Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[C:18]([CH3:19])=[CH:17][C:16]([Br:20])=[CH:15][N:14]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>C1(C)C=CC=CC=1.O>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([Br:20])=[CH:15][N:14]=2)([OH:34])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1cc(Br)cnc1Br
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1cc(Br)cnc1C1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.7 %

Procedure:
Under nitrogen atmosphere, 1.6M n-hexane solution of n-butyl lithium (65.6 ml) was added dropwise to a solution of 2,5-dibromo-3-picoline (25.1 g) in toluene (200 ml) at −78° C. and stirred at the same temperature for two hours. Next, a solution of 1-(tert-butoxycarbonyl)-4-piperidone (20.9 g) in toluene (200 ml) was added slowly dropwise. After the addition, the mixture was stirred at the same temperature for an hour. Then, the reaction solution was gradually warmed up to room temperature under stirring. After completion of the reaction, water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) and the product was solidified with n-hexane to give 4-(5-bromo-3-methylpyridin-2-yl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (11.4 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][NH:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([OH:21])[CH:15]=2)=O)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[O:22][C:13]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([OH:21])[CH:15]=3)=[N:12][N:11]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)NNC(=O)Cc2ccc(Cl)cc2)cc1O
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2nnc(Cc3ccc(Cl)cc3)o2)cc1O
Reaction time: 0.08 h

Procedure:
To a solution of 3-hydroxy-4-methyl-benzoic acid N′-[2-(4-chloro-phenyl)-acetyl]-hydrazide (0.91 g, 2.85 mmol) (from Example 39 supra) in acetonitrile (20 mL) was added diisopropylethylamine (3.0 mL, 17.1 mmol) and triphenylphosphine (1.50 g, 5.70 mmol). After stirring 5 minutes, hexachloroethane (1.01 g, 4.28 mmol) (Aldrich) was added and the mixture was allowed to stir for 2 days at room temperature. The solvent was evaporated. The residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (1×). The combined organic phase was washed with water and brine, dried (magnesium sulfate) and concentrated. The residue was purified by flash chromatography eluting with 20% ethyl acetate in hexanes to 5-[5-(4-chloro-benzyl)-[1,3,4]-oxadiazol-2-yl]-2-methyl-phenol. (Yield 0.68 g, 79%).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C@@H:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[CH:8]=[CH:9][CH:10]=1.Br[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:16]([O:15][C:14]([NH:13][C@H:11]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[O:4][C:3]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:2]=1[NH:1][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:12])=[O:20])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)CCCBr
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Oc2cc(Cl)ccc2N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCNc1ccc(Cl)cc1Oc1cccc([C@H](C)NC(=O)OC(C)(C)C)c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 66.7 %

Procedure:
A mixture of tert-butyl(1S)-1-[3-(2-amino-5-chlorophenoxy)phenyl]ethylcarbamate (3.2 g, 8.8 mmols), ethyl 4-bromobutyrate (14 g, 70 mmols), potassium carbonate (3.6 g, 26 mmols) and N,N-dimethylformamide (50 ml) was stirred at 80° C. for 48 hours. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 4-[N-[2-[3-[(1S)-1-tert-butoxycarbonylaminoethyl]phenoxy]-4-chlorophenyl]]aminobutyrate (2.8 g, 66%).
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[F:30][C:27]([F:28])([F:29])[O:26][C:23]1[CH:24]=[CH:25][C:20]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[CH:12]=[CH:13][C:8]([OH:7])=[CH:9][CH:10]=3)[CH2:15][CH2:16]2)=[CH:21][CH:22]=1
Reactant: FC(F)(F)Oc1ccc(N2CCN(c3ccc(OC4CCCCO4)cc3)CC2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: Oc1ccc(N2CCN(c3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 91.9 %

Procedure:
A mixture of 1-[4-(tetrahydropyran-2-yloxy)phenyl]-4-(4-trifluoromethoxyphenyl)piperazine (2.65 g, 6.27 mmol) prepared in Reference Example 185 and pyridinium p-toluene sulfonate (473 mg, 1.88 mmol) in ethanol (50 ml) was stirred at 70° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and methylene chloride and a saturated sodium hydrogencarbonate aqueous solution were added to the residue, which was stirred for a while. The mixture was extracted with methylene chloride, and the extract was dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=10/1) to afford 4-[4-(4-trifluoromethoxyphenyl)-piperazin-1-yl]phenol (1.95 g, yield 92%) as a white powder.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH:14]=[CH:13][C:11]([OH:12])=[CH:10][CH:9]=1)[OH:8].[Br:15][CH2:16][CH2:17]Br>CC(C)=O>[Br:15][CH2:16][CH2:17][O:8][C:7]1[CH:14]=[CH:13][C:11]([OH:12])=[CH:10][CH:9]=1
Reactant: Oc1ccc(O)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Oc1ccc(OCCBr)cc1

