Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]([CH3:20])(C)[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:7][CH:6]=1.I[C:22]1[S:23]C=C[CH:26]=1.[OH-].[K+].P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(N(CC)CC)C.CCOCC.[Pd].[Cu]I>[S:23]1[CH:22]=[CH:26][CH:20]=[C:2]1[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][N:14]([CH2:15][CH3:16])[CH2:17][CH3:18])=[CH:9][CH:10]=1
Reactant: Ic1cccs1
Reactant: CCN(CC)CCOc1ccc(C#CC(C)(C)O)cc1
Agent: [Cu]I
Agent: [Pd]
Agent: [K+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCN(CC)CCOc1ccc(C#Cc2cccs2)cc1
Reaction time: 20 h
Yield: 75.1 %

Procedure:
To a solution of 11.07 g (0.04 mole) of 1-(3-hydroxy-3-methyl-1-butyn-1-yl)-4-(2-diethylaminoethoxy)benzene and 8.4 g (0.04 mole) of 2-iodothiophene in 135 ml of triethylamine are added, under nitrogen, 4.95 g of pulverised potassium hydroxide. Then 310 mg of the palladium complex PdCl2 [P(C6H5)3 ]2 and 180 ml of copper(I) iodide are added and the reaction mixture is stirred for 20 hours at boiling temperature. The reaction mixture is taken up in 250 ml of ether and the solution is washed 3 times with 100 ml of water and once with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue is chromatographed on silica gel with 96% of ether/4% of methanol (saturated with NH3), affording 9 g (75%) of 1-[4-(2-thienylethynyl)phenoxy]-2-diethylaminoethane in the form of a colourless oil with a refractive index of nD30 :1.6170.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:3]=1[NH:13]C(=O)C(F)(F)F.[OH-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:3]=1[NH2:13]
Reactant: CS(=O)(=O)Cc1cccc(Cl)c1NC(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)Cc1cccc(Cl)c1N
Temperature: 120 °C
Yield: 90 %

Procedure:
The crystalline N-(2-Chloro-6-methanesulfonylmethyl-phenyl)-2,2,2-trifluoro-acetamide of Step 3 was taken up into 200 ml of 2N solution of sodium hydroxide and stirred and heated in an oil bath heated to 120° C. The homogeneous solution was stirred at this temperature for 90 minutes and slowly allowed to cool to room temperature. The flask was immersed in an ice bath and the suspension of the product was stirred at this temperature until all was crystalline. Filtration, washing well with water and thorough drying afforded 13.96 g of pure crystalline 2-chloro-6-methanesulfonylmethyl-phenylamine (90%).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][NH:5][C:6](=[O:27])[C@H:7]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH:8][C:9](=[O:22])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([NH:8][C@H:7]([C:6]([NH:5][CH2:4][C:3]([OH:28])=[O:2])=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:22])=[O:16])([CH3:20])([CH3:21])[CH3:19]
Reactant: COC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reaction time: 2 h

Procedure:
The thus obtained N-t-butoxycarbonyl-prolylleucyl-glycine methyl ester in an amount of 294.6 g was dissolved in 1.6 l of methanol. To this, 1.6 l of 1N-NaOH was added dropwise with ice cooling and the reaction was carried out at room temperature for 2 hours. Subsequently, 20% citric acid was added dropwise to the reaction mixture to make the pH 3 to 4. Then, the whole reaction mixture was extracted with 5 l of ethyl acetate, and the extract was washed well with 5% citric acid solution and saturated sodium chloride aqueous solution, and dried. After removing the solvent by distillation, a white solid was obtained. The resulting solid of N-t-butoxycarbonyl-prolyl-leucyl-glycine was purified by washing with petroleum ether. Yield: 269.3 g (94.7%). Melting point 87°-90° C. [α]D20 =-80.5° (C=1, ethanol). Rf =0.46 (TLC, chloroform: methanol: acetic acid =95:5:3 by volume).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15](O)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:52][C:53]([F:62])([F:61])[C:54]1[CH:55]=[C:56]([CH:58]=[CH:59][CH:60]=1)[NH2:57]>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:57][C:56]3[CH:58]=[CH:59][CH:60]=[C:54]([C:53]([F:52])([F:61])[F:62])[CH:55]=3)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncc2c(n1)CCN(c1cccc(C(=O)Nc3cccc(C(F)(F)F)c3)c1)C2
Temperature: 40 °C
Reaction time: 16 h

