Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:14][C:15]1[C:24]2[C:19](=[C:20]([NH:25][C:26](=[O:35])[C:27]3[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:34])[CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37].O>CN(C)C=O>[Cl:34][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([Cl:33])[C:27]=1[C:26]([NH:25][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:19]=1[N:18]=[CH:17][C:16]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:15]2[CH2:14][S:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1)=[O:35]
Reactant: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CBr
Reactant: Sc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CSc1ncc[nH]1
Reaction time: 0.25 h
Yield: 92.2 %

Procedure:
To a solution of 2-mercaptoimidazole (27.4 mg) in dimethylformamide (1.5 ml) was added potassium carbonate (51.6 mg) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature. To the mixture was added 4-bromomethyl-8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonylquinoline (120 mg) under ice-cooling, and the mixture was stirred for 1 hour at ambient temperature. To the mixture was added water under ice-cooling, and the resulting precipitate was collected by filtration and washed with water to give 8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonyl-4-[(imidazol-2-yl)thiomethyl]quinoline (115 mg).
Reaction SMILES: [O-]S([O-])=O.[Na+].[Na+].[C:7]([O-])(O)=O.[Na+].[C:12]([C:16]1[O:17][C:18]2[C:24]([S:25](Cl)(=[O:27])=[O:26])=[C:23]([Cl:29])[CH:22]=[CH:21][C:19]=2[N:20]=1)([CH3:15])([CH3:14])[CH3:13].IC>O.CCO>[C:12]([C:16]1[O:17][C:18]2[C:24]([S:25]([CH3:7])(=[O:27])=[O:26])=[C:23]([Cl:29])[CH:22]=[CH:21][C:19]=2[N:20]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Reactant: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CI
Solvent: O
Product: CC(C)(C)c1nc2ccc(Cl)c(S(C)(=O)=O)c2o1
Temperature: 25 °C

Procedure:
A solution of 204 mg of Na2SO3 and 409 mg of NaHCO3 in 4 ml H2O is heated to 75° and treated portionwise with 0.5 g of 2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl chloride (US 2007/0249672 page 9). A mixture obtained is heated at 75° for 2 hours and 4 ml of EtOH are added followed by 0.11 ml of iodomethane. A mixture obtained is heated at 90° overnight and allowed to cool to rt. A mixture obtained is extracted with 3×30 ml of EtOAc and the combined organic extracts obtained are washed with brine, dried over MgSO4 and solvent is evaporated. The title compound is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:10]=[N:9][C:8](SC)=[N:7][C:6]=2[N:13]=1.[CH3:14][O:15][CH2:16][CH2:17][NH2:18]>CCOC(C)=O>[CH3:14][O:15][CH2:16][CH2:17][NH:18][C:8]1[N:9]=[CH:10][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[N:13][C:6]=2[N:7]=1
Reactant: CSc1ncc2ccc(C)nc2n1
Reactant: COCCN
Solvent: CCOC(C)=O
Product: COCCNc1ncc2ccc(C)nc2n1
Temperature: 25 °C
Yield: 91 %

Procedure:
Heat a solution of 7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidine (2.6 g, 13.6 mmol) and 2-methoxyethanamine (6 mL) with microwave irradiation at 180° C. for 2 h. Cool the mixture to RT, dissolve in EtOAc, wash with water, then brine, dry over Na2SO4 and concentrate under reduced pressure to give N-(2-methoxyethyl)-7-methylpyrido[2,3-d]pyrimidin-2-amine (2.7 g, 91%). Treat a solution of N-(2-methoxyethyl)-7-methylpyrido[2,3-d]pyrimidin-2-amine (2.35 g, 10.7 mmol) in THF (100 mL) portion wise with NBS (1.8 g, 10.7 mmol) and stir at RT for 2 h. Concentrate the reaction mixture to dryness, dissolve in EtOAc, wash with water, then brine, dry the organics over Na2SO4, concentrate and purify by HPLC to afford the title compound (0.55 g, 26%). MS (m/z): 297.0 (M+1+).
Reaction SMILES: [C:1]([NH:5][C:6]([CH:8]([NH:24][C:25]([CH:27]([NH:32][C:33]([N:35]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:34])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.CO.[Pd]>[C:1]([NH:5][C:6]([CH:8]([NH:24][C:25]([CH:27]([NH:32][C:33]([N:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1)=[O:34])[CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:15]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(C#Cc2ccccc2)cc1)C(=O)NC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(CCc2ccccc2)cc1)C(=O)NC(C)(C)C
Reaction time: 20.5 h
Yield: 64.6 %

