Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1([C:17]#[N:18])[C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[NH2:20][OH:21]>C(O)C>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1([C:17](=[NH:18])[NH:20][OH:21])[C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:10]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: NO
Reactant: CC(C)(C)OC(=O)NCC1(C#N)CC12CCCCC2
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC1(C(=N)NO)CC12CCCCC2
Temperature: 25 °C
Yield: 54.3 %

Procedure:
To a solution of (1-cyano-spiro[2.5]oct-1-ylmethyl)-carbamic acid tert-butyl ester (10.0 g, 37.8 mmol) in ethanol (150 mL) was added 50% aqueous hydroxylamine (12 mL, 189 mmol). The solution was heated to reflux for 14 hours, cooled to room temperature and the solvent removed under reduced vacuum. The residue was partitioned between water (200 mL) and ether (300 mL). An emulsion formed in the ether layer, which was separable. The aqueous layer was extracted with ether (2×300 mL). The combined organic layers were filtered to remove emulsified material. The organic layer was washed with brine (200 mL), dried over sodium sulfate, filtered and evaporated to give 6.1 g (54%) of [1-(N-hydroxycarbamimidoyl)-spiro[2.5]oct-1-ylmethyl]-carbamic acid tert-butyl ester as a white solid: 1H NMR (300 MHz, CDCl3) δ 0.52 (d, J=4.8 Hz, 1H), 0.90 (d, J=4.8 Hz, 1H), 1.4 (m, 1H), 1.43 (s, 9H), 1.3-1.7 (m, 9H), 3.11 (s, 1H), 3.23 (dd, J=5.2, 13.9 Hz, 1H), 3.47 (dd, J=5.2, 13.9 Hz, 1H), 4.68 (s, 2H), 5.12 (s, 1H); MS (APCI) m/z 298 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](Cl)=[O:5].[C:8]1([C:14]#[C:15][C:16]2[CH:34]=[CH:33][C:19]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29](=[O:32])(=[O:31])[NH2:30])=[O:21])=[CH:18][CH:17]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:1][C:2]([CH3:7])=[CH:3][C:4]([NH:30][S:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:33]=[CH:34][C:16]([C:15]#[C:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:17][CH:18]=1)(=[O:31])=[O:32])=[O:5]
Reactant: CC(C)=CC(=O)Cl
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)=CC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
In a stream of nitrogen and at 0° C., 0.10 ml (0.96 mmol) of 3,3-dimethylacryloyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 300 mg (0.80 mmol) of 4-phenylethynyl-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 10 and 195 mg (1.60 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 183 mg (yield: 50.0%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[C:7](=[O:15])[C:6]=2[CH:16]=1.[Br:17]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl>O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:17][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[C:7](=[O:15])[C:6]=2[CH:16]=1
Reactant: Cc1ccc2oc3ncccc3c(=O)c2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1c2cc(CBr)ccc2oc2ncccc12
Reaction time: 2 h
Yield: 81.6 %

Procedure:
A mixture of 42 g of 7-methyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine, 36 g of N-bromosuccinimide, 0.4 g of benzoyl peroxide and 420 ml of carbon tetrachloride is refluxed with stirring under ultraviolet light for 2 hours. The reaction mixture is filtered rapidly while it is hot. The crystals thus obtained are suspended in hot water (about 60°C). The suspension is stirred thoroughly, and filtered. The crystals are recrystallized from dioxane to give 47.1 g of 7-bromomethyl-5-oxo-5H-[1]benzopyrano[2,3-b]-pyridine melting at 211°-212.5°C.
Reaction SMILES: [CH2:1]([S:5](Cl)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[NH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]3[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=3)[CH:16]=2)[CH2:11]1.C(N(CC)CC)C.Cl>C(Cl)(Cl)Cl>[CH2:1]([S:5]([NH:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19]3[CH2:20][CH2:21][C:22](=[O:25])[NH:23][N:24]=3)[CH:16]=2)[CH2:11]1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)Cl
Reactant: NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCS(=O)(=O)NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Reaction time: 1 h
Yield: 74.9 %

