Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]2)[CH2:9]O)=[N:6][CH:7]=1.[H-].[Na+].CI.CN([CH:28]=[O:29])C>O.C(OCC)(=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C@H:11]2[CH2:12][CH2:13][C@H:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:15][CH2:16]2)([O:29][CH3:28])[CH3:9])=[N:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: COC(=O)[C@H]1CC[C@H](C(CO)c2ccc(Br)cn2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)[C@H]1CC[C@H](C(C)(OC)c2ccc(Br)cn2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Racemic methyl trans-4-[1-(5-bromopyridin-2-yl)hydroxyethyl]cyclohexanecarboxylate (500 mg, 1.461 mmol) was dissolved in DMF (7.3 mL) and cooled to 0° C. Sodium hydride (60 wt %, 117 mg, 2.92 mmol) was added in one portion. The mixture was stirred and allowed to warm to room temperature. After 20 minutes, methyl iodide (0.183 mL, 2.92 mmol) was added, and the reaction was stirred at room temperature for 30 minutes. The mixture was diluted with water, ethyl acetate, and brine. The layers were separated, and the organic portion dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel column chromatography (20% EtOAc:hexanes) gave racemic methyl trans-4-[1-(5-bromopyridin-2-yl)-1-methoxyethyl]cyclohexanecarboxylate as a colorless oil. MS ESI calcd. for C16H23BrNO3 [M+H]+ 356 and 358. found 356 and 358. 1H NMR (500 MHz, DMSO-d6) 8.64 (d, J=2.2 Hz, 1H), 8.01 (dd, J=2.3, 8.5 Hz, 1H), 7.37 (d, J=9.1 Hz, 1H), 3.54 (s, 3H), 2.98 (s, 3H), 2.20-1.50 (m, 5H), 1.55 (s, 3H), 1.40-0.75 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.[CH3:10][C:11]([S@:14]([NH2:16])=[O:15])([CH3:13])[CH3:12]>C(OCC)(=O)C.C1COCC1.S([O-])([O-])(=O)=O.[Cu+2]>[F:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[N:16]/[S:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(F)cn1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)/N=C/c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-fluoropyridine-2-carbaldehyde (18.49 g, 148 mmol) in ethyl acetate (850 mL), THF (250 mL) and hexanes (300 mL) were added (R)-(+)-2-methyl-2-propanesulfinamide (19.71 g, 163 mmol) and anhydrous copper(II) sulfate (59.0 g, 370 mmol). The mixture was stirred at ambient temperature. After 18 h, the mixture was filtered through Celite. The filtered cake was washed with ethyl acetate and the filtrate was concentrated. Purification by silica gel chromatography (100% dichloromethane→98% dichloromethane/methanol) gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=O)[CH:5]=[CH:6][C:7](=[O:9])[CH:8]=1.C1(C)C=CC(S([NH:20][NH2:21])(=O)=O)=CC=1>ClCCl>[N+:20](=[C:4]1[CH:5]=[CH:6][C:7](=[O:9])[CH:8]=[C:3]1[O:2][CH3:1])=[N-:21]
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: COC1=CC(=O)C=CC1=O
Solvent: ClCCl
Product: COC1=CC(=O)C=CC1=[N+]=[N-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.6 %

Procedure:
An ice-cold soluton of 2 -methoxy-p-benzoquinone (69 mg, 0.5 mmol) in dichloromethane (2 ml) was added to an ice-cold solution of p-toluenesulfonhydrazide (102 mg, 0.55 mmol) in 2 ml of dichloromethane and the resulting solution was stirred at 0° C. for 1 hour. Additional p-toluenesulfonhydrazide (50 mg, 0.27 mmol) was added to the reaction mixture and the resulting mixture was stirred at 0° C. for two hours. The solvent was then removed under reduced pressure and the residue was chromatographed on a silica gel column (2.5×18 cm) with chloroform:methanol (9:1, v/v). The bioactive fractions were combined and concentrated in vacuo to give 26.7 mg of 4-diazo-3-methoxy-2,5-cyclohexadien-1-one as a yellow solid: UV max in CH3OH (E1 cm1%) 335 (730), 250 (120): 1H NMR in CDCl3 δ: 3.90 (s,3H)., 6.05 (d, 1H, 1.5 Hz), 6.30 (dd, 1H, 9.5, 1.6 Hz), 7.28 (d, 1H, 9.5 Hz); 13C NMR in CDCl3 δ: 56.4, 71.2, 103.8, 122.9, 126.7, 161.5, 182.6; IR in chloroform: 2110, 1635, 1600 cm-1 ; and molecular weight by mass spectrum 150; Rf equals 0.25 in a TLC system on silica gel with chloroform:methanol, 9:1, v/v, as the solvent.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])[C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CO.[IH:33]>C(OCC)C>[IH:33].[F:26][C:23]([F:24])([F:25])[CH2:22][CH2:21][CH2:20][N:19]1[C:18]2[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=2[N:16]=[C:15]1[N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2CCCC(F)(F)F)CC1