Procedure:
Potassium carbonate (7.53 g, 0.05448 mol) was added to the acetone solution (50 ml) of hydroquinone (2.00 g, 0.01816 mol) and 1,2-dibromoethane (3.39 g, 0.01805 mol). The mixture was heated at reflux for 6 h under nitrogen. The resulting mixture was filtered, water was added and pH was adjusted to 2-3. The mixture was extracted with ethyl acetate. The extracts were washed with water, dried over anhydrous Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography on silica gel, using heptane/ethyl acetate as a gradient eluent (95:5-70:30) to afford the pure desired compound as white crystals. 1H NMR (400 MHz, DMSO-d6): 3.74 (2H, t, 3J=5.5 Hz), 4.19 (2H, t, 3J=5.5 Hz), 6.67 (2H, d, 3J=8.9 Hz), 6.78 (2H, d, 3J=8.9 Hz), 8.95 (1H, s, —OH).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N+:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)([O-:7])=[O:6].[C:17]1([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[N+](C1C=CC=CC=1)([O-])=O>[N+:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([C:20]2[CH:19]=[CH:18][C:17]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([C:12](=[O:13])[C:11]5[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:16][CH:15]=5)=[CH:35][CH:36]=4)=[CH:26][CH:25]=3)=[CH:22][CH:21]=2)=[O:13])=[CH:10][CH:9]=1)([O-:7])=[O:6]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(Cc2ccc(Cc3ccccc3)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(c1ccc(Cc2ccc(Cc3ccc(C(=O)c4ccc([N+](=O)[O-])cc4)cc3)cc2)cc1)c1ccc([N+](=O)[O-])cc1
Reaction time: 40 h
Yield: 36 %

Procedure:
In a 2-liter four-necked flask equipped with a stirring device, a thermometer, a condenser and a nitrogen substituting device, 177.4 g of aluminum chloride and 300 milliliters of nitrobenzene were mixed and then 99.54 g of paranitrobenzoyl chloride was introduced with ice cooling to be dissolved. Then, a solution of 46.10 g of 1,4-bis(phenylmethyl)benzene in 100 milliliters of nitrobenzene was added dropwise for 30 minutes. 30 minutes after the end of the dropwise adding, an ice bath was removed and stirring was carried out at room temperature for 40 hours. After the end of the reaction was confirmed by a liquid chromatography, the reaction solution was poured on 1.5 liters of ice, and then extracted with 1.0 liter of chloroform. The solution was filtered through a Celite, washed with a 6N-HCl aqueous solution, an aqueous solution of sodium hydrogencarbonate, brine and water, removed off chloroform by a rotary evaporator, and thereafter removed off nitrobenzene by a steam distillation. By dissolving the solution in chloroform, purifying it with a silica gel column, and recrystallizing it from ethyl acetate, 35.72 g of 1,4-bis(4-(4-nitrobenzoyl)phenylmethyl)benzene was obtained as crystals.
Reaction SMILES: C(O)(=O)C.[OH:5][C:6]1[C:13](O)=[CH:12]C=C[C:7]=1[CH:8]=[O:9].C([O-])(=O)C.[Na+].[N+:20]([CH2:23][CH3:24])([O-])=O>O.C(OCC)(=O)C>[OH:9][C:8]1[CH:7]=[C:6]([OH:5])[CH:13]=[CH:12][C:24]=1[C:23]#[N:20]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1cccc(O)c1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(O)cc1O
Yield: 64.1 %

Procedure:
In an acetic acid (10 mL) solvent, a solution including 2,3-dihydroxybenzaldehyde (3.0 g, 21.7 mmol), sodium acetate (NaOAc) (3.54 g, 43.4 mmol), and nitroethane (3.24 g, 43.4 mmol) was refluxed for 8 hours. After cooling, the reaction mixture was distributed between ethyl acetate and water. Until a pH of the residual aqueous layer reached 8, an organic layer was washed with a saturated NaHCO3 solution. The organic layer was evaporated, the residual was purified by silica gel column chromatography using hexane and ethyl acetate (2:1) as a developer to obtain Compound 101a (1.88 g, 59%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1.[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)C>CN(C)C=O.O>[CH2:11]([O:10][C:8]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][CH:13]=1)=[O:9])[CH3:12]
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCc2ccccc2)cc1

