Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]1)(=[O:21])[C:2]1[CH:20]=[CH:19][CH:18]=[C:4]([C:5]([O:7][CH:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]2)=[O:6])[CH:3]=1.[C:33]([O:37]O)([CH3:36])([CH3:35])C>[Mo](=O)(=O)=O.C1CCCCC1>[C:5]([O:7][CH:8]1[CH2:9][C:10]([CH3:17])([CH3:16])[N:11]([O:37][CH:33]2[CH2:36][CH2:18][CH2:4][CH2:5][CH2:35]2)[C:12]([CH3:14])([CH3:15])[CH2:13]1)(=[O:6])[C:4]1[CH:18]=[CH:19][CH:20]=[C:2]([C:1]([O:22][CH:23]2[CH2:24][C:25]([CH3:32])([CH3:31])[N:26]([O:37][CH:33]3[CH2:36][CH2:3][CH2:2][CH2:1][CH2:35]3)[C:27]([CH3:30])([CH3:29])[CH2:28]2)=[O:21])[CH:3]=1
Reactant: CC1(C)CC(OC(=O)c2cccc(C(=O)OC3CC(C)(C)NC(C)(C)C3)c2)CC(C)(C)N1
Reactant: CC(C)(C)OO
Agent: O=[Mo](=O)=O
Solvent: C1CCCCC1
Product: CC1(C)CC(OC(=O)c2cccc(C(=O)OC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)c2)CC(C)(C)N1OC1CCCCC1
Temperature: 140 °C
Yield: 143.5 %

Procedure:
A mixture of 35.0 g (78.7 mmol) of di-(2,2,6,6-tetramethyl-piperidin-4-yl) isophthalate, 47.3 g (472 mmol) of 90% aqueous t-butyl hydroperoxide, 2.0 g of molybdenum trioxide, and 300 ml of cyclohexane is heated two hours at 140° C. in a Fischer-Porter bottle. The red reaction mixture is treated with an additional 20.0 g (90%, 200 mmol) of t-butyl hydroperoxide and heated at 140° C. for 120 minutes to discharge the red color. The reaction mixture is cooled, filtered, and the filtrate is evaporated to an oil which is crystallized from ethanol to afford 36.2 g (72% yield) of a white solid, m.p. 135°-141° C.
Reaction SMILES: C(OP(CC(OCC)=O)(OCC)=O)C.[H-].[Na+].N1C=C2N3C(=CC=CC=13)SC(C=O)=C2.[N:31]1[CH:32]=[C:33]2[N:42]3[C:37](=[CH:38][CH:39]=[CH:40][C:41]=13)[S:36][C:35]([CH:43]=[CH:44][C:45]([O:47]CC)=[O:46])=[CH:34]2.[OH-].[Na+].Cl>C1(C)C=CC=CC=1.CN(C)C=O.O.C(O)C>[N:31]1[CH:32]=[C:33]2[N:42]3[C:37](=[CH:38][CH:39]=[CH:40][C:41]=13)[S:36][C:35]([CH:43]=[CH:44][C:45]([OH:47])=[O:46])=[CH:34]2
Reactant: CCOC(=O)C=CC1=Cc2cnc3cccc(n23)S1
Agent: CCOC(=O)CP(=O)(OCC)OCC
Agent: Cl
Agent: O=CC1=Cc2cnc3cccc(n23)S1
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: O=C(O)C=CC1=Cc2cnc3cccc(n23)S1
Reaction time: 0.5 h