Procedure:
6.3 g of n-butanesulfonyl chloride was added under ice cooling to 5.61 g of 2-amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane and 4.1 g of triethyl amine suspended in 50 ml of chloroform, and the mixture was stirred for 1 hour. Diluted hydrochloric acid was added to the reaction mixture, the chloroform layer was collected by separation, washed and dried, and then the solvent was removed. The resulting crystals were recrystallized from tetrahydrofuran-isopropyl ether to obtain 6.40 g of 2-n-butylsulfonylamino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[C:17]1([C:23]2[O:27][N:26]=[CH:25][C:24]=2[CH2:28][CH2:29][C:30](O)=[O:31])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:12]([O:11][P:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][C:24]2[CH:25]=[N:26][O:27][C:23]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:16][CH:15]=1)([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2cnoc2-c2ccccc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (1.25 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (1.00 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.80 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.08 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(4-diethylphosphonomethylphenyl)-3-(5-phenyl-4-isoxazolyl)propionamide (1.89 g, yield 93%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 139–140° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH3:24])[N:18]=3)=[O:15])[N:12]=2)[CH:5]=[CH:4][N:3]=1.[CH3:25][CH2:26][O-:27].[Na+].CCO>O>[CH2:26]([O:27][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[C:11]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH3:24])[N:18]=3)=[O:15])[N:12]=2)[CH:5]=[CH:4][N:3]=1)[CH3:25]
Reactant: CCc1cccc(NC(=O)Nc2csc(-c3ccnc(Cl)c3)n2)n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1cc(-c2nc(NC(=O)Nc3cccc(CC)n3)cs2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 10 mL round bottom flask containing 1-[2-(2-chloropyridin-4-yl)thiazol-4-yl]-3-(6-ethylpyridin-2-yl)urea (40 mg, 0.11 mmol) (prepared similar to that described for Example 95) was charged a 21 wt % NaOEt/EtOH solution (5 mL). The reaction mixture was heated to reflux. After 2 h, the reaction mixture was cooled to RT and diluted with H2O then concentrated in vacuo. The solid residue was washed with CH2Cl2 and EtOAc then the solid was diluted with MeOH and concentrated in vacuo. The residue was diluted with EtOAc; washed with saturated NH4Cl and H2O, dried (MgSO4) and concentrated in vacuo to afford the title compound as a light-orange solid. MS m/z: 370.2 (M+H). Calc'd for C18H19N5O2S: 369.13.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>ClCCl>[CH2:39]([O:38][C:36](=[O:37])[NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc(OCCNC(=O)OCc3ccccc3)c(-c3ccnn3C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a mixture of N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl), phenyl)-3-methoxybenzamide (50 mg, 136 μmol) and triethylamine (0.038 mL, 0.27 mmol) in dichloromethane was added benzyl chloroformate (26 mg, 150 μmol), dropwise at room temperature. The mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with dichloromethane (3×20 mL) and dried over anhydrous MgSO4. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography. (EtOAc/Hexane=50-90%). {2-[4-(3-Methoxy-benzoylamino)-2-(2-methyl-2H-pyrazol-3-yl)-phenoxy]-ethyl}-carbamic acid benzyl ester was obtained as white solid in 37% yield. LCMS m/z (%)=501 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ ppm 3.5 (q, J=5.4 Hz, 2 H), 3.7 (s, 3 H), 3.9 (s, 3 H), 4.0 (t, J=5.1 Hz, 2 H), 4.9 (t, J=5.8 Hz, 1 H), 5.1 (s, 2 H), 6.3 (d, J=2.0 Hz, 1 H), 7.0 (d, J=8.6 Hz, 1 H), 7.1 (m, 1 H), 7.3 (m, 5 H), 7.4 (m, 1 H), 7.5 (m, 2 H), 7.7 (dd, J=8.8, 2.8 Hz, 1 H), 7.8 (s, 1 H).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1([CH:19]2[CH2:23][CH2:22][CH2:21][NH:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([N:20]2[CH2:21][CH2:22][CH2:23][CH:19]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: c1ccc(C2CCCN2)cc1
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC(=O)c1cc(Cl)cnc1N1CCCC1c1ccccc1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
To a solution of Methyl 2,5-dichloronicotinate (120 mg, 0.58 mmol,) in isopropanol (10 ml), 2-phenylpyrrolidine (86 mg, 0.58 mmol, available from Matrix Scientific #018619) and N,N-Diisopropylethylamine (90 mg, 0.70 mmol) were added. The mixture was heated under reflux overnight. After cooling to room temperature, the mixture was evaporated and the residue was dissolved in ethyl acetate (10 ml), washed with water (10 ml) and brine (10 ml), dried over Na2SO4 and evaporated in vacuo. The crude residue was purified by flash chromatography on silica gel eluting with a mixture petroleum ether/ethyl acetate 20:1 to afford the title compound (D72) (167 mg) as colorless oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][C:24](=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH2:31][CH2:30][N:29]4[C:38]([CH:41]=[O:42])=[CH:39][N:40]=[C:28]34)[CH2:23][CH2:22]2)=[CH:15][CH:14]=1.[O-:43][C:44]#N.[Na+].C(O)(=O)C>CO.[O-2].[O-2].[Mn+4]>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][C:24](=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH2:31][CH2:30][N:29]4[C:38]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][N:40]=[C:28]34)[CH2:25][CH2:26]2)=[CH:15][CH:14]=1
Reactant: N#C[O-]
Reactant: O=Cc1cnc2n1CCc1ccccc1C2=C1CCN(CCc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Agent: [Mn+4]
Agent: [Na+]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cnc2n1CCc1ccccc1C2=C1CCN(CCc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Temperature: 25 °C
Yield: 87.9 %

