Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([CH3:11])[CH3:10])[C:4]=1[OH:12])[CH3:2].[OH2:13]>>[CH2:1]([C:3]1[CH:8]=[C:7]([OH:13])[CH:6]=[C:5]([CH:9]([CH3:11])[CH3:10])[C:4]=1[OH:12])[CH3:2]
Reactant: CCc1cccc(C(C)C)c1O
Reactant: O
Product: CCc1cc(O)cc(C(C)C)c1O
Reaction time: 3 h

Procedure:
To a solution of K2S2O8 (8.2 g) in 80 mL of water, was added at once a solution of the above 2-ethyl-6-isopropylphenol (2 g, 12.2 mmol in 25 mL 5% NaOH solution). The mixture was stirred for 3 h and extracted with hexane (3×60 mL). The organic extract was stirred with Na2S2SO4 solution (8.5 g, in 100 mL water) for one hour and the layers were separated. The organic layer was dried over Na2S2O4 and concentrated and dried under high vacuum to give 2-ethyl-6-isopropylbenzene-1,4-diol. To a solution of the crude 2-ethyl-6-isopropylbenzene-1,4-diol in dichloromethane (50 mL) was added acetyl chloride (2.9 g, 36 mmol) and then triethylamine (6 g, 60 mmol) slowly at 0° C. The mixture was stirred at room temperature for 2 h and diluted with hexane/EtOAc (4:1). The mixture was filtered and the filtrate was washed with water (3×80 mL) and dried over Na2SO4 and concentrated. The crude product was purified to afford 2-ethyl-6-isopropyl-1,4-phenylene diacetate as a yellow oil (750 mg).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26][C:27]([C:30]([O:32][CH3:33])=[O:31])([CH3:29])[CH3:28])/[C:9]1=[O:34])=O)(C)(C)C.[CH3:35][C:36]1[CH:37]=[CH:38][C:39]([O:51][CH3:52])=[C:40]([CH:42]=[N:43][C:44]([O:46][Si](C)(C)C)=[CH2:45])[CH:41]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:34])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=4[O:26][C:27]([C:30]([O:32][CH3:33])=[O:31])([CH3:29])[CH3:28])[CH2:45][C:44](=[O:46])[NH:43][CH:42]3[C:40]3[CH:41]=[C:36]([CH3:35])[CH:37]=[CH:38][C:39]=3[O:51][CH3:52])[C:11]2=[CH:12][CH:13]=1
Reactant: C=C(N=Cc1cc(C)ccc1OC)O[Si](C)(C)C
Reactant: COC(=O)C(C)(C)Oc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(C)ccc2OC)C12C(=O)Nc1cc(Cl)ccc12
Yield: 2.3 %

Procedure:
In a manner similar to the method described in Example 10d, E/Z-6-chloro-3-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (5 g, 10.31 mmol) prepared in Example 1c was reacted with 1-(5-methyl-2-methoxy-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (51 mmol) in toluene to give the title compound as a white solid (143 mg).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH:22]([C:28]([OH:30])=[O:29])[CH2:23][S:24][C:25](=[O:27])[CH3:26])[CH2:18][CH2:17]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:31][C:32](=[CH2:34])[CH3:33]>ClCCl>[CH2:6]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH:22]([C:28]([O:30][C:32]([CH3:34])([CH3:33])[CH3:31])=[O:29])[CH2:23][S:24][C:25](=[O:27])[CH3:26])[CH2:18][CH2:17]1)=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)SCC(C(=O)O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(=O)SCC(C(=O)OC(C)(C)C)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 8 h
Yield: 60 %

Procedure:
Sulfuric acid (1.15 ml) was added slowly to a solution of 4-(2-acetylsulfanyl-1-carboxy-ethyl)-piperidine-1-carboxylic acid benzyl ester (20.32 g) in dichloromethane (60 ml). The mixture was cooled in an acetone/dry ice bath and cooled isobutylene (60 ml) added. The mixture was transferred to a Parr high pressure apparatus and left to stir overnight then washed with water (30 ml), saturated sodium bicarbonate solution (30 ml) and brine (30 ml). After drying (Na2SO4) and filtering the solvent was removed under reduced pressure and the residue purified by column chromatography (SiO2, 20% ethyl acetate in hexane) to give the title compound (11.22 g, 60%) as an orange oil.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][O:10][C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:13].C(O)(=O)C>>[Br:13][CH2:11][CH2:12][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C1OCCC1c1ccccc1
Reactant: Br
Solvent: CC(=O)O
Product: O=C(O)C(CCBr)c1ccccc1

Procedure:
The product of Example 3 (14.5 g, 90 mM) in 48% of HBr/acetic acid (100 ml) was left at room temperature overnight. The reaction was poured onto water (500 ml) and extracted with IPE 2x). The organic phase was washed with water, dried and evaporated to give the crystalline product (22 g) m.p. (cyclohexane).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21][CH2:22][CH3:23])[N:14]([CH2:15][C:16]([CH3:19])([CH3:18])[OH:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C(N(CC)CC)C.[C:31](Cl)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(#N)C>[CH2:22]([O:21][CH2:20][C:13]1[N:14]([CH2:15][C:16]([CH3:19])([OH:17])[CH3:18])[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH:1][C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:11]=2[N:12]=1)[CH3:23]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(NC(c3ccccc3)(c3ccccc3)c3ccccc3)nc3ccccc3c2n1CC(C)(C)O
Yield: 83.6 %

Procedure:
4-Amino-2-(ethoxymethyl)-α,α-dimethyl-1H-Imidazo[4,5-c]quinoline-1-ethanol (CAN 144875-48-9, 1.6 g, 5.09 mmol) was combined with acetonitrile (60 mL) to give a white suspension. Then triethylamine (1.77 mL, 12.