Agent: I
Solvent: CO
Solvent: CCOCC
Product: FC(F)(F)CCCn1c(N2CCCNCC2)nc2ccccc21
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Combine 1-t-butoxycarbonyl-4-(1-(4,4,4-trifluorobutyl)-1H-benzimidazol-2-yl)[1,4]diazepane (1.80 g, 4.22 mmol) and methanol (15 mL). Cool in an ice bath. Add aqueous hydriodic acid (3.8 g, 2.23 mL, 57%, 16.9 mmol) and warm to ambient temperature. After 30 minutes, add aqueous hydriodic acid (1.12 mL) and heat to 50° C. After 2 hours, cool to ambient temperature and evaporate to remove most of the methanol to give a residue. Combine the residue and methanol (10 mL). Add diethyl ether (200 mL) and stir to give a solid. Decant the solvent, add diethyl ether (200 mL) and stir, collect the solid by filtration to give, after drying, the title compound: mp; 206-208° C.
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C@:16]12[CH2:33][CH2:32][C@H:31]3[C@@H:21]([CH2:22][CH2:23][C:24]4[C@:29]3([CH3:30])[CH2:28][CH2:27][C:26](=[O:34])[CH:25]=4)[C@@H:20]1[CH2:19][CH2:18][C@@H:17]2[C:35](O)=[O:36].C(N(CC)CC)C.C1(S(Cl)(=O)=O)C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:14][C:35]([C@H:17]2[CH2:18][CH2:19][C@H:20]3[C@H:21]4[C@H:31]([CH2:32][CH2:33][C@:16]23[CH3:15])[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:34])[CH2:27][CH2:28]2)[CH2:23][CH2:22]4)=[O:36])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Reactant: NC(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccccc1)c1ccccc1
Yield: 85 %

Procedure:
0.108 ml of benzhydrylamine was added to a solution of 100 mg of androsta-4-ene-3-one-17β-carboxylic acid, a catalytic amount of 4-dimethylaminopyridine and 0.132 ml of triethylamine in 4 ml of methylene chloride. 0.060 ml of benzenesulfonyl chloride was divided into three portions and added to this reaction mixture at intervals of 30 minutes at room temperature, whilst stirring. One hour after finishing the addition of benzenesulfonyl chloride, the reaction mixture was diluted with methylene chloride, washed with 1N aqueous hydrochloric acid, with water, with an aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. It was then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was crystallized from acetone to give 130.1 mg (yield 85%) of the title compound, having the same properties as the product of Preparation 17.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH2:11][C:12]2=O)=[CH:7][CH:6]=1)=[O:4].C[Si]([C:20]#[N:21])(C)C.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(C1C=CC(C(CC)C(O)=O)=CC=1)(O)=O.[I-].[Zn+2].[I-]>[C:20]([C:12]1[C:13]2[CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=[CH:7][C:8]=2[CH2:9][CH2:10][CH:11]=1)#[N:21]
Reactant: COC(=O)c1ccc2c(c1)C(=O)CCC2
Reactant: C[Si](C)(C)C#N
Agent: CCC(C(=O)O)c1ccc(C(=O)O)cc1
Agent: [I-]
Agent: [Zn+2]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc2c(c1)C(C#N)=CCC2
Yield: 47.1 %

Procedure:
Part B--A solution of 1-tetralon-7-carboxylic acid methyl ester (3.50 g, 0.017 mol), trimethylsilylcyanide (1.98 g, 0.02 mol) and zinc iodide (0.10 g) in benzene 5 (20 mL) was stirred at ambient temperature over 15 hours. Then added, sequentially and dropwise, was pyridine (20 mL) and phosphorous oxychloride (4.0 mL, 6.55 g, 0.0425 mol). The reaction mixture was stirred at reflux over 1 hour then evaporated to dryness under reduced pressure. The residue was taken up in chloroform, backwashed with water, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give methyl 8-cyano-5,6-dihydro-2-naphthoate (1.70 g, 0.008 mol, 47%) as a yellow solid. mp=73°-75° C.; 1H NMR (CDCl3) d 8.0-7,9 (m, 1H), 7.3-7.2 (m, 1H), 6.95 (t, 1H, J=4.8 Hz), 3.95 (s, 3H), 2.9 (t, 2H, J=8.3 Hz), 2.6-2.4 (m, 3H)
