Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:11][C@H:12]1[O:17][C@@H:16]([CH3:18])[CH2:15][NH:14][CH2:13]1>>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([N:14]2[CH2:13][C@H:12]([CH3:11])[O:17][C@H:16]([CH3:18])[CH2:15]2)=[N:6][CH:7]=1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: COc1nc(Cl)ncc1Br
Product: COc1nc(N2C[C@@H](C)O[C@@H](C)C2)ncc1Br
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of 5-bromo-2-chloro-4-methoxypyrimidine (17.2 g, 77 mmol) stirred in air at 0° C. was added neat cis-2,6-dimethylmorpholine (24.5 g, 213 mmol) dropwise in 10 minutes. The reaction mixture was stirred at 45° C. for 30 minutes. The organic phase was evaporated in vacuo to give the crude product as a white solid. The crude product was added to a silica gel column and was eluted with hexane/ethyl acetate (20/1). Collected fractions were evaporated to give the title compound as white solid (17.4 g, 49.3 mmol, 64.1% yield). LC/MS [M+H]+=302/304.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[C:9]([OH:13])(=[O:12])[CH2:10][CH3:11].C([O-])(=O)CC.[K+]>[Mn+3]>[CH3:11][CH:10]1[CH2:1][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[O:13][C:9]1=[O:12]
Reactant: CCC(=O)O
Reactant: C=CCCCCCC
Agent: [Mn+3]
Agent: CCC(=O)[O-]
Agent: [K+]
Product: CCCCCCC1CC(C)C(=O)O1

Procedure:
Octene-1 in an amount of 2.24 g. and 11.65 g. of manganic acetate, Mn(C2H3O2)3. 2H2O, (comprising two equivalents of Mn+3 based on titration value), were refluxed under nitrogen in 200 ml. propionic acid containing 20 g. potassium propionate. In less than an hour a good yield of alphamethyl-gamma-n-hexyl-butyrolactone was obtained.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C@@H:8]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C@H:10]([C:21]([OH:23])=O)[CH2:9]1.[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[F:29][C:28]([F:31])([F:30])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C@@H:8]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C@H:10]([C:21]([N:44]2[CH2:43][CH2:42][N:41]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[F:34])[CH2:46][CH2:45]2)=[O:23])[CH2:9]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1C[C@@H](C(=O)O)N(Cc2cccc(Cl)c2)C1
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1C[C@@H](C(=O)N2CCN(c3ccccc3F)CC2)N(Cc2cccc(Cl)c2)C1
Yield: 11 %

Procedure:
As described for Example 64e, (2S,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methyl-amino]-1-(3-chloro-benzyl)-pyrrolidine-2-carboxylic acid (μmol) was converted, using 1-(2-fluoro-phenyl)-piperazine instead of 2-cyclohexyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one, to the title compound (72 mg) in 11% yield as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([O:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1)[CH:7]=[N:6]2.[H-].[Na+].[CH3:25]I>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([O:15][CH:16]1[CH2:21][CH2:20][CH:19]([O:22][CH3:25])[CH2:18][CH2:17]1)[CH:7]=[N:6]2
Reactant: CI
Reactant: COc1cc2ncc(O[C@H]3CC[C@H](O)CC3)nc2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2ncc(OC3CCC(OC)CC3)nc2cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.9 %

Procedure:
