Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1)[CH3:2].C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C)C=O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([Cl:16])=[O:12])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(CC(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1ccc(CC(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-Ethylphenylacetic acid (3.0 g) (see Japanese Unexamined Patent Publication 63-233975) was dissolved in dichloromethane (15 ml), and thereto were added oxalyl chloride (6.0 ml) and N,N-dimethylformamide (one drop). The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was evaporated under reduced pressure, and the residue was subjected to azeotropic distillation with toluene to give a crude 4-ethylphenylacetyl chloride, which was used in the subsequent step without further purification. (2) A suspension of magnesium chloride (1.74 g) in dichloromethane (30 ml) was cooled to 0° C., and thereto were added t-butyl acetoacetate (3.03 ml) and pyridine (2.96 ml), and successively was added a solution of the above 4-ethylphenylacetyl chloride in dichloromethane (30 ml). The mixture was stirred at the same temperature for 2.5 hours, and an aqueous citric acid solution was added thereto. The mixture was extracted with chloroform. The extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to give t-butyl 2-acetyl-4-(4-ethylphenyl)-3-oxobutyrate (4.75 g) as pale yellow oil. APCI-Mass m/Z 322 (M+NH4). (3) A solution of the above t-butyl 2-acetyl-4-(4-ethylphenyl)-3-oxobutyrate in trifluoroacetic acid (60 ml) was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate, and the mixture was washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine. The mixture was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give 1-(4-ethylphenyl)-4-hydroxy-3-penten-2-one (4.00 g) as yellow oil. APCI-Mass m/Z 205 (M+H). (4) A solution of the above 1-(4-ethylphenyl)-4-hydroxy-3-penten-2-one (3.98 g) and hydrazine hydrate (4.0 ml) in toluene (20 ml) was stirred under heating at 100° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and washed successively with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:ethyl acetate=2:1) to give 3-(4-ethylphenylmethyl)-5-methyl-1H-pyrazole (3.12 g) as yellow oil. APCI-Mass m/Z 201 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH2:9][OH:10])[CH2:7][S:8][C@H:3]12.[OH-].[Na+:17].[CH3:18][O:19][C:20]1[CH:38]=[CH:37][C:23]([CH2:24][O:25][C:26](SC2C=C(C)C=C(C)N=2)=[O:27])=[CH:22][CH:21]=1.O1CCOCC1>O.C(OCC)(=O)C>[CH3:18][O:19][C:20]1[CH:38]=[CH:37][C:23]([CH2:24][O:25][C:26]([NH:1][C@@H:2]2[C:14](=[O:15])[N:4]3[C:5]([C:11]([O-:13])=[O:12])=[C:6]([CH2:9][OH:10])[CH2:7][S:8][C@H:3]23)=[O:27])=[CH:22][CH:21]=1.[Na+:17]
Reactant: COc1ccc(COC(=O)Sc2cc(C)cc(C)n2)cc1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(COC(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(CO)CS[C@H]23)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
In 50 ml of water is suspended 2.30 g of 7β-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid and the suspension is adjusted to pH 8.5 with 1N-aqueous sodium hydroxide solution, whereupon a clear solution is obtained. To this solution are added 4.56 g of S-p-methoxybenzyloxycarbonyl-4,6-dimethyl-2-mercaptopyridine and 50 ml of dioxane and the mixture is stirred at room temperature for 7 hours. The reaction mixture is diluted with water and ethyl acetate and the water layer is separated and concentrated under reduced pressure. The residue is subjected to XAD-II (500 ml) column chromatography and after the column is washed with water, elution is carried out with 10% (v/v) ethanol. The eluate is concentrated under reduced pressure and freeze-dried to give 1.63 g of sodium 7β-(p-methoxybenzyloxycarbonylamino)-3-hydroxymethyl-3-cephem-4-carboxylate as colorless powders.
Reaction SMILES: [OH:1][CH:2]([CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[C:3]#[N:4].[CH3:21]I.[H-].[Na+]>CN(C=O)C.O>[CH3:21][O:1][CH:2]([CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[C:3]#[N:4]
Reactant: CI
Reactant: COc1ccccc1OC(c1ccccc1)C(O)C#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1OC(c1ccccc1)C(C#N)OC
Yield: 68.9 %

