Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([CH:9](Br)[CH:10](Br)[C:11]#[N:12])=[CH:5][CH:4]=1.C[O-].[Na+].C[CH2:21][O:22]CC>CO>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([O:22][CH3:21])=[CH:10][C:11]#[N:12])=[CH:5][CH:4]=1
Reactant: N#CC(Br)C(Br)c1ccc(C(F)(F)F)cc1
Reactant: CCOCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=CC#N)c1ccc(C(F)(F)F)cc1
Temperature: 5 °C
Reaction time: 33 h

Procedure:
3-(4-(Trifluoromethyl)phenyl)-2,3-dibromopropionitrile (2098 grams) was dissolved in methanol and chilled to 5° C. in an ice-bath. Next, over a 2 hour period, sodium methylate (95%) was added keeping the temperature between 5°-10° C. Following this the reaction mixture was allowed to warm to room temperature, was stirred for 33 hours, and was then stripped to near dryness. Upon the addition of 8 l. ether the mixture was slurried, slowly filtered, and stripped again, resulting in a brown oil. NMR analysis confirmed that the oil was the desired mixture of product.
Reaction SMILES: Br[CH2:2][C:3]1([CH2:7]Br)[CH2:6][O:5][CH2:4]1.[CH2:9]([OH:14])[C:10]([F:13])([F:12])[F:11].[OH-:15].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:11][C:10]([F:13])([F:12])[CH2:9][O:14][CH2:2][C:3]1([CH2:7][O:15][CH2:9][C:10]([F:13])([F:12])[F:11])[CH2:6][O:5][CH2:4]1
Reactant: [OH-]
Reactant: OCC(F)(F)F
Reactant: BrCC1(CBr)COC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: FC(F)(F)COCC1(COCC(F)(F)F)COC1
Temperature: 85 °C

Procedure:
A 2 L round-bottom flask fitted with a mechanical stirrer, condenser and a thermometer was charged with 3,3-bis-(bromomethyl)oxetane (300 g, 1.2 mol), trifluoroethanol (284 g, 2.8 mol), tetrabutylammonium bromide (39.9 g, 0.12 mol) and water (265 mL). The mixture was heated to 85° C. and a 50% aqueous potassium hydroxide solution (672 g, 5.1 mol) was added via an addition funnel over a period of 3 h. The progress of the reaction was monitored by GLC and when greater than 99% of 3,3-bis-(bromomethyl)oxetane was consumed, the reaction mixture was cooled to room temperature and diluted with water (500 mL). The organic phase was separated and washed with 2% aqueous potassium hydroxide solution (500 mL) and water (500 mL). The crude product was then distilled under reduced pressure (bp=103° C./5 mm/Hg) to give 278 g (80%) of greater than 99% pure (GLC) 3,3-bis-(2,2,2-trifluoroethoxymethyl)oxetane, a colorless oil. Spectral analysis revealed that the product prepared by this process was identical with B6-FOX monomer prepared by Procedure A.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]([CH2:11][CH:12]([CH2:17][C:18](OC)=[O:19])[C:13](OC)=[O:14])[CH:6]=[N:7]2)=[N:3][CH:2]=1.C(O)(C)(C)C.[BH4-].[Li+]>O>[OH:19][CH2:18][CH2:17][CH:12]([CH2:13][OH:14])[CH2:11][N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][C:9]=2[NH2:10]
Reactant: COC(=O)CC(Cn1cnc2c(N)ncnc21)C(=O)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: CC(C)(C)O
Solvent: O
Product: Nc1ncnc2c1ncn2CC(CO)CCO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dimethyl 2-(adenine-9-ylmethyl)succinate (2.93 g, 0.010 mol) was dissolved by warming with tert. butanol (120 ml), lithium borohydride (1.10 g, 0.05 mol) was added in portions and the mixture was stirred at ambient temperature for 3 h, water (10 ml) was added and stirring was continued over night. Inorganic material was filtered off and washed with tert. butanol and the filtrate evaporated to small volume. Chromatography on silica (ethyl acetate+methanol+water 7+2+1) afforded pure 9-(4-hydroxy-2-hydroxymethylbutyl) adenine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[CH:17]12[CH2:22][CH:21]1[CH2:20][N:19]([CH2:23][C:24]1[S:25][CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[N:28]=1)[CH2:18]2>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(N(C)C)=O>[CH:21]12[CH2:22][CH:17]1[CH2:18][N:19]([CH2:23][C:24]1[S:25][C:26]([C:2]3[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=3)=[C:27]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[N:28]=1)[CH2:20]2
Reactant: Clc1ccc(-c2csc(CN3CC4CC4C3)n2)cc1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: NS(=O)(=O)c1ccc(-c2sc(CN3CC4CC4C3)nc2-c2ccc(Cl)cc2)cc1
Temperature: 150 °C
Yield: 22 %