A mixture of cis/trans-4-(6,7-dimethoxy-quinoxalin-2-yloxy)-cyclohexanol (170 mg, 0.56 mmole) and NaH (60%, 22.4 mg, 0.56 mmole) in anhydrous THF/DMF (10 mL/2 mL) is stirred at 0° C. for 10 min. before addition of methyl iodide (50 μL, 0.56 mmole). After being stirred at ROOM TEMPERATURE for four hours, the reaction is quenched with water (0.5 mL) and concentrated. The aqueous layer is extracted with methylene chloride (2×20 mL) and the combined organic solutions are washed with brine (5 mL). The residue after concentration is chromatographed on silica gel (30% ethyl acetate/hexane) to give 80 mg (45%) of the desired product (m.p. 85-90° C.).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13]Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[NH:18][CH:19]=[N:20]2.C(N(CC)CC)C.Cl.C(N(CC)CC)C>CN(C)C=O>[Cl:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH2:13][O:12][CH2:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: O=C(OCCOCCl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(OCCOCn1cnc2c(Cl)ncnc21)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Following substantially the procedure of Schaeffer, et al. supra but with minor modifications, 1-benzoyloxy-2-chloromethoxyethane (4.4g) was added with stirring to a dry solution of 6-chloropurine (3.1g) and triethylamine (6.5ml) in dimethylformamide (50ml). The reaction was exothermic, immediately precipitating triethylamine hydrochloride. The reaction mixture was stirred at room temperature for 24 hours and filtered. The filtrate was evaporated on a rotary evaporator at 70° C. The remaining thick amber oil was dissolved in the minimum amount of benzene and purified by column chromatography using a silica gel column. Benzene elution removed a trace of an unidentified material. Elution with ether first removed a small amount of ethylene glycol monobenzoate and then 6-chloro-9-(2-benzoyloxyethoxymethyl)purine. Recrystallization from ether gave a white material, m.p. 108.5°-111° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9](C)[C:10](O)=O)C=[CH:6][C:7]=1[F:8].[C:14](Cl)(=[O:18])[C:15](Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-]>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:6][C:7]=1[F:8])[C:14](=[O:18])[CH2:10][CH2:9]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C(=O)O)c1ccc(F)c(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCc2cc(F)c(F)cc21
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a solution of 3,4-difluorophenyl propionic acid (30.45 g; 163.6 mmol) and 2 drops of DMF in CH2Cl2 (200 mL) was added oxalyl chloride (41.4 g, 327 mmol) over 20 min. The resulting solution was stirred for 24 hr and concentrated in vacuo (chased 1×PhMe, ca. 100 mL). The residue was dissolved in CS2 (300 mL), cooled to 0° C. and AlCl3 (76.4 g, 573 mmol) was added over 10 min. The mixture was stirred 30 min at 0° C., then heated under reflux for 4 hr. Upon cooling to room temperature the solution was carefully poured onto crushed ice, the carbon disulfide layer was separated and the aqueous layer extracted with EtOAc. Combined organics were dried over MgSO4 and the concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.50 (t, 1H, J=8.0 Hz), 7.24 (t, 1H, J=6.6 Hz), 3.09 (t, 2H, J=5.5 Hz), 2.72-2.69 (m, 2H).
Reaction SMILES: FC1C=C(C=CC=1)[O:5]C1N=C(CO)C=CC=1.[CH:17]([CH:20]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:21](Cl)=[O:22])([CH3:19])[CH3:18].C(N(CC)CC)C>CCOCC>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH:20]([CH:17]([CH3:19])[CH3:18])[C:21]([OH:5])=[O:22])=[CH:25][CH:26]=1
Reactant: CC(C)C(C(=O)Cl)c1ccc(Cl)cc1