Procedure:
A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (162 mg, 0.60 mmol), triethylamine (0.335 mL, 2.4 mmol), and HBTU (250 mg, 0.66 mmol) in 4.0 mL DMF was briefly warmed to approx. 40° C. to dissolve solids. After 3 minutes 3-(trifluoromethyl)aniline (0.149 mL, 1.2 mmol) was added and the reaction stirred at 50° C. for 3 hours, at rt for 16 hours, then an additional 1 hour at 50° C. The reaction mixture was partitioned between EtOAc and aqueous NaHCO3 solution, the EtOAc layer washed with brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting oily solid was chromatographed eluting with CHCl3, warm EtOAc, CHCl3:EtOAc (1:1), then 5% MeOH in CHCl3:EtOAc (1:1) giving a pale yellow solid. This solid was recrystallized from EtOAc giving a white solid (100 mg, 40%). 1H NMR (DMSO-d6) δ: 10.46 (s, 1H), 8.25 (s, 1H), 8.13 (s, 1H), 8.05 (d, J=8.8 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.53 (s, 1H), 7.34-7.48 (m, 3H), 7.22-7.27 (m, 1H), 6.41 (s, 2H), 4.30 (s, 2H), 3.66 (t, J=6.0 Hz, 2H), 2.77 (t, J=5.9 Hz, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:23]=[CH:22][C:6]2[NH:7][C:8]([C@@H:10]3[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:9][C:5]=2[CH:4]=1)=O.[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.CC(O)=O.C([BH3-])#N.[Na+]>CO>[F:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][CH2:1][C:3]2[CH:23]=[CH:22][C:6]3[NH:7][C:8]([C@@H:10]4[CH2:14][CH2:13][CH2:12][N:11]4[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:9][C:5]=3[CH:4]=2)=[CH:27][CH:26]=1
Reactant: Nc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(C=O)ccc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(CNc3ccc(F)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a mixture of the product from Example 95A (1.0 g, 3.17 mmol), 4-fluoroaniline (304 μL, 3.17 mmol) and AcOH (150 μL) in MeOH (30 mL) was added sodium cyanoborohydride (199 mg, 3.17 mmol). The mixture was stirred at rt overnight, and was then quenched with aqueous 1N HCl followed by stirring for 5 minutes. A few drops of aqueous NH4OH were added, and the mixture was diluted with EtOAc and washed with saturated aq. NaHCO3, H2O, and brine. The organic layer was dried (MgSO4), filtered and concentrated to afford the title compound (1.3 g, 100%). MS (ESI) m/z 411 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23]([OH:25])=O)[CH:18]=2)[CH2:13][CH2:12]1.[S:26]1[C:30]2[CH2:31][NH:32][CH:33]([CH2:35][OH:36])[CH2:34][C:29]=2[CH:28]=[CH:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[OH:36][CH2:35][CH:33]1[N:32]([C:23]([C:19]2[N:20]=[CH:21][N:22]=[C:17]([N:14]3[CH2:13][CH2:12][CH:11]([N:3]4[C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:10][C:2]4=[O:1])[CH2:16][CH2:15]3)[CH:18]=2)=[O:25])[CH2:31][C:30]2[S:26][CH:27]=[CH:28][C:29]=2[CH2:34]1
Reactant: OCC1Cc2ccsc2CN1
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1Cc2sccc2CC1CO
Temperature: 25 °C
Reaction time: 5 h