Procedure:
To a solution of 7.777 g (38.076 mM) of 5-thia-1,8b-diazaacenaphthylene-4-methanol in ethyl acetate (50 ml)-N,N-dimethylformamide (50 ml) was added 23 g of active manganese dioxide and the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered and the precipitate was washed with N,N-dimethylformamide. The pooled filtrate was distilled under reduced pressure to remove the solvent. The crude 5-thia-1,8b-diazaacenaphthylene-4-carbaldehyde thus obtained was not purified but used as it was in the next reaction. To a solution of 9.39 g (41.9 mM) of ethyl diethylphosphonoacetate in 50 ml of toluene was added 1.68 g (41.9 mM) of a 60% suspension of sodium hydride in liquid paraffin at room temperature and the mixture was stirred for 0.5 hour. This mixture was added to a solution of the above crude 5-thia-1,8b-diazaacenaphthylene-4-carbaldehyde in N,N-dimethylformamide (50 ml)-toluene (200 ml) under ice cooling and the mixture was stirred at room temperature for one hour. This reaction mixture was poured in water and extracted with 3 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The resulting crude ethyl 3-(5-thia-1,8b-diazaacenaphthylen-4-yl)acrylate was not purified but used as it was in the next reaction. To a solution of the above crude ethyl 3-(5-thia-1,8b-diazaacenaphthylen-4-yl)acrylate in 300 ml of ethanol was added 60 ml (120 mM) of 2N-aqueous solution of sodium hydroxide and the mixture was stirred at room temperature for 3 hours. To this reaction mixture was added concentrated hydrochloric acid (ca 10 ml) with stirring to bring the pH into the range of 4-5 and the resulting precipitate was recovered by filtration and rinsed serially with ethanol and diethyl ether to provide the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Na+].[C:11]1([S:17]([O-:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CS(C)=O>[C:11]1([S:17]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1F
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccccc1S(=O)(=O)c1ccccc1
Temperature: 100 °C

Procedure:
To a solution of 2-fluoro benzaldehyde (5.00 ml, 47.6 mmol) in dimethyl sulfoxide (45 ml) was added benzene sulfinic acid sodium salt (8.60 g, 52.4 mmol) and the resulting mixture heated to 100° C. Upon heating the sulfinic acid salt dissolved. The solution was heated at 100° C. for 3 days. The reaction was cooled to room temperature and water (50 ml) added. This mixture was extracted with ethyl acetate, the combined organic extracts were washed with saturated brine, dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography on silica eluting with 25% ethyl acetate: petroleum ether (40-60° C.) to 33% ethyl acetate: petroleum ether (40-60° C.) to give (4.12 g, 16.7 mmol, 35%). δH (300 MHz, d6-DMSO) 10.68 (1H, s, CHO), 8.26-8.17 (1H, m, Ar), 8.08-7.99 (2H, m, Ar), 7.99-7.89 (3H, m, Ar) and 7.80-7.62 (3H, m, Ar).
Reaction SMILES: [CH:1]([N:4]1[CH:12]=[N:11][C:10]2[C:5]1=[N:6][C:7]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=1)=[N:8][C:9]=2[NH:13][C:14]1[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=1)([CH3:3])[CH3:2].[NH4+].[Cl-]>CCOC(C)=O.O.[Fe]>[NH2:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[O:20][C:7]1[N:6]=[C:5]2[C:10]([N:11]=[CH:12][N:4]2[CH:1]([CH3:3])[CH3:2])=[C:9]([NH:13][C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)[N:8]=1
Reactant: CC(C)n1cnc2c(Nc3cnn(C)c3)nc(Oc3cccc([N+](=O)[O-])c3)nc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)n1cnc2c(Nc3cnn(C)c3)nc(Oc3cccc(N)c3)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
A mixture of 9-isopropyl-N-(1-methyl-1H-pyrazol-4-yl)-2-(3-nitrophenoxy)-9H-purin-6-amine (50 mg, 0.14 mmol), Fe (39 mg, 0.7 mmol), NH4Cl (75 mg, 1.4 mmol) in EtOAc (10 mL) and water (10 mL) was stirred at rt overnight. The mixture was filtered and the filtrate was extracted with EtOAc (2×10 mL). The combined organic layers were dried over Na2SO4 and concentrated to give crude product (46 mg, 100% yield), which was used the next step directly without further purification.
Reaction SMILES: [NH2:1][CH:2]([C:5]([F:12])([F:11])[CH2:6][CH2:7][CH2:8][O:9][CH3:10])[CH:3]=[CH2:4].C(N1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])(OCC)=O>C1C=CC=CC=1>[C:19]1(=[O:28])[N:1]([CH:2]([C:5]([F:11])([F:12])[CH2:6][CH2:7][CH2:8][O:9][CH3:10])[CH:3]=[CH2:4])[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: C=CC(N)C(F)(F)CCCOC
Solvent: c1ccccc1
Product: C=CC(N1C(=O)c2ccccc2C1=O)C(F)(F)CCCOC
Reaction time: 8 h
Yield: 85.7 %