Reactant: OCc1cccc(Oc2cccc(F)c2)n1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)C(C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 1.8 grams (0.0078 mole) of cyano(6-(3-fluorophenoxy)-2-pyridine methanol and 2.4 grams (0.0098 mole) of 2-isopropyl-2-(4-chlorophenyl)-acetic acid chloride in 50 milliliters of anhydrous ether was added 3 milliliters of triethylamine. A white precipitate separated out immediately. The reaction mixture was stirred at room temperature for one-half (1/2) hour. The mixture was successively washed with water, dilute hydrochloric acid, dilute sodium hydroxide, dilute sodium bicarbonate, dilute hydrochloric acid and water and thereafter dried over anhydrous magnesium sulfate and concentrated under vacuo to give 3.6 grams of 4-chloro-α-(1-methylethyl)benzeneacetic acid:cyano(6-(3-fluorophenoxy)-2-pyridinyl)methyl ester product as a viscous yellow oil having a refractive index of nD25 =1.5560. The structure of the product was confirmed by its nuclear magnetic resonance spectrum (NMR). In addition, upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 65.52, 4.74 and 6.18 percent, respectively, as compared with theoretical contents of 65.66, 4.59 and 6.38 percent, respectively, as calculated for the above-named compound (Compound No. 3).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[O:10][C:3]=12.[CH3:18][C:19]1[C:27]([NH2:28])=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][NH:23]2>>[CH3:18][C:19]1[C:27]([NH:28][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=4)[O:10][C:3]=23)=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][NH:23]2
Reactant: Cc1ccc(-c2cc3nccc(Cl)c3o2)cc1
Reactant: Cc1c(N)ccc2[nH]ccc12
Product: Cc1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4C)c3o2)cc1

Procedure:
The title compound was prepared by procedure E using 7-chloro-2-(4-methylphenyl)furo[3,2-b]pyridine (27.00 mg; 0.11 mmol; 1.00 eq.) instead of 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine, and 4-methyl-1H-indol-5-ylamine (17.01 mg; 0.12 mmol; 1.05 eq.) instead of 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one, and was obtained as a beige solid (19 mg, 48%). (HPLC (method F): 95%, RT: 4.21 min); 1H NMR (500 MHz, DMSO-d6) δ [ppm] 11.14 (s, 1H), 8.53 (s, 1H), 7.94 (d, J=5.5, 1H), 7.85 (d, J=8.1, 2H), 7.38 (t, J=2.7, 1H), 7.35 (s, 1H), 7.33-7.27 (m, 3H), 7.00 (d, J=8.4, 1H), 6.52 (s, 1H), 6.09 (d, J=5.5, 1H), 2.37 (s, 3H), 2.36 (s, 3H); MS (m/z) 354 [M+H]+, RT: 4.1 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+].Cl[C:40]([O:42][C:43]1[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][CH:44]=1)=[O:41]>C1COCC1.O>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][CH2:12][N:11]([C:40]([O:42][C:43]2[CH:44]=[CH:45][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:51][CH:52]=2)=[O:41])[CH2:10]1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(=O)N2CCC(c3ccccc3)C(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.9 %

Procedure:
To a solution of 238 mg of the crude tert-butyl[(1R)-1-(1-naphthyl)ethyl][(4-phenylpiperidin-3-yl)methyl]carbamate in 3 mL of THF was added 200 mg of sodium hydrogen carbonate while suspending it in 2 mL of water. The reaction mixture was added 170 mg of methyl 4-[(chlorocarbonyl)oxy]benzoate (Fluka). After stirring at room temperature overnight, the mixed solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 4-(methoxycarbonyl)phenyl 3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidine-1-carboxylate (353 mg, colorless foamy substance) as a crude product. ESI+: 623
Reaction SMILES: [N:1]#[C:2]Br.[CH3:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[NH:13][CH2:14][CH2:15][NH2:16]>C(O)C>[CH3:12][C:7]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:5]([CH3:4])[C:6]=1[N:13]1[CH2:14][CH2:15][N:16]=[C:2]1[NH2:1]
Reactant: N#CBr
Reactant: Cc1cc(C)c(NCCN)c(C)c1
Solvent: CCO
Product: Cc1cc(C)c(N2CCN=C2N)c(C)c1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
