Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:5]=1[N:6]2[CH2:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15].C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(#N)C.C(OCC)C>[CH3:15][N:14]([CH3:16])[CH2:13][CH2:12][CH2:11][N:6]1[C:7]2[C:3](=[C:2]([NH:1][C:31](=[O:32])[O:33][CH2:34][CH3:35])[CH:10]=[CH:9][CH:8]=2)[C:4]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:5]1=2
Reactant: CCOC(=O)Cl
Reactant: CN(C)CCCn1c2c(c3c(N)cccc31)CCCCCC2
Solvent: CCOCC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1cccc2c1c1c(n2CCCN(C)C)CCCCCC1
Reaction time: 18 h

Procedure:
To a solution of 1-amino-5-(3-dimethylaminopropyl)-6,7,8,9,10,11-hexahydro-5H-cyclooct[b]indole (5 g, 0.024 mol) and 5 mL of triethylamine in 80 mL dry acetonitrile (under nitrogen), stirred and kept below 20° C., was added 5 mL ethyl chloroformate. The reaction mixture was stirred at 25°-28° C. for 18 hours. The mixture was diluted with diethyl ether and the precipitate (Et3N.HCl) was filtered off and washed with diethyl ether. The filtrate was dried over sodium sulfate, filtered and the filtrate treated with dry hydrogen chloride. On standing a blueish solid separated. This was filtered, washed with diethyl ether, and dried in a vacuum pistol. There was obtained 1.15 g of the title compound as the hydrochloride.
Reaction SMILES: [CH2:1]1C2C(CCCC2)CC[CH2:2]1.[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13].[CH3:17][CH:18]1[CH:23](CO)[CH2:22][CH2:21][CH:20]=[CH:19]1>C(Cl)(Cl)Cl>[CH2:1]=[CH2:2].[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13].[CH3:16][O:15][C:11](=[O:14])[CH:12]=[CH2:13].[CH3:17][C:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=1
Reactant: CC1C=CCCC1CO
Reactant: C1CCC2CCCCC2C1
Solvent: ClC(Cl)Cl
Solvent: C=CC(=O)OC
Product: C=C
Product: CC1=CCCCC1
Temperature: 170 °C

Procedure:
550 ml of decalin® was placed in a flask. To this was added 350 g of Chevron EMAC SP-2260 which has 24 weight % of methyl acrylate (0.9767 moles of methyl acrylate) and 0.48 g of Irganox®1076 (0.1 mole). The temperature of the mixture was gradually raised while stirring. When the temperature reached approximately 120° C., 127.1 g (0.9767 moles) of 3-methyl-cyclohex-1-ene-4-methanol (97%) was added. When the temperature reached approximately 140° C., 4.8 g of the catalyst Ti(OC2H5)4 was added a portion at a time. The temperature was maintained at 170° C. while stirring. The course of the reaction was observed by subjecting samples of the mixture to NMR at hourly intervals. The percent conversion is given in Table 1 below. After 5 hours of reaction, the mixture was cooled and 400 ml of CHCl3 was added and the mixture was then precipitated by adding it to 4 liters of CH3OH in a Waring blender. The precipitate is filtered and washed with CH3OH and dried in a vacuum oven at 50° C. The dried mixture yielded 407.5 g of ethylene/methyl acrylate/methyl cyclohexene methyl acrylate (EMCM).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[F:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH3:28][O:27][C:25]([C:21]1[CH2:22][CH2:23][N:24]([CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=2[F:30])[C:18]2[CH:17]=[CH:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][CH:13]=3)=[CH:29][C:19]=2[CH:20]=1)=[O:26]
Reactant: O=Cc1ccccc1F
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 100 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (300 mg) and 2-fluorobenzaldehyde (471 mg) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (402 mg), and the mixture was stirred under nitrogen atmosphere at room temperature for 5 days. Then, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) to give methyl-7-(4-butoxyethoxyphenyl)-1-(2-fluorobenzyl)-2,3-dihydro-1-benzazepine-4-carboxylate (382 mg) as yellow oil.
Reaction SMILES: [Mg].[CH:2](Br)=[CH2:3].[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH:15]=[O:16].[Cl-].[NH4+]>O1CCCC1>[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH:15]([OH:16])[CH:2]=[CH2:3]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: C=CBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1ccc2ccccc2c1
Reaction time: 1 h