Procedure:
A mixture of 3-amino-4,4-difluoro-7-methoxy-1-heptene (420 mg, 2.3 mmoles) and N-carbetoxyphthalimide (506 mg, 2.3 mmoles) in benzene (9 ml) is kept at 25° C. overnight. After concentration under reduced pressure, the residue is dissolved in dichloromethane (5 ml) and treated with triethylamine (0.7 ml) for 41/2 hours. After addition of dichloromethane, the solution is washed with 1N HCl and water. Usual work-up affords an oil (610 mg) which is purified by chromatography on silica (ethyl acetate/petroleum ether: 20/80 RF: 0.4): 440 mg (62%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][NH:3]1.[C:5]([O:9][CH2:10][CH2:11][O:12][C:13](=[O:16])[CH:14]=[CH2:15])(=[O:8])[CH:6]=[CH2:7]>>[CH3:1][CH:2]1[CH2:4][N:3]1[CH2:7][CH2:6][C:5]([O:9][CH2:10][CH2:11][O:12][C:13](=[O:16])[CH2:14][CH2:15][N:3]1[CH2:4][CH:2]1[CH3:1])=[O:8]
Reactant: C=CC(=O)OCCOC(=O)C=C
Reactant: CC1CN1
Product: CC1CN1CCC(=O)OCCOC(=O)CCN1CC1C

Procedure:
2-Methylaziridine (9.1 gm) was charged in a 100 ml round bottle reaction vessel equipped with a condenser and dropping funnel. Ethylene glycol diacrylate (13.5 gm) was slowly added to the solution while stirring with a magnetic stirrer to maintain the solution temperature below about 40°-45° C. The resulting solution was further stirred at 50° C. for 30 minutes and at room temperature for 30 minutes. Ethylene glycol di(2-methyl-1-aziridinepropionate) was formed as a slightly yellowish viscous liquid and used without further purification. Trimethylolpropane tris[3-(2-methyl-1-aziridinyl)propionate] was also prepared by adding trimeylolpropane triacrylate (9.87 gm) to 2-methylaziridine (5.7 gm) using the foregoing method.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:25]([O:27][CH3:28])=[O:26])=[N:11][N:12]2[CH:17]([C:18]([O:20]CC)=[O:19])[CH2:16][N:15]([CH3:23])[C:14](=[O:24])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:8][C:9]1[C:10]([C:25]([O:27][CH3:28])=[O:26])=[N:11][N:12]2[CH:17]([C:18]([OH:20])=[O:19])[CH2:16][N:15]([CH3:23])[C:14](=[O:24])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CN(C)C(=O)c2c(OCc3ccccc3)c(C(=O)OC)nn21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2C(=O)O
Reaction time: 1 h

