Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].Cl.[CH:13]([N:16]([CH:20]([CH3:22])[CH3:21])[CH2:17][CH2:18]Cl)([CH3:15])[CH3:14].[H-].[Na+]>C1(C)C=CC=CC=1.CN(C)C=O>[CH:13]([N:16]([CH:20]([CH3:22])[CH3:21])[CH2:17][CH2:18][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])([CH3:15])[CH3:14]
Reactant: CC(C)N(CCCl)C(C)C
Reactant: O=C1Nc2ccccc2C1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)N(CCN1C(=O)C(=O)c2ccccc21)C(C)C
Temperature: 80 °C

Procedure:
2.94 Grams of isatin and 4.00 g of 2-diisopropylaminoethyl chloride hydrochloride were suspended in a mixture of 50 ml of dry toluene and 10 ml of dry N,N-dimethylformamide, and 1.60 g of sodium hydride (60% dispersion in mineral oil) was added to the suspension with stirring under ice-cooling. The mixture was stirred for 30 minutes at room temperature, and then heated at 80° C. for 19 hours. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with benzene, and the benzene layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane to obtain 4.62 g of 1-(2-diisopropylaminoethyl)isatin having a melting point of 60°-61° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[O:18][C:17](=[O:19])[N:16]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[N:15]=1.C(Cl)Cl>N1C=CC=CC=1>[CH3:12][O:13][C:14]1[O:18][C:17](=[O:19])[N:16]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:9](=[O:10])[CH2:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:22][CH:21]=2)[N:15]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: COc1nn(-c2ccc(N)cc2)c(=O)o1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1nn(-c2ccc(NC(=O)Cc3ccc(Cl)cc3)cc2)c(=O)o1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
201 mg of 4-chlorophenylacetyl chloride were added dropwise to a mixture consisting of 200 mg of 5-methoxy-3-(4-aminophenyl)-3H-(1,3,4)oxadiazol-2-one, 20 ml of methylene chloride and 0.1 ml of pyridine cooled in ice, and the mixture was stirred at room temperature for 5 hours. Volatiles were removed in vacuo. The residue was stirred with water and the solid was filtered off with suction and dried at 40° C. in vacuo.
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:3].[NH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[CH:15]=[C:14]2[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[O:32][CH3:33].CN1CCOCC1.Cl>ClCCl>[CH:5]1([O:4][C:2]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[CH:15]=[C:14]3[CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=2[O:32][CH3:33])=[O:3])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(Cl)OC1CCCC1
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(N)cc23)c(OC)c1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(NC(=O)OC4CCCC4)cc23)c(OC)c1
Reaction time: 2 h
Yield: 77.4 %

Procedure:
Cyclopentyl chloroformate (0.11 g.) was added to a stirred solution of methyl 4-(5-amino-1-methylindol-3-ylmethyl)-3-methoxybenzoate (D) (0.25 g.) and N-methylmorpholine (0.23 g.) in dichloromethane (3 ml.), under an atmosphere of nitrogen. The mixture was stirred for 2 hours and then poured into 1M hydrochloric acid (20 ml.). This acid mixture was extracted with ethyl acetate (2×30 ml.). The combined extracts were washed with saturated brine (20 ml.), dried (MgSO4), and evaporated to give a viscous oil. This was purified by flash chromatography on silica gel (50 ml.), eluting with 3:7 v/v ethyl acetate:hexane, to give the title compound as a foam (0.25 g., 74%); NMR: 1.62[m,8H, (CH2)4 ], 3.68(s,3H, NCH3), 3.83(s,3H, CO.OCH3), 3.91(s,3H, OCH3), 3.95(s, 2H, CH2.Ar), 5.05(m,1H, --CHO--), 7.11(m,2H), 7.26(d, 1H), 7.43(m,2H), 7.59(br,1H), 9.18 (br,1H, NH).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([C:14](=[CH:20][NH:21][CH:22]2[CH2:24][CH2:23]2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:26])=[C:7]([F:25])[CH:8]=2)[N:3]=1>C(O)C.O.C(OC(C)C)(C)C>[CH:22]1([N:21]2[C:2]3[N:3]=[C:4]4[CH:5]=[C:6]([F:26])[C:7]([F:25])=[CH:8][C:9]4=[CH:10][C:11]=3[C:12](=[O:13])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20]2)[CH2:24][CH2:23]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc2cc(F)c(F)cc2nc1Cl
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Temperature: 20 °C
Yield: 74.9 %

