Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH:4]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[CH:14][N:15]4[C:24]5[C:19](=[C:20](Cl)[CH:21]=[CH:22][CH:23]=5)[C:18](=[O:26])[N:17]([CH3:27])[C:16]=34)[N:8]=2)[CH2:6][CH2:5]1>CN(C)C=O>[CH:4]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[CH:14][N:15]4[C:24]5[C:19](=[C:20]([N:2]([CH3:3])[CH3:1])[CH:21]=[CH:22][CH:23]=5)[C:18](=[O:26])[N:17]([CH3:27])[C:16]=34)[N:8]=2)[CH2:6][CH2:5]1
Reactant: Cn1c(=O)c2c(Cl)cccc2n2cnc(-c3noc(C4CC4)n3)c12
Reactant: CNC
Solvent: CN(C)C=O
Product: CN(C)c1cccc2c1c(=O)n(C)c1c(-c3noc(C4CC4)n3)ncn21
Yield: 86 %

Procedure:
Gaseous dimethylamine was passed through a stirred solution of 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methyl-5-oxo-6-chloro-4,5-dihydro-imidazo(1,5-a)quinazoline (0.4 g, 1.2 mmol) in 25 ml of dry dimethylformamide at 110° C. for 2 h. The reaction mixture was evaporated in vacuo and the residue was triturated with 20 ml of water, filtered off and dried to give 0.35 g (86%) of 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methyl-5-oxo-6-dimethylamino-4,5-dihydro-imidazo(1,5-a)quinazoline, M.p. 170°-171° C.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.Br[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1>>[CH3:16][C:13]1([CH3:17])[N:12]([CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: BrCc1ccc2ccccc2c1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccc2ccccc2c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-(bromomethyl)naphthalene were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.Br[C:18]1[CH:23]=[N+:22]([O-:24])[C:21]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:20][CH:19]=1>>[CH3:28][N:27]([CH3:29])[C:25]([C:21]1[N+:22]([O-:24])=[CH:23][C:18]([O:1][C:2]2[C:7]3[CH:8]=[C:9]([CH3:11])[O:10][C:6]=3[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=2)=[CH:19][CH:20]=1)=[O:26]
Reactant: CCOC(=O)c1cc(O)c2cc(C)oc2c1
Reactant: CN(C)C(=O)c1ccc(Br)c[n+]1[O-]
Product: CCOC(=O)c1cc(Oc2ccc(C(=O)N(C)C)[n+]([O-])c2)c2cc(C)oc2c1

Procedure:
The title compound was synthesized in a similar fashion as described for Intermediate 252d, by reacting ethyl 4-hydroxy-2-methylbenzofuran-6-carboxylate and 5-bromo-N,N-dimethylpyridine-2-carboxamide 1-oxide. LC-MS (ESI, pos): 386.00.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23].Cl>CCCCC>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([C:19]1[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[C:17]([O:22][CH3:23])[CH:18]=1)=[O:5]
Reactant: COc1ccccc1OC
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Solvent: CCCCC
Product: COc1ccc(C(=O)c2cc([N+](=O)[O-])ccc2Cl)cc1OC
Temperature: 150 °C
Yield: 77.7 %

Procedure:
2-Chloro-5-nitrobenzoyl chloride (11 g; 0.05 mole), 1,2-dimethoxybenzene (20 ml; 0.15 mole) and anhydrous ferric chloride (0.5 g) are successively introduced into a flask. The mixture is progressively heated to 150° C., and maintained at this temperature for 1 hour. After cooling, the reaction mixture is poured into 1N HCl (200 ml), then extracted with dichloromethane (3×200 ml). After washing with a sodium bicarbonate solution, the organic phase is dried over MgSO4 and then concentrated under reduced pressure to provide a brown oil. By trituration with pentane (300 ml), 2-chloro-3',4'-dimethoxy-5-nitrobenzophenone (12.5 g; yield: 78%) is isolated in the form of a beige solid of m.p. 138° C. (compound no. 171).
Reaction SMILES: Br[C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:26]B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH3:26][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CB(O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)OC(C)(C)C