Procedure:
b 2.69 g of 2-hydroxy-3-phenyl-3-(2-methoxy-phenoxy)-propionitrile dissolved in 25 ml of anhydrous DMF and 7.1 g of methyl iodide were stirred at 0° C. Addition was made, in portions, of 2.18 g of 55% NaH. After the addition, the whole was stirred at 0°-5° C. for 1 and a half hours. Under an atmosphere of nitrogen the whole was then decomposed cautiously with water, diluted with plentiful water, extracted with ethyl acetate and washed with water. The organic phase was dried over Na2SO4 and evaporated to dryness, in this way obtaining 1.95 g of 2-methoxy-3-phenyl-3-(2-methoxy-phenoxy)-propionitrile as an oil. Yield=69%. Analogously, all the 2-methoxy-propionitrile derivatives useful for the preparation of the 2-methoxy-propylamines listed in example 2 and obtained according to the reduction of Example 3, were prepared.
Reaction SMILES: Br[CH2:2][C:3]([O:11][CH3:12])=[CH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7].[C:13]([O-:16])(=[O:15])[CH3:14].[K+].C(O)(=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[C:13]([O:16][CH2:2][C:3]([O:11][CH3:12])=[CH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7])(=[O:15])[CH3:14]
Reactant: COC(=CC(=O)C(F)(F)F)CBr
Reactant: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=CC(=O)C(F)(F)F)COC(C)=O

Procedure:
24.8 g (0.1 mol) of 5-bromo-1,1,1-trifluoro-4-methoxypent-3-en-2-one, 20 g of potassium acetate, 5 g of tetrabutylammonium bromide and 8 g of acetic acid were stirred in 300 ml of acetonitrile at 40° C. for 20 h. The precipitate was filtered off and the solvent was removed completely under reduced pressure.
Reaction SMILES: [CH3:1][C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])=[CH2:3].O.[Ru:9](Cl)(Cl)Cl.[CH3:13][C:14]1[CH2:18][CH:17]=[C:16]([CH3:19])[CH:15]=1>CO>[CH3:3][C:2]1([Ru:9][CH:17]=[C:16]([CH3:19])[CH:15]=[C:14]([CH3:13])[CH3:18])[CH:1]=[CH:6][C:5]([CH3:7])=[CH:4]1
Reactant: C=C(C)C=C(C)C
Reactant: Cl[Ru](Cl)Cl
Reactant: CC1=CCC(C)=C1
Solvent: CO
Solvent: O
Product: CC(C)=CC(C)=C[Ru]C1(C)C=CC(C)=C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A dry 1 liter 3-neck round-bottom flask was charged with a magnetic stir bar and equipped with three septa. A nitrogen purge was introduced through a needle with output, also via a needle, to an oil bubbler. A thermocouple lead was placed through a side neck septa. Excess zinc (150 grams, ‘dust’ was found more conducive to stirring) was added to the flask. By syringe, 2,4-dimethyl-1,3-pentadiene (25 grams, 0.26 mol) was added to the flask. By cannula, ruthenium trichloride hydrate (6.0 grams, 0.023 mol based on 3 hydrate equivalents) was added as a methanol (250 milliliters) solution in spurts of about 10 milliliters over 45 minutes. The mixture was stirred for 30 minutes at 25° C. after the addition was complete, then, upon equipping a condenser, the contents were brought to gentle reflux. Stirring was continued for 2 hours. The mixture was cooled to 25° C., followed by the addition of freshly distilled 1,3-dimethylcyclopentadiene (2.2 grams, 0.023 mol) by syringe over 20 minutes. Stirring was continued at 25° C. for 20 additional minutes, followed by gentle reflux for 2 hours.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[H-].[Na+].[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ClCCl>CN(C=O)C.O>[C:17]1([S:23]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[C:2]2[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1

Procedure:
To a stirred and cooled (to about 0° C.) solution of ethyl indole-2-carboxylate 10 (1 eq.) in DMF (2 ml/mmol) under N2, was added NaH (60% in oil, 1.2 eq.) portionwise. When gas evolution stopped, benzenesulfonyl chloride (1.2 eq.) was added. The reaction mixture was stirred for about 1 hour (TLC monitoring, eluent dichloromethane); a small amount of water then was added carefully and the DMF was evaporated. The crude residue was dissolved in ethyl acetate and washed with water and brine. After drying and evaporation of the solvents, the compound was purified by chromatography on silica gel (eluent: C6H12/EtOAc 9/1 to 7/3) to give the ethyl 1-phenylsulfonylindole-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:28])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[C@H:29]1(O)[CH2:34][CH2:33][C@H:32]([OH:35])[CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:28][CH:29]3[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: O[C@H]1CC[C@H](O)CC1
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Product: O=C1c2ccccc2C(OC2CCC(O)CC2)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 67.9 %