Procedure:
85 mg (0.25 mmol) 6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid and 50 mg (0.32 mmol) (4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-5-yl)-methanol in 50 μL (0.36 mmol) TEA and 0.90 mL DMF were combined with 80 mg (0.25 mmol) TBTU and the mixture was stirred for 5 h at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].Cl[CH2:11][C:12]([OH:14])=[O:13].[OH-].[Na+].C1(O)C=CC=CC=1>O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)CCl
Reactant: Cc1cccc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Oc1ccccc1
Product: Cc1cccc(C)c1OCC(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2,6-Dimethylphenol (102.8 g, 0.842 mol) and chloroacetic acid (159.6 g, 1.68 mol) in 1000 ml of H2O was added to a 3-L, 3-necked round bottom flask with mechanical stirring and a water-cooled condenser. A solution of NaOH (134.9 g, 3.37 mol) dissolved in 500 ml of water was slowly added to the above mixture via addition funnel and heat to reflux. After 2 hours, additional chloroacetic acid (79.4 g, 0.84 mol) and NaOH solution (67.2 g, 1.68 mol in 200 ml water) was added to the reaction mixture. After 19 hours, additional chloroacetic acid (39.8 g, 0.42 mol) and NaOH solution (33.6 g, 0.84 mol in 100 ml water) was added to the reaction mixture and refluxing was continued until starting phenol was consumed. The reaction flask was cooled in and ice-water bath and acidified to pH=1 with conc. HCl, causing a precipitate to form. The resulting slurry was stirred in the ice bath for 1 hour then filtered. The solid was dissolved in hot (100° C.) water and cooled to crystallize the product as white plates, mp=136-137° C., yield=78.8 g, 52%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][C:6]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:22][C@H:23]3[CH2:28][CH2:27][C@H:26]([C:29]([F:32])([F:31])[F:30])[CH2:25][CH2:24]3)[C:17]=2[I:21])[CH:12]=1)([N+:8]([O-:10])=[O:9])[CH3:7].[N+](C(C1C=CC2C(=CC=C(O[C@H]3CC[C@@H](C(F)(F)F)CC3)C=2)C=1)(C)CCC(O)=O)([O-])=O>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][C:6]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:22][C@H:23]3[CH2:28][CH2:27][C@@H:26]([C:29]([F:32])([F:30])[F:31])[CH2:25][CH2:24]3)[C:17]=2[I:21])[CH:12]=1)([N+:8]([O-:10])=[O:9])[CH3:7]
Reactant: COC(=O)CCC(C)(c1ccc2c(I)c(O[C@H]3CC[C@H](C(F)(F)F)CC3)ccc2c1)[N+](=O)[O-]
Agent: CC(CCC(=O)O)(c1ccc2cc(O[C@H]3CC[C@@H](C(F)(F)F)CC3)ccc2c1)[N+](=O)[O-]
Product: COC(=O)CCC(C)(c1ccc2c(I)c(O[C@H]3CC[C@@H](C(F)(F)F)CC3)ccc2c1)[N+](=O)[O-]
Yield: 51 %

Procedure:
4-[5-Iodo-6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-4-nitro-pentanoic acid methyl ester was synthesized as per 4-[5-iodo-6-(trans-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-4-nitro-pentanoic acid methyl ester (Example 281) in 51% yield, using 4-nitro-4-[6-(cis-4-trifluoromethyl-cyclohexyloxy)-naphthalen-2-yl]-pentanoic acid as the starting material.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1>O1CCCC1>[NH2:7][C:4]1[CH:5]=[CH:6][C:1]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]\[C:12]([OH:14])=[O:13])=[CH:2][CH:3]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc(N)cc1
Solvent: C1CCOC1
Product: Nc1ccc(NC(=O)/C=C\C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
Under a nitrogen atmosphere, into a reaction vessel were charged 15.00 g (138.7 mmol) of 1,4-phenylenediamine and 255 ml of tetrahydrofuran. A solution prepared by dissolving 9.07 g (92.5 mmol) of maleic anhydride in 45 ml of tetrahydrofuran was dropped into this under cooling with ice over a period of about 3 hours, then, the mixture was stirred at room temperature overnight. After completion of the reaction, the deposited crystal was isolated by filtration, washed with 30 ml of tetrahydrofuran, and dried at 40° C. to obtain 18.14 g of coarse (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoic acid as an orange powder. To 18.14 g of coarse (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoic acid was added 36 ml of water and the mixture was cooled to 0 to 10° C., and 17.59 ml of a 5N sodium hydroxide aqueous solution was dropped. Thereafter, the solvent was distilled off under reduced pressure to obtain a residue to which 270 ml of ethanol was added, and the mixture was stirred at 70° C. for 1 hour, cooled down to room temperature, then, the solid was filtrated and washed twice with 25 ml of methanol. The resultant solid was dried at 45° C. for 2 hours, to obtain 16.2 g of sodium (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoate as a pale brown-white powder. Yield: 76.8%
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])=O.[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[NH:21])=[CH:18][CH:17]=1>C(#N)C>[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]2[NH:22][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N+:11]([O-:13])=[O:12])[N:21]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(C(=N)N)cc1
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Solvent: CC#N
Product: COc1ccc(-c2nc(-c3ccccc3[N+](=O)[O-])c[nH]2)cc1
Temperature: 40 °C
Yield: 78.1 %