Procedure:
To a solution of the product from Example 134 (0.187 g, 0.33 mmol) in 16 mL of 1:1 THF/methanol mixture was added 20% Pd/C (0.1 g). The resulting solution was hydrogenated for 20.5 hours at 20 psi. The crude mixture was evaporated to dryness and was purified by chromatography (silica gel, 30% ethyl acetate/hexane). It was further purified by crystallizing from petroleum ether and toluene to give the title compound (0.12 g, 65%) as a white solid, mp 155-156° C. Anal. Calc'd for C34H50N4O3: C, 72.56; H, 8.95; N, 9.95. Found: C, 72.2; H, 9.03; N, 9.80
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][CH3:14])=[C:10]([CH:15]3[C:23](=[O:24])[CH:22]4[CH:17]([CH:18]5[O:25][CH:21]4[CH:20]=[CH:19]5)[C:16]3=[O:26])[CH:9]=2)=[CH:4][CH:3]=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][CH3:14])=[C:10]([CH:15]3[C:23](=[O:24])[CH:22]4[CH:17]([CH:18]5[O:25][CH:21]4[CH2:20][CH2:19]5)[C:16]3=[O:26])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCc1sc(-c2ccc(Cl)cc2)cc1C1C(=O)C2C3C=CC(O3)C2C1=O
Solvent: CO
Product: CCc1sc(-c2ccc(Cl)cc2)cc1C1C(=O)C2C3CCC(O3)C2C1=O
Yield: 28 %

Procedure:
A solution of 4-[5-(4-chloro-phenyl)-2-ethyl-thiophen-3-yl]-10-oxa-tricyclo[5.2.1.0*2,6*]dec-8-ene-3,5-dione (180 mg, 0.47 mmol) in methanol (5 ml) is stirred under hydrogen (3 bars) for 7 hours. The reaction solution is filtered through a Celite pad and the filtrate concentrated to give 4-[5-(4-chloro-phenyl)-2-ethyl-thiophen-3-yl]-10-oxa-tricyclo[5.2.1.0*2,6*]decane-3,5-dione (51 mg).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][NH:16][C:17]2[N:26]=[C:25]([N:27]([CH3:29])[CH3:28])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:11][CH2:10]1)(C)(C)C.Cl.N1C=CC=CC=1.[F:38][C:39]([F:52])([F:51])[O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[S:47](Cl)(=[O:49])=[O:48]>CCOC(C)=O.C(Cl)Cl>[CH3:28][N:27]([CH3:29])[C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([NH:16][CH2:15][C@H:12]2[CH2:11][CH2:10][C@H:9]([CH2:8][NH:7][S:47]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[O:40][C:39]([F:38])([F:51])[F:52])(=[O:49])=[O:48])[CH2:14][CH2:13]2)[N:26]=1
Reactant: CN(C)c1nc(NC[C@H]2CC[C@H](CNC(=O)OC(C)(C)C)CC2)nc2ccccc12
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)c1nc(NC[C@H]2CC[C@H](CNS(=O)(=O)c3ccccc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a suspension of trans-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]cyclohexylmethyl}-carbamic acid tert-butyl ester obtained in step G of example 1 (500 mg, 1.21 mmol) in EtOAc (8 mL) was added 4 M hydrogen chloride in EtOAc (7 mL). The mixture was stirred at ambient temperature for 40 min and concentrated to give a white solid. To a suspension of the solid in CH2Cl2 (7 mL) was added pyridine (215 μL, 2.66 mmol). The mixture was cooled at 4° C. and a solution of 2-trifluoromethoxy-benzenesulfonyl chloride (331 mg, 1.27 mmol) in CH2Cl2 (2 mL) was added below 5° C. The reaction mixture was stirred at 4° C. for 2 hr. The reaction was quenched with saturated aqueous NaHCO3 The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 20% EtOAc in hexane) to give trans-N-{4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-2-trifluoromethoxy-benzenesulfonamide (231 mg, 36%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][CH:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.[Cl:22][CH2:23][C:24](Cl)=O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:24]([CH2:23][Cl:22])=[N:13][N:12]=[C:10]3[CH2:9][CH:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1
Reactant: O=C(Cl)CCl
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=CC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Fc1ccccc1C1=CCc2nnc(CCl)n2-c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 18.2 g of 7-chloro-5-(2-fluorophenyl)-2-hydrazino-3H-1-benzazepine in 220 ml of glacial acetic acid is treated dropwise at 15° with 5.1 ml of chloroacetyl chloride. The mixture is stirred at room temperature for a further 2 hours. The mixture is treated with 7.5 g of sodium acetate, stirred at room temperature for 2 hours. and at boiling under reflux for 20 minutes, then evaporated in vacuo and the residue is partitioned between chloroform and water. The organic phase is washed with sodium hydrogen carbonate solution and water and evaporated. The crude product obtained is chromatographed on silica gel while eluting with chloroform/ethanol (98.5:1.5) and there is obtained 8-chloro-1-(chloromethyl)-6-(2-fluorophenyl)-4H-s-triazolo[4,3-a][1]benzazepine as white crystals of melting point 180° (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].[CH2:34]=[O:35]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:34][OH:35])[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(-c2nnc3n2CCCC3c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Reactant: C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(-c2nnc3n2CCCC3(CO)c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Reaction time: 1 h
Yield: 13.3 %