Procedure:
To a solution of methyl 3-benzyloxy-7-ethoxycarbonyl-5-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (195 mg, 0.503 mmol) in MeOH/THF (0.5 mL) was added aqueous 1N NaOH (554 μL, 0.554 mmol). The mixture was stirred for 1 hour and quenched by the addition aqueous 3N HCl (170 μL). Purification by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA) and collection and concentration of the appropriate fractions afforded the title product as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 7.49-7.47 (m, 2H), 7.40-7.33 (m, 3H), 5.44 (br s, 1H), 5.21 (dd, J=11.2, 30.4 Hz, 2H), 4.18 (dd, J=4.8, 13.6 Hz, 1H), 3.91 (d, J=13.6 Hz, 1H), 3.80 (s, 3H), 3.01 (s, 3H); ES MS (M+H)=360.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH:2]=[CH2:3].[CH2:11]([CH:13]1[O:15][CH2:14]1)Cl>>[O:15]1[CH:13]([CH2:11][O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:1][CH:2]=[CH2:3])[CH2:14]1
Reactant: C=CCc1ccccc1O
Reactant: ClCC1CO1
Product: C=CCc1ccccc1OCC1CO1

Procedure:
The title compound was synthesized from 2-allylphenol and epichlorohydrin by the method of Brandstrom et al. (Chem. Abs. 72, 12342n).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])C.Cl.FC1C=C(C=CC=1)COC1C=CC2CC[NH:42]CCC=2C=1.C(C(C(Cl)=O)C(Cl)=O)C>C(N(CC)CC)C>[F:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][N:8]([C:6](=[O:7])[CH2:5][C:4]([NH2:42])=[O:3])[CH2:14][CH2:13][C:12]=2[CH:15]=1
Reactant: Fc1cccc(COc2ccc3c(c2)CCNCC3)c1
Reactant: CCOC(=O)CC(=O)N1CCc2ccc(OCc3cccc(F)c3)cc2CC1
Agent: CCC(C(=O)Cl)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: NC(=O)CC(=O)N1CCc2ccc(OCc3cccc(F)c3)cc2CC1
Yield: 70 %

Procedure:
3-[7-(3-Fluoro-benzyloxy)-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl]-3-oxo-propionic acid ethyl ester: The title compound was prepared in analogy to Example 1d) from 7-(3-fluoro-benzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride [Example 1c)] and ethyl malonic acid chloride with triethylamine as the base. Yield: 70% of theory as a colourless oil; MS: m/e=386 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[C:13]([NH:15][NH2:16])=[O:14].N1C=CC=CC=1.[C:23](Cl)(Cl)=[O:24]>C(COC)OC>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[C:13]1[O:14][C:23](=[O:24])[NH:16][N:15]=1
Reactant: O=C(Cl)Cl
Reactant: NNC(=O)c1c(Cl)ccc2cc(Cl)cnc12
Solvent: c1ccncc1
Solvent: COCCOC
Product: O=c1[nH]nc(-c2c(Cl)ccc3cc(Cl)cnc23)o1
Yield: 62 %

