressure to give 2.0 g of the title compound.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[NH2:11])=O.[O-:12][C:13]#[N:14].[K+]>>[F:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:11][C:13](=[O:12])[N:14]=[C:2]2[CH3:1]
Reactant: N#C[O-]
Reactant: CC(=O)c1cc(F)ccc1N
Agent: [K+]
Product: Cc1nc(=O)[nH]c2ccc(F)cc12

Procedure:
6-Fluoro-4-methyl-2(1H)-quinazolinone is prepared by treatment of 2-amino-5-fluoroacetophenone with potassium cyanate as in Example 18 and is isolated as the 1/4 hydrate, (mp 294°-296° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:22][C:12]([C:9]1[O:10][C:11]2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=2[CH:8]=1)=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc2cc(C(=O)O)oc12
Reactant: NCc1ccccc1
Product: COc1cccc2cc(C(=O)NCc3ccccc3)oc12

Procedure:
Substantially the same procedure as in Example 219 was repeated using a starting material, 7-methoxybenzofuran-2-carboxylic acid, and benzylamine to give N-benzyl-7-methoxybenzofuran-2-carboxamide (Compound 269a). Successively, it was formylated to give N-benzyl-4-formyl-7-methoxybenzofuran-2-carboxamide (Compound 269b), then compound 269b was reacted with methylamine hydrochloride to give compound 269 as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:24]=[CH:23][C:22]([OH:25])=[C:21]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:41])C(=O)C1.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:24]=[C:23]([Br:41])[C:22]([OH:25])=[C:21]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)c1c(OCc2ccccc2)ncc(O)c1OCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1c(OCc2ccccc2)nc(Br)c(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67 %

Procedure:
A mixture of benzyl 2,4-bis(benzyloxy)-5-hydroxynicotinate (0.29 g, 0.66 mmol) and NBS (0.13 g, 0.72 mmol) in DMF (1.2 mL) was stirred at room temperature for 5 min then treated with water. The mixture was extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over sodium sulfate, evaporated and purified by silica chromatography (0-30% ethyl acetate in hexanes) to give benzyl 2,4-bis(benzyloxy)-6-bromo-5-hydroxynicotinate (0.23 g, 68%).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[CH2:21]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>O1CCOCC1>[CH2:29]([N:28]([CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C1Nc2cccnc2N(C(=O)CN(Cc2ccccc2)Cc2ccccc2)c2ccccc21

Procedure:
6 gm of 11-chloroacetyl-5,11-dihydro-6H-pyrido [2,3-b][1,4]benzodiazepin-6-one, 4.2 gm of dibenzylamine and 2.1 gm of triethylamine were refluxed in 100 ml of absolute dioxane for 15 hours. After cooling, the formed triethylamine hydrochloride was separated, and the filtrate was evaporated in vacuo to dryness. The residue was then recrystallized twice from ethanol.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[F:10][C:11]([F:22])([F:21])[O:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[O:16]>>[N+:6]([C:18]1[CH:19]=[CH:20][C:13]([O:12][C:11]([F:10])([F:21])[F:22])=[C:14]([CH:17]=1)[CH:15]=[O:16])([O-:9])=[O:7]
Reactant: O=Cc1ccccc1OC(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=Cc1cc([N+](=O)[O-])ccc1OC(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a mixture of concentrated sulfuric acid (81 mL) and concentrated nitric acid (15.5 mL), cooled to 0° C., was added 2-trifluoromethoxybenzaldehyde (25 g, 0.13 mol) portionwise while maintaining the temperature of the reaction below 0° C. After 1.5 hours, the reaction mixture was poured cautiously over 1000 mL of ice in a large beaker and left to stand for 0.5 hours. The resulting suspension was filtered, washed well with H2O and air dried to give crude 5-nitro-2-trifluoromethoxybenzaldehyde, m.p. 32°-34° C.
Reaction SMILES: [C:1]1([N:7]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:10][CH2:9][C:8]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:21].S(Cl)(Cl)(=O)=O>C(Cl)(Cl)Cl>[Cl:21][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:10][CH2:9][C:8]2=[O:19])=[CH:2][CH:3]=1
Reactant: O=C1CCCC(c2ccccc2)N1c1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: O=S(=O)(Cl)Cl
Product: O=C1CCCC(c2ccccc2)N1c1ccc(Cl)cc1
Yield: 73.9 %

Procedure:
To 0.25 g of 1,6-diphenyl-2-piperidone were added 0.30 g of phosphorus pentachloride, 0.5 ml of sulfuryl chloride and 5 ml of chloroform, and the mixture was refluxed for 1.5 hours. The reaction mixture was concentrated under reduced pressure, made alkaline with an aqueous sodium hydrogen carbonate solution, and extracted with 30 ml of ethyl acetate. The ethyl acetate extract was washed with water, dried, and concentrated to give 0.21 g of 1-(4-chlorophenyl)-6-phenyl-2-piperidone.