Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]1=[O:11].[H-].[Na+].CS(O[CH2:19][CH2:20][CH2:21][C:22]1([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)(=O)=O.Cl>O.C(OCC)(=O)C.CN(C)C=O>[O:11]=[C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]1[CH2:19][CH2:20][CH2:21][C:22]1([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:24][CH2:23]1
Reactant: CCOC(=O)C1(CCCOS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=c1cnc2ccccc2[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(CCCn2c(=O)cnc3ccccc32)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To 5 mL of an N,N-dimethylformamide suspension containing 0.25 g of quinoxalin-2(1H)-one, 0.10 g of 60% sodium hydride was added at room temperature, and the mixture was stirred at 50° C. for 30 minutes. Thereto was dividedly added 0.68 g of 1-tert-butyl 4-ethyl 4-(3-((methanesulfonyl)oxy)propyl)piperidine-1,4-dicarboxylate at the same temperature, and the mixture was stirred at 80 to 90° C. for 2 hours. The reaction mixture was cooled to room temperature, ethyl acetate and water were added thereto, and the resultant solution was adjusted to pH 2.0 with 6 mol/L hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed sequentially with water and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=1:1] to obtain 0.18 g of a yellow brown oily substance, 1-tert-butyl 4-ethyl 4-(3-(2-oxoquinoxalin-1(2H)-yl)propyl)piperidine-1,4-dicarboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:15])[N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)=[O:5])[CH3:2].S(Cl)([Cl:19])(=O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:15])[N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:10]=1[Cl:19])=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1C
Solvent: ClCCl
Product: CCOC(=O)c1c(Cl)c(C(C)(C)C)nn1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-tert-butyl-2-methyl-pyrazole-3-carboxylic acid ethyl ester (2.10 g, 10.0 mmol) in 25 mL of DCM was added sulfuryl chloride (1.05 ml, 13.0 mmol) slowly under Ar. After stirring at room temperature for 3 h under Ar, the resulting mixture was treated with DCM (30 mL), washed with ice H2O, saturated aqueous NaHCO3 and brine, and dried with Na2SO4. Removal of the solvent under reduced pressure yielded the title compound as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 4.40 (q, J=7.2 Hz, 2H), 4.07 (s, 3H), 1.42 (t, J=7.2 Hz, 3H), 1.40 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calculated For C11H17ClN2O2: 245.1 (M+H), Measured: 245.1.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:7][CH:8]([OH:10])[CH3:9].[CH3:11]COC(C)=O>>[CH:7]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:1]=2)[CH:11]=[CH:9][C:8]=1[OH:10]
Reactant: CC(C)O
Reactant: CCCCCC
Reactant: CCOC(C)=O
Product: Oc1ccc2ccccc2c1

Procedure:
A reaction flask described in example 9 was charged with a solution of catalyst 1c (12.2 mg, 0.02 mmol) in anhydrous CCl4 (1 mL). The solution was stirred for 10 min under an oxygen atmosphere and then treated with a solution of 6-bromo-2-naphthol (44 mg, 0.2 mmol) in anhydrous CCl4 (1 mL) under 0° C. The reaction mixture was stirred at 0° C. until the reaction was complete (monitored by TLC). The crude mixture was concentrated under reduced pressure, and purified by column chromatography (Ethyl acetate/Petroleum ether-⅓) to give (R)-BINOL 3c, Yield 99%. [α]D25=−33.7 (c=0.4 in EtOAc), 1H NMR (300 MHz, CDCl3) δ (ppm) 8.06 (d, J=1.8 Hz, 2H, 2×HC (4)), 7.89 (d, J=9.0 Hz, 2H, 2×HC (5)), 7.37 (d, J=6.9 Hz, 2H, 2×HC (8)), 7.36 (dd, J=9.0 Hz, 1.8 Hz, 2H, 2×HC (7)), 6.96 (d, J=9.0 Hz, 2H, 2×HC (3)), 5.08 (s, 2H, 2×OH). e.e. 90%, and the configuration was R (Kromasil CHI-TBB column, Hexane/propan-2-ol=80: 20; flow rate 1 mL/min; S-isomer, tR 6.68 min and R-isomer, tR 7.51 min).
Reaction SMILES: C([O:8][NH:9][C:10]([C@H:12]1[CH2:16][C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:14](=[O:25])[NH:13]1)=[O:11])C1C=CC=CC=1.C(OCC)(=O)C.CCCCCC>CO.[Pd]>[OH:8][NH:9][C:10]([C@H:12]1[CH2:16][C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:14](=[O:25])[NH:13]1)=[O:11]
Reactant: COc1ccc([C@@H]2C[C@H](C(=O)NOCc3ccccc3)NC2=O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: COc1ccc([C@@H]2C[C@H](C(=O)NO)NC2=O)cc1
Yield: 96.3 %

