Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11](OC(C)(C)C)=O)[CH2:7]1.ClC1[N:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:23]=1[C:24]([NH:26][C:27]1([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=2)[CH2:29][CH2:28]1)=[O:25]>>[Cl:44][C:41]1[CH:42]=[N:43][C:11]([N:8]2[CH2:9][CH2:10][C@H:6]([O:5][C:4]3[CH:18]=[CH:19][CH:20]=[C:2]([F:1])[CH:3]=3)[CH2:7]2)=[C:23]([CH:40]=1)[C:24]([NH:26][C:27]1([C:30]2[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=2)[CH2:29][CH2:28]1)=[O:25]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3Cl)CC2)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccc(F)c2)C1
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC[C@H](Oc4cccc(F)c4)C3)CC2)cc1
Yield: 111.9 %

Procedure:
The title compound (D204) (101 mg) was prepared according to the experimental procedure described in Description 160 starting from (S)-tert-butyl 3-(3-fluorophenoxy)pyrrolidine-1-carboxylate (D46) (100 mg, 0.355 mmol) and reacting in the second step with methyl 4-(1-(2,5-dichloronicotinamido)cyclopropyl)benzoate (D) (D021/056/3) (65 mg, 0.177 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[C:4]([Cl:10])[C:5]([Cl:9])=[C:6]([Cl:8])[CH:7]=1.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18]>>[Cl:1][C:2]1[C:7]([N+:17]([O-:19])=[O:18])=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4]([Cl:10])[C:3]=1[Cl:11]
Reactant: Clc1cc(Cl)c(Cl)c(Cl)c1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Temperature: 125 °C

Procedure:
Into a three-neck 750 ml flask equipped with a mechanical agitator, thermometer and condenser were charged 250 g of 99.7% pure granular pentachlorobenzene and 440 g of 92% sulfuric acid which was heated to 104°-108° C. by means of an electric heating mantle. The flask was then charged with 100 g of 99% pure concentrated nitric acid. This concentrated nitric acid was gradually added over a period of 0.83 hours while the reaction mixture was stirred and the temperature of the mixture maintained at 104°-108° C. Following this addition, the reaction mixture was heated to 125° C. for one hour followed by further heating at 135° C. The reaction mixture was heated again to raise the reaction temperature to above 145° C. and to form a liquid melt of pentachloronitrobenzene. The reaction mixture was maintained at this temperature for about 30 minutes. Next, the reaction mixture was cooled to 30°-70° C. by switching off the heating mantle and blowing cool air on the flask for about 30 minutes. The reaction mixture was then filtered by suction. The pentachloronitrobenzene product in the filter cake was washed twice with about 500 ml of distilled water each time. After drying at room temperature for 24 hours, the product was analyzed by Vapor Phase Chromatography (VPC). In this specific example, the product was of exceptional quality with an assay of 99.74% pentachloronitrobenzene, less than 0.01% pentachlorobenzene and 0.26% hexachlorobenzene.
Reaction SMILES: C(OC(=O)C(C)(C)CC1C=CC(S)=CC=1)C.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([OH:39])([CH3:38])[C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([C:27]1[CH:32]=[CH:31][C:30]([C@@:33]([OH:39])([CH3:38])[C:34]([F:36])([F:37])[F:35])=[CH:29][CH:28]=1)(=[O:26])=[O:25]
Reactant: CC(O)(c1ccc(S(=O)(=O)c2ccccc2Cl)cc1)C(F)(F)F
Agent: CCOC(=O)C(C)(C)Cc1ccc(S)cc1
Product: C[C@](O)(c1ccc(S(=O)(=O)c2ccccc2Cl)cc1)C(F)(F)F