Procedure:
The named compound was synthesised from 3-(4-Chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (400 mg, 1.01 mmol, 1 equiv.) and cis/trans-1,4-cyclohexanediol (586 mg, 5.05 mmol, 5 equiv.) using General Procedure A and obtained as a white solid (338 mg, 68%). 1H NMR (300 MHz, CDCl3): mixture of diastereoisomers: 7.93-7.90 (m, 3H, O2N—C—CH and C(O)═C═CH), 7.56-7.51 (m, 2H, Ar—H), 7.18-7.02 (m, 7H, Ar—H), 4.78 and 4.24 (d: AB, J=15.0 Hz, 2H, N—CH2); 3.70-3.62 (m, 1H, HOCH—), 3.26-3.09 (m, 1H, OCH), 1.86-1.26 (m, 10H, CH2). 13C NMR (75 MHz, CDCl3): mixture of diastereoisomers: 168.33, 147.16, 146.01, 144.80, 137.66, 134.74, 132.72, 131.58, 130.21, 130.16, 129.68, 128.31, 128.28, 128.23, 128.19, 123.81, 123.09, 94.30, 94.28, 71.41, 69.22, 68.61, 67.66, 42.65, 32.51, 32.32, 30.95, 30.65, 30.33, 29.19, 29.03. m/z (ES): 493 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](OC)=[C:11]([CH:16]=[CH:17]OC)[C:12]([Br:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:22].[NH:23]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)[NH2:24].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:42]([OH:44])C>>[ClH:22].[CH2:1]([O:8][C:9]1[C:14]([O:44][CH3:42])=[CH:13][C:12]([Br:15])=[C:11]([CH2:16][CH:17]=[N:24][NH:23][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: COC=Cc1c(Br)ccc(OCc2ccccc2)c1OC
Reactant: NNc1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Product: COc1cc(Br)c(CC=NNc2ccncc2)cc1OCc1ccccc1
Yield: 72.2 %

Procedure:
A mixture of 5-benzyloxy-2-bromo-4-methoxy-3-(2-methoxyvinyl)benzene (42.1 g), 4-hydrazinopyridine hydrochloride (19.0 g), p-toluenesulfonic acid (0.23 g) and ethanol (350 ml) was heated under reflux overnight, with stirring. The reaction mixture was cooled and filtered. Recrystallization of the precipitate from methanol yielded 40.2 g, (72.2%) of product, mp 232-233° C.
Reaction SMILES: [CH3:1][C@:2]1([CH2:8][O:9][CH2:10][CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[F:19][C:20]1[CH:21]=[CH:22][C:23]2[O:28][CH2:27][C@H:26]([CH2:29]OS(C)(=O)=O)[O:25][C:24]=2[CH:35]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]2[O:28][CH2:27][C@H:26]([CH2:29][N:4]3[CH2:5][CH2:6][CH2:7][C:2]([CH3:1])([CH2:8][O:9][CH2:10][CH2:11][O:12][C@H:13]4[CH2:18][CH2:17][CH2:16][CH2:15][O:14]4)[CH2:3]3)[O:25][C:24]=2[CH:35]=1
Reactant: C[C@]1(COCCOC2CCCCO2)CCCNC1
Reactant: CS(=O)(=O)OC[C@H]1COc2ccc(F)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(COCCO[C@H]2CCCCO2)CCCN(C[C@H]2COc3ccc(F)cc3O2)C1
Yield: 23.6 %