Procedure:
A solution of (2R, 4S)-4-(4-methoxyphenyl)-5-oxopyrrolidine-2-carboxylic acid benzyloxyamide (150 mg, 0.44 mmol) in methanol (15 mL) was treated with 5% palladium on barium sulfate (40 mg) and hydrogenated in a Parr™ shaker at 3 atmospheres pressure for 2.5 hours. The catalyst was removed by filtration and the solvent was evaporated to provide a solid. The title compound (106 mg, 96%) was isolated by crystallization from a mixture of ethyl acetate and hexane.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([CH2:12][C:13](=[O:35])[NH:14][O:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2].[O:37]([CH2:44][CH2:45][NH2:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:1]([O:5][C:6](=[O:36])[CH2:7][CH:8]([C:9](=[O:10])[NH:46][CH2:45][CH2:44][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:12][C:13](=[O:35])[NH:14][O:15][C:16]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: NCCOc1ccccc1
Reactant: CC(C)(C)OC(=O)CC(CC(=O)NOC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)CC(CC(=O)NOC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCOc1ccccc1

Procedure:
This compound was prepared by reacting the compound of Example 63 with 2-phenoxy ethylamine.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:10]12([NH2:15])[CH2:14][CH:12]([CH2:13]1)[CH2:11]2>C(#N)C>[C:10]12([NH:15][C:3]3[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=3)[CH2:14][CH:12]([CH2:13]1)[CH2:11]2
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: NC12CC(C1)C2
Solvent: CC#N
Product: Clc1ncc(Br)c(NC23CC(C2)C3)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82 %

Procedure:
To a solution of 5-Bromo-2,4-dichloro-pyrimidine (6 g, 26.3 mmol) and bicyclo[1.1.1]pent-1-ylamine (4.7 g, 39.5 mmol) in acetonitrile (60 mL), was added TEA (16.5 mL, 118 mmol), and the mixture was stirred at 25° C. for 18 hours. The volatiles were removed in vacuo and the residue partitioned between water and EtOAc. The organic phase was dried (Na2SO4) and evaporated in vacuo. Purification by column chromatography on silica gel (EtOAc:Hexane 1:99) afforded the title compound as a white solid in 82% yield, 4.8 g.
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:16]=[C:17]3[C:23]([C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:22][N:21](COCC[Si](C)(C)C)[C:18]3=[N:19][CH:20]=2)=[CH:10][CH:9]=1)[C:4]([NH2:6])=[O:5])#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3](=[CH:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[N:16]=[C:17]3[C:23]([C:24](=[O:29])[C:25]([CH3:27])([CH3:26])[CH3:28])=[CH:22][NH:21][C:18]3=[N:19][CH:20]=2)=[CH:12][CH:13]=1)[C:4]([NH2:6])=[O:5])#[N:2]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C(C#N)C(N)=O)cc3)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(Nc3ccc(C=C(C#N)C(N)=O)cc3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.7 %