Procedure:
A stirred suspension of 5.27 g of ethyl 2-(2-chloro-6,7-difluoroquinoline-3-carbonyl)-3-cyclopropylaminoacrylate in 2.22 g of 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU) and 120 cm3 of ethanol is heated at a temperature close to 75° C. for 35 minutes. After cooling to about 20° C., the reaction mixture is taken up in 100 cm3 of water and extracted once with 100 cm3 and twice with 50 cm3 of trichloromethane. The combined organic extracts are washed with 3 times 50 cm3 of water, dried over magnesium sulphate, filtered and concentrated under reduced pressure (20 kPa) at a temperature close to 20° C. The dry extract obtained is taken up in 30 cm3 of diisopropyl ether, drained and recrystallized from a mixture of 75 cm3 of ethanol and 75 cm3 of dimethylformamide. 3.57 g of 1-cyclopropyl-3-ethoxycarbonyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 229°-230° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH2:7]([CH:16]1[CH2:20][CH2:19][CH2:18][C:17]1=O)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.O.[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25]>C(O)(=O)C.CCOCC>[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25].[CH3:1][NH:2][CH2:3][CH2:4][CH2:5][N:6]1[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][C:16]2[CH2:20][CH2:19][CH2:18][C:17]1=2
Reactant: CNCCCN
Reactant: O=C(CC1CCCC1=O)c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CNCCCn1c(-c2ccccc2)cc2c1CCC2

Procedure:
8.82 g (0.1 mole) of methylaminopropylamine are added to a solution of 20.35 g (0.1 mole) of 2-phenacylcyclopentanone in glacial acetic acid under nitrogen. After refluxing for 12 hours, water is added and the aqueous solution is washed with ether. The aqueous phase is basified with sodium carbonate and extracted with ether to give a reddish oil. The oil is dissolved in ether and is added to an ether solution of oxalic acid to give 1-(3-methylaminopropyl)-2-phenyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole oxalate, m.p. 184°-185° C.
Reaction SMILES: [C:1]12[C:14](=[O:15])[O:13][C:11](=[O:12])[C:2]=1[CH2:3][CH2:4][C:5]1[C:10]2=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:16][C:17]([CH3:22])([CH2:20][NH2:21])[CH2:18][OH:19].O>C1(C)C=CC=CC=1>[OH:19][CH2:18][C:17]([CH3:22])([CH3:16])[CH2:20][N:21]=[C:14]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[C:11]([OH:13])=[O:12])[OH:15]
Reactant: O=C1OC(=O)C2=C1CCc1ccccc12
Reactant: CC(C)(CN)CO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(CO)CN=C(O)C1=C(C(=O)O)CCc2ccccc21

Procedure:
20.0 g (0.1 mol) of 3,4-dihydronaphthalene-1,2-dicarboxylic acid anhydride and 10.3 g (0.1 mol) of 2,2-dimethyl-3-aminopropanol are dissolved in 60 ml of toluene and the solution is refluxed for 2 hours, the water formed being separated off by means of a water separator. After the reaction has ended, the reaction mixture is concentrated to dryness in vacuo at 60° C. The residue is recrystallised from ethanol. This yields 25.1 g (87.9% of theory) of N-(3'-hydroxy-2',2'-dimethylpropyl)-3,4-dihydronaphthalene-1,2-dicarboxylic acid imide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:16])[CH2:12][CH2:11][N:10]([CH2:13][CH3:14])[C:9]2=[O:15])=[CH:4][CH:3]=1.[N:17]([O-])=O.[Na+].C(Cl)Cl>Cl.O>[CH2:13]([N:10]1[CH2:11][CH2:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][NH2:17])=[CH:3][CH:4]=2)([CH3:16])[C:9]1=[O:15])[CH3:14]
Reactant: CCN1CCC(C)(c2ccc(N)cc2)C1=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCN1CCC(C)(c2ccc(NN)cc2)C1=O
Reaction time: 0.75 h