Procedure:
4-bromobenzenesulfonamide (0.37 g, 1.57 mmol) and potassium acetate (0.28 g, 2.87 mmol) were added to a solution of 2-(3-azabicyclo[3.1.0]hexan-3-ylmethyl)-4-(4-chlorophenyl)thiazole (Step-2 of compound 102, 0.42 g, 1.43 mmol) in a DMA (5 ml) in a tube at 25° C. Nitrogen gas was bubbled through the reaction mixture for 15 minutes. Palladium acetate (0.032 g, 0.14 mmol) was then added to the reaction mixture under nitrogen atmosphere and the tube was sealed. The reaction mixture was heated at 150° C. for 20 hrs under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite. The celite cake was washed with ethyl acetate (20 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography using 30% ethyl acetate in hexanes as an eluent to obtain the title compound (0.14 g, 21.4%). MS: m/z 446 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11](O)[C:12]3[CH:13]=[CH:14][CH:15]=[N:16][C:17]=3[CH:18]=2)=[CH:5][CH:4]=1.C(N(CC)C1C=CC=CC=1)C.O=P(Cl)(Cl)[Cl:34]>>[Cl:34][C:11]1[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:20])[CH3:1])=[CH:4][CH:5]=2)[CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[N:16]2
Reactant: CN(C)c1ccc(-c2cc3ncccc3c(O)n2)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: CN(C)c1ccc(-c2cc3ncccc3c(Cl)n2)cc1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
A mixture of 7-(4-dimethylaminophenyl)-[1,6]naphthyridin-5-ol (Example 1) (1.2 g, 5 mmol), POCl3 (10 mL) and N,N-diethylaniline (0.15 g, 1.0 mmol) were stirred at 110° C. for 16 hours. The contents were cooled to room temperature and excess POCl3 was removed in vacuo. The residue was quenched with water and neutralized with aqueous sodium carbonate. The aqueous solution was then extracted with dichloromethane (2×30 mL). The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated in vacuo to give a tan oil. Purification by flash chromatography eluting with hexanes/EtOAc (1:1) afforded the title compound as a yellowish solid (1.1 g). 1H NMR (CDCl3, 400 MHz) δ 9.03 (dd, 1H), 8.54 (d, 1H), 8.13 (s, 1H), 8.08 (d, 2H), 7.46 (dd, 1H), 6.81 (d, 2H), 3.05 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:27])[N:10]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:13]=1.[CH3:28][N:29]([CH2:31][CH2:32]Cl)[CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:27])[N:10]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:32][CH2:31][N:29]([CH3:30])[CH3:28])=[CH:24][CH:25]=2)[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:13]=1
Reactant: O=c1c(-c2ccccc2Cl)cc(-c2ccccn2)cn1-c1ccc(O)cc1
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCOc1ccc(-n2cc(-c3ccccn3)cc(-c3ccccc3Cl)c2=O)cc1
Temperature: 60 °C
Yield: 27.7 %