Procedure:
To a 25 ml one necked round bottom flask 2-cyano-3-(4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)acrylamide (0.1 g, 0.0002 mole) was taken in CH2Cl2 (10 ml). To this reaction mixture TFA (2.0 ml) was added dropwise at 0° C. After completion of the addition, the reaction mixture was warmed up to RT and then stirred for 16 hr. After completion of the reaction, CH2Cl2 was distilled out and the pH was adjusted to 8 to 9 using saturated NaHCO3 solution at 5° C. The reaction mixture was stirred for 15 min, solid was filtered, washed with n-pentane and dried. In a 25 ml RBF, dried solid was taken in ethanol and NaOAc. 3H2O (0.27 g, 0.002 mole) was added at RT. The reaction mixture was stirred for 20 hr at RT, diluted with ethyl acetate and distilled out under vacuum. To the resultant residual solid water was added, the mixture was stirred for 15 min, filtered, wash with water and n-pentane was added. The product was filtered and dried under vacuum to yield 20 mg of 2-cyano-3-(4-(7-pivaloyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)acrylamide.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][N:3]=[C:2]1[NH:7][C:8]([CH2:10][CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)=[O:9].S(Cl)([Cl:23])=O.S(=O)=O>C1(C)C=CC=CC=1>[ClH:23].[NH:1]1[CH2:6][CH2:5][CH2:4][N:3]=[C:2]1[NH:7][C:8]([CH2:10][CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([Cl:23])=[O:17])=[CH:14][CH:13]=1)=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(CCc1ccc(C(=O)O)cc1)NC1=NCCCN1
Agent: O=S=O
Solvent: Cc1ccccc1
Product: Cl
Product: O=C(CCc1ccc(C(=O)Cl)cc1)NC1=NCCCN1
Temperature: 70 °C

Procedure:
110.2 g (0.4 mol) of 4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoic acid were suspended in 1.5 l of toluene, then 35 ml of thionyl chloride were added and the mixture was heated to 70° C. for 2 h. Then further 16 ml of thionyl chloride were added and heating was continued until the evolution of sulfur dioxide had ceased. The almost clear solution was evaporated to dryness to give 139.5 g of the crude title compound as a yellow powder. This product was directly used in the subsequent reaction.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:12]1[N:13]([CH2:25][CH2:26][CH2:27][NH2:28])[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=1)[CH2:9][CH2:10][CH3:11].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH2:8]([C:12]1[N:13]([CH2:25][CH2:26][CH2:27][NH:28][S:30]([CH3:29])(=[O:32])=[O:31])[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc2cnc3ccccc3c2n1CCCNS(C)(=O)=O
Reaction time: 8 h
Yield: 74.1 %