Procedure:
A mixture of tert-butyl N-[(1S,2S)-2-{[3-bromo-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]carbamate (1.26 g, 2.96 mmol), methylboronic acid (CAS number 13061-96-6; 0.532 g, 8.88 mmol), tetrakis(triphenylphosphine)palladium (0.342 g, 0.296 mmol) and potassium carbonate (1.303 g, 9.43 mmol) in 1,4-dioxane (10 ml) and water (1.5 ml) was sealed, evacuated and purged with nitrogen and subjected to microwave irradiation at 140° C. for 1 hour. The mixture was partitioned between ethyl acetate (10 ml) and water (10 ml). The organics were extracted with ethyl acetate (2×20 ml). The combined organics were washed with brine (20 ml), filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-60% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.Cl[CH2:14][CH2:15][N:16]([CH2:27][CH2:28]Cl)S(C1C=CC(C)=CC=1)(=O)=O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:28][CH2:27][NH:16][CH2:15][CH2:14]2)=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: Cc1ccc(N)c(C(F)(F)F)c1
Reactant: Cc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Product: Cc1ccc(N2CCNCC2)c(C(F)(F)F)c1
Yield: 26.4 %

Procedure:
Using 4-methyl-2-trifluoromethylphenylamine (1 g) and N,N-bis(2-chloroethyl)-p-toluenesulfonamide (1.69 g) and by the reaction and treatment in the same manner as in Preparation Example 95, the title compound (368 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[C:17](N(OC)C)=[O:18])[CH:5]=[CH:6][CH:7]=1.[CH3:23][Mg]Br.CCOCC>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[C:17](=[O:18])[CH3:23])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1cc2ccccc2n1-c1cccc(F)c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1cc2ccccc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a mixture of 1-(3-fluorophenyl)-N-methoxy-N-methyl-1H-indole-2-carboxamide (0.52 g, 1.7 mmol) in tetrahydrofuran (10 mL) was added 3.0 M methylmagnesium bromide in ether (4.6 mL, 0.014 mol). The reaction was stirred at room temperature overnight. The reaction was quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4, and concentrated to give crude product (0.4 g, 91%). The crude product was used directly in next step. LCMS calculated for C16H13FNO(M+H)+: m/z=254.1. Found: 254.1.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([OH:33])[CH:27]=1)[C:10]([O:12][CH2:13][C@H:14]([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18])[CH3:15])=[O:11])=O)(C)(C)C.[ClH:34]>O1CCOCC1>[ClH:34].[NH2:8][C@@H:9]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([OH:33])[CH:27]=1)[C:10]([O:12][CH2:13][C@H:14]([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18])[CH3:15])=[O:11]
Reactant: C[C@H](COC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C)OC(=O)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](COC(=O)[C@@H](N)Cc1ccc(O)c(O)c1)OC(=O)c1ccccc1
Yield: 87 %