Procedure:
A solution of 676 mg (3.1 mmol) of (±)-3-(4-aminophenyl)-1-ethyl-3-methylpyrrolidin-2-one (from Step 3) in 3.1 mL of concentrated hydrochloric acid was then stirred at about −5° C. in an ice-acetone bath as a solution of 222 mg (3.2 mmol) of sodium nitrite in 1.25 mL of water was added dropwise over about 15 minutes. Stirring was continued at −10° to −5° C. for 45 minutes. The mixture was kept cold and added gradually to a solution of 3.50 g (15.5 mmol) of stannous chloride dihydrate in 2.5 mL of concentrated hydrochloric acid stirred under nitrogen at <0° C. in an ice-acetone bath. After completion of the addition, stirring was continued in the cooling bath for about 30 minutes, and then the mixture was partitioned between 25 mL of ethyl acetate and 4 mL of water. The aqueous layer was washed with an additional 10 mL of ethyl acetate. The combined ethyl acetate fractions were treated cautiously with 25 mL of saturated aqueous sodium carbonate solution, resulting in heavy precipitation and some gas evolution. After dilution with additional ethyl acetate and water, the mixture was filtered. The filtrate was transferred to a separatory funnel, and the ethyl acetate layer was washed with saturated aqueous sodium chloride solution. The organic phase was then dried over magnesium sulfate, filtered, and concentrated in vacuo at room temperature to yield 396 mg (55%) of a viscous, yellow oil; primarily one spot by TLC in 95:5 CH2Cl2. 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[O:12])[C:2]=1[CH:13]=[O:14].[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>O1CCCC1>[C:15]1([CH:13]([C:2]2[C:3]([CH:11]([OH:12])[C:1]3[CH:10]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[OH:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=Cc1cc2ccccc2cc1C=O
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1cc2ccccc2cc1C(O)c1ccccc1
Yield: 86.6 %

Procedure:
2,3-Naphthalenedicarboxaldehyde (10.0 g) in dry tetrahydrofuran (100ml) was added to phenylmagnesium bromide [derived from bromobenzene (53 g) and magnesium (8 g)] in dry tetrahydrofuran (500 ml) over 1 hr. and the solution was refluxed for a further 3 hr. On cooling, water (500 ml) was added and the ethereal layer was decanted. The aqueous slurry was washed with ether (4 × 500 ml) and the combined ethereal extracts were dried (magnesium sulphate) and evaporated to dryness. The residue was purified by chromatography on silica gel and recrystallised from dichloromethane/petroleum ether (b.p. 40°-60°) to yield two isomers of 2,3-bis(1-phenyl-1-hydroxymethyl)naphthalene (III) (8.0 g. m.p. 145° and 3.0 g, m.p. 164°).
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:21]=[CH:20][C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:11]([N+:22]([O-:24])=[O:23])[CH:10]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:47]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH:48]=[CH2:49]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[N+:22]([C:11]1[CH:10]=[C:9]([CH:49]=[CH:48][CH2:47][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:21]=[CH:20][C:12]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([O-:24])=[O:23]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: C=CCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(C=CCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
19 mg of palladium acetate (II) was added to 5 mL of toluene solution containing 0.50 g of tert-butyl 4-bromo-2-nitrobenzoate, 50 mg of tri(o-tolyl)phosphine, 0.44 mL of allylbenzene and 0.46 mL of triethylamine, and the resulting mixture was heated to reflux under nitrogen atmosphere for 2 hours. After the reaction mixture was cooled to room temperature, 20 mg of palladium acetate (II) was added and the resulting mixture was heated to reflux for 7 hours. After the reaction mixture was cooled to room temperature, Insoluble were removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=30:1] to obtain 0.31 g of tert-butyl 2-nitro-4-(3-phenyl-1-propenyl)benzoate.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:14][C:13]=2[Cl:27])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH3:29][O:30][C:31](=[O:34])[C:32]#[CH:33]>>[CH3:29][O:30][C:31]([C:32]1[N:3]=[N:2][N:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10](=[O:11])[C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])=[CH:14][C:13]=3[Cl:27])[CH:9]=2)[CH:33]=1)=[O:34]
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: C#CC(=O)OC
Product: COC(=O)c1cn(-c2ccc(C)c(C(=O)c3ccc(Nc4ccc(F)cc4F)cc3Cl)c2)nn1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 434 (0.50 mmol) and propynoic acid methyl ester (0.50 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 0:100 to 50:50 as the eluent to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([S:17](=[O:20])(=[O:19])[NH2:18])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][OH:6].CI.[C:23](=O)([O-])O.[Na+].CN(C)P(=O)(N(C)C)N(C)C>O>[CH3:23][NH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([S:17](=[O:20])(=[O:19])[NH2:18])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][OH:6]
Reactant: Nc1cc(CO)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CNc1cc(CO)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 18 h