Reaction SMILES: [C:1]1([CH:7]([CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[CH2:8][CH2:9][CH2:10]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[NH:22][CH2:23][CH2:24][CH3:25].[CH2:26](O)C>>[C:1]1([C:7]([NH:22][CH2:23][CH2:24][CH3:25])([CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[CH2:8][CH2:9][CH2:10][CH3:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCC(c1ccccc1)C1Cc2ccccc2C1
Reactant: CCO
Reactant: CCCNC
Product: CCCCC(NCCC)(c1ccccc1)C1Cc2ccccc2C1
Temperature: 100 °C

Procedure:
A solution of 1-phenyl-1-(2-indanyl)-4bromobutane in ethanol was stirred at room temperature while methylpropylamine was added. The reaction mixture was stirred several hours at about 100°C. After cooling the reaction mixture to room temperature, the solvent was removed under reduced pressure, affording 1-phenyl-1-(2-indanyl)-4-methyl-n-propylaminobutane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:15]2[CH2:17][CH2:16]2)=[C:9]2SCCCS2)=[CH:4][CH:3]=1.[OH2:18].[CH3:19][OH:20]>C(OCC)C.[Hg](Cl)Cl>[CH:15]1([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]([O:20][CH3:19])=[O:18])[CH2:17][CH2:16]1
Reactant: CO
Reactant: Clc1ccc(C(=C2SCCCS2)C2CC2)cc1
Reactant: O
Agent: Cl[Hg]Cl
Solvent: CCOCC
Product: COC(=O)C(c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 10.0 grams (0.036 mole) of 2-[(4chlorophenyl)cyclopropylmethylene]-1,3-dithiane, 24.0 grams (0.086 mole) of mercury (II) chloride, and 5 mL of water in 50 mL of methanol was stirred at ambient temperature for 18 hours. The reaction mixture was heated at reflux for one hour, cooled, and then was diluted with diethyl ether. The mixture was filtered through diatomaceous earth and then was dried with magnesium sulfate. The mixture was filtered through silica gel, and the filtrate was concentrated under reduced pressure, yielding 5.9 grams of methyl 2-cyclopropyl-2-(4-chlorophenyl)acetate as an oil. The nmr spectrum was consistent with the proposed structure. The reaction was run again to produce an additional 7.1 grams of the acetate.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.I[CH:30]([CH3:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C>[CH3:31][CH:30]([N:3]1[C:2](=[O:1])[C:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]12)[CH3:32]
Reactant: CC(C)I
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C(C)C)c2ncnn12
Temperature: 100 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.8 g), 2-iodopropane (0.43 mL), potassium carbonate (0.6 g) and N,N-dimethylacetamide (10 mL) was stirred at 100° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.48 g, 53%).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([CH3:32])[C:12]=1[C:13](=[O:31])[NH:14][C:15]1[C:20]([Br:21])=[CH:19][N:18]2[CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=[C:17]2[CH:16]=1)=[O:7])C.O.Cl>C1COCC1.CO>[Br:21][C:20]1[C:15]([NH:14][C:13]([C:12]2[N:11]([CH3:32])[N:10]=[CH:9][C:8]=2[C:6]([OH:7])=[O:5])=[O:31])=[CH:16][C:17]2[N:18]([CH:22]=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:24]=2)[CH:19]=1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2cc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaOH (3N, 0.65 ml) was added to a solution of 5-(6-bromo-2-phenyl-imidazo[1,2-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (460 mg, 0.98 mmol) in a mixture of THF (5 ml) and methanol (5 ml), and the reaction mixture was stirred at r.t. overnight. An additional amount of NaOH (3N, 0.65 ml) and water (2 ml) were added and the mixture was heated to reflux (1 h). After cooling to r.t., HCl (conc., ˜0.7 ml) was added to the cooled mixture, and the brown suspension was stirred at r.t. (15 min). The suspension was then filtered, and the precipitated title compound (150 mg, 35%) was washed with a small amount of water, dried under vacuum, and used in the next step without further purification. MS (m/e)=440.3 [M+H+].