Procedure:
A solution of (2R)-2-phenylcarbonyloxypropyl (2S)-2-(tert-butoxycarbonyl)amino-3-(3,4-dihydroxyphenyl)propanoate 1c (6.3 g, 13.7 mmol) in 50 mL of 4N HCl in dioxane was stirred at room temperature for 30 min. The mixture was concentrated to dryness under reduced pressure. The resulting residue was dissolved in ca. 20 mL of anhydrous acetonitrile and 4 mL of ether. The solution was refrigerated, and the resulting white precipitate was filtered, washed with ether, and dried under vacuum to afford 4.7 g (87% yield) of the hydrochloride salt 1d as a white solid. 1H NMR (400 MHz, CD3OD): δ 1.40 (d, J=6.4 Hz, 3H), 2.99 (dd, J=7.6, 14.4 Hz, 1H), 3.10 (dd, J=5.6, 14.4 Hz, 1H), 4.24 (dd, J=6, 8 Hz, 1H), 4.38 (dd, J=6.8, 11.6 Hz, 1H), 4.52 (dd, J=3.2, 11.6 Hz, 1H), 5.40 (m, 1H), 6.52 (dd, J=2.2, 8.4 Hz, 1H), 6.66 (d, J=2.2 Hz, 1H), 6.69 (d, J=8.2 Hz, 1H), 7.47 (t, J=7.6 Hz, 2H), 7.60 (t, J=7.6 Hz, 1H), 8.02 (d, J=7.6 Hz, 2H). MS (ESI) m/z 360.15 (M+H)+ and 358.09 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:67]=[C:68]([CH:72]=[CH:73][CH:74]=1)[C:69]([NH2:71])=[O:70]>C(Cl)Cl>[C:69]([C:68]1[CH:67]=[C:66]([NH:65][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:29])[CH:74]=[CH:73][CH:72]=1)(=[O:70])[NH2:71]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: NC(=O)c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2cccc(C(N)=O)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.172 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.258 mmol) was added followed by the addition of DIPEA (90 uL, 0.52 mmol) and 3-amino benzamide (Oakwood, 35 mg, 0.26 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (24 g column, eluent, 30% EtOAc/methylene chloride) to give a white solid. 58 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:19](=[O:36])[NH:20][C:21]3[S:22][C:23]([S:26][CH2:27][CH2:28][O:29]C4CCCCO4)=[CH:24][N:25]=3)[C:5]2=[CH:6][CH:7]=1.Cl.C(=O)([O-])O.[Na+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:19](=[O:36])[NH:20][C:21]3[S:22][C:23]([S:26][CH2:27][CH2:28][OH:29])=[CH:24][N:25]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: COC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(SCCOC3CCCCO3)s1)c1ccc(Cl)cc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(SCCO)s1)c1ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.4 %

Procedure:
The methyl 5-chloro-1-((5-((2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)thio)thiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (90.0 mg, 0.163 mmol) obtained in Example 136 was dissolved in tetrahydrofuran (1 mL) and methanol (1 mL). Thereafter, a 12 N aqueous solution of hydrochloric acid (0.2 mL) was added to the above obtained solution, and the thus obtained mixture was then stirred at room temperature for 10 minutes. Thereafter, the reaction solution was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and was then extracted with chloroform. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain the captioned compound (63.0 mg, 82%) in the form of a white solid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][NH:4]1.S(C1C=CC(C)=CC=1)(O[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: COc1ccc(CCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: OC[C@H]1CCCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CCN2CCCC[C@@H]2CO)cc1
Temperature: 90 °C

Procedure:
(R)-2-hydroxymethylpiperidine [prepared by a process described in Japanese Patent Unexamined Published Application (hereinafter referred to as “J. P. KOKAI”) No. Sho 48-19597] (600 mg, 5.22 mmol), 4-methoxyphenethyl tosylate (1.76 g, 5.74 mmol), sodium carbonate (608 mg, 5.74 mmol) and sodium iodide (100 mg, 0.67 mmol) were added to acetonitrile (50 ml), and they were heated under reflux at 90° C. for 3.5 hours. The solvent was evaporated under reduced pressure. The residue was distributed in ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with water and dried over magnesium sulfate. Then the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with hexane and dichloromethane (1:1), then with dichloromethane and finally with dichloromethane and methanol (20:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-2-hydroxymethyl-1-(4-methoxyphenethyl)piperidine in the form of a light yellow oil (617 mg, 47%).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([NH2:9])[NH:4][N:3]=1.IC.[C:12](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([NH2:9])[N:4]([CH3:12])[N:3]=1
Reactant: N#Cc1c(N)n[nH]c1N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cn1nc(N)c(C#N)c1N
Yield: 16.2 %