Procedure:
Sodium hydride (4.8g. of 50% suspension in oil) was added to a solution of ethyl p-hydroxybenzoate (166g.) in dimethylformamide (1 l). Benzyl chloride (126 g.) was added dropwise to the solution and the mixture heated on a steam bath for 2 hours. The solution was allowed to cool and ethanol (100 mls.) was added and the mixture poured into water (3 l) and then extracted with chloroform. The organic layer was dried (anhydrous MgSO4), filtered and the solvent removed under high vacuum. The resulting crude product was recrystallized from ethanol to yield pure 4-ethoxycarbonylphenoxyphenyl methane (154.2g.), b.pt. 172-3 at 10mm Hg.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([O:18][C:19]2[CH:20]=[C:21]([CH2:25]O)[CH:22]=[CH:23][CH:24]=2)=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]([N:31](CC)C(C)C)(C)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>C(Cl)Cl.CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([O:18][C:19]2[CH:20]=[C:21]([CH2:25][C:28]#[N:31])[CH:22]=[CH:23][CH:24]=2)=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1c(Oc2cccc(CO)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(Oc2cccc(CC#N)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
[3-(1-Benzyl-6-chloro-2-methyl-1H-indol-3-yloxy)-phenyl]-methanol (0.092 g, 0.243 mmol) and N,N-diisopropylethylamine (3 μL, 0.486 mmol) were dissolved in DCM at 0° C. Methanesulfonyl chloride (28 μL, 0.365 mmol) was added and the reaction stirred for 5 minutes then sodium cyanide (0.024 g, 0.486 mmol) and DMF (2 mL) were added. The reaction was then concentrated under vacuum and DMF (2 mL) was added. The reaction was heated to 60° C. for 20 minutes then submitted to aqueous workup to give the title compound.
Reaction SMILES: [CH:1]1([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].O1CCCC1.Br[CH2:24][CH2:25][CH2:26][Cl:27]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.CC1C=CC=CC=1>[Cl:27][CH2:26][CH2:25][CH2:24][N:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=[C:7]1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: ClCCCBr
Reactant: c1ccc2[nH]c(C3CCCCC3)nc2c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: ClCCCn1c(C2CCCCC2)nc2ccccc21
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
A mixture of 20 parts of 2-cyclohexyl-1H-benzimidazole, 2 parts of N,N,N-triethylbenzenemethanaminium chloride, 225 parts of a sodium hydroxide solution 50% and 140 parts of tetrahydrofuran is stirred and heated to about 40° C. Then there are added 31.5 parts of 1-bromo-3-chloropropane and stirring is continued for 15 minutes at 60° C. The reaction mixture is cooled, methylbenzene is added and the layers are separated. The aqueous phase is extracted with methylbenzene. The combined methylbenzene-phases are washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 1-(3-chloropropyl)-2-cyclohexyl-1H-benzimidazole as an oily residue.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:6]1[C:9](=[O:10])[NH:8][C@@H:7]1[CH2:11][C:12]([OH:14])=O)([CH3:5])[CH3:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:27]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)(=[O:32])[CH2:28]C([O-])=O>O1CCCC1>[CH3:1][O:2][C:3]([C@H:6]1[C:9](=[O:10])[NH:8][C@@H:7]1[CH2:11][C:12](=[O:14])[CH2:28][C:27]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:32])([CH3:4])[CH3:5]
Reactant: COC(C)(C)[C@H]1C(=O)N[C@@H]1CC(=O)O
Reactant: O=C([O-])CC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(C)(C)[C@H]1C(=O)N[C@@H]1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.6 %