Procedure:
1.8 g of magnesium are covered with 10 ml of absolute tetrahydrofuran. About 1 ml of a solution of 8 g of vinyl bromide in 8 ml of absolute tetrahydrofuran is added dropwise and the reaction is initiated by slight warming. Then, the remainder of the vinyl bromide solution is added dropwise. The mixture is left to react until it reaches room temperature. A solution of 7 g of 2-naphthaldehyde in 50 ml of absolute tetrahydrofuran is then added slowly dropwise, as the temperature rises to 40° C. The reaction is completed within 1 hour. The mixture is then hydrolyzed by the addition with stirring of 20 ml of saturated ammonium chloride solution at 0° C. The residue is filtered and rinsed with ether. The filtrate is diluted with water and extracted twice with ether. The ether extracts are washed with semi-saturated and saturated sodium chloride solution, dried over sodium sulfate and evaporated to yield 1-(2-naphthyl)-2-propen-1-ol which, without further purification, is esterified with cyclopropane carboxylic acid chloride in the process of Example 2. The resulting product is cyclopropane carboxylic acid 1-(2-naphthyl)allyl ester of melting point 30°-32° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([C:22](O)=[O:23])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:27]([CH:31]([CH3:33])[CH3:32])C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1(N)CC1>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([CH:20]([C:22](=[O:23])[NH:27][CH:31]3[CH2:33][CH2:32]3)[CH3:21])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C(=O)O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: NC1CC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C(=O)NC1CC1)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 3.00 g (9.00 mmol) 4-[4-(1-carboxy-ethyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (IX.1) and 3.85 mL (22.5 mmol) DIPEA in 5 mL DMF, 4.33 g (13.5 mmol) TBTU are added. The mixture is stirred for 15 min at rt. After that time, 0.94 mL (13.5 mmol) cyclopropylamine are added and the mixture is stirred for 12 h at rt. After that time, water is added and the mixture is extracted with EtOAc.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1([OH:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].I[CH:26]([CH2:28][CH3:29])[CH3:27]>C(#N)C>[CH:26]([N:15]1[CH2:16][CH2:17][C:12]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:10])([F:11])[F:9])[C:2]=2[F:1])([OH:18])[CH2:13][CH2:14]1)([CH2:28][CH3:29])[CH3:27]
Reactant: OC1(c2cccc(C(F)(F)F)c2F)CCNCC1
Reactant: CCC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCC(C)N1CCC(O)(c2cccc(C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 2: 4-[2-fluoro-3-(trifluoromethyl)phenyl]piperidin-4-ol (0.02 g, 0.076 mmol), acetonitrile (2 ml), potassium carbonate (0.02 g, 0.14 mmol), 2-iodobutane (0.009 ml, 0.082 mmol). MS m/z (relative intensity, 70.eV) 319 (M+, 2), 290 (72), 191 (28), 177 (14), 56 (bp).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:41]=[CH:40][C:18]([O:19][C:20]2[CH:25]=[C:24]([NH:26][C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])[CH2:31][CH2:30]3)=[O:28])[N:23]=[CH:22][N:21]=2)=[C:17]([F:42])[CH:16]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(O)C>[CH3:38][N:37]([CH3:39])[CH2:36][CH2:35][N:32]1[CH2:33][CH2:34][N:29]([C:27]([NH:26][C:24]2[CH:25]=[C:20]([O:19][C:18]3[CH:40]=[CH:41][C:15]([NH:14][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[S:13])=[CH:16][C:17]=3[F:42])[N:21]=[CH:22][N:23]=2)=[O:28])[CH2:30][CH2:31]1
Reactant: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ncn2)CC1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)CC1
Reaction time: 2 h
Yield: 38 %

Procedure:
After adding a solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.2 M, 3.5 ml) to a solution of 4-(4-amino-2-fluorophenoxy)-6-{[4-(2-dimethylaminoethyl)piperazin-1-yl]carbonylamino}pyrimidine (150 mg) and (+)-10-camphorsulfonic acid (173 mg) in ethanol (3.5 ml) at room temperature, the mixture was stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine in that order and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5) to provide the title compound (84.8 mg, 38%) as white powder.
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[CH:6][C:7]=1Cl)=[O:2].[Na+].[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([O-:18])=[O:17]>>[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([C:7]1[CH:6]=[CH:5][S:4][C:3]=1[CH:1]=[O:2])(=[O:18])=[O:17]
Reactant: O=Cc1sccc1Cl
Reactant: O=S([O-])c1ccccn1
Agent: [Na+]
Product: O=Cc1sccc1S(=O)(=O)c1ccccn1