Procedure:
12.8 g (50 millimoles) of 3,7-dichloroquinoline- 8-carboxylic hydrazide (compound No. 1) were suspended in 100 ml of dimethoxyethane, 7.9 g (100 millimoles) of pyridine were added and phosgene was then passed in over a period of 4 hours at 25° C. Excess phosgene and the solvent were removed, the residue was stirred into water and the mixture was filtered under suction to give 8.7 g (62%) of a product of melting point of 87° C. (compound No. 33).
Reaction SMILES: [C:1]([C:3]1[CH:39]=[CH:38][C:6]([CH:7]=[CH:8][C:9]([NH:11][CH2:12][C:13]([N:15]([C:17]2[C:18]([Cl:37])=[C:19]([C:33]([Cl:36])=[CH:34][CH:35]=2)[CH2:20][O:21][C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[C:31]=2[N:30]=[C:29]([CH3:32])[CH:28]=[CH:27]3)[CH3:16])=[O:14])=[O:10])=[CH:5][CH:4]=1)#[N:2].C[Sn]([N:44]=[N+:45]=[N-:46])(C)C.ClC1C(N(C)C(=O)CNC(=O)C=CC2C=CC(C(=O)N(CC(=O)NC)C)=CC=2)=CC=C(Cl)C=1COC1C=CC=C2C=1N=C(C)C=C2>C1(C)C(C)=CC=CC=1>[Cl:37][C:18]1[C:17]([N:15]([CH3:16])[C:13](=[O:14])[CH2:12][NH:11][C:9](=[O:10])[CH:8]=[CH:7][C:6]2[CH:38]=[CH:39][C:3]([C:1]3[NH:46][N:45]=[N:44][N:2]=3)=[CH:4][CH:5]=2)=[CH:35][CH:34]=[C:33]([Cl:36])[C:19]=1[CH2:20][O:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[C:29]([CH3:32])[CH:28]=[CH:27]2
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(C#N)cc4)c3Cl)c2n1
Agent: CNC(=O)CN(C)C(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cc1
Solvent: Cc1ccccc1C
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(-c5nnn[nH]5)cc4)c3Cl)c2n1
Temperature: 125 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
A mixture of 8-[3-[N-(4-cyanocinnamoylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (76 mg) and trimethyltin azide (109 mg) in xylene (1 ml) was heated at 125° C. for 20 hours. After cooled, methanol-chloroform (1:4 V/V, 10 ml) and silica gel (296 mg) was added to the reaction mixture. The resulting suspension was stirred at ambient temperature for one hour. The silica gel was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by preparative thin-layer chromatography eluting with methanol -chloroform (1:6) to afford 8-[2,6-dichloro-3-[N-methyl-N-[4-(5-tetrazolyl)cinnamoylglycyl]amino]benzyloxy]-2-methylquinoline (40 mg) as a pale yellow glass.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]([C:14](=O)[CH3:15])[NH2:13].[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(O)(=O)C>[C:17]([NH:13][N:12]1[C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=2[N:1]=[C:14]1[CH3:15])(=[O:19])[CH3:18]
Reactant: CC(=O)N(N)c1ccc(C(F)(F)F)cc1N
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nn1c(C)nc2cc(C(F)(F)F)ccc21
Yield: 90 %

Procedure:
After boiling 23.3 g of 2-amino-4-trifluoromethyl-N-acetylphenylhydrazine [prepared as described in: J. Org. Chem. 42, 542 (1977)] with 120 ml of acetic acid and 20 ml of acetic anhydride for 6 hours, the orange-red solution obtained was evaporated under reduced pressure and the residue was triturated with water. The separated crystals were filtered by suction, washed with water and dried at 80° C. to yield 23.2 g (90%) of 1-acetylamino-2-methyl-5-trifluoromethylbenzimidazole, m.p.: 214°-216° C. after recrystallization from acetone.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(=NC1CCCCC1)C.[CH:18]1([C:24](=[C:27]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)C=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[O:42]1C[CH2:45][CH2:44][CH2:43]1>>[CH:18]1([C:24](=[C:27]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)[CH:45]=[CH:44][CH:43]=[O:42])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)C1CCCCC1
Reactant: C1CCOC1
Agent: CC(C)[N-]C(C)C
Agent: CC=NC1CCCCC1
Agent: [Li+]
Product: O=CC=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)C1CCCCC1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
Lithium diisopropylamide (40 mL of 1.5M solution, 60 mmol) was added to a solution of N-ethylidenecyclohexanamine (30 mL of 2M solution, 60 mmol) in tetrahydrofuran at -10° C. After stirring for 30 minutes and further cooling to -50° C., 2-cyclohexyl-3,3-bis(4-fluorophenyl)propenal (8.4 g, 25.8 mmol) was added and the solution stirred for 3 hours during which time it was allowed to warm to 20° C. The solution was quenched with 2N hydrochloric acid and the mixture extracted with diethyl ether. The extracts were dried with magnesium sulfate and concentrated in vacuo. The residue was stirred for 4 days with a mixture of 100 mL benzene, 60 mL acetic acid and 40 mL water. The mixture was diluted with an additional 100 mL water and the layers separated. The organic phase was washed with water and saturated sodium bicarbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue was cyrstallized from hexane to give 6.0 g of the title compound; m.p. =116°-118° C.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[CH2:10][CH2:11][CH2:12][C:13]([N:15]1[CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][O:17][C:16]1=[O:26])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:34][C:35]1[CH:40]=[CH:39][C:38]([N:41]=[CH:42][C:43]2[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=2)=[CH:37][CH:36]=1.C(N(C(C)C)C(C)C)C.C[Si](Cl)(C)C.C(O)(=O)C(C(C(O)=O)O)O.S([O-])(O)=O.[Na+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C>[Si:1]([O:8][CH:9]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[CH2:10][CH2:11][CH:12]([CH:42]([NH:41][C:38]1[CH:39]=[CH:40][C:35]([F:34])=[CH:36][CH:37]=1)[C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1)[C:13]([N:15]1[CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][O:17][C:16]1=[O:26])=[O:14])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC(CCCC(=O)N1C(=O)OCC1c1ccccc1)c1ccc(F)cc1
Reactant: Oc1ccc(C=Nc2ccc(F)cc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[Si](C)(C)Cl
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(CCC(C(=O)N1C(=O)OCC1c1ccccc1)C(Nc1ccc(F)cc1)c1ccc(O)cc1)c1ccc(F)cc1
Temperature: -10 °C