A solution of cyanogen bromide (1.8 g, 18.5 mmol) in anhydrous ethanol (3 mL) was added at 0° C. to a solution of N1-(2,4,6-trimethyl-phenyl)-ethane-1,2-diamine (3.0 g, 16.9 mmol) in anhydrous ethanol (9 mL) under nitrogen. The reaction mixture was warmed up to room temperature for 10 min, then was heated at 155° C. for 40 min with a flow of nitrogen to remove ethanol. Upon cooling to r.t., the resulting solids were transferred to a separatory funnel via dichloromethane (70 mL), and washed sequentially with 1 N sodium hydroxide (2×35 mL), water and brine. The organic layer was dried over anhydrous sodium sulfate and solvents were removed in vacuo to afford the title compound as a pale white solid (3.08 g, 90% yield). The solids were used for the next step without further purification. 1H NMR (CDCl3, 300 MHz) δ 6.70 (s, 2H), 3.46 (s, 4H), 2.06 (s, 3H), 1.99 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 160.1, 138.2, 137.8, 132.2, 129.5, 48.8, 43.5, 20.8, 17.5. LC/MS: tR=0.99 min., (MH+)=204.12.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[N:9]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[CH:11][C:3]=12.C([Sn](CCCC)(CCCC)[C:33]1[S:37][CH:36]=[N:35][CH:34]=1)CCC.O>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:8][C:7]1[C:2]([C:33]2[S:37][CH:36]=[N:35][CH:34]=2)=[C:3]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)[N:9]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=3)(=[O:19])=[O:20])[C:4]2=[N:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(Cl)c(Cl)cnc32)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(-c4cncs4)c(Cl)cnc32)cc1
Temperature: 100 °C

Procedure:
A solution of Example 113C (0.148 g, 0.351 mmol) and 5-(tributylstannyl)thiazole (0.184 g, 0.492 mmol), in N,N-dimethylformamide (1.3 mL) was degassed via nitrogen sparge for 5 minutes. The reaction was treated with bis(triphenylphosphine)palladium (II) chloride (0.025 g, 0.35 mmol) and heated at 100° C. for 6 hours. The reaction was cooled to ambient temperature, treated with water (20 mL) and extracted with ethyl acetate (80 mL). The aqueous layer was extracted with additional ethyl acetate (40 mL). The combined organic layers were washed with water (2×25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by flash chromatography on a silica gel column, eluting with a gradient of from 0% to 50% ethyl acetae in hexanes, to provide the title compound as an off-white solid. MS ESI(+) m/z 470.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[Cl:18][C:19]1[CH:35]=[CH:34][C:22]([CH2:23][N:24]2[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:33])[CH2:31][NH2:32])[CH2:25]2)=[CH:21][CH:20]=1.C(N(CC)CC)C.N>C(Cl)(Cl)Cl>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([NH:32][CH2:31][C:30]([NH:29][C@H:26]1[CH2:27][CH2:28][N:24]([CH2:23][C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[CH:35][CH:34]=2)[CH2:25]1)=[O:33])=[O:7]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NCC(=O)N[C@H]1CCN(Cc2ccc(Cl)cc2)C1
Agent: N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CNC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N[C@H]1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 3,5-bis(trifluoromethyl)benzoyl chloride (0.060 mmol) in chloroform. (0.4 mL) was added to a solution of (S)-1-(4-chlorobenzyl)-3-(glycylamino)pyrrolidine (0.050 mmol) and triethylamine (0.070 mmol) in chloroform (1.0 mL). After the reaction mixture was agitated at room temperature for 2.5 h, (aminomethyl)polystyrene resin (1.04 mmol/g, 50 mg, 50 mmol) was added and the mixture was agitated at room temperature for 12 h. The reaction mixture was filtered and the resin was washed with dichloromethane (0.5 mL). The filtrate and washing were combined, dichloromethane (4 mL) was added, and the solution was washed with 2 N aqueous NaOH solution (0.5 mL) to give (S)-3-[N-{3,5-bis(trifluoromethyl)benzoyl}glycyl]amino-1-(4-chlorobenzyl)pyrrolidine (compound No. 5) (14.4 mg, 57%): The purity was determined by RPLC/MS (97%); ESI/MS m/e 508.0 (M++H, C22H20ClF6N3O2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=3)[S:17][C:10]=12.FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1C=CN=C2C=C(C3C=CC(S(C)(=O)=O)=CC=3)SC=12.