Procedure:
Triethylamine (1.1 g, 10.6 mmol) was added with stirring to a solution of 3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylamine (2.00 g, 7.08 mmol) in dichloromethane (˜150 mL). Methanesulfonyl chloride (892 mg, 7.79 mmol) was added and the reaction was stirred under nitrogen overnight. The reaction mixture was washed with aqueous 1% sodium bicarbonate solution (3×50 mL). The aqueous washes were extracted with dichloromethane (2×20 mL). The organics were combined, dried over magnesium sulfate and then concentrated under reduced pressure to provide 1.89 g of N-[3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]methanesulfonamide as a light brown solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([S:9]([CH3:12])(=[O:11])=[O:10])[N:3]=1.Cl[C:14]1[C:19]2[O:20][CH2:21][CH2:22][N:23]([CH:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)[C:18]=2[N:17]=[CH:16][N:15]=1>>[CH3:1][C:2]1[C:7]([NH:8][C:14]2[C:19]3[O:20][CH2:21][CH2:22][N:23]([CH:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]4)[C:18]=3[N:17]=[CH:16][N:15]=2)=[CH:6][CH:5]=[C:4]([S:9]([CH3:12])(=[O:11])=[O:10])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCOc3c(Cl)ncnc32)CC1
Reactant: Cc1nc(S(C)(=O)=O)ccc1N
Product: Cc1nc(S(C)(=O)=O)ccc1Nc1ncnc2c1OCCN2C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
By the procedure described in Example 3, with the exception that 2-methyl-6-(methylsulfonyl)pyridin-3-amine was used instead of 2-fluoro-4-(methylsulfonyl)-aniline, tert-butyl 4-(4-chloro-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate from Example 3C was converted into Example 123. 1H NMR (500 MHz, CDCl3) δ ppm 1.45 (s, 9 H) 1.55-1.65 (m, 2 H) 1.66-1.72 (m, 2 H) 2.61 (s, 3 H) 2.82-2.90 (m, 2 H) 3.15 (s, 3 H) 3.45-3.48 (m, 2 H) 4.25-4.28 (m, 4 H) 4.79-4.88 (m, 1 H) 6.86-7.00 (m, 1 H) 7.91 (d, J=8.25 Hz, 1 H) 8.06 (s, 1 H) 8.91 (m, 1 H). LRMS (ESI): 505.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18](Cl)[N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:28][S:29]([C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][NH2:35])(=[O:31])=[O:30].C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:35][CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=3[S:29]([CH3:28])(=[O:31])=[O:30])[N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(Cl)ncc2[N+](=O)[O-])CC1
Reactant: CS(=O)(=O)c1ccccc1CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCc3ccccc3S(C)(=O)=O)ncc2[N+](=O)[O-])CC1
Reaction time: 24 h
Yield: 69.1 %

Procedure:
{4-[(2-Chloro-5-nitro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (100 mg, 0.26 mmol) was dissolved in DMF (3 mL). 2-Methanesulfonyl-benzylamine hydrochloride (115 mg, 0.52 mmol) and diisopropylethylamine (0.14 mL, 0.78 mmol) were added sequentially. After 24 h, the reaction was partitioned between water (10 mL) and DCM (10 mL). The organic layer was washed with 5% AcOH (aq), saturated Na2CO3 and water, dried over MgSO4, filtered and concentrated. Chromatography (silica, 0-15% MeOH in DCM; Rf=0.3 10% MeOH in DCM) yielded 96 mg of (4-{[2-(2-methanesulfonyl-benzylamino)-5-nitro-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester as a pale yellow solid, m/z 535.7 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C@H:18]([CH3:27])[CH2:19][N:20]2[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)=[CH:15][C:14]([C:28]([CH3:33])([CH3:32])[C:29]([OH:31])=O)=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl.[CH:35]12[NH:41][CH:38]([CH2:39][CH2:40]1)[CH2:37][CH2:36]2.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(N(CC)CC)C>[CH:38]12[N:41]([C:29](=[O:31])[C:28]([C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[NH:10][C:9]([C:4]3[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=3)=[C:17]4[C@H:18]([CH3:27])[CH2:19][N:20]3[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]3)([CH3:33])[CH3:32])[CH:35]([CH2:40][CH2:39]1)[CH2:36][CH2:37]2
Reactant: C1CC2CCC1N2
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)O)cc3c2[C@H](C)CN2CCC(=O)CC2)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2[C@H](C)CN2CCC(=O)CC2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 73.5 %

Procedure:
To a solution of (S)-2-(2-(3,5-dimethylphenyl)-3-[1-methyl-2(4-oxo-piperidin-1-yl)-ethyl]-1H-indol-5-yl]-2-methylpropionic acid (148 mg in 2 mL dry methylene chloride) was added 58 mg 7-aza-bicyclo[2.2.1]heptane hydrochloride followed by 0.185 mL triethylamine and 173 mg of the PyBOP reagent and the mixture stirred at room temperature. After 14 hours, the mixture was concentrated in vacuo and the residue dissolved in ethyl acetate, washed with water and brine and the organic portion dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane, 3:2) gave the title compound (128 mg).
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([O:23][CH3:24])[CH:17]=[C:16]2[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1.[I:32][C:33]1[CH:44]=[CH:43][C:36]([C:37](N(OC)C)=[O:38])=[CH:35][CH:34]=1>C1COCC1>[Cl:31][C:27]1[CH:26]=[C:25]([C:16]2[C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:37]([C:36]4[CH:43]=[CH:44][C:33]([I:32])=[CH:34][CH:35]=4)=[O:38])[CH:14]=3)[N:19]=[C:18]([O:23][CH3:24])[CH:17]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(Br)ccc2n1
Reactant: CON(C)C(=O)c1ccc(I)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccc(I)cc3)ccc2n1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 127.9 %