Procedure:
The title compound was prepared by the method of Preparation 5a using 2-formyl-3-chlorothiophene and pyridine-2-sulfinic acid sodium salt.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[C:15]([C:16]2[C:17]3[N:18]([N:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=3)[C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[N:14][NH:13][C:12](=[O:31])[CH2:11]1)C1C=CC=CC=1.[H][H]>C(O)C.C(OCC)(=O)C.[C].[Pd]>[OH:8][CH2:9][CH:10]1[C:15]([C:16]2[C:17]3[N:18]([N:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=3)[C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[N:14][NH:13][C:12](=[O:31])[CH2:11]1
Reactant: [H][H]
Reactant: COc1ccc(C2=NNC(=O)CC2COCc2ccccc2)c2cc(C(F)(F)F)nn12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(C2=NNC(=O)CC2CO)c2cc(C(F)(F)F)nn12
Yield: 25.3 %

Procedure:
The compound of Example 322 (60 mg) was dissolved in ethanol (25 mL) and ethyl acetate (25 mL). To this solution, 10% palladium carbon (30 mg) was added and the mixture was stirred at room temperature for 8 hours in a stream of hydrogen gas (1 atm). The insoluble material was removed by filtration through Celite. Evaporation of the solvent and subsequent purification by thin-layer chromatography (silica gel, ethyl acetate:methanol=10:1) afforded the title compound as a pale yellow powder (12 mg).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([OH:14])[CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH3:13].N1C=CC=CC=1.Cl>ClCCl.CN(C1C=CC=CN=1)C.CCOCC>[CH2:8]([O:14][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[CH2:9][CH:10]=[CH:11][CH2:12][CH3:13]
Reactant: O=C1CCC(=O)O1
Reactant: CC/C=C\CCO
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC=CCCOC(=O)CCC(=O)O
Yield: 92.5 %

Procedure:
A mixture of 100 g succinic anhydride, 100 g cis-3-hexen-1-ol, 88.5 ml pyridine and 7.3 g dimethylaminopyridine in 500 ml dichloromethane was refluxed for 4 hours. Ether was added and the mixture was acidified with HCl 2N then washed with brine. The organic layer was dried over magnesium sulfate and concentrated. The residue was distilled under vacuum to afford 185 g of product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10]([O:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:21]1)(=[O:15])[CH2:11][C:12]([CH3:14])=O.[NH2:39]/[C:40](/[CH3:46])=[CH:41]\[C:42]([O:44][CH3:45])=[O:43]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:41]([C:42]([O:44][CH3:45])=[O:43])=[C:40]([CH3:46])[NH:39][C:12]([CH3:14])=[C:11]2[C:10]([O:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][N:23]([CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:24][CH2:25]2)=[O:15])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC(=O)CC(=O)OCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)C1c1cccc(Cl)c1

Procedure:
A mixture of m-chlorobenzaldehyde, 3-(4-benzhydryl-1-piperazinyl)propyl acetoacetate and methyl 3-aminocrotonate was worked up in isopropyl alcohol in the same manner as Example 1 to give 3-(4-benzhydryl-1-piperazinyl)propyl methyl 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate as an oil. This product was further treated with methanolic hydrogen chloride. Recrystallization from methanol gave the dihydrochloride as colorless crystals, m.p. 169°-172° C. Yield 45.6%.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[CH3:17][O:18][C:19](OC)(OC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OC(=O)C)(=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:19]([O:18][CH3:17])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)Cc2cc([N+](=O)[O-])ccc21
Reactant: COC(OC)(OC)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: COC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
30.0 g (0.137 mol) of 1-acetyl-5-nitro-2-indolinone are dissolved in 200 ml of acetic anhydride and after the addition of 50.0 g (0.274 mol) of trimethyl orthobenzoate stirred for 3 hours at 100° C. After cooling it is evaporated down to half the quantity, diluted with ether/petroleum ether, the precipitate is suction filtered and dried.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH2:33])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:14]=2[CH:32]=1.[F:35][C:36]([F:48])([F:47])[C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([NH:33][S:43]([C:40]2[CH:39]=[CH:38][C:37]([C:36]([F:35])([F:47])[F:48])=[CH:42][CH:41]=2)(=[O:45])=[O:44])=[CH:12][C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:14]=2[CH:32]=1
Reactant: COC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccc(OC)cc1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Product: COC(=O)CCCCCOc1cc2c(cc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1)nc(-c1ccccc1)n2-c1ccc(OC)cc1