Procedure:
(S)-3-Methyl-3-[2-(tetrahydropyran-2-yloxy)ethoxymethyl]piperidine (100 mg, 0.39 mmol), methanesulfonic acid (R)-(7-fluoro-2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl ester (102 mg, 0.39 mmol), K2CO3 (59 mg, 0.43 mmol) and KI (3 mg) were refluxed in dry DMF (3 ml) for 5 h. Water was added to the cooled mixture, followed by extraction with EtOAc (3×15 ml). The extracts were washed several times with water and finally with brine. After drying and filtering, the solvent was evaporated to give 143 mg of the crude product. This was chromatographed on silica (heptane/EtOAc, 70:30) to give 39 mg of the title compound as a colorless oil.
Reaction SMILES: [BH4-].[Na+].[C:3]1([CH2:9][N:10]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:11]2[C:20]([N+:21]([O-])=O)=[C:19]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO.C(Cl)Cl.O.[Ni](Cl)Cl>[C:33]1([CH2:32][N:10]([CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:11]2[C:20]([NH2:21])=[C:19]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:12]=2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=[N+]([O-])c1c(N(Cc2ccccc2)Cc2ccccc2)nc2c(c1NCc1ccccc1)CCCC2
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Nc1c(N(Cc2ccccc2)Cc2ccccc2)nc2c(c1NCc1ccccc1)CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
Sodium borohydride (0.82 g, 22 mmole) was added to a solution of nickel(II) chloride hydrate (1.43 g, 6 mmole) in methanol (300 mL). The addition caused a black solid to form along with gas evolution. The resulting heterogeneous mixture was stirred at ambient temperature for about 30 minutes. A solution containing N2,N2,N4 -Tris(phenylmethyl)-5,6,7,8-tetrahydro-3-nitroquinolin-2,4-diamine (5.73 g, 12 mmole) in methylene chloride (20 mL) was added followed by 5 successive additions of sodium borohydride (0.38 g, 10 mmole each addition). The reaction mixture was stirred at ambient temperature for about 15 minutes then filtered through a layer of silica gel. The filtrate was evaporated. The residue was taken up in a minimum amount of methylene chloride then placed on a layer of silica gel. The silica gel was eluted with hexane:ethyl acetate 80:20. The organic phase was collected then evaporated to provide 5.0 g of the desired product as a green oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=4)=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(F)c(Cl)c1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(F)c(Cl)c4)nc23)ccn1
Yield: 42.3 %

Procedure:
Reaction of 1-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (134 mg, 0.5 mmol), prepared from commercially available 3-chloro-4-fluoro-acetophenone according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis of amino-pyrazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (86 mg, 42%). MS (ISP) 407.3 [(M+H)+]; mp 292° C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1>ClCCl>[N+:1]([C:4]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][C:5]=1[NH:6][C:17](=[O:19])[NH:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)([O-:3])=[O:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: Nc1cc(-c2cccs2)ccc1[N+](=O)[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)Nc2cc(-c3cccs3)ccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.7 %

Procedure:
To a solution of 2-nitro-5-(thiophen-2-yl)aniline (0.60 g, 2.72 mmol, 1.0 equiv.) in dichloromethane at 0° C. were added TEA (5 mL, 35.4 mmol, 13 equiv.) and triphosgene (0.81 g, 2.72 mmol, 1.0 equiv.). The mixture was warmed to room temperature and stirred 3 h. The reaction was then cooled to 0° C. and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (0.88 g, 4.09 mmol, 1.5 equiv.) was then added slowly. The reaction mixture was slowly warmed to room temperature and stirred for 2 h. The reaction was diluted with dichloromethane, washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude residue was purified by column chromatography (silica gel, EtOAc/hexanes) to afford tert-butyl 4-((3-(2-nitro-5-(thiophen-2-yl)phenyl)ureido)methyl)piperidine-1-carboxylate (0.31 g, 25% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].[C:16]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([F:13])([F:9])([F:10])([F:11])[F:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH3:16]
Reactant: Oc1c(Cl)cc(S(F)(F)(F)(F)F)cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(Cl)cc(S(F)(F)(F)(F)F)cc1Br
Yield: 78.6 %

Procedure:
4.20 g of 2-bromo-6-chloro-4-pentafluorosulfanylphenol were stirred together with 3.48 g of K2CO3 and 2.68 g of CH3I in 50 ml of anhydrous DMF at RT for 24 hours. The solvent was then removed under reduced pressure and subsequently taken up with 100 ml each of water and EA. The phases were left to separate and extraction was then effected twice more with 100 ml each time of EA. Drying was effected over Na2SO4 and the solvent was removed under reduced pressure. Chromatography on silica gel using 1:1 DIP/HEP afforded 3.44 g of a colorless viscous liquid.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH3:14][C:15]1[CH:16]=[CH:17][C:18]2[O:22][CH2:21][C:20](=O)[C:19]=2[CH:24]=1.O>C1COCC1>[CH3:14][C:15]1[CH:16]=[CH:17][C:18]2[O:22][C:21]([CH2:5][C:3]#[N:4])=[CH:20][C:19]=2[CH:24]=1
Reactant: Cc1ccc2c(c1)C(=O)CO2
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2oc(CC#N)cc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.6 %