[F:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[CH2:72][C:73]([N:75]=[C:76]=[S:77])=[O:74]>>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:76]([NH:75][C:73](=[O:74])[CH2:72][C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][C:66]=2[F:65])=[S:77])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=3)[S:17][C:10]=12
Reactant: O=C(Cc1ccccc1F)N=C=S
Reactant: Cn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Agent: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)cc1
Product: Cn1cnc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5F)cc4F)c3s2)c1
Yield: 24 %

Procedure:
Starting from the amine 177, following the procedure described above for the synthesis of compound 50 (scheme 10, example 55) but replacing 2-phenylacetyl isothiocyanate with 2-(2-fluorophenyl)acetyl isothiocyanate, title compound 178 was obtained in 24% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.44 (s, 1H), 11.88 (s, 1H), 8.46 (d, 1H, J=5.5 Hz), 8.34 (dd, 1H, J=12.3/2.2 Hz), 7.87 (d, 1H, J=1.2 Hz), 7.72 (d, 1H, J=1.2 Hz), 7.69 (s, 1H), 7.57-7.49 (m, 2H), 7.43-7.31 (m, 2H), 7.23-7.15 (m, 2H), 6.59 (d, 1H, J=5.5 Hz), 3.94 (s, 2H), 3.73 (s, 3H). LRMS (M+1) 536.1 (100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:9]2[CH2:13][C@@:12]3([CH2:18][CH2:17][CH2:16][C@@:15]([CH2:20][N:21]4[C:25]5[CH:26]=[C:27]([C:30]#[N:31])[CH:28]=[CH:29][C:24]=5[N:23]=[CH:22]4)([CH3:19])[CH2:14]3)[O:11][C:10]2=[O:32])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:39][N:40]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[N:41]1>O1CCOCC1.O.C([O-])(O)=O.[Na+]>[CH3:19][C@:15]1([CH2:20][N:21]2[C:25]3[CH:26]=[C:27]([C:30]#[N:31])[CH:28]=[CH:29][C:24]=3[N:23]=[CH:22]2)[CH2:16][CH2:17][CH2:18][C@:12]2([O:11][C:10](=[O:32])[N:9]([CH2:8][C:4]3[CH:3]=[C:2]([C:43]4[CH:42]=[N:41][N:40]([CH3:39])[CH:44]=4)[CH:7]=[CH:6][N:5]=3)[CH2:13]2)[CH2:14]1
Reactant: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@]2(CN(Cc3cc(Br)ccn3)C(=O)O2)C1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2ccnc(CN3C[C@@]4(CCC[C@](C)(Cn5cnc6ccc(C#N)cc65)C4)OC3=O)c2)cn1
Reaction time: 0.33 h
Yield: 98.9 %

Procedure:
To a microwave vial was added 1-(((5S,7S)-3-((4-bromopyridin-2-yl)methyl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (100 mg, 0.202 mmol), sodium carbonate (64.3 mg, 0.607 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (63.1 mg, 0.303 mmol), and PdCl2(dpV) (14.80 mg, 0.020 mmol) in 1,4-Dioxane (3.0 mL) and Water (1.000 mL). The mixture was subjected to the microwave at 120° C. for 20 minutes. The mixture was diluted with saturated NaHCO3 and extracted with DCM (3×). The combined DCM extracts were passed through a phase separator and concentrated. The residue was purified via reverse HPLC (Waters Sunfire 30×150 mm Acetonitrile:Water TFA 20-60%, 50 mL/min, 15 min). The product was free based with PL-HCO3 resin SPE to yield 1-(((5S,7S)-7-methyl-3-((4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (99 mg, 94%). 1H NMR (400 MHz, DMSO-d6) δ 8.50-8.61 (m, 3H), 8.38 (s, 1H), 8.22 (s, 1H), 7.85 (d, J=8.28 Hz, 1H), 7.73-7.82 (m, 2H), 7.61 (dd, J=8.28, 1.25 Hz, 1H), 4.53 (dd, J=21.83, 16.31 Hz, 2H), 4.07-4.20 (m, 2H), 3.93 (s, 3H), 3.28 (dd, J=19.07, 8.78 Hz, 2H), 1.97 (d, J=13.30 Hz, 1H), 1.79 (d, J=14.56 Hz, 1H), 1.52-1.73 (m, 3H), 1.25-1.49 (m, 3H), 1.05 (s, 3H). MS (m/z) 496.3 (M+H+).