Procedure:
A mixture of 3-amino-4-phenoxy-5-sulfamylbenzyl alcohol (8.8 g; prepared as described in Example 2), methyl iodide (2.1 ml), sodium hydrogen carbonate (5.0 g) and hexamethylphosphoric triamide (45 ml) is stirred at 22°-25° C. for 18 hours. The mixture is then diluted with water (about 500 ml) to precipitate crude 3-methylamino-4-phenoxy-5-sulfamylbenzyl alcohol. After recrystallization from aqueous ethanol it is obtained with a melting point of 167°-168° C.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:8]=O)[CH:2]=[CH2:3].[CH:24]([NH2:27])([CH3:26])[CH3:25].CO.[BH4-].[Na+]>O.C(O)(=O)C>[CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8][NH:27][CH:24]([CH3:26])[CH3:25])[CH:2]=[CH2:3]
Reactant: C=CCNc1cc(C=O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: CC(C)N
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: C=CCNc1cc(CNC(C)C)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 24 h

Procedure:
A mixture of 3-allylamino-4-phenoxy-5-sulfamylbenzaldehyde (10 g; prepared as described in Example 91), isopropylamine (4.0 ml) and methanol (100 ml) is stirred at 22°-25° C. for 24 hours and is then refluxed for 2 hours. To the stirred solution, sodium borohydride (4.0 g) is added in small portions during about 45 minutes, keeping the temperature at 0°-5° C. by external cooling. After the addition is completed, the reaction mixture is stirred at 0°-5° C. for a further 2 hours, whereafter acetic acid (4 ml) followed by water (300 ml) are cautiously added to precipitate crude (3-allylamino-4-phenoxy-5-sulfamylbenzyl)isopropylamine. After filtration and recrystallization from aqueous ethanol it is obtained with a melting point of 98°-100° C. The material (IR, analysis) is identical with the material prepared as in Example 113.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][NH2:24])[CH:18]=[CH:19][CH:20]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH2:38])=[S:37])=[C:31]([CH3:39])[CH:30]=1.[C:40]([O-])(=[O:42])C.[Na+]>>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][C:40]([NH:24][CH2:23][CH2:22][CH2:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:12]3[N:13]=[CH:14][N:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=4)[N:11]=3)[CH:16]=2)=[O:42])=[S:37])=[C:31]([CH3:39])[CH:30]=1
Reactant: COc1ccc(NC(N)=S)c(C)c1
Reactant: CC(=O)[O-]
Reactant: NCCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Agent: [Na+]
Product: COc1ccc(NC(=S)NC(=O)NCCCc2cccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)c2)c(C)c1