Procedure:
To a solution of 2-[(2R, 3S)-3-(1-methoxy-1-methylethyl)-4-oxoazetidin-2-yl]acetic acid (65.6 mg) in tetrahydrofuran (3.25 ml) was added carbonyldiimidazole (58.1 mg) at ambient temperature. After stirring for 6 hours at ambient temperature, magnesium salt of mono-p-nitrobenzyl malonate (179.7 mg) was added thereto and the resultant mixture was stirred overnight at ambient temperature. The solvent was distilled off and the residue was dissolved in ethyl acetate (10 ml) and filtered. The filtrate was washed in turn with 1N hydrochloric acid, water, 10% aqueous sodium bicarbonate, water, 5% aqueous citric acid, water and a saturated aqueous sodium chloride. After drying over magnesium sulfate, the ethyl acetate extract was filtered and evaporated in vacuo. The residue (101.2 mg) was chromatographed on silica gel (2 g) eluting with a mixture of methylene chloride and acetone (80:1 to 4:1) to give 4-nitrobenzyl 4-[(2R, 3S)-3-(1-methoxy-1-methyl-ethyl)-4-oxoazetidin-2-yl] -3-oxobutanoate (71.0 mg) as an amorphous solid.
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([C:11]1[C:12]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[N:13][N:14]([C:16]2([CH2:22][C:23]#[N:24])[CH2:21][CH2:20][NH2+:19][CH2:18][CH2:17]2)[CH:15]=1)(=[O:10])[NH2:9].[NH:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35](O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].BrC1C=CC=CN=1>CS(C)=O.[Cu]I>[C:23]([CH2:22][C:16]1([N:14]2[CH:15]=[C:11]([C:8]([NH2:9])=[O:10])[C:12]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[N:13]2)[CH2:21][CH2:20][N:19]([C:40]2[CH:39]=[CH:38][CH:34]=[CH:35][N:33]=2)[CH2:18][CH2:17]1)#[N:24]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CC[NH2+]CC1
Agent: [Cu]I
Agent: Brc1ccccn1
Agent: O=C([O-])C(F)(F)F
Solvent: CS(C)=O
Product: N#CCC1(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CCN(c2ccccn2)CC1
Temperature: 90 °C
Reaction time: 72 h

Procedure:
A mixture of 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-5) (52 mg, 0.11 mmol), copper (I) iodide (2 mg, 0.01 mmol), L-proline (3 mg, 0.02 mmol) and K3PO4 (48 mg, 0.23 mmol) was dissolved in DMSO (0.16 mL). 2-Bromopyridine (0.011 mL, 0.11 mmol) was added, and the resulting mixture was heated to 90° C. and allowed to stir for 72 hours. The reaction mixture was then allowed to cool to ambient temperature and was filtered. The filtrate was purified by reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[C:8]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:7][CH:6]=[C:5]([N+:14]([O-])=O)[C:3]=1[NH2:4]>C(O)C.[Ni]>[F:1][C:2]1[C:8]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:7][CH:6]=[C:5]([NH2:14])[C:3]=1[NH2:4]
Reactant: Nc1c([N+](=O)[O-])ccc(N2CCCC2)c1F
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc(N2CCCC2)c(F)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.5 %

Procedure:
To a mixture of 2-fluoro-6-nitro-3-pyrrolidin-1-ylaniline (285 mg, 1.26 mmol) in ethanol (20 ml) was added a slurry of Raney nickel (approximately 100 mg) in ethanol. The mixture was stirred under a hydrogen atmosphere (1 atm) at rt overnight. The reaction was purged of hydrogen, flushed with nitrogen and then filtered through a pad of Celite® using ethanol to rinse. The filtrate was concentrated under reduced pressure to afford crude product (43 mg, 17%) which was used without purification. 1H NMR (300 MHz, DMSO-d6) 6.19 (dd, J=8.4, 1.5 Hz, 1H), 5.89 (dd, J=8.4, 8.4 Hz, 1H), 4.30 (s, 2H), 4.20 (s, 2H), 2.94-3.07 (m, 4H), 1.72-1.89 (m, 4H); ES-MS m/z 196.3 (MH)+; HPLC RT (Method B) 1.08 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.Cl.CN(C)CCCN=C=NCC.[Na].[CH3:24][O:25][C:26]1[CH:31]=[C:30]([Cl:32])[N:29]=[C:28]([CH2:33][C:34](O)=[O:35])[N:27]=1.Cl>CN(C=O)C.N1C=CC=CC=1.C(OCC)C.O.C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:34](=[O:35])[CH2:33][C:28]1[N:27]=[C:26]([O:25][CH3:24])[CH:31]=[C:30]([Cl:32])[N:29]=1
Reactant: Fc1cccc2c1CCN2
Reactant: COc1cc(Cl)nc(CC(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cc(Cl)nc(CC(=O)N2CCc3c(F)cccc32)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.32 g of 4-fluoro-2,3-dihydro-1H-indole and 5.56 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are added to a solution of 5.4 g of the sodium salt of (4-methoxy-6-chloropyrimidin-2-yl)acetic acid in 50 ml of DMF and 4.3 ml of pyridine. The reaction medium is stirred at ambient temperature for one hour. 200 ml of ethyl acetate and 100 ml of water are added, and also 1N hydrochloric acid to pH=5-6. After settling out, the organic phase is dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The oil obtained is taken up with ethyl ether. The solid formed is filtered off so as to give 2.2 g of 1-(4-fluoro-2,3-dihydroindol-1-yl)-2-(4-methoxy-6-chloropyrimidin-2-yl)ethanone in the form of an orangey-colored solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([NH+:4]([CH2:8][CH2:9][CH3:10])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[CH3:11][CH2:12][N:13]([C:16]([SH:18])=[S:17])[CH2:14][CH3:15].C(=S)=S.C(N(CCC)CCC)CC.C(NCC)C>>[CH2:12]([N:13]([CH2:14][CH3:15])[C:16](=[S:17])[S-:18])[CH3:11].[CH2:1]([NH+:4]([CH2:8][CH2:9][CH3:10])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCN(CC)C(=S)S
Agent: CCCN(CCC)CCC
Agent: CCC[NH+](CCC)CCC
Solvent: CCNCC
Solvent: S=C=S
Product: CCN(CC)C(=S)[S-]
Temperature: 50 °C