Procedure:
A mixture of compound 4 (164 g), sodium cyanate (80 g) and manganese dioxide (500 g) in methanol (5.5l) was stirred at room temperature. Ethanoic acid (122 g) was added dropwise and the resulting reaction mixture was stirred and refluxed overnight. The reaction mixture was filtered over dicalite, and the filter residue was rinsed with CH3OH/CH2Cl2. The filtrate was evaporated. The residue was partitioned between DCM and aqueous K2CO3 solution. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from ACN. The precipitate was filtered off and dried, yielding 152 g (87%) of methyl 6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]-benzazepine-3-carboxylate (compound 6, mp. 179.3° C.).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]23[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]4)[CH2:11]2)[CH2:17]3)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28]#[C:29][CH3:30].CN(C=O)C>C1C=CC=CC=1>[CH2:27]([N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]23[CH2:11][CH:12]4[CH2:18][CH:16]([CH2:15][CH:14]([CH2:13]4)[CH2:19]2)[CH2:17]3)=[CH:7][CH:8]=1)[C:28]#[C:29][CH3:30]
Reactant: CNc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC#CCN(C)c1ccc(OC23CC4CC(CC(C4)C2)C3)cc1

Procedure:
A mixture of 2.0 g. (0.0079 mole) of N-methyl-p-(1-adamantyloxyl)aniline, 1.07 g. K2CO3 and 1.03 g. of 1-bromo-2-butyne in 10 ml. DMF and 40 ml. C6H6 was heated at reflux for 17 hours. The mixture was allowed to cool and washed well with H2O and brine. The gum which remained when the organic layer was taken to dryness was dissolved in Et2O. The solid which precipitated on addition of HCl in Et2O was recrystallized from CH2Cl2 :EtOAc. There was obtained 2.09 g. (77%) of N-(2-butynyl)-N-methyl-p-(1-adamontyloxy)aniline, m.p. 180°-181°.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][OH:45])[CH2:39][CH2:38]1>>[F:25][C:18]1[CH:19]=[C:20]([CH3:24])[C:21]([F:23])=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][OH:45])[CH2:39][CH2:38]2)=[O:29])[S:14][N:13]=1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Reactant: NCCCCCCN1CCN(CCO)CC1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCCCN3CCN(CCO)CC3)c2C(N)=O)cc1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 2-[4-(6-amino-hexyl)-piperazin-1-yl]-ethanol by the procedure analogous to Example 6. HPLC ret. time: 3.0 minutes. 1H NMR (400 MHz, CD3OD) δ 7.17 (d, 1H, J=6.4, 9.6 Hz), 7.01 (m, 1H), 5.44 (s, 2H), 3.64 (t, 2H, J=5.6 Hz), 3.18 (t, 2H, J=6.8 Hz), 2.7-2.4 (bm, 8H), 2.50 (t, 2H, J=6.0 Hz), 2.33 (m, 2H), 2.23 (s, 3H), 1.50 (m, 4H), 1.35 (m, 4H) ppm; MS (APCl, m/z): 555 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.C(N(CC)C(C)C)(C)C.[F:49][C:50]([F:60])([F:59])[C:51]1[CH:58]=[CH:57][C:54]([CH2:55][NH2:56])=[CH:53][CH:52]=1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:56][CH2:55][C:54]2[CH:53]=[CH:52][C:51]([C:50]([F:49])([F:59])[F:60])=[CH:58][CH:57]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ccc(C(=O)NCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C