Procedure:
To a mixture of 8-(3,4-dichlorophenyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine (300 mg) in DMF (5 mL) was added sodium hydride (60%, 31.6 mg) under ice-cooling, and the mixture was stirred for 1 hr under a nitrogen atmosphere. Paraformaldehyde (39.6 mg) was added to the reaction mixture, and the mixture was stirred for 30 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (42.5 mg).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15](=[O:18])[C:14]2([CH3:21])SC)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni].O.O1CCCC1>[C:1]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15](=[O:18])[CH:14]2[CH3:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSC1(C)C(=O)Nc2c(C(=O)c3ccccc3)cccc21
Agent: [Ni]
Solvent: C1CCOC1
Solvent: O
Product: CC1C(=O)Nc2c(C(=O)c3ccccc3)cccc21
Yield: 89 %

Procedure:
A stirred solution of 8 g. (0.027 mole) of 7-benzoyl-3-methyl-3-methylthioindolin-2-one in 80 ml. of tetrahydrofuran was treated under N2 with 40 g. of a commercial Raney nickel-water mixture over a 2 hr. period. At the end of this period the mixture was filtered and the residue washed thoroughly with tetrahydrofuran. One drop of concentrated hydrochloric acid was added to the filtrate and the dark orange solution turned pale yellow. The solution was stripped under vacuum to a yellow oil which crystallized on seeding. The material was recrystallized from toluene petroleum ether to give a white crystalline material. The solid (6.0 g., 89% yield) melted at 125°-127° C.
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH2:12]([O:14][C:15](=[O:21])[CH2:16][C:17](=[O:20])[CH2:18][CH3:19])[CH3:13].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1>O1CCCC1.O>[CH2:12]([O:14][C:15](=[O:21])[CH:16]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:17](=[O:20])[CH2:18][CH3:19])[CH3:13]
Reactant: CCOC(=O)CC(=O)CC
Reactant: Clc1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCOC(=O)C(Cc1ccc(Cl)cc1)C(=O)CC
Temperature: 70 °C

Procedure:
A suspension of potassium tert-butoxide (2.8 g) in anhydrous tetrahydrofuran (400 mL) at 0° C. was treated with a mixture of tert-butanol (1.0 mL) and 3-oxopentanoic acid ethyl ester (3.0 g). After stirring at room temperature for 45 minutes a solution of 1-bromomethyl-4-chlorobenzene (4.3 g) in tetrahydrofuran (100 mL) was added and the resulting mixture heated at 70° C. for 24 hours. The mixture was cooled to room temperature, diluted with water and the tetrahydrofuran removed under reduced pressure. The residue was extracted with ethyl acetate and the combined extracts dried over magnesium sulfate and then the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of cyclohexane and methyl tert-butyl ether (4:1 by volume) to afford title compound. 4.8 g.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH:9]([C:10]#[N:11])[CH2:8][C:7]2=[CH:12][CH:13]=1)([O-])=O.C(O)C.C(O)(=O)C.[H][H]>[Pd].C(N(CC)CC)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[NH2:1][C:4]1[CH:5]=[C:6]2[CH:9]([C:10]#[N:11])[CH2:8][C:7]2=[CH:12][CH:13]=1
Reactant: [H][H]
Reactant: N#CC1Cc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#CC1Cc2ccc(N)cc21
Reaction time: 1 h
Yield: 86.4 %