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].[CH3:25][C:26]1[NH:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[CH:30][CH:29]=2.[CH2:35](Cl)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CCOCC.O>[CH2:35]([N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[C:26]1[CH3:25])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: ClCc1ccccc1
Reactant: Cc1cc2ccccc2[nH]1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc2ccccc2n1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 2.39 g (9.04 mmoles) of 18-crown-6 in 250 mL of dry ether was added 13.1 g (116.7 mmoles) of potassium tert-butoxide. The mixture was stirred while 13.11 g (100 mmoles) of 2-methylindole was added. The stirring was continued for 0.5 hour. Most of the solid dissolved. Then 20 g (116.9 mmoles) of benzyl chloride in 120 mL of ether was added during 45 minutes. The stirring was continued for 21.5 hours. Water (200 mL) was added. The layers were separated. The aqueous layer was extracted with ether (2×75 mL). The combined ether phases were washed with 50 mL of brine and dried over MgSO4. Evaporation of the solvent left 25.85 g of dark brown oil. The oil was chromatographed on a 1100 g column of silica gel. The column was eluted with 25% CH2Cl2 -Skellysolve B and 200 mL fractions were collected. The fractions were assayed by silica gel tlc (1×4") (25% CH2Cl2 -Skellysolve B). Fractions 22-25 were combined giving 2.28 g (10%) of slightly impure 1-benzyl-2-methylindole as a pale yellow oil which solidified upon standing. Fractions 26-35 were combined giving 8.42 g of 1-benzyl-2-methylindole and 1,3-dibenzyl-2-methylindole as a pale yellow oil. The 8.42 g was combined with the 7.50 g of a similar mixture from fractions 23-28, and chromatographed on a 1100 g column of silica gel. The column was eluted with 25% CH2Cl2 -Skellysolve B and 200 mL fractions were collected. The fractions were assayed as before. Fractions 21-24 were combined giving 3.59 g of 1-benzyl-2-methylindole as a pale yellow oil which solidified. Fractions 25-30 were combined giving 7.66 g of a mixture of 1-benzyl-2-methylindole and 1,3-dibenzyl-2-methylindole as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@:4]([CH3:16])([CH2:6][C:7]1[N:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=[CH:9][N:8]=1)[NH2:5].Cl[C:19]([O:21][CH:22]1[CH:29]2[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:31][CH:23]1[CH2:24]3)[CH2:28]2)=[O:20].C(N(CC)CC)C>C1COCC1>[CH3:1][O:2][C:3](=[O:17])[C@:4]([CH3:16])([CH2:6][C:7]1[N:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=[CH:9][N:8]=1)[NH:5][C:19]([O:21][CH:22]1[CH:23]2[CH2:31][CH:27]3[CH2:26][CH:25]([CH2:30][CH:29]1[CH2:28]3)[CH2:24]2)=[O:20]
Reactant: COC(=O)[C@@](C)(N)Cc1ncc2ccccn12
Reactant: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@](C)(Cc1ncc2ccccn12)NC(=O)OC1C2CC3CC(C2)CC1C3
Reaction time: 2 h

Procedure:
To a stirred solution of the crude compound of Step 3 (0.83 g, 3.56 mmol) in dry THF (10 mL) was added a solution of 2-adamantyl chloroformate (0.80g, 3.7 mmol) in dry THF (3 mL) followed by a solution of triethylamine (0.38 g, 3.8 mmol) in dry THF (5 mL) dropwise. After 2 hours stirring, thereaction mixture was filtered, and the solvent removed in vacuo to give theproduct (1.2 g, 82%) as a colorless amorphous solid, which was used withoutfurther purification; IR (KBr) 1737 and 1699 cm-1.