Procedure:
BuLi 1.6M in hexane (0.0316 mol) was added dropwise at −70° C. to a mixture of 6-bromo-4-(3-chlorophenyl)-2-methoxyquinoline (0.0287 mol) in TBIF (100 ml). The mixture was stirred at −70° C. for 30 minutes and a solution of 4-iodo-N-methoxy-N-methyl-benzamide (0.0244 mol) in THF (30 ml) was added. The mixture was stirred at −70° C. for 30 minutes, poured out into ice water and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness, yielding 15.6 g (>100%) of [4-(3-chlorophenyl)-2-methoxy-6-quinolinyl](4-iodophenyl)methanone, (intermediate 18).This product was used without further purification.
Reaction SMILES: C(OC(N1CCC[C@@H]1C([N:18]1[C:26]2[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=2)[CH:20]=[CH:19]1)=O)=O)C1C=CC=CC=1.[CH2:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])C.[C:36](OCC)(=O)C>>[CH3:28][O:27][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[NH:18][CH:19]=[C:20]2[CH2:33][C@H:32]1[CH2:36][CH2:35][CH2:34][N:31]1[CH3:29]
Reactant: CCN(CC)CC
Reactant: CCOC(C)=O
Reactant: COc1ccc2c(ccn2C(=O)[C@H]2CCCN2C(=O)OCc2ccccc2)c1
Product: COc1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1
Yield: 13 %

Procedure:
(R)-(N-Benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5-methoxy-1H-indole was used. The chromatographic eluent was 8% triethylamine in ethyl acetate to afford the title compound (yields ranged from 13 to 61%) as an oil whose spectral and physical properties were identical with the spectral and physical properties of the title compound of Example 1A with the exception of specific rotation of plane polarized light: [α]25D =+100° (CHCl3, c=1.0). HRMS: calculated for C15H20N2O: 244.1573; found: 244.1547.
Reaction SMILES: C1(C2C=CC([CH:8]=[O:9])=CC=2)CC1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:22][CH3:23])([CH3:21])[CH3:20])=[C:15]([Cl:24])[CH:14]=1.[Li]CCCC.CCCCCC.CN(C=O)C>>[Cl:24][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[C:19]([O:22][CH3:23])([CH3:21])[CH3:20])[CH:8]=[O:9]
Reactant: COC(C)(C)c1ccc(Br)cc1Cl
Reactant: O=Cc1ccc(C2CC2)cc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COC(C)(C)c1ccc(C=O)cc1Cl
Yield: 62 %

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S53) using 310 mg of 4-bromo-2-chloro-1-(1-methoxy-1-methyl-ethyl)-benzene (1.18 mmol), 1.1 ml of a 1.6 molar solution of n-BuLi in hexane (1.76 mmol) and 457 μl of DMF (5.88 mmol). The isolated residue was purified by flash column chromatography (1:9 ether/pentane) to give 154 mg of 3-chloro-4-(1-methoxy-1-methyl-ethyl)-benzaldehyde (62%) as a colorless liquid. 1H NMR (CDCl3, 300 MHz): δ 1.69 (s, 6H), 3.18 (s, 3H), 7.69 (d, J=8.2 Hz, 1H), 7.75 (dd, J=8.2 and 1.7 Hz, 1H), 7.58 (d, J=1.7 Hz, 1H), 9.97 (s, 1H).
Reaction SMILES: [OH-:1].[Na+].C([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]#[N:29])=[C:26]([CH:30]([OH:34])[CH:31]([CH3:33])[CH3:32])[N:25]=[C:24]2[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:18][CH:17]=1)=[O:9])(C)(C)C>C(O)C>[CH2:8]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]([NH2:29])=[O:1])=[C:26]([CH:30]([OH:34])[CH:31]([CH3:32])[CH3:33])[N:25]=[C:24]2[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:18][CH:17]=1)=[O:9])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCc1nc(C(O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCCCOC(=O)c1ccccc1-c1ccc(Cn2c(CCCC)nc(C(O)C(C)C)c2C(N)=O)cc1