Procedure:
Using the methods described above in Example 12, but substituting 2-chlorobenzenethiol for 3-(4-mercaptophenyl)-2,2-dimethylpropionic acid ethyl ester in step a, 2-[4-(2-chlorobenzenesulfonyl)phenyl]-1,1,1-trifluoropropan-2-ol was prepared. 1H NMR (CDCl3, 400 MHz) δ 8.27 (dd, J=2.0 Hz, 7.6 Hz, 1H), 7.98 (d, J=8.6 Hz, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.57-7.44 (m, 3H), 2.61 (s, 1H), 1.80 (s, 3H). The racemic product was resolved by chiral HPLC. The flow rate was 20 mL/min on a Chiralcel OD-H 20 mm i.d.×250 mm, 5μ column (Daciel chemical Industries LTD), using isopropyl alcohol/hexanes (10/90) as the eluent.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[N:15]([CH3:18])[CH:16]=[N:17][C:7]=2[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].[N+:20]([O-])([OH:22])=[O:21]>S(=O)(=O)(O)O>[CH2:1]([N:5]1[C:14]2[CH:13]=[CH:12][C:11]([N+:20]([O-:22])=[O:21])=[CH:10][C:9]=2[C:8]2[N:15]([CH3:18])[CH:16]=[N:17][C:7]=2[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c2ncn(C)c2c2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCCCn1c(=O)c2ncn(C)c2c2cc([N+](=O)[O-])ccc21
Reaction time: 0.5 h

Procedure:
A solution of 100 mg (0.39 mmol) of Compound 1 obtained in Example 1 in 0.13 ml of sulfuric acid was added dropwise to an acid mixture consisting of 0.045 ml of 61% nitric acid and 0.35 ml of 96% sulfuric acid with ice cooling, followed by stirring for 30 minutes. After neutralization with an aqueous 50% sodium hydroxide, the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluting solvent: chloroform/methanol=10/1) to afford 13 mg of Compound 14.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[N:10][CH:11]=1.[S:19](=[O:21])=[O:20].[ClH:22]>O.C(O)(=O)C>[Cl:22][S:19]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[N:10][CH:11]=1)(=[O:21])=[O:20]
Reactant: COC(=O)CCCc1ccc(N)cn1
Reactant: Cl
Reactant: O=S=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)CCCc1ccc(S(=O)(=O)Cl)cn1
Temperature: -10 °C

Procedure:
Sodium nitrite (6.08 g) in water (12 ml) was added over 20 minutes to a solution of methyl 4-(5-aminopyrid-2-yl)butanoate (7.48 g, 0.04 mole) in glacial acetic acid (20 ml) and concentrated hydrochloric acid (32 ml) stirred at -10° C. The solution was stirred for 15 minutes then added over 15 minutes to a solution of cuprous chloride (2 g) in glacial acetic acid saturated with sulphur dioxide at 10° C. The resulting solution was stirred at room temperature for 1 hour then poured into ice water (250 ml) and extracted with chloroform (3×200 ml). The chloroform extracts were dried over magnesium sulphate and the solvent was removed to give the title compound as a pale green oil which was used without further purification.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])=[O:3].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[C:17]([N:19]1[C:28]2[C:23](=[CH:24][C:25]([C:29]3[CH:34]([CH3:35])[S:33][C:32](=[O:36])[NH:31][N:30]=3)=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1)=[O:18].C(N(CC)CC)C>ClCCl>[CH2:8]([N:7]([CH2:6][CH2:5][O:4][C:2]([N:31]1[N:30]=[C:29]([C:25]2[CH:24]=[C:23]3[C:28](=[CH:27][CH:26]=2)[N:19]([C:17](=[O:18])[C:16]2[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:14]([O:13][CH3:12])[CH:15]=2)[CH2:20][CH2:21][CH2:22]3)[CH:34]([CH3:35])[S:33][C:32]1=[O:36])=[O:3])[CH2:10][CH3:11])[CH3:9]
Reactant: COc1ccc(C(=O)N2CCCc3cc(C4=NNC(=O)SC4C)ccc32)cc1OC
Reactant: CCN(CC)CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)CCOC(=O)N1N=C(c2ccc3c(c2)CCCN3C(=O)c2ccc(OC)c(OC)c2)C(C)SC1=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
6 g of 2-(N,N-diethylamino)ethyl chloroformate dissolved in 50 ml of dichloromethane are added dropwise with stirring to a solution of 10 g of 3,6-dihydro-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-6-quinolyl]-6-methyl-2H-1,3,4-thiadiazin-2-one ("A") and 9.8 ml of triethylamine in 100 ml of dichloromethane, and the mixture is subsequently stirred at 20° C. for one hour. The solvent is removed, and the mixture is worked up in the conventional manner to give 3-[2-(N,N-diethylamino)ethoxycarbonyl]-5-[1,2,3,4-tetrahydro-1-(3,4-dimethoxybenzoyl)-6-quinolyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one; hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:18]=[C:17]([CH3:19])[CH:16]=[C:11]2[O:12][C:13]=1[CH2:14][CH3:15].[CH2:20]([NH:23][CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22].[CH2:27]=O>CC(O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:18]=[C:17]([CH3:19])[C:16]([CH2:27][N:23]([CH2:24][CH2:25][CH3:26])[CH2:20][CH2:21][CH3:22])=[C:11]2[O:12][C:13]=1[CH2:14][CH3:15]
Reactant: CCCNCCC
Reactant: CCc1oc2cc(C)nn2c1-c1ccc(Cl)cc1Cl
Reactant: C=O
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1c(C)nn2c(-c3ccc(Cl)cc3Cl)c(CC)oc12
Temperature: 50 °C