Procedure:
Into a 1-liter, three-necked flask equipped with a gas dipersion tube, reflux condenser, rubber septum and nitrogen inlet is placed 7 g (0.04 mole) of 5-nitro-1-cyanobenzocyclobutene and 400 ml of absolute 2B ethanol. The mixture is stirred under nitrogen and heat is applied to dissolve the solid. After adding 2.4 ml of glacial acetic acid and 1.6 g of 5 percent palladium on carbon, hydrogen flow is initiated and the mixture is hydrogenated at atmospheric pressure and ambient temperature. The hydrogenation is followed by thin-layer chromatography (silica gel; 70 percent toluene, 25 percent ethyl acetate, 5 percent triethylamine as eluent) and this shows the reaction is essentially complete in 1 hour. After 3 hours, the hydrogen flow is stopped and the system is purged with nitrogen for 15 minutes to remove excess hydrogen gas. The catalyst is removed by filtration using Celite and quickly quenched in water. The filtrate is evaporated to dryness on a rotary evaporator and the residue is treated with aqueous 10 percent sodium hydroxide. The aqueous solution is extracted with three 100-ml portions of ethyl ether, and the solutions are combined and washed once with 100 ml of water. The ethyl ether solution is dried over anhydrous potassium carbonate, filtered and evaporated on a rotary evaporator to give an amber-colored oil that solidified on standing. The product is pumped under vacuum overnight to remove the last traces of ethyl ether and stored under nitrogen. The infrared, 'H and 13C nuclear magnetic resonance are run. The yield is 86.4 percent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:3]=1.C([Li])CCC.[O:21]1[CH2:25][CH2:24]OS1(=O)=O.Cl>C1COCC1>[Cl:8][C:6]1[C:7]([CH2:24][CH2:25][OH:21])=[C:2]([Cl:1])[N:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:5]=1
Reactant: O=S1(=O)OCCO1
Reactant: C[C@H]1COCCN1c1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H]1COCCN1c1nc(Cl)c(CCO)c(Cl)n1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a solution of (3S)-4-(4,6-dichloropyrimidin-2-yl)-3-methylmorpholine (992 mg, 4.0 mmol) in THF (20 mL) was added n-butyllithium (1.56 mL, 1.6 M) dropwise at −78° C. and the mixture was stirred for 30 min. 1,3,2-dioxathiolane 2,2-dioxide (672 mg, 5.41 mmol) was added, and stirring was continued for 30 min, whereupon 6 N HCl (13.3 mL) was added. The reaction mixture was stirred for 18 h and then heated at 40° C. for 4 h. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried with MgSO4, filtered and concentrated by rotary evaporation.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:33].[C:34](Cl)(=[O:45])[O:35][C:36]1[CH:41]=[CH:40][C:39]([N+]([O-])=O)=CC=1.C1(CO)CC1>ClCCl>[F:33][C:3]1[CH:4]=[C:5]([C:8]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:24]([F:25])([F:26])[F:27])[C:28]([F:30])([F:31])[F:29])=[CH:19][CH:18]=3)[CH2:14][CH2:15]2)=[O:9])[CH:6]=[CH:7][C:2]=1[NH:1][C:34](=[O:45])[O:35][CH2:36][CH:41]1[CH2:39][CH2:40]1
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: OCC1CC1
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F)OCC1CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 18.2 %

Procedure:
(4-Amino-3-fluorophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-benzyl)piperazin-1-yl)methanone (0.209 mmol, 0.1 g) and 4-nitrophenyl carbonochloridate (0.209 mmol, 0.042 g) were combined and stirred in dichloromethane (1 mL) at room temperature for 30 minutes. Cyclopropylmethanol (0.417 mmol, 0.030 g) and N,N-dimethylaminopyridine (0.003 g, 0.0209 mmol) were added and the reaction stirred at room temperature for 17 hours. The reaction was concentrated under vacuum and purified by acidic reverse phase HPLC to afford the title compound (22 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[C:4]([C:12]2[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=2)=[CH:3]1.Cl.[OH-].[Na+]>C1COCC1>[CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:5](=[O:6])[C:4]([C:12]2[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=2)=[CH:3]1
Reactant: Cn1nccc1C1=CC(C)(C)CCC12OCCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1nccc1C1=CC(C)(C)CCC1=O
Yield: 90.4 %

Procedure:
A solution of the 5-(8,8-dimethyl-1,4-dioxaspiro[4.5]dec-6-en-6-yl)-1-methyl-1H-pyrazole (580 mg, 2.34 mmol) prepared in Example 67b and 2 M hydrochloric acid (2.0 mL) in THF (5.0 mL) was stirred for 1 hour under reflux. After allowing to cool, a 1 M aqueous sodium hydroxide solution (5.0 mL) was added to the reaction solution, followed by extraction with ethyl acetate (50 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=1:1) to yield the title compound (432 mg, 91%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH3:14]>CC(C)=O>[CH2:11]([C:10]1[N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]2[CH:9]=1)[CH2:12][CH2:13][CH3:14]
Reactant: Nc1ccccn1
Reactant: CCCCC(=O)CBr
Solvent: CC(C)=O
Product: CCCCc1cn2ccccc2n1
Yield: 53.1 %