Procedure:
6-[(5-Amino-1-(4-methoxyphenyl)-2-phenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid methyl ester was reacted with 4-(trifluoromethyl)benzenesulfonic acid chloride according to general operating instructions 13.
Reaction SMILES: [NH2:1][CH:2]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]1=[O:4].C(N(CC)CC)C.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>CN(C)C=O>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([NH:1][CH:2]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]2=[O:4])=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: NC1CCCCNC1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1NCCCCC1Nc1ccc([N+](=O)[O-])cc1
Reaction time: 48 h
Yield: 28 %

Procedure:
5 g (39 mmol) of α-amino-ε-caprolactam are dissolved in 50 ml of dimethylformamide and 5.5 ml (1 eq) of triethylamine in a 100 ml three-necked flask equipped with a reflux condenser and a thermometer. 4.1 ml (1.5 eq) of 4-fluoronitrobenzene are then run into the reaction mixture, which is subsequently brought to a temperature of 70° C. for 48 hours. The mixture is cooled and is then precipitated from water. An orangy-yellow precipitate is isolated by filtration and is then purified on a silica column (eluent: dichloromethane 95/methanol 5). 2.7 g of a yellow product are obtained, i.e. a final yield of 28%.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(O)C.O>[Cl:1][C:2]1[N:11]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: C1COCCN1
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: O
Solvent: CCO
Product: Clc1nc(N2CCOCC2)c2ccccc2n1
Reaction time: 0.17 h
Yield: 73.7 %

Procedure:
Twenty grams of 2,4-dichloroquinazoline was suspended in 200 ml of ethanol. To this suspension was added 17.4 g of morpholine. A mildly exothermic reaction ensued with the concomitant dissolution of the suspended dichloroquinazoline. When the reaction subsided, after about 10 minutes, the mixture was heated at reflux for 15 minutes, and then was allowed to cool. The reaction mixture then was diluted with 800 ml of water. The solid which precipitated was collected by filtration and was washed with water. After drying, the solid was recrystallized from 1:2 benzene-hexane, to give 18.5 g of 2-chloro-4-morpholinoquinazoline; m.p. 103°-105°. The following analytical data were obtained:
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH2:27])=[O:26])=[C:20]([F:28])[CH:19]=1>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:32]=[C:31]([C:33]([F:34])([F:36])[F:35])[CH:30]=[CH:29][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=2[F:13])=[O:8])=[O:26])=[C:20]([F:28])[CH:19]=1
Reactant: NC(=O)Nc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: O=C(NC(=O)Nc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F)NC(=O)c1c(F)cccc1F
Temperature: 20 °C
Reaction time: 48 h
Yield: 88.1 %