Procedure:
3-(2-Chlorophenyl)-5-(2-pyridyl)-1-(4-hydroxyphenyl)-1,2-dihydropyridin-2-one (82 mg) and 57 mg of N,N-dimethylaminoethyl chloride were dissolved in 2 ml of dimethylformamide, 55 mg of potassium carbonate were added thereto at 60° C. and the mixture was stirred for one night. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated in vacuo and purified by an NH silica gel column chromatography (hexane-ethyl acetate system) to give 27 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([OH:22])=O)=[CH:18][NH:17][C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.Cl.[CH:44]1([C:47]([NH2:50])([CH3:49])[CH3:48])[CH2:46][CH2:45]1>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[CH:44]1([C:47]([NH:50][C:20]([C:19]2[C:13]3[C:14](=[N:15][CH:16]=[C:11]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=5)[NH:8][N:7]=4)[N:12]=3)[NH:17][CH:18]=2)=[O:22])([CH3:49])[CH3:48])[CH2:46][CH2:45]1
Reactant: CC(C)(N)C1CC1
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)O)c4n3)n[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)C5CC5)c4n3)n[nH]c2c1
Reaction time: 16 h
Yield: 9.4 %

Procedure:
To a stirred solution of 2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.34 mmol), EDCI (130 mg, 0.68 mmol), DMAP (83 mg, 0.68 mmol) and DIEA (88 mg, 0.68 mmol) in 6 mL of DMF was added 2-cyclopropylpropan-2-amine hydrochloride (92 mg, 0.68 mmol) in one portion at room temperature, then the mixture was stirred for 16 hours. The reaction mixture was poured into 40 mL of water, filtered and the filter cake was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 45% acetonitrile/55% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 75% acetonitrile/25% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give N-(2-cyclopropylpropan-2-yl)-2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (12 mg, 9.4%) as a yellow solid. MS: (M+H)+=375; 1H NMR (300 MHz, DMSO): δ 13.38 (s, 1H), 12.80 (s, 1H), 9.16 (s, 1H), 8.41-8.35 (m, 2H), 7.95 (s, 1H), 7.41 (s, 1H), 7.06 (d, 1H, J=8.4 Hz), 2.57 (s, 3H), 1.67-1.54 (m, 1H), 1.59 (s, 6H), 0.48-0.44 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[CH2:13][C:14](=[O:20])[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[C:29](#N)[C:30](C)=[O:31]>C1COCC1>[C:30]([CH:15]1[C:14](=[O:20])[CH2:13][CH:12]2[N:11]([S:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)(=[O:9])=[O:10])[CH:16]1[CH2:17][CH2:18][CH2:19]2)(=[O:31])[CH3:29]
Reactant: O=C1CC2CCCC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(=O)C#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)C1C(=O)CC2CCCC1N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
The ketone (9-[(4-chlorophenyl)sulfonyl]-9-azabicyclo[3.3.1]nonan-3-one, 94 mg, 0.30 mmol) under nitrogen was dissolved in THF (1.5 mL), and with good stirring at room temperature, lithium diisopropylamide (1.0 M in cyclohexane/THF, 1.0 mL, 1.0 mmol) was added all at once by syringe. After stirring for 15 min, pyruvonitrile (140 mg, 2.0 mmol) was added all at once to the reaction mixture and stirred vigorously for 30 min at RT and for 24 h in a 60° C. bath. The reaction mixture was partially evaporated under a stream of nitrogen while being warmed in a 70° C. bath. The black residue was dissolved with water and dichloromethane and acidified with aq NaHSO4. The organic phase was separated and combined with one additional dichloromethane extraction of the aq phase. The organic phase was washed with 0.1 M NaOH (3×), and the basic washes were combined and acidified to pH 1-2 using aq NaHSO4. The acidic phase was extracted with dichloromethane (3×), and the combined dichloromethane extracts were washed with brine (2×), and then dried (Na2SO4) and evaporated to yield the brown solid product. MS (ES) m/e 356.0 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[Br:29][C:30]1[CH:31]=[C:32]([CH:41]=[CH:42][CH:43]=1)[CH2:33][C:34]1[O:35][C:36]([CH3:40])=[C:37]([CH3:39])[CH:38]=1>CN(C)C=O.C(Cl)Cl>[Br:29][C:30]1[CH:31]=[C:32]([CH:41]=[CH:42][CH:43]=1)[CH2:33][C:34]1[O:35][C:36]([CH3:40])=[C:37]([CH3:39])[C:38]=1[C:7]([C:6]1[CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:13][CH3:14])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:9]
Reactant: COc1c(C(C)C)cc(C(=O)O)cc1C(C)C
Reactant: Cc1cc(Cc2cccc(Br)c2)oc1C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C(C)C)cc(C(=O)c2c(Cc3cccc(Br)c3)oc(C)c2C)cc1C(C)C
Yield: 65.1 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 3,5-diisopropyl-p-anisic acid (1.02 g, 4.32 mmol, RN-1 17439-59-5), oxalyl chloride (0.415 mL, 4.75 mmol), N,N-dimethylformamide (2 drops), tin (IV) chloride (0.556 mL, 4.75 mmol) and 2-(3-bromo-benzyl)-4,5-dimethyl-furan (1.15 g, 4.32 mmol) in CH2Cl2. Purification on Biotage KP-Sil eluting with 3% EtOAc/pet ether gave 1.36 g (65%) of the title compound as a yellow clear oil. 1H NMR (DMSO-d6) δ1.17 (d, 12 H), 1.80 (s, 3 H), 2.20 (s, 3 H), 3.28 (septet, 2 H), 3.74 (s, 3 H), 3.87 (s,2 H), 7.06 (d, 1 H), 7.19 (d, 1 H), 7.24 (s, 1 H), 7.38 (dd, 1 H), 7.46 (s, 2 H ).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH3:7][O:8][C:9]1[C:14]([O:15][CH3:16])=[C:13]([C:17](Cl)=[O:18])[CH:12]=[CH:11][C:10]=1[C:20](Cl)=[O:21]>C(Cl)Cl>[OH:4][CH2:3][C:2]([NH:1][C:17]([C:13]1[CH:12]=[CH:11][C:10]([C:20]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[O:21])=[C:9]([O:8][CH3:7])[C:14]=1[O:15][CH3:16])=[O:18])([CH3:6])[CH3:5]
Reactant: COc1c(C(=O)Cl)ccc(C(=O)Cl)c1OC
Reactant: CC(C)(N)CO
Solvent: ClCCl
Product: COc1c(C(=O)NC(C)(C)CO)ccc(C(=O)NC(C)(C)CO)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
In 8 mL of anhydrous methylene chloride, was dissolved 6.06 g (68.0 mmol) of 2-amino-2-methyl-1-propanol. Thereto, a solution of 4.47 g (17.0 mmol) of 2,3-dimethoxy-1,4-benzenedicarboxylic chloride in 8 mL of anhydrous methylene chloride was added by keeping the inner temperature at 5°-10° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and washed with water. The filtrate and the wash water were combined and concentrated under a reduced pressure. Methylene chloride was added to the obtained residue, and the mixture was dried over anhydrous sodium sulfate. The solvent was removed. The product was recrystallized from benzene to obtain 6.27 g (100%) of N,N'-bis(2-hydroxy-1,1-dimethylethyl)-2,3-dimethoxy-1,4-phenylenedicarboxamide in a colorless prism crystal state.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:14])[C:10](=[CH2:13])[CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[OH:15].C(=O)([O-])[O-].[K+].[K+].Br[CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:14])[C:10](=[CH2:13])[CH2:11][CH3:12])[CH:5]=[CH:4][C:3]=1[O:15][CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: C=C(CC)C(=O)c1ccc(O)c(Cl)c1Cl
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(CC)C(=O)c1ccc(OC(C)C(=O)OCC)c(Cl)c1Cl