Procedure:
The title compound was prepared as described in Example 63 using 3-(3-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine (CA18) and 1-(4-methoxy-2-methylphenyl)thiourea. Sodium acetate was used in place of sodium bicarbonate. The title compound was isolated as a white solid (0.103 g, 31%): 1H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 10.00 (s, 1H), 9.40 (s, 1H), 8.13-8.04 (m, 2H), 8.02-7.92 (m, 2H), 7.67-7.57 (m, 2H), 7.46 (t, J=7.6 Hz, 1H), 7.42-7.30 (m, 2H), 7.08 (t, J=5.6 Hz, 1H), 6.83 (d, J=2.9 Hz, 1H), 6.76 (dd, J=8.7, 2.9 Hz, 1H), 3.74 (s, 3H), 3.17 (q, J=6.5 Hz, 2H), 2.73 (t, J=7.6 Hz, 2H), 2.16 (s, 3H), 1.93-1.72 (m, 2H); 19F NMR (376 MHz, DMSO-d6) δ −56.97; ESIMS m/z 585 ([M+H]+), 583 ([M−H]−).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:26])[C@@H:15]([NH2:25])[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C:10]([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)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:46](OC(=O)C)(=[O:48])[CH3:47]>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:26])[C@@H:15]([NH:25][C:46](=[O:48])[CH3:47])[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C:10]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC(c2ccccc2)(c2ccccc2)OC[C@@H]1[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1COC(c2ccccc2)(c2ccccc2)CN1C(=O)OC(C)(C)C
Reaction time: 1.5 h

Procedure:
Dissolve (R)-5-[(1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2,2-diphenylmorpholine-4-carboxylic acid tert-butyl ester (0.163 g, 0.31 mmol) in tetrahydrofuran (4 mL). Add triethylamine (0.044 g, 0.44 mmol) and acetic anhydride (0.036 g, 0.35 mmol). Stir 90 minutes and dilute with ethyl acetate (50 mL). Wash with 0.1 N aqueous citric acid, water, and saturated aqueous sodium chloride. Dry (magnesium sulfate), filter and concentrate. Purify on silica gel, eluting with 10:90 to 50:50 ethyl acetate:hexanes to give the title compound.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[CH3:7][O:8][N:9]=[CH:10][C:11]1[CH:16]=[C:15]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[NH:19][C:18]2=O)[C:14]([F:29])=[CH:13][C:12]=1[Cl:30].CI.O>CN(C)C=O>[CH3:7][O:8][N:9]=[CH:10][C:11]1[CH:16]=[C:15]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[N:19]([CH3:18])[C:1]2=[O:4])[C:14]([F:29])=[CH:13][C:12]=1[Cl:30]
Reactant: O=C([O-])[O-]
Reactant: CON=Cc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CON=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 20 °C
Reaction time: 20 h

Procedure:
First, 117.1 g (0.85 mol) of potassium carbonate were added to a solution of 281.6 g (0.77 mol) of 2-chloro-4-fluoro-5-(6-trifluoromethyl-2,4(1H,3H)-pyrimidinedion-3-yl)benzaldehyde (O-methyl)oxime in 0.8 l of dimethylformamide, whereupon a solution of 120.2 g of methyl iodide (0.85 mol) in 0.1 l of dimethylformamide was added dropwise in the course of 1 hour. The reaction mixture was subsequently stirred for 20 hours at approximately 20° C., and 0.9 l of water was subsequently added dropwise with ice-cooling. The product of value was extracted from the resulting solution using 1 l of dichloromethane. The extract was washed three times using 300 ml of water, dried over sodium sulfate and finally concentrated. Yield: 241 g; m.p.: 141-142° C. (diisopropyl ether).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16]([SH:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CC(N(C)C)=O>[CH2:16]([S:24][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCS
Reactant: N#Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCCCCCCSc1ccc(C#N)cc1
Temperature: 0 °C
Yield: 104.1 %