Procedure:
To a solution of 3-(2,4-dichloro-phenyl)-2-ethyl-6-methyl-pyrazolo[5,1-b]oxazole (Intermediate HO)(30 mg, 0.10 mmol, 1 eq.) and dipropylamine (0.042 ml, 0.31 mmol, 3 eq.) in AcOH (0.3 ml) is added formaldehyde (36.5% in water, 0.025 ml, 0.31 mmol, 3 eq.) at RT. The reaction mixture is heated at 50° C. for 2 h then cooled to RT and directly subjected to purification by reverse phase prep-HPLC (Waters system) to yield the title compound (TFA salt) as a colourless resin. HPLC: AtRet=1.89; MS: m/z 408.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 0.96 (t, 6H), 1.22 (t, 3H), 1.73-1.83 (m, 4H), 2.30 (s, 3H), 2.68 (q, 2H), 2.96-3.05 (m, 4H), 4.34 (m, 2H), 7.68 (m, 2H), 7.93 (m, 1H).
Reaction SMILES: C[O-].[Na+].[C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])#[N:5].[Cl-].[NH4+:22].[CH3:23][C:24]1([CH3:35])[CH2:29][CH:28]([C:30](OC)=[O:31])[C:27](=O)[CH2:26][CH2:25]1>CO>[OH:31][C:30]1[C:28]2[CH2:29][C:24]([CH3:35])([CH3:23])[CH2:25][CH2:26][C:27]=2[N:22]=[C:4]([C@H:6]2[CH2:10][CH2:9][CH2:8][N:7]2[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[N:5]=1
Reactant: [NH4+]
Reactant: COC(=O)C1CC(C)(C)CCC1=O
Reactant: N#C[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)CCc2nc([C@H]3CCCN3C(=O)OCc3ccccc3)nc(O)c2C1
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To sodium methoxide (30 wt % in methanol, 8 mg, 0.05 mmol) was added a solution of (R)-benzyl 2-cyanopyrrolidine-1-carboxylate (189 mg, 0.82 mmol) in methanol (1 mL) at room temperature and the reaction mixture was stirred for one hour. Ammonium chloride (44 mg, 0.82 mmol) was introduced and the stirring was continued for an additional two hours, followed by the addition of methyl 5,5-dimethyl-2-oxocyclohexanecarboxylate (100 mg, 0.54 mmol) and sodium methoxide (30 wt % in methanol, 293 mg, 1.63 mmol). The stirring was continued for two more hours. The reaction mixture was quenched with water (10 mL), neutralized with 1 N hydrochloric acid and extracted with ethyl acetate (3×10 mL). The combined extract was washed with water (20 mL) and brine, dried over sodium sulfate, filtered, concentrated and purified by gradient flash chromatography (25% to 95% ethyl acetate in hexane) to give phenylmethyl(2R)-2-(4-hydroxy-6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-2-yl)pyrrolidine-1-carboxylate (186 mg, 90%). MS (EI) for C22H27N3O3: 381 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@@H:15]([CH2:16]I)[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:25]1[NH:26][C:27](=[O:31])[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@@H:15]([CH2:16][N:26]3[C:27](=[O:31])[CH:28]=[CH:29][CH:30]=[N:25]3)[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CI)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: O=c1cccn[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cn2ncccc2=O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 60 °C
Yield: 795.3 %