Procedure:
To a solution of 2,3-dichloro-4-(2-methylenebutyryl)-phenol (4.90 g., 0.02 mole) in dimethylformamide (20 ml.) is added potassium carbonate (6.08 g., 0.044 mole) and ethyl 2-bromopropionate (7.97 g., 0.044 mole). The reaction mixture is heated at 55°-60° C. for one hour with stirring. The reaction mixture is cooled. Water (50 ml.) is added and the resulting oil is extracted with ether (3 × 100 ml.). The combined ether extracts are dried over anhydrous magnesium sulfate, filtered and the ether is evaporated under reduced pressure to afford ethyl 2-[2,3-dichloro-4-(2-methylenebutyryl)phenoxy]propionate. The ester is dissolved in ethanol (75 ml.) and treated with a solution of sodium bicarbonate (5.04 g., 0.06 mole) in water (150 ml.). The mixture is heated on a steam bath with stirring for 5 hours and then concentrated under reduced pressure to a volume of 50 ml. Water (50 ml.) is added and the solution is acidified to a pH of 4 with hydrochloric acid (6N). The resulting oil is extracted with ether (3 × 100 ml.) and the combined extracts are dried over anhydrous magnesium sulfate. The ether is evaporated under reduced pressure to afford 6.34 g. (100%) of a white, waxy solid. Recrystallization from cyclohexane affords 5 g. (79%) of crude product, m.p. 115°-119° C. Further purification by recrystallization from butyl chloride affords substantially pure 2-[2,3-dichloro-4-(2-methylenebutyryl)phenoxy]propionic acid, m.p., 122.5°-123.5° C.
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[CH:27]=O.[CH:29]([C:31]1[N:35]([CH3:36])[CH:34]=[C:33]([C:37]([OH:39])=[O:38])[CH:32]=1)=O>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[C:20]2[CH2:27][N:2]1[C:29]([C:31]2[N:35]([CH3:36])[CH:34]=[C:33]([C:37]([OH:39])=[O:38])[CH:32]=2)=[C:4]2[C:3]([N:8]([CH2:9][CH:10]([CH3:11])[CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2=[O:15])=[N:1]1
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: Cn1cc(C(=O)O)cc1C=O
Reactant: O=Cc1ccnc2ccc(Cl)cc12
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3ccnc4ccc(Cl)cc34)nc21