Procedure:
A mixture of 2-bromo-2'-nitroacetophenone (18 g), 4-methoxybenzamidine (20 g), and silica gel (20 g) in acetonitrile (500 ml) is heated at 40° C. for 24 hours. The reaction is evaporated and the residue put on a layer of silica gel and eluted with 50% ethyl acetate/hexane (1500 ml). The solution is evaporated under reduced pressure to approximately 250 ml and extracted with 5% HCl (3×250 ml) . The combined aqueous solution is basified with K2CO3 and extracted with ethyl acetate (3×400 ml) to afford 2-(4-methoxyphenyl)-4-(2-nitrophenyl)-imidazole (17 g) as a dark yellow oil which is used in the next step without further purification.
Reaction SMILES: [CH2:1]([S:5][C:6]1[CH:11]=[CH:10][N+:9]([O-])=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].C(OC(=O)C)(=[O:15])C.[OH-].[Na+]>CO>[CH2:1]([S:5][C:6]1[CH:11]=[CH:10][NH:9][C:8](=[O:15])[CH:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CSc1cc[n+]([O-])cc1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CSc1cc[nH]c(=O)c1

Procedure:
A mixture of 500 mg of 4-(isobutylthio)pyridine-N-oxide, 5 ml of acetic anhydride was heated at reflux for 10 hours. The mixture was cooled, then added MeOH and 3N NaOH was added dropwise at pH 9˜11 and stirred. After 1 hour solution was evaporated and 3N HCl was added dropwise at pH6.5˜7.5, extracted with ethyl acetate and subjected to silica gel column chromatography (hexane/ethyl acetate) to obtain the compound (90 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([Se:14][C:15]#[C:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)[CH:5]=[C:4]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=3)[C:3]1=2.[OH-].[Na+]>>[F:36][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][C:32]=1[F:35])[CH2:28][O:27][C:4]1[C:3]2[C:2]([CH3:1])([CH3:37])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=[C:6]([Se:14][C:15]#[C:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(C#C[Se]c2cc(OCc3ccc(F)c(F)c3)c3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)CCC(C)(C)c2c(OCc3ccc(F)c(F)c3)cc([Se]C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
In a manner similar to that of Example 1g, by reacting 680 mg (1.2 mmol) of methyl 4-[5,5,8,8-tetramethyl-4-(3,4-difluorobenzyloxy)-5,6,7,8-tetrahydro-2-naphthylselanylethynyl]benzoate with 240 mg of sodium hydroxide. A yellow crystallized solid is obtained (m=402 mg; yield=61%; m.p.=218° C.).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13]C)=[O:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:34])[CH2:17][CH:18]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26][C:25]=1[O:32][CH3:33])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([Mg]Br)[CH3:36]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:34])[CH2:17][CH:18]([C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:31])[CH2:35][CH3:36])=[CH:26][C:25]=1[O:32][CH3:33])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC[Mg]Br
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)OC)ccc1C(C)(C)C)c1ccc(C=O)cc1OC
Product: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(C(=O)CC)cc1OC

Procedure:
Following a similar procedure to that described in Preparation 64A(i), but using N-(2-t-butyl-5-methoxycarbonylphenyl)-3-(4-formyl-2-methoxyphenyl)octanamide (prepared as described in Preparation 63A) and ethylmagnesium bromide, the title compound was obtained as a foam-like substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][NH:6][C:7]([C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=1[NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][NH:6][C:7]([C:9]1[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=1[NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[S:27]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCOC(=O)CNc1ccccc1C(=O)NCc1ccc(Cl)c(Cl)c1
Solvent: C1COCCO1
Product: CCOC(=O)CNc1ccccc1C(=S)NCc1ccc(Cl)c(Cl)c1
Yield: 80.8 %

Procedure:
A mixture of ethyl 2-[2-{N-(3,4-dichlorobenzyl)-carbamoyl}anilino]acetate (16.3 g), phosphorus pentasulfide (19.0 g) and 1,4-dioxane (320 ml) was refluxed for 1 hour. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel (300 g) eluting with chloroform to give ethyl 2-[2-{N-(3,4-dichlorobenzyl)thiocarbamoyl}anilino]-acetate (13.72 g).
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)#[N:2].N>[Ni].C(O)C>[NH3:2].[NH2:2][CH2:1][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C#N)C1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Reaction time: 8 h
Yield: 195.3 %