Procedure:
To a solution of tert-butyl (6R,7S)-6-(3,4-dichlorophenyl)-7-(iodomethyl)-1,4-oxazepane-4-carboxylate (335 mg) in DMF (7.0 mL) were added 3(2H)-pyridazinone (79 mg) and potassium carbonate (143 mg), and the mixture was heated at 60° C. for 4 hr. The reaction solution was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (2.49 g).
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH:16]=O)[CH:5]=1.[CH3:19][NH:20][C:21](=[O:34])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[F:1][CH:2]([F:18])[O:3][C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH2:16][N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([C:21]([NH:20][CH3:19])=[O:34])=[CH:27][CH:26]=3)[CH2:33][CH2:32]2)[CH:5]=1
Reactant: CC1Oc2c(cc(C=O)cc2OC(F)F)NC1=O
Reactant: CNC(=O)c1ccc(N2CCNCC2)cc1
Product: CNC(=O)c1ccc(N2CCN(Cc3cc4c(c(OC(F)F)c3)OC(C)C(=O)N4)CC2)cc1

Procedure:
Using 403A and N-methyl-4-(piperazin-1-yl)benzamide 282 in the general procedure for reductive aminations, the title compound was obtained as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (d, J=6.82 Hz, 3H) 2.45-2.49 (m, 4H) 2.73 (d, J=4.55 Hz, 3H) 3.24 (d, J=4.80 Hz, 4H) 3.43 (s, 2H) 4.74 (q, J=6.74 Hz, 1H) 6.80 (s, 2H) 6.93 (d, J=9.09 Hz, 2H) 6.95-7.35 (m, 1H) 7.70 (d, J=8.84 Hz, 2H) 8.10-8.17 (m, 1H) 10.80 (s, 1H). ESI-MS: m/z 461.4 (M+H)+. mp 210.4-213.0° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[O:21][CH:22]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1coc(-c2ccccc2)n1
Product: c1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)cc1
Yield: 42 %

Procedure:
In substantially the same manner as in Working Example 37, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-phenyloxazole to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-phenyloxazole. The yield was 42%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 111-112° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[S:7][C:6]=2[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21]([O:28][C:29]([NH:31][CH2:32][CH2:33]Br)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)(=O)C>CN(C)C=O.O>[CH2:21]([O:28][C:29]([NH:31][CH2:32][CH2:33][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[S:7][C:6]=2[CH:14]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Oc1ccc2c(c1)sc1ccccc12
Reactant: O=C(NCCBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCCOc1ccc2c(c1)sc1ccccc12)OCc1ccccc1
Temperature: 60 °C
Yield: 91.2 %