Procedure:
To a mixture of p-aminobenzoic acid (5.0 g, 36 mmol) and HBTU (14 g, 36 mmol) in DMF (50 mL, 600 mmol) at 0° C. were added N,N-diisopropylethylamine (19 mL, 110 mmol) and 4-(trifluoromethyl)benzylamine (6.2 mL, 44 mmol). The reaction mixture was slowly warmed to ambient temperature. The reaction mixture was quenched with an equal volume of saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic layers were washed successively with water, aqueous lithium chloride, and brine, dried over sodium sulfate, filtered and concentrated in vacuo (8.2 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]2[CH:14]=[N:13][S:12][N:11]=2)=[C:6]([CH:9]=1)[CH:7]=O.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]2[CH:14]=[N:13][S:12][N:11]=2)=[C:6]([CH:9]=1)[CH2:7][NH:22][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=Cc1cc(Cl)ccc1-c1cnsn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc(CNCc2cc(Cl)ccc2-c2cnsn2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 5-chloro-2-(1,2,5-thiadiazol-3-yl)benzaldehyde (0.155 g, 0.69 mmol), 4-methoxybenzylamine (0.09 mL, 0.69 mmol) and acetic acid (0.05 mL, 0.83 mmol) in 1,2-dichloroethane (5.2 mL) was added sodium triacetoxyborohydride (0.731 g, 3.45 mmol). The solution was stirred at ambient temperature for 16 h then partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate. The organic phase was dried (Na2SO4) and reduced in vacuo. The residue was purified by automated preparative chromatography on silica (eluting with 5% CH2Cl2/EtOAc/hexanes gradient, 5–50% EtOAc). N-[5-Chloro-2-(1,2,5-thiadiazol-3-yl)benzyl]-N-(4-methoxybenzyl)amine was isolated as an oil. 1H NMR (CDCl3, 400 MHz) δ 3.74 (s, 2H), 3.81 (s, 3H), 3.82 (s, 2H), 6.86 (d, J=8.6 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 8.84 (s,1H); MS m/z=346.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].C(S)CC.Br[C:21]([F:30])([F:29])[C:22]([F:28])([Br:27])[C:23]([F:26])([F:25])[F:24]>CN(C)C=O>[Br:27][C:22]([F:28])([C:23]([F:26])([F:25])[F:24])[C:21]([F:30])([F:29])[O:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8]
Reactant: Oc1c(Cl)cccc1Cl
Reactant: FC(F)(F)C(F)(Br)C(F)(F)Br
Agent: CCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)C(F)(Br)C(F)(F)Oc1c(Cl)cccc1Cl
Yield: 84.2 %