Procedure:
Preparation of tripropylammonium salt of diethyl dithiocarbamate is as follows: 76 grams (1 mole) carbon disulfide and 143 grams (1 mole) tripropylamine are mixed at 10° C. under nitrogen. 80.5 grams (1.1 mole) diethylamine is added slowly and drop wise to the mixture and the mixture is maintained at a temperature below 30° C. Then the mixture is heated to 50° C. for 1 hour. The solution is then stripped out under vacuum to remove the excess amine and for the removal of low volatiles to obtain final product. The acid number (normally below 30) is measured to check the acidity. The product purity (ranging between 85-95%) is measured by LC-MS and NMR.
Reaction SMILES: [OH:1][CH:2]([C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([N:12]([CH3:24])[C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1)[CH3:3].N1C=CC=CC=1.[C:31](Cl)(=[O:42])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=[CH2:41]>C(Cl)Cl>[CH3:24][N:12]1[C:13](=[O:23])[CH2:14][CH2:15][C@@:16]2([CH3:17])[C@H:11]1[CH2:10][CH2:9][C@@H:8]1[C@@H:18]2[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@H:7]1[CH2:6][CH2:5][C@@H:4]2[CH:2]([O:1][C:31](=[O:42])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=[CH2:41])[CH3:3]
Reactant: C=CCCCCCCCCC(=O)Cl
Reactant: CC(O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCCCCCCCCC(=O)OC(C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 20-hydroxy-4-methyl-5α-4-azapregnan-3-one (0.167 g, 0.5 mM) and pyridine (0.1 mL) in anhydrous methylene chloride (4.5 mL) at ice-bath temperatures was added 10-undecenoyl chloride (0.13 mL, 0.6 mM) dropwise. After 10 minutes, the reaction mixture was allowed to warm to room temperature and stir overnight. After diluting further with methylene chloride the mixture was washed with dilute hydrochloric acid, water, and brine, and dried (Na2SO4). The residue obtained from concentration of the filtered solution was flash chromatographed on silica gel using ethyl acetate as eluant to give the title compound as a glaze. MS M+ calculated for C32H53NO3, mw=499.78; observed m/e 499.
Reaction SMILES: [Na].CO.[OH:4][C:5]1[N:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=1.Br[CH:17]([CH2:23][CH2:24][CH2:25][CH3:26])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>CS(C)=O>[CH2:21]([O:20][C:18]([CH:17]([O:4][C:5]1[N:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=1)[CH2:23][CH2:24][CH2:25][CH3:26])=[O:19])[CH3:22]
Reactant: CCCCC(Br)C(=O)OCC
Reactant: Oc1ncn(-c2ccccc2)n1
Agent: [Na]
Solvent: CO
Solvent: CS(C)=O
Product: CCCCC(Oc1ncn(-c2ccccc2)n1)C(=O)OCC
Yield: 27.7 %

Procedure:
The process was carried out as shown in Example 7 above, beginning with 1.4 g of sodium, 30 ml of methanol, 150 ml of dimethylsulfoxide, 10 g of 3-hydroxy-1-phenyl-1,2,4-1H-triazole and 13.8 g of ethyl 2-bromohexanoate. The product was distilled at 205° and 1 mm of mercury to obtain 5.2 g of the desired product, an oil.