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 6-chloroquinoline-4-carbaldehyde, followed by 5-formyl-1-methyl-1H-pyrrole-3-carboxylic acid. Mass: 521.09 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:15]([CH2:18][C:19]#[N:20])[C:16]#[N:17].[C-]#N.[Na+].O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH:14][CH:15]([CH2:18][C:19]#[N:20])[C:16]#[N:17]
Reactant: N#CCC(C#N)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=C([O-])O
Agent: [C-]#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#CCC(C#N)NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 40 %

Procedure:
2-(2,6-Dichloro-4-trifluoromethylphenylhydrazono)succinonitrile (0.296 g, 1 mmol), sodium cyanide (0.196 g, 4 equivalents), water (1 ml) and acetic acid (5 ml) were added successively to a tube, which was sealed and reacted at 20° C. for 40 hours. The mixture was added to saturated sodium bicarbonate solution, extracted (dichloromethane), washed (water), dried (magnesium sulfate) and evaporated to give a mixture which contained 40% of the desired title compound, NMR 3.1 (m, 2H), 4.5 (m, 1H), 5.89 (m, 1H), 6.94 (d, 1H), 7.71 (s, 2H), together with 60% of unchanged starting hydrazone.
Reaction SMILES: CN(C)C1CCCCC1.[Cl:10][C:11]1[CH:17]=[C:16]([SH:18])[CH:15]=[CH:14][C:12]=1[NH2:13].[C:19](Br)([CH3:22])([CH3:21])[CH3:20].O>C(Cl)Cl>[Cl:10][C:11]1[CH:17]=[C:16]([S:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=[CH:14][C:12]=1[NH2:13]
Reactant: Nc1ccc(S)cc1Cl
Reactant: CC(C)(C)Br
Solvent: CN(C)C1CCCCC1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)Sc1ccc(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 68 h

Procedure:
Dimethylcyclohexylamine (22.86 g., 0.18 mole) in methylene chloride (125 ml.) is added dropwise to a stirred solution of 2-chloro-4-mercaptoaniline (27.0 g., 0.17 mole) and tert-butyl bromide (22.86 g., 0.18 mole) in methylene chloride (125 ml.) and the mixture is allowed to stir at room temperature for about 68 hours. An additional quantity of dimethylcyclohexylamine (2.3 g.) and tert-butyl bromide (2.5 g., 0.018 mole) is added and stirring is continued overnight. The reaction is poured into water, and the product is extracted with methylene chloride. The combined extracts are washed with dilute hydrochloric acid, water and dried. Removal of the drying agent and methylene chloride gives impure 2-chloro-4-tert-butylthioaniline as a beige solid.
Reaction SMILES: [OH:1][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][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[CH3:21]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].CI>O>[CH3:21][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:13])[F:14])[CH:7]=2)[C:2](=[O:1])[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4]1
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: CCOC(=O)c1cn(C)c2cc(C(F)(F)F)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 105 %