Procedure:
To a solution of 370.6 mg of 3-hydroxydibenzothiophene [prepared by the method reported by H. Kudo in J. Heterocycl. Chem., 22 (1), 215-218 (1985)] and 768 mg of potassium carbonate in 4 ml of dimethylformamide, 720 mg of Intermediate 0 were added and the mixture was heated at 60° C. for 30 hours. Thereto were added ethyl acetate and water to effect extraction, whereupon the organic layer was dried and the solvent was distilled off under a reduced pressure to thereby obtain 637 mg of the above-identified compound after purification by a column chromatography (mathanol/chloroform of 1/100). Rf=0.17 (ethyl acetate/n-hexane of 1/5).
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].[Br:19][C:20]([C:22]([F:25])([F:24])[F:23])=[CH2:21].Cl>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[F:1][C:2]([F:18])([C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])[CH2:3][C:4]([CH2:21][CH:20]([Br:19])[C:22]([F:25])([F:24])[F:23])([C:7]#[N:8])[C:5]#[N:6]
Reactant: C=C(Br)C(F)(F)F
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: N#CC(C#N)(CC(Br)C(F)(F)F)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 0 °C
Reaction time: 5 h
Yield: 0.9 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile was dissolved in 6 ml of a solution (1 mol/L) of tetrabutylammonium fluoride in tetrahydrofuran and then cooled to 0° C. Thereto 1.1 g of 2-bromo-3,3,3-trifluoropropene dissolved in 3 ml of tetrahydrofuran was added dropwise, and the mixture was stirred at room temperature for 8 hours and at 60° C. for 5 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.02 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-(2-bromo-3,3,3-trifluoropropyl)malononitrile (hereinafter, referred to as the present compound (57)).
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([F:10])=[CH:5][C:4]=1[CH2:11][C:12]([OH:14])=O.C1N=CN(C([N:22]2[CH:26]=NC=C2)=O)C=1.C1C[O:30][CH2:29]C1>O>[CH3:29][O:30][N:22]([CH3:26])[C:12](=[O:14])[CH2:11][C:4]1[CH:5]=[C:6]([F:10])[CH:7]=[C:8]([F:9])[C:3]=1[F:2]
Reactant: O=C(O)Cc1cc(F)cc(F)c1F
Reactant: C1CCOC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: O
Product: CON(C)C(=O)Cc1cc(F)cc(F)c1F
Temperature: 5 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a solution of NHMe(OMe).HCl (20.3 g, 0.21 mol) in THF (110 mL), H2O (40 mL) and TEA (26.3 g, 0.22 mol) was added 2,3,5-trifluorophenylacetic acid (42, 24.7 g, 0.13 mol) and CDI (24.3 g, 0.15 mol) at 0-10° C. The reaction mixture was stirred at 0-10° C. for 5 h. After HPLC showed that the reaction was complete, the mixture was filtered through celite and the filtrate was partitioned with water and EtOAc. The organic solution was dried over Na2SO4 and concentrated. The crude residual was further purified by flash chromatography on silica gel (5-10% EtOAc/PE) to give 43 (24.0 g, 80% yield). 1H NMR (CDCl3, 400 MHz): δ 6.76-6.72 (m, 2H), 3.72 (m, 2H), 3.66 (d, 3H), 3.15 (d, 3H); MS (ESI) m/e [M+H]+: 234.07.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.N12CCCN=C1CCCCC2.Cl.[CH3:37][O:38][C:39](=[O:46])[C@@H:40]([NH2:45])[CH2:41][CH2:42][CH2:43][CH3:44]>N1C=CC=CC=1.CCOC(C)=O>[CH3:37][O:38][C:39](=[O:46])[C@@H:40]([NH:45][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:2]=1[NH2:1])[CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCC[C@H](N)C(=O)OC
Reactant: COc1ccc(C(=O)O)c(N)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCC[C@H](NC(=O)c1ccc(OC)cc1N)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
To a solution of 2-amino-4-methoxy-benzoic acid (1.0 g, 5.98 mmol) and 1,1′-carbonyldiimidazole (980 mg, 6.04 mmol) in pyridine (5 mL) is added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.9 mL, 6.02 mmol). The mixture is stirred at room temperature for 2 hours follows by the addition of (S)-2-amino-hexanoic acid methyl ester hydrochloride (1.1 g, 6.06 mmol). The reaction mixture is stirred at room temperature for 16 hours and diluted with EtOAc (100 mL), the solution is washed with H2O (50 mL×3). The organic layer is dried over sodium sulfate, and is concentrated. The resulting residue is purified by flash chromatography with 60% EtOAc in hexanes as the eluent to afford (S)-2-(2-amino-4-methoxy-benzoylamino)-hexanoic acid methyl ester (1.03 g, 59%).
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][CH:21]=[C:22]2[N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[CH:17][CH:16]=1>CC(C)=O>[C:5]([NH:3][C:2]([NH:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][CH:21]=[C:22]2[N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[CH:17][CH:16]=1)=[S:1])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N#C[S-]
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Agent: [NH4+]
Solvent: CC(C)=O
Product: CN1CCN(c2cccc3ccc(NC(=S)NC(=O)c4ccccc4)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
To a mixture of ammonium thiocyanate (0.376 g, 4.94 mmol) in acetone (5 mL) was added benzoyl chloride (0.57 mL, 4.94 mmol) dropwise. The mixture (white precipitate) was refluxed 45 minutes which resulted in a yellow heterogeneous solution. A solution of 7-Amino-1-(4-methyl-1-piperazinyl)-naphthalene (1.0 g, 4.14 mmol) in acetone (25 mL) was added dropwise (10 mL acetone rinse also added). The mixture was refluxed 4 hours and allowed to stir overnight at ambient temperature. The mixture was concentrated onto silica gel and flash chromatographed (2×3.5 inches). Gradient elution with ethyl acetate/hexane of from 50% to 100% gave an unweighed forerun. Continued gradient elution with 10 to 40% ethanol/ethyl acetate gave 1.3 g (77%) of title product as a yellow foam which was suitable for use without further purification. The compound was found to slowly decompose at room temperature. A sample recrystallized from ethyl acetate/methylene chloride for analysis: mp 160°-250° C. 1H NMR (DMSOd6, D2O) δ 8.74 (s, 1H), 7.97 (d, J=7.5 Hz, 1H), 7.91 (d, J=9 Hz, 1H), 7.70-7.51 (m, 5H), 7.42 (t, J=8 Hz, 1H), 7.12 (d, J=7 Hz, 1H), 3.11 (m, 4 H), 2.79 (br s, 4H), 2.39 (s, 3H). HRMS m/e calculated for C23H24N4OS: 404.1661. Observed m/e: 404.1633.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12]C(C2C=NC3C(C=2Cl)=CC(C(F)(F)F)=CC=3)=O)[CH2:8][CH2:7]1>C(N(CC)CC)C>[ClH:3].[CH3:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8][CH2:7]1
Reactant: C[C@H]1CC[C@H](NC(=O)c2cnc3ccc(C(F)(F)F)cc3c2Cl)CC1
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: C[C@H]1CC[C@H](N)CC1
Product: Cl