Procedure:
3,5-Diamino-4-cyanopyrazole (6.1 g) prepared as in Example 3, iodomethane (3.1 ml), anhydrous potassium carbonate (7.6 g) and acetone (120 ml) were heated under reflux for 18 hours. The mixture was filtered, and the filtrate was concentrated to a viscous oil. Trituration of the oil with water gave a precipitate of 3,5-diamino-4-cyano-1-methylpyrazole (1.1 g), m.p. 194°-196° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][N:7]([C:14](=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:32][C@@H:33]([C@@H:40]1[C@@:44]2([CH3:62])[CH2:45][CH2:46][CH:47]3[C@@:52]4([CH3:61])[CH2:53][CH2:54][CH:55]([O:57][C:58](Cl)=[O:59])[CH2:56][C:51]4=[CH:50][CH2:49][CH:48]3[CH:43]2[CH2:42][CH2:41]1)[CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38]>ClCCl>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][N:7]([C:14](=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:58]([O:57][CH:55]1[CH2:56][C:51]2[C:52]([CH3:61])([CH:47]3[CH:48]([CH2:49][CH:50]=2)[CH:43]2[C:44]([CH3:62])([CH:40]([CH:33]([CH3:32])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:38])[CH3:39])[CH2:41][CH2:42]2)[CH2:45][CH2:46]3)[CH2:53][CH2:54]1)=[O:59])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Reactant: CCOC(=O)CCN(CC(=O)OCC)C(=O)CCCCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CCN(CC(=O)OCC)C(=O)CCCCCNC(=O)OC1CCC2(C)C(=CCC3C2CCC2(C)C(C(C)CCCC(C)C)CCC32)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Hydrochloride salt of 3-[(6-Amino-hexanoyl)-ethoxycarbonylmethyl-amino]-propionic acid ethyl ester AC (4.7 g, 14.8 mmol) was taken in dichloromethane. The suspension was cooled to 0° C. with ice. To the suspension diisopropylethylamine (3.87 g, 5.2 mL, 30 mmol) was added. To the resulting solution cholesteryl chloroformate (6.675 g, 14.8 mmol) was added. The reaction mixture was stirred overnight. The reaction mixture was diluted with dichloromethane and washed with 10% hydrochloric acid. The product was purified flash chromatography (10.3 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:13]([C@@H:22]([CH2:30][CH3:31])[CH2:23][NH:24][S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])[C:12](=[O:32])[C@:11]([CH2:34][C:35]([OH:37])=[O:36])([CH3:33])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].I[CH3:41]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:14]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[N:13]([C@@H:22]([CH2:30][CH3:31])[CH2:23][N:24]([CH3:41])[S:25]([CH2:28][CH3:29])(=[O:26])=[O:27])[C:12](=[O:32])[C@:11]([CH2:34][C:35]([OH:37])=[O:36])([CH3:33])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CI
Reactant: CC[C@@H](CNS(=O)(=O)CC)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cc(F)cc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H](CN(C)S(=O)(=O)CC)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cc(F)cc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-((3R,5R,6S)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (Example 393, Step D, 26.6 mg, 0.046 mmol) in DMF (464 μl) at rt was added a dispersion of 60% sodium hydride in mineral oil (5.57 mg, 0.139 mmol). The grey slurry was stirred at rt for 30 min then iodomethane (5.80 μl, 0.093 mmol) was added. The mixture was stirred at rt for 1 h. The mixture was quenched with 1 M HCl and diluted with EtOAc. The aqueous layer was extracted with EtOAc 2×. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by reverse phase preparatory HPLC (column: Gemini™ Prep C18 10 um column; Phenomenex, Torrance, Calif.; eluent: 0 to 100% MeCN+0.1% TFA in water+0.1% TFA, over 20 minutes) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:13]1(=[O:17])[CH2:16][CH2:15][CH2:14]1.[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1.C([Li])CCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]2([OH:17])[CH2:16][CH2:15][CH2:14]2)=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: FC(F)(F)c1cc(Br)ccc1I
Reactant: O=C1CCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC1(c2ccc(Br)cc2C(F)(F)F)CCC1
Reaction time: 0.42 h
Yield: 71.3 %