Procedure:
A slurry of ethyl 4-hydroxy-7-(trifluoromethyl)quinoline-3-carboxylate (10.0 g, 35.1 mmol), DMF (50 mL), potassium carbonate (12.11 g, 88.00 mmol), and methyl iodide (11.00 ml, 175.0 mmol) was heated to 90° C. After 20 minutes, the dark solution was cooled to room temperature and water (25 mL) was added slowly, keeping the temperature <40° C. The reaction mixture was cooled to ambient temperature, and the brown slurry was filtered and washed with 2:1 DMF/water (20 mL×2) and water (20 mL×2). The solids were partially dried on the frit giving the title compound (11.0 g, 36.8 mmol, 105% yield), which was used without further purification in the next step.
Reaction SMILES: [O:1](C1C=C(C=CC=1)C=O)C1C=CC=CC=1.[Na:16].[CH3:17][C:18]1([CH3:30])[C@@H:20]([CH:21]([Br:26])[C:22]([Br:25])([Cl:24])[Cl:23])[C@@H:19]1[C:27](Cl)=[O:28]>[Cl-].[Zn+2].[Cl-]>[Na:16].[CH3:17][C:18]1([CH3:30])[C@@H:20]([CH:21]([Br:26])[C:22]([Br:25])([Cl:24])[Cl:23])[C@@H:19]1[C:27]([O-:1])=[O:28]
Reactant: CC1(C)[C@@H](C(=O)Cl)[C@@H]1C(Br)C(Cl)(Cl)Br
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Agent: [Cl-]
Agent: [Na]
Agent: [Zn+2]
Product: CC1(C)[C@@H](C(=O)[O-])[C@@H]1C(Br)C(Cl)(Cl)Br
Temperature: 20 °C
Reaction time: 17 h

Procedure:
A mixture of 8 g of 3-phenoxy-benzaldehyde and 15.5 g of 1R, trans 2,2-dimethyl-3-(1',2'-dibromo-2',2'-dichloroethyl)-cyclopropane-1-carboxylic acid chloride was warmed to obtain a homogeneous liquid and the mixture was cooled to 20° C. 0.150 g of anhydrous zinc chloride were added thereto and the mixture was stirred at 20° C. for 17 hours to obtain raw RS α-chloro-3-phenoxy-benzyl 1R, trans 2,2-dimethyl-3-(1',2'-dibromo-2',2'-dichloroethyl)-cyclopropane-1-carboxylate whose IR spectrum showed an absorption at 1750 cm-1 (carbonyl) and whose RMN Spectrum showed the absence of an aldehydic proton.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:23]=[CH:22]C(C=C)=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C[N+]1([O-])CC[O:30]CC1.[CH3:34][C:35]([CH3:37])=[O:36]>O.C(=O)(O)[O-].[Na+]>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:34]([CH:35]([OH:36])[CH2:37][OH:30])=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)=O
Reactant: C=Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cl
Product: OCC(O)c1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
To a solution of 2-(3-chlorophenyl)-N-(4-vinylphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (0.100 μg, 0.29 mmol) in acetone (10 mL) and water (5 mL) was added 4-methylmorpholine N-oxide (0.189 g, 1.44 mmol), followed by potassium osmate dehydrate (0.002 g, 0.06 mmol) and the reaction mixture was stirred at rt overnight. After this time, the mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate), followed by the formation of the hydrochloride salt to afford the title compound (0.033 g, 32%) as a light yellow solid. MW=417.33. 1H NMR (DMSO-d6, 500 MHz) δ 14.03 (s, 1H), 9.79 (s, 1H), 7.89 (t, J=2.0 Hz, 1H), 7.72-7.64 (m, 2H), 7.63-7.57 (m, 1H), 7.45 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 7.00 (s, 1H), 4.57 (t, J=6.0 Hz, 1H), 3.51-3.45 (m, 2H), 3.15 (t, J=7.6 Hz, 2H), 2.92 (t, J=7.6 Hz, 2H), 2.29-2.20 (m, 2H); APCI MS m/z 381 [M+H]+.