Procedure:
10 g of 3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)pentanoyl]-4-phenyloxazolidin-2-one are dissolved in 80 ml of absolute dichlormethane. 9.12 g of 4-[(4-fluorophenylimino)methyl]phenol and 19.6 ml of ethyldiisopropylamine are added, and the solution is then cooled to −10° C. 6.7 ml of trimethylsilyl chloride are then added dropwise, the temperature of the reaction mixture being maintained at below −5° C. The reaction solution is stirred at −10° C. for half an hour and then cooled to −30° C., and 2.7 ml of titanium tetrachloride are added dropwise, the temperature being maintained between −30° C. and −15° C. This gives a black reaction solution which is stirred at −20° C. for another 3 h and then allowed to warm to 0° C. In the stated order, in intervals of 10 minutes, 6 ml of glacial acetic acid, 60 ml of 7% strength aqueous tartaric acid solution and finally 100 ml of 20% strength aqueous sodium hydrogensulfite solution are then added with stirring. The mixture is then extracted three times with dichloromethane and the organic phase is washed once with saturated sodium chloride solution and dried over sodium sulfate. The solvent is removed using a rotary evaporator and the residue is purified by column chromatography (SiO2; ethyl acetate/heptane 1:4). The product is obtained from diethyl ether/pentane as white crystals. C39H44F2N2O5Si (686) MS (ESI): M+-241
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:3])[CH3:2].[C:22]([C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)#[CH:23]>CCCCCCC.CCOC(C)=O>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([C:22]#[C:23][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:1](=[O:3])[CH3:2])=[CH:25][CH:26]=1
Reactant: CC(=O)Nc1ccccc1OS(=O)(=O)c1ccc(C)cc1
Reactant: C#Cc1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(=O)Nc1ccccc1C#Cc1ccc(N)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-acetylamino-phenyl ester and 4-ethynyl-phenylamine following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 9:1; yield (47 mg, 50%); 1H NMR δ (CDCl3): 8.39 (d, J=8.52 Hz, 1H), 7.9 (br s, 1H), 7.59-7.67 (m, 2H), 7.58-7.52 (m, 2H), 7.41-7.35 (m, 2H), 7.02 (t, J=7.21 Hz, 1H), 3.82 (b, 2H), 2.21 (s, 3H); LCMS m/z: 250.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:12][C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)[N:8]=[CH:9]2)=[CH:4][CH:3]=1.Br.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:12][C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(Oc2cc3ccc(Cl)cc3cn2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(Oc2cc3ccc(Cl)cc3cn2)cc1
Yield: 90.7 %