Procedure:
A mixture of tert-butyl (3R)-3-cyano-1-pyrrolidinecarboxylate (preparation 79) (1.60 g, 8.13 mmol) and Raney® Nickel (1 g) in 0.88 ammonia (20 ml) and ethanol (150 ml), was hydrogentaed at 60 psi and room temperature for 8 hrs. The mixture was filtered through Arbocel®, and the filtrate concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (100:0:0 to 90:10:1) to yield the desired product as an oil, (1.59 g, 98%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([OH:9])=O)[N:3]=[CH:2]1.[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([N:26]3[CH2:31][CH2:30][NH:29][C@@H:28]([CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:27]3)[CH:19]=[CH:20][C:21]=2[O:22][CH:23]([F:25])[F:24])[CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([N:26]3[CH2:31][CH2:30][N:29]([C:7](=[O:9])[CH2:6][C:4]4[N:3]=[CH:2][NH:1][CH:5]=4)[C@@H:28]([CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:27]3)[CH:19]=[CH:20][C:21]=2[O:22][CH:23]([F:24])[F:25])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: CC(C)C[C@H]1CN(c2ccc(OC(F)F)c(OC3CCCC3)c2)CCN1
Product: CC(C)C[C@H]1CN(c2ccc(OC(F)F)c(OC3CCCC3)c2)CCN1C(=O)Cc1c[nH]cn1

Procedure:
Prepared by the method outlined for Example 189 using 2-(1H-imidazol-4-yl)acetic acid and (S)-1-(3-cyclopentyloxy-4-difluoromethoxy-phenyl)-3-isobutyl-piperazine (Example 36, Compound 124) as starting materials. Product as an off-white solid (20%). LC/MS (Method B) 3.04 min, [M+1]+ 477.1. Potency class B.
Reaction SMILES: [Na].[Cl:2][C:3]1[N:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Cl.[OH2:11]>>[Cl:2][C:3]1[C:4]([CH2:5][OH:11])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: ClCc1cccnc1Cl
Reactant: O
Agent: [Na]
Product: OCc1cccnc1Cl

Procedure:
In 100 ml of cold water was dissolved 8.98 g of sodium horohydride and with ice-cooling and stirring, 11.7 g (0.0665 mole) of 2-chloronicotinyl chloride was added in small portions. The mixture was further stirred at the same temperature for 30 minutes and, then, extracted with Et2O (100 ml×3). The extract was dried over MgSO4 and distilled to remove Et2O. The procedure gave 8.75 g of (2-chloro-3-pyridyl)methanol as a pale yellow oil. When left standing at room temperature, this product solidified thoroughly.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[O:8][C:7]([CH3:14])([CH3:13])[CH2:6][CH2:5]2.[Li]CCCC.CN([CH:23]=[O:24])C>C1COCC1>[Cl:12][C:10]1[CH:11]=[C:2]([CH:23]=[O:24])[CH:3]=[C:4]2[C:9]=1[O:8][C:7]([CH3:14])([CH3:13])[CH2:6][CH2:5]2
Reactant: CC1(C)CCc2cc(Br)cc(Cl)c2O1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)CCc2cc(C=O)cc(Cl)c2O1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
6-Bromo-8-chloro-2,2-dimethyl-3,4-dihydro-2H-chromene (483 mg, 1.75 mmol) in THF (8.76 mL) was cooled to −78° C. and n-BuLi (841 μL, 2.10 mmol) was added dropwise via a syringe. The reaction mixture was stirred at −78° C. for 10 minutes and then DMF (543 μL, 7.01 mmol) was added dropwise via a syringe. The resulting mixture was allowed to warm to room temperature, and wet silica gel (5.0 g/0.5 mL of water) was added. The mixture was allowed to stir at room temperature for 10 minutes before it was filtered. The silica gel was rinsed with EtOAc, and the filtrate was concentrated under vacuum. The crude mixture was purified by silica gel chromatography eluting with 0-15% EtOAc/hexanes to obtain the desired product as a pale-yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:5]([N:7]([CH:9]1[CH2:11][CH2:10]1)[CH3:8])=O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[CH3:15])[CH2:5][N:7]([CH:9]1[CH2:10][CH2:11]1)[CH3:8]
Reactant: Cc1ccc(C(=O)N(C)C2CC2)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(CN(C)C2CC2)cc1Br
Temperature: 25 °C
Yield: 63.7 %

Procedure:
A solution of 3-bromo-N-cyclopropyl-4,N-dimethyl-benzamide (Intermediate 96, 5.3 g, 19.77 mmol) in anhydrous tetrahydrofuran (50 mL) was treated with borane-methyl sulfide complex (10 mL, 100 mmol) and the resulting reaction mixture was refluxed for 2 h. It was cooled to ambient temperature and carefully treated with saturated, aqueous sodium carbonate solution till cessation of effervescence, and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent afforded the title product as an oil (3.2 g, 63%).