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([C:40]2[C:41]([C:46]#[N:47])=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:39])[N:23]([CH:34]([CH3:38])[CH2:35][O:36][CH3:37])[C:24]2[N:25]([N:30]=[C:31]([CH3:33])[N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[C:46]2[NH:3][C:4](=[O:7])[O:5][N:47]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:39])[N:23]([CH:34]([CH3:38])[CH2:35][O:36][CH3:37])[C:24]2[N:25]([N:30]=[C:31]([CH3:33])[N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C(C)COC)c2nc(C)nn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n(C(C)COC)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
A mixture of hydroxylammonium chloride (0.62 g), sodium hydrogen carbonate (0.99 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 3′-fluoro-4′-{[4-(2-methoxy-1-methylethyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.28 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.12 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.097 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.15 g, 49%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.CN(C(ON1N=[N:26][C:21]2[CH:22]=[CH:23][CH:24]=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:33][CH2:34][N:35](C(C)C)[CH:36](C)[CH3:37]>CN(C=O)C.C(OCC)(=O)C>[CH:21]1([N:26]2[CH2:37][CH2:36][N:35]([C:8]([C@H:5]3[CH2:4][CH2:3][C@@H:2]([OH:1])[CH2:7][CH2:6]3)=[O:10])[CH2:34][CH2:33]2)[CH2:22][CH2:23][CH2:24]1
Reactant: O=C(O)[C@H]1CC[C@@H](O)CC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(C(C)C)C(C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C([C@H]1CC[C@@H](O)CC1)N1CCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 214 mg (1.5 mmol) of cis-4-hydroxycyclohexanecarboxylic acid (commercially available), 316 mg (1.5 mmol) of 1-(2-cyclobutyl)-piperazine dihydrogen chloride (WO 2004101546), 572 mg (1.8 mmol) of TBTU and 751 mg (7.4 mmol) of DIPEA in 5 ml DMF was stirred for 8 h at room temperature. The mixture was diluted with ethyl acetate, washed with water and brine, and evaporated. The residue was purified by column chromatography on silica eluting with CH2Cl2 and methanol=9:1. Evaporation of the combined product fractions yielded 300 mg (76%) of the title compound as light brown oil. MS (m/e): 267.1 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22]CC=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])C=CC=CC=1.[C:51]1(C)C=CC=C[CH:52]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:51][CH:52]=[CH:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC=O)N(C(=O)OCc2ccccc2)C1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C=CCOC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1

Procedure:
A solution of (2S,4R)-1-benzyloxycarbonyl-2-(2-oxoethyl)oxymethyl-4-methanesulfonyloxypyrrolidine (15.7 g) and ethyl 2-triphenylphosphoranylideneacetate (16.2 g) in toluene (150 ml) was heated under refluxing for 3 hours. The solvent was removed in vacuo to give a residue, which was chromatographed on silica gel (700 ml) eluting with a mixture of hexane and ethyl acetate (2:1-1:1 V/V) to give (2S,4R)-1-benzyloxycarbonyl-2-[{3-(ethoxycarbonyl)-2-propenyl}oxymethyl]-4-methanesulfonyloxypyrrolidine (12.86 g).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)CCC.FC(F)(F)S(O[C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][C:27]=1[O:34][CH3:35])(=O)=O.[Cl-].[Li+]>CN(C=O)C.C(OCC)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:35][O:34][C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][C:26]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[C:32]#[N:33]
Reactant: COc1cc(C#N)ccc1OS(=O)(=O)C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: COc1cc(C#N)ccc1-c1ccccn1