Procedure:
Reaction under N2 atmosphere. NaH 60% (0.17 mol) was stirred in TBF (350 ml). A solution of diethyl (cyanomethyl)phosphonate (0.17 mol) in THF (150 ml) was added dropwise over ±20 minutes. (exothermic temperature rise to 30° C.). The mixture was stirred for 20 minutes at RT, then cooled to 0° C. A solution of 5-methyl-3-benzo-furanone (0.15 mol) in THF (350 ml) was added dropwise over 30 minutes at 0° C. reaction mixture was stirred overnight at RT, then poured out into water (1500 ml) and stirred. This mixture was extracted with ether, DIPE (2×), dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/hexane 50/50). The desired fractions were collected and the solvent was evaporated, yielding 21.2 g (82%) of 5-methyl-3-benzofuranacetonitrile (interm. 3).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[O:23][CH3:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)=[CH:18][C:17]=1[O:23][CH3:24]
Reactant: COc1cc(N)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1F
Yield: 63 %

Procedure:
A solution of 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (1.41 g, 7.1 mmol) and 4-fluoro-3-methoxyaniline (1 g, 7.1 mmol) was stirred at room temperature for 1 h. Sodium tri(acetoxy)borohydride (1.95 g, 9.2 mmol) was then added and stirring continued over-weekend. The reaction mixture was diluted with DCM, washed with saturated aqueous NaHCO3 solution, dried and then concentrated in vacuo. Column chromatography eluting with 0-50% Et2O/petroleum ether gave the title compound as a white solid (1.45 g). δH (CDCl3, 400 MHz) 6.89 (1H, dd), 6.22 (1H, dd), 6.09 (1H, m), 4.03 (2H, br s), 3.84 (3H, s), 3.36 (1H, br s), 2.92 (2H, m), 2.03 (2H, m), 1.46 (9H, s), 1.32 (2H, m).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=3)[CH2:28][CH2:27]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[Cl:38][C:34]1[CH:33]=[C:32]([N:29]2[CH2:28][CH2:27][N:26]([S:23]([C:20]3[CH:21]=[CH:22][C:17]([NH:16][C:2]4[C:11]5[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=5)[N:5]=[CH:4][CH:3]=4)=[CH:18][CH:19]=3)(=[O:25])=[O:24])[CH2:31][CH2:30]2)[CH:37]=[CH:36][CH:35]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: Nc1ccc(S(=O)(=O)N2CCN(c3cccc(Cl)c3)CC2)cc1
Product: O=S(=O)(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCN(c2cccc(Cl)c2)CC1

Procedure:
In the matter given in Example 1C, 4-chloro-7-(trifluoromethyl)quinoline is heated with 1-[(p-aminophenyl)sulfonyl]-4-(m-chlorophenyl)piperazine to give 1-(m-chlorophenyl)-4-[[4-[[7-(trifluoromethyl)4-quinolinyl]amino]phenyl]sulfonyl]piperazine.
Reaction SMILES: Cl[C:2]1[C:3]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[N:7]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:25][NH2:26]>CN1CCCC1=O>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:25][NH:26][C:2]1[C:3]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[N:7]=1
Reactant: COC(=O)CCc1nc(Cl)c2c3c(sc2n1)CCCC3
Reactant: COc1ccc(CN)cc1Cl
Solvent: CN1CCCC1=O
Product: COC(=O)CCc1nc(NCc2ccc(OC)c(Cl)c2)c2c3c(sc2n1)CCCC3
Yield: 95.4 %

Procedure:
1.9 g of methyl 3-(4-chloro-5,6,7,8-tetrahydro-[1]benzothieno[2,3-d]pyrimidin-2-yl)propionate [obtainable by cyclization of methyl 2-amino-4,5,6,7-tetrahydrobenzothiophene-3-carboxylate with methyl 3-cyanopropionate and subsequent chlorination with phosphorus oxychloride/dimethylamine] and 2.3 g of 3-chloro-4-methoxybenzylamine (“A”) in 20 ml of N-methylpyrrolidone are stirred at 110° for 5 hours. The solvent is removed and worked up in the customary manner. 2.6 g of methyl 3-[4-(3-chloro-4-methoxybenzylamino)-5,6,7,8-tetrahydro[1]benzothieno-[2,3-d]pyrimidin-2-yl]propionate are obtained as a colourless oil.