Procedure:
2,6-Difluorobenzoyl isocyanate (1.8 g) was added to a solution of N-(4-(2-chloro-4-(trifluoromethyl)phenoxy)-2-fluorophenyl)urea (3.2 g) in dry toluene (50 ml), and the resulting solution was stirred at ambient temperature (20° C.) for 48 hours. The product was then filtered from the reaction mixture, washed with a small amount of 1:2 v/v diethyl ether/light petroleum ether, and dried to yield N-(((((4-(2-chloro-4-(trifluoromethyl)phenoxy)-2-fluorophenyl)-amino)carbonyl)amino)carbonyl)-2,6-difluorobenzamide as a colourless crystalline solid (4.3 g, 90%), mp 190-192° C.
Reaction SMILES: [O:1]=[C:2]([C:10]([F:13])([F:12])[F:11])[C:3]([F:9])([F:8])[S:4]([OH:7])(=[O:6])=[O:5].[C:14]([F:17])([F:16])=[CH2:15]>>[O:1]=[C:2]([C:10]([F:13])([F:11])[F:12])[C:3]([F:8])([F:9])[S:4]([O:7][C:14]([F:17])([F:16])[CH3:15])(=[O:6])=[O:5]
Reactant: O=C(C(F)(F)F)C(F)(F)S(=O)(=O)O
Reactant: C=C(F)F
Product: CC(F)(F)OS(=O)(=O)C(F)(F)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A metal tube containing 2-oxopentafluoropropanesulfonic acid (23.8 g, 0.10 mol) was cooled below -40° C. and vinylidene fluoride (1,1-difluoroethene) (13 g, 0.20 mol) was added. The mixture was shaken and warmed to 25° C. where it was kept for 4 hours. Distillation of the liquid product gave 20.4 g (0.07 mol, 70%) of 1,1-difluoroethyl 2-oxopentafluoropropanesulfonate, bp 62°-63° C. (50 mm Hg): λmax (CCl4) 5.54 (C=O), 6.96 (SO2O) and 7.5-9 μm (CF, SO2); 1H NMR, δ 2.06 ppm (t J=14.3 Hz) CH3 ; 19F NMR, -58.3 (q J=14.3 Hz, each member t J=7.1 Hz) 2F, OCF2, -75.0 (t J=8.0 Hz) 3F, CF3 and -106.1 ppm (q J= 8.0 Hz, each member t J=7.1 Hz) 2F, CF2SO2.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[N:5]([CH3:13])[C:3]1=[O:4].C(=O)([O-])[O-].[K+].[K+].[O:20]([C:28]1[CH:43]=[CH:42][C:31]([C:32]([C:34]2[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=2)=[O:33])=[CH:30][CH:29]=1)[Si](C(C)(C)C)(C)C>CN(C=O)C.O>[OH:20][C:28]1[CH:29]=[CH:30][C:31]([C:32]([C:34]2[CH:41]=[CH:40][C:37]([CH2:38][N:9]3[C:10]4[C:11](=[O:12])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:13])[C:6]=4[N:7]=[CH:8]3)=[CH:36][CH:35]=2)=[O:33])=[CH:42][CH:43]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(O)cc3)cc2)n(C)c1=O
Yield: 109.7 %

Procedure:
A solution of 1,3-dimethylxanthine (742 mg), potassium carbonate (569 mg) and 4-(4-t-butyldimethylsiloxybenzoyl)benzyl bromide (2292 mg) in DMF (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate =1:3) and recrystallized from chloroform-isopropyl ether to provide the title compound as colorless solid (1763 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])=[O:8])[CH2:3][CH2:2]1.[CH:19]1([CH2:22][CH2:23][NH:24][C:25]([C:27]2[N:28]=[N:29][C:30](Cl)=[CH:31][CH:32]=2)=[O:26])[CH2:21][CH2:20]1>>[CH:19]1([CH2:22][CH2:23][NH:24][C:25]([C:27]2[N:28]=[N:29][C:30]([N:1]3[CH2:2][CH2:3][CH:4]([C:7](=[O:8])[C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:15]([F:16])([F:17])[F:18])[CH2:5][CH2:6]3)=[CH:31][CH:32]=2)=[O:26])[CH2:21][CH2:20]1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Reactant: O=C(c1ccccc1C(F)(F)F)C1CCNCC1
Product: O=C(NCCC1CC1)c1ccc(N2CCC(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Yield: 42 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use piperidin-4-yl-(2-trifluoromethylphenyl)methanone in place of piperidin-4-yl-(2-trifluoromethylphenyl)amine to react with 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder in 42% yield. 1H NMR (300 MHz, CDCl3) δ 8.0 (d, J=10.0 Hz, 1H), 7.99 (m, 1H), 7.72 (m, 1H), 7.60 (m, 2H), 7.40 (m, 1H), 6.97 (d, J=10.0 Hz, 1H), 4.49 (m, 2H), 3.53 (q, J=7.0 Hz, 2H), 3.24-3.07 (m, 4H), 2.1-1.9 (m, 3H), 1.85-1.65 (m, 2H), 1.5 (q, J=7.0 Hz, 2H), 0.75 (m, 1H), 0.48-0.42 (m, 2H), 0.09-0.07 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 205.3, 174.6, 163.2, 159.9, 144.6, 138.9, 130.3, 128.9, 127.5, 127.1, 127.0, 121.7, 112.2, 65.8, 51.9, 48.0, 44.5, 39.6, 34.5, 27.1, 8.6, 4.2. MS (ES+) m/z 447.2 (M+1).