Procedure:
20 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 297 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxy-2-methylpropyl)imidazole-5-carbonitrile [prepared as described in step (b) above] in 20 ml of ethanol, and the resulting mixture was heated under reflux for 8 hours. An the end of this time, the reaction mixture was worked up in a similar manner to that described in Example 45(c), to afford 151 mg of the title compound as an amorphous solid.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.[C:17]1([C:23](OC)=[O:24])[CH2:22][CH2:21][CH:20]=[CH:19][CH:18]=1>C1COCC1.O>[C:1]([NH:5][C:23]([C:17]1[CH2:22][CH2:21][CH:20]=[CH:19][CH:18]=1)=[O:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: COC(=O)C1=CC=CCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)NC(=O)C1=CC=CCC1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 33471.2 %

Procedure:
t-Butylamine (2.38 g, 0.033 mmol) was dissolved in THF (20 ml), 1.6M solution of n-butyl lithium in hexane (20 ml, 0.032 mol) was added thereto at 0° C. and the mixture was stirred as it was for 40 minutes. A solution of methyl 1,3-cyclohexadiene-1-carboxylate (3 g, 0.0217 mol) synthesized in Example 12 in THF (3 ml) was added dropwise and the solution was further stirred for 30 minutes. The reaction mixture was poured in water, extracted with methylene chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (silica gel 60 g, ethyl acetate:hexane=1:5) to obtain 1,3-cyclohexadiene-1-carboxylic acid t-butylamide (1.98 g, 5 1%). This compound has the following NMR spectrum.
Reaction SMILES: [NH:1]1[CH2:4][C:3](=[CH:5][C:6]2[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=2[Cl:16])[CH2:2]1.C(N(CC)CC)C.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH:33]=O)[CH:31]=2)[CH:26]=[CH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(Cl)Cl.C(Cl)Cl>[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH2:33][N:1]3[CH2:4][C:3](=[CH:5][C:6]4[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=4[Cl:16])[CH2:2]3)[CH:31]=2)[CH:26]=[CH:25]1
Reactant: COC(=O)c1ccc(C=C2CNC2)c(Cl)c1
Reactant: O=Cc1ccc2cc[nH]c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C=C2CN(Cc3ccc4cc[nH]c4c3)C2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 112 %

Procedure:
A solution of the hydrochloride salt of methyl 4-(azetidin-3-ylidenemethyl)-3-chlorobenzoate (0.20 g, 0.73 mmol) in THF:DCM (2:1) (25 mL) was neutralized by addition of triethylamine (0.14 mL, 0.88 mmol). After stirring at room temperature for 20 mins, indole-6-carboxaldehyde (0.16 g, 1.00 mmol) and sodium triacetoxyborohydride (0.50 g, 2.37 mmol) were added and the reaction mixture was heated at 50° C. overnight. It was then diluted with DCM (50 mL) and washed with saturated sodium bicarbonate (3×25 mL) and brine (1×15 mL). The organic layer was separated, dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum to give the crude product which was purified by silica gel column chromatography using 10-40% EtOAc in hexanes as eluent. Fractions containing the pure product were pooled and evaporated to give 0.3 g of methyl 4-((1-((1H-indol-6-yl)methyl)azetidin-3-ylidene)methyl)-3-chlorobenzoate (0.30 g) as a colorless oil. ES+(M+H)+367