Procedure:
In a manner similar to Step A of Example 1, the reaction of 16.3 g (0.10 mole) 2,6-dichlorophenol, 13.8 g (0.10 mole) potassium carbonate, 1.0 g (0.013 mole) propanethiol, 62.0 g (0.20 mole) 1,2-dibromohexafluoropropane, and 125 ml of N,N-dimethylformamide produced 33.0 g of 2-(2-bromo-1,1,2,3,3,3-hexafluoropropanoxy)-1,3-dichlorobenzene as an oil. The ir spectra was consistent with the proposed structure.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[Cl-].[CH3:6][N:7]([CH3:13])[CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1>CC(C)=O>[CH3:6][N:7]([CH3:13])[CH:8]1[CH2:12][CH2:11][N:10]([C:2](=[S:1])[NH2:3])[CH2:9]1
Reactant: N#C[S-]
Reactant: CN(C)C1CCNC1
Agent: [Cl-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)C1CCN(C(N)=S)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 23.9 %

Procedure:
To a suspension of potassium thiocyanate (2.02 g, 20.8 mmol) in acetone (10.7 mL) at 0° C. was slowly added pivolyl chloride (2.6 mL, 21.1 mmol). The mixture was stirred at 0° C. for 3 h. Dimethylpyrrolidin-3-yl-amine (2.44 g, 21.3 mmol) was added slowly at 0° C., and the reaction was allowed to warm to room temperature. After stirring at room temperature overnight, the reaction was concentrated, and concentrated hydrochloric acid (10 mL) was added. The reaction was heated to 95° C. with stirring for 1 h. The mixture was allowed to cool to room temperature, and was extracted with dichloromethane. The aqueous layer was made basic with 20% aqueous sodium hydroxide. The basic solution was extracted with dichloromethane. The organics were combined, washed with brine, dried with anhydrous sodium sulfate, filtered, and concentrated. The mixture was diluted with diethyl ether and filtered to provide pure 3-dimethylamino-pyrrolidine-1-carbothioic acid amide (135) (0.863 g, 23.3%) as a white solid.
Reaction SMILES: [C:1]([N:5]([C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[NH2:6])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:25]=1)[C:22](O)=[O:23].CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[C:1]([N:5]([C:7](=[O:15])[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1)[NH:6][C:22](=[O:23])[C:21]1[CH:25]=[C:17]([Br:16])[CH:18]=[N:19][CH:20]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CC(C)(C)N(N)C(=O)c1ccc(Cl)cc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)N(NC(=O)c1cncc(Br)c1)C(=O)c1ccc(Cl)cc1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A solution of N'-t-butyl-N'-(4-chlorobenzoyl)hydrazine (0.5 g, 0.0022 mol) and 5-bromonicotinic acid (0.44 g, 0.0022 mol) in 10 ml of methylene chloride containing triethylamine (0.33 g) was added to a solution of methanesulfonyl chloride (0.25 g, 0.0022 mol) in 10 ml of methylene chloride at 0° C. The resulting mixture was stirred at 23° C. for 2 hours and then was allowed to stand overnight at 23° C. Aqueous sodium bicarbonate was added and the layers were separated. The aqueous layer was re-extracted with methylene chloride. The organic extracts were evaporated to give a yellow solid which was triturated with hexane/methylene chloride to afford N'-t-butyl-N-(5-bromonicotinoyl)-N'-(4-chlorobenzoyl)hydrazine as an off-white solid. m.p. 193°-197° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH2:21][CH:20]([N:23]([CH3:25])[CH3:24])[CH2:19]2)=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:22][CH2:21][CH:20]([N:23]([CH3:25])[CH3:24])[CH2:19]3)=[CH:14][CH:13]=2)=[O:8])=[CH:4][N:3]=1
Reactant: CN(C)C1CCN(c2ccc(N)cc2)C1
Reactant: O=C(O)c1ccc(Cl)nc1
Product: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(Cl)nc3)cc2)C1

Procedure:
6-Chloronicotinic acid was reacted with [1-(4-amino-phenyl)pyrrolidin-3-yl]dimethylamine by method E-b. This resulted in the product with the molecular weight of 344.14 (C18H21ClN4O); MS (ESI): 345 (M+H+) as hydrotrifluoroacetate.