Procedure:
A mixture of 6 g of 2-amino pyridine and 60 ml of anhydrous acetone was added to a mixture of 16 g of the product of Stage B and 20 ml of acetone at ambient temperature. The mixture was refluxed for one hour and the acetone was partially distilled. The mixture was allowed to return to ambient temperature, ice-cooled, separated and washed with ethyl ether. The insoluble part was dissolved in a saturated solution of sodium carbonate and extraction was carried out with ethyl acetate. The extracts were washed with water saturated in sodium chloride, dried and filtered to obtain 5.9 g of the expected product in the form of a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][N:15]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:7][CH:6]=1)=[O:4].[C:27](O)(=O)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][N:15]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:27])=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(=O)O
Reactant: COC(=O)c1ccc(CNCC2CCCCN2C(=O)OC(C)(C)C)cc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc(CN(C)CC2CCCCN2C(=O)OC(C)(C)C)cc1
Reaction time: 72 h
Yield: 50.5 %

Procedure:
A solution of 1,1-dimethylethyl 2-((4-(methoxycarbonyl)phenylmethylamino)methyl)-1-piperidinecarboxylate (0.7 g, 2 mmol) in dichloroethane (10 mL) was treated with acetic acid (180 mg, 3 mmol) and formaldehyde (37% solution in water). After the addition of sodium triacetoxyborohydride (487 mg, 2.3 mmol) the reaction was stirred for 3 days. The reaction was poured into water and extracted with methylene chloride (2×). The organic phase was dried over sodium sulfate, filtered, and concentrated. Purification on silica gel using a gradient of ethyl acetate in hexane gave 0.38 g of 1,1-dimethylethyl 2-(((4-(methoxycarbonyl)phenylmethyl)(methyl)amino)methyl)-1-piperidinecarboxylate.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[CH3:6][Cl:7].[C:8]([O:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])(=[O:11])[CH:9]=[CH2:10].CN(C)[C:20](=O)[CH:21]=[CH2:22].S([O-])([O-])(=O)=O.[NH4+].[NH4+]>>[C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[CH2:6]([Cl:7])[C:8]1[CH:9]=[CH:10][CH:22]=[CH:21][CH:20]=1.[C:8]([O:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])(=[O:11])[CH:9]=[CH2:10]
Reactant: CCl
Reactant: C=CC(=O)N(C)C
Agent: C=CC(=O)OCCN(C)C
Agent: C=CC(N)=O
Agent: O=S(=O)([O-])[O-]
Product: ClCc1ccccc1

Procedure:
To a 1000 cc reaction kettle was added 18.38 grams of acrylamide AMD (53% aqueous solution), 66.36 grams of dimethylaminoethyl acrylate methyl chloride quaternary (80% aqueous solution), 27.45 grams of N,N-dimethyl acrylamide (99%), 90.00 grams of ammonium sulfate, 7.5 grams of the homopolymer of dimethylaminoethyl acrylate methyl chloride quaternary (AETAC, CAS 44992-01-0); 7.5 grams of a terpolymer of acrylamide with (AETAC) and with a quaternary ammonium salt obtained by the reaction of benzyl chloride and dimethylaminoethyl acrylate (AEBAC, CAS 7737-18-5) in a 2/1/1 molar ratio; 0.50 grams of diethylenetriamine pentaacetic acid; pentasodium salt (Versenex 80, 40% aqueous) and 231.61 grams of deionized water. The mixture was stirred until a homogeneous solution was obtained. The kettle was sealed and equipped with an overhead stirrer, thermocouple, reflux condenser, nitrogen sparge tube, addition port with septum and a heating mantle. The mixture was then heated to 50° C. under constant nitrogen sparge while stirring at 500 rpm. After reaching 50° C, 0.50 grams of a 1% aqueous solution of 2,2'-azobis(2-amidinopropane)dihydrochloride (Wako V-50) was shot into the reactor and the temperature was held for four hours. A second shot of 1.00 gram of 1% aqueous solution of 2,2'-azobis(2-amidinopropane)dihydrochloride was then added and heating was continued for another two hours to yield a smooth, milky white dispersion. After cooling to room temperature, the bulk viscosity was found to be 732 cps. Diluting the dispersion to 0.5% active polymer in deionized water produced a polymer solution with a Brookfield viscosity of 100 cps.