Procedure:
7-Chloro-3-(4-methoxyphenoxy)isoquinoline (3.50 g) was refluxed in a mixture of acetic acid (25 ml) and a solution of hydrogen bromide (25 ml, 48%) for 3 hrs. The mixture was cooled, poured into water, neutralized with sodium carbonate and extracted with ethyl acetate. The extract was washed thoroughly with water, dried (MgSO4) and evaporated to give 4-[(7-chloroisoquinolin-3-yl)oxy]phenol (3.02 g) as brown solid, mp 190° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:9]([F:20])=[C:8]([O:21][CH3:22])[N:7]=1)=[CH2:5])C.C(#N)C.C(=O)(O)[O-].[Na+].[F:31][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>O>[F:20][C:9]1[CH:10]=[C:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]([C:4](=[O:5])[CH2:3][F:31])=[N:7][C:8]=1[O:21][CH3:22]
Reactant: F[B-](F)(F)F
Reactant: C=C(OCC)c1nc(OC)c(F)cc1NC(=O)OC(C)(C)C
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1nc(C(=O)CF)c(NC(=O)OC(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1,1-dimethylethyl [2-[1-(ethyloxy)ethenyl]-5-fluoro-6-(methyloxy)-3-pyridinyl]carbamate (6.72 g, 21.54 mmol), acetonitrile (70 ml), and saturated aqueous sodium bicarbonate solution (15 ml) was treated portionwise over 5 minutes at 0° C. under argon with [1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor™) (8.9 g, 25.05 mmol). After the addition the mixture was stirred at room temperature for 0.5 hour then treated with saturated aqueous sodium bicarbonate solution (50 ml), stirred for 10 minutes, then diluted with water (100 ml) and extracted with ethyl acetate (3×200 ml). The combined organic extracts were dried over magnesium sulphate and evaporated. The residue was chromatographed eluting with 0-50% dichloromethane in hexane affording the product as a white solid (3.72 g, 57%).
Reaction SMILES: C1CN(C(CNCC2C=CC3OCOC=3C=2)=O)CC1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][N:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]3[N:39]=[N:40][CH:41]=[CH:42][CH:43]=3)=[CH:32][C:31]2=[O:44])=[CH:24][CH:23]=1.[NH:45]1[CH2:50][CH2:49][CH:48]([NH:51][C:52](=[O:54])[CH3:53])[CH2:47][CH2:46]1>>[O:44]=[C:31]1[CH:32]=[C:33]([O:36][CH2:37][C:38]2[N:39]=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:34]=[CH:35][N:30]1[CH2:29][CH2:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:45]2[CH2:50][CH2:49][CH:48]([NH:51][C:52](=[O:54])[CH3:53])[CH2:47][CH2:46]2)=[CH:23][CH:24]=1
Reactant: O=c1cc(OCc2cccnn2)ccn1CCc1ccc(CBr)cc1
Reactant: CC(=O)NC1CCNCC1
Agent: O=C(CNCc1ccc2c(c1)OCO2)N1CCCC1
Product: CC(=O)NC1CCN(Cc2ccc(CCn3ccc(OCc4cccnn4)cc3=O)cc2)CC1

Procedure:
N-[1-(4-{2-[2-Oxo-4-(pyridazin-3-ylmethoxy)-2H-pyridin-1-yl]-ethyl}-benzyl)-piperidin-4-yl]-acetamide is prepared as example 15.1c from 110 mg (0.28 mmol) 1-[2-(4-bromomethylphenyl)-ethyl]-4-(pyridazin-3-ylmethoxy)-1H-pyridin-2-one (example 15.1b) and 156 mg (1.10 mmol) N-piperidin-4-yl-acetamide.