Procedure:
4-Hydroxy-6-trifluoromethyl-3-carboxylic acid (514 mg, 2 mmol), thionyl chloride, trans-4-methylcyclohexylamine hydrochloride (225 mg, 1.5 mmol), and triethylamine (2 mL) afforded crude N-(trans-4-methylcyclohexyl)-4-chloro-6-trifluoromethylquinoline-3-carboxamide:
Reaction SMILES: Cl[CH2:2][O:3][CH3:4].[Br:5][C:6]1[C:7]([F:13])=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[Br:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:2][O:3][CH3:4])[C:7]=1[F:13]
Reactant: COCCl
Reactant: Oc1cccc(Br)c1F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cccc(Br)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Chloro(methoxy)methane (11.8 mL) was added at 0 C to a THF (150 mL) solution of 3-bromo-2-fluorophenol (15.0 g) and N,N-diisopropylethylamine (41.1 mL). The reaction mixture was stirred overnight at room temperature in a nitrogen atmosphere and then filtered through celite. The obtained filtrate was washed with 1 M hydrochloric acid and a saturated aqueous solution of sodium bicarbonate in this order, and then, the solvent was distilled off under reduced pressure. The obtained residue was passed through a short silica gel column (NH, hexane/ethyl acetate), and the solvent was distilled off under reduced pressure to obtain the title compound (17.9 g)