Procedure:
103.2 g (0.75 mol) of p-chlorobenzonitrile, 140 g of potassium carbonate and 143.2 ml (0.825 mol) of octanethiol in dimethylacetamide are stirred at 100° C. for about 16 hours in a sulfonation flask under a protective-gas atmosphere. The white suspension obtained is cooled, poured into ice water and extracted a number of times with dichloromethane. The organic phases are combined, washed with water, dried over MgSO4, filtered and evaporated, giving 193.1 g of crude product, which is distilled at 92° C./0.1 mm Hg.
Reaction SMILES: Cl[Si@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[C:10]([F:18])[CH:9]=2)[CH2:4][CH2:3]1.[CH2:19]1[CH2:23]O[CH2:21][CH2:20]1>>[F:18][C:10]1[CH:9]=[C:8]([C@H:5]2[CH2:6][CH2:7][Si@H:2]([CH2:21][CH2:20][CH2:19][CH2:23][C@H:19]3[CH2:23][CH2:3][C@H:4]([CH2:5][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:21][CH2:20]3)[CH2:3][CH2:4]2)[CH:13]=[CH:12][C:11]=1[O:14][CH:15]([F:17])[F:16]
Reactant: C1CCOC1
Reactant: Fc1cc([C@H]2CC[Si@H](Cl)CC2)ccc1OC(F)F
Product: CCCCC[C@H]1CC[C@H](CCCC[Si@H]2CC[C@H](c3ccc(OC(F)F)c(F)c3)CC2)CC1

Procedure:
28.9 g (0.1 mol) of trans-4-(4-bromobutyl)-1-n-pentylcyclohexane was dropped in a mixture of 2.5 g (0.11 mols) of magnesium and 300 ml of THF to obtain a Grignard reagent. The resultant solution was then dropped in a solution, in 500 ml of THF, of 29.5 g (0.1 mol) of 4-(trans-4-chloro-4-silacyclohexyl)-2-fluoro-1-difluoromethoxybenzene. The resultant product consisted of a mixture of trans and cis isomers with respect to the cyclohexane ring. The product was subjected to ordinary aftertreatments to obtain trans-4-(4-(trans-4-(3-fluoro-4-difluoromethoxyphenyl)-1-silacyclohexyl)butyl)-1-n-pentylcyclohexane, followed by isolation through chromatography to obtain 41.8 g (yield: 89%) of the intended trans isomer product.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([O:11]C)=[CH:8][C:9]=1[OH:10])=O.[NH2:13][CH2:14][C:15]([O-:17])=[O:16].NCC([O-])=O.[Zn+2:23]>O>[Zn:23].[OH:10][C:9]1[CH:8]=[C:7]([OH:11])[CH:6]=[CH:5][C:4]=1[CH2:2][CH:1]=[N:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: COc1ccc(C(C)=O)c(O)c1
Reactant: NCC(=O)[O-]
Reactant: [Zn+2]
Solvent: O
Product: O=C(O)CN=CCc1ccc(O)cc1O
Product: [Zn]

Procedure:
Ingredients. (1) Water 51.4 (2) 2,4-Dihydroxyacetophenone 1.5 (3) Zinc Bis-Glycinate
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#N)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-:22].[Na+].[OH2:24]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:24])=[O:22])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: N#CCCCCCCCCNS(=O)(=O)c1ccc(Br)cc1
Reactant: [OH-]
Reactant: O
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCCCCCCCNS(=O)(=O)c1ccc(Br)cc1

Procedure:
9-(4-Bromobenzenesulphonamido)nonanenitrile (0.6 g, 0.0016 mol) was treated with sodium hydroxide (2 g, 0.05 mol) in 10 ml water plus 20 ml ethanol by the method described in Example 6(ii) to give the title compound (0.35 g, m.p. 124°-5° C.) after recrystallisation from chloroformpetroleum ether 40°-60°.