Temperature: 100 °C

Procedure:
A solution of 2-(tributylstannyl)pyridine (18 g of 80% pure, 39.2 mmol) and 4-cyano-2-methoxyphenyl trifluoromethanesulfonate (9.2 g, 32.7 mmol) were dissolved in DMF (65 mL) and treated with lithium chloride (1.39 g, 32.7 mmol) and Pd(PPh3)4 (1.9 g, 1.6 mmol), then degassed by bubbling argon through the solution for 15 min. The reaction mixture was heated to 100° C. while under an atmosphere of argon for 12 h. The cooled reaction mixture was diluted with diethyl ether (100 mL) and water (100 mL). The organic layer was separated and washed with a 1M solution of sodium hydroxide (50 mL) and brine (50 mL), then dried (MgSO4) and concentrated. The residue was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (1:9 to 1:1) to afford 3-methyoxy-4-pyridin-2-ylbenzonitrile.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:20])=[O:30])=[CH:24][CH:23]=1
Reactant: Cc1ccc(-c2nn(N)c(=O)c3ccccc23)cc1C
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: Cc1ccc(-c2nn(NC(=O)Cc3ccc(Cl)cc3)c(=O)c3ccccc23)cc1C

Procedure:
The product of Example 163A and 2-(4-chlorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.69 (s, 1H), 8.38-8.40 (m, 1H), 7.88-8.02 (m, 2H), 7.74 (d, J=6.5 Hz, 1H), 7.38-7.44 (m, 4H), 7.33-7.36 (m, 1H), 7.27-7.33 (m, 2H), 3.70 (s, 2H), 2.32 (s, 3H), 2.31 (s, 3H); MS (APCI+) M/Z 418 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:55][C@@H:56]([C:58]1[CH:59]=[C:60]([CH:65]=[CH:66][CH:67]=1)[C:61]([O:63][CH3:64])=[O:62])[CH3:57]>CN(C=O)C.O>[CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([NH:55][C@@H:56]([C:58]3[CH:59]=[C:60]([CH:65]=[CH:66][CH:67]=3)[C:61]([O:63][CH3:64])=[O:62])[CH3:57])=[O:21])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2]
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cn2)C1
Reactant: COC(=O)c1cccc([C@@H](C)N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)N[C@H](C)c3cccc(C(=O)OC)c3)cn2)C1
Temperature: 22.5 °C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
To a stirred solution of (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid (797 mg, 2.32 mmol) in dry DMF (2.5 mL) at 0° C. were added triethylamine (0.36 mL, 2.5 mmol), 1-hydroxybenzotriazole (470 mg, 3.48 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1666 mg, 3.48 mmol). The mixture was stirred for 5 min and methyl (R)-3-(1-aminoethyl)benzoate (500 mg, 2.32 mmol) was added. The reaction mixture was allowed to warm to 20-25° C. and was stirred for 16 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (3 times with 25 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified via column chromatography to afford methyl 3-((R)-1-(2-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)ethyl)benzoate (890 mg, 76%). MS (ES+) 505.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8]([CH:12]=O)=[CH:7]2.C([O-])(=O)C.[NH4+].[N+:19]([CH3:22])([O-:21])=[O:20]>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8](/[CH:12]=[CH:22]/[N+:19]([O-:21])=[O:20])=[CH:7]2
Reactant: Cn1c(C=O)cc2cccc(F)c21
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: Cn1c(/C=C/[N+](=O)[O-])cc2cccc(F)c21

Procedure:
To a solution of 7-fluoro-1-methyl-1H-indole-2-carboxaldehyde (1.80 g) in nitromethane (20 ml) was added ammonium acetate (780 mg) and the mixture was heated at reflux for 1 h. The solvent was removed in vacuo and the residue was suspended in ethyl acetate (300 ml). This suspension was washed with 8% aqueous sodium bicarbonate solution (2×300 ml), dried, and the solvent was removed in vacuo to leave the title compound (1.26 g) as a solid, m.p. 153°-155.5°.