Procedure:
To a solution of 5-bromo-2-iodobenzotrifluoride (5.00 g) in dehydrated tetrahydrofuran (140 mL), n-butyl lithium (2.69 mol/L, solution in n-hexane, 5.30 mL) was added at −78° C. and the mixture was stirred at that temperature for 25 minutes. After adding a solution of cyclobutanone (999 mg) in tetrahydrofuran (5.00 mL), the mixture was brought to room temperature and stirred for 3 days. After adding a saturated aqueous solution of ammonium chloride under cooling with ice, two extractions were conducted with ethyl acetate. The combined organic layers were washed with water and thereafter dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=98:2-80:20) to give 1-[4-bromo-2-(trifluoromethyl)phenyl]cyclobutanol as a pale yellow oil (3.00 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][N:38]=[C:37]([C:41]#[N:42])[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][N:38]=[C:37]([C:41]#[N:42])[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Product: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1

Procedure:
The title compound was prepared from (2-amino-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J1) (181 mg, 0.5 mmol) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example K3) (123 mg, 0.5 mmol) according to the general procedure M. Obtained as an off-white solid (137 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].Br[CH2:12][CH2:13][Cl:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:12][CH2:13][Cl:14])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1OCCCl
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A suspension of 2-nitrophenol (50.0 g, 0.36 mol), 1-bromo-2-chloroethane (45 mL, 0.54 mol), and K2CO3 (100.0 g, 0.72 mol) in DMF (200 mL) was stirred at 90° C. for 2 h, cooled to room temperature, poured into ice-water, filtered, washed with H2O and dried to give Compound 7, 70.3 g (96%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]([C:11]1[CH:16]=[CH:15]C=[CH:13][CH:12]=1)(C)[C:7]([OH:9])=[O:8])=[O:4].N[C:18]([C:23]1[CH:28]=CC=C[CH:24]=1)(C)C(O)=O>>[C:23]([O:4][C:3]([N:5]1[CH2:13][CH2:12][CH:11]([CH:6]([C:7]([OH:9])=[O:8])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:16][CH2:15]1)=[O:2])([CH3:18])([CH3:24])[CH3:28]
Reactant: CC(N)(C(=O)O)c1ccccc1
Reactant: COC(=O)NC(C)(C(=O)O)c1ccccc1
Product: COC(=O)NC(C(=O)O)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 97 %

Procedure:
4-(Carboxy-methoxycarbonylamino-methyl)-piperidine-1-carboxylic acid tert-butyl ester (1.2 g, 97%) was prepared following the procedure for 2-Methoxycarbonylamino-2-phenyl-propionic acid, substituting 4-(Amino-carboxy-methyl)-piperidine-1-carboxylic acid tert-butyl ester for 2-Amino-2-phenyl-propionic acid. LCMS-ESI+: calc'd for C14H24N2O6: 316.16 (M+); Found: 339.02 (M+Na+).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([CH3:29])[C@H:26]([C:30]([N:32]3[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]3)=[O:31])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[SH:23][C@@H:24]1[CH2:28][N:27]([CH3:29])[C@H:26]([C:30]([N:32]2[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]2)=[O:31])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C)CC3)N(C)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10 ml of trifluoroacetic acid, followed by 510 liters of trifluoromethanesulfonic acid were added, whilst ice-cooling, to a solution of 1050 mg of (2S,4S)-4-(4-methoxybenzylthio)-2-(4-methyl-1-piperazinylcarbonyl)-1-methylpyrrolidine [prepared as described in step (i) above] in 3 ml of anisole, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was triturated with diethyl ether to cause solidification. The solid was washed with diethyl ether five times and dried, to give 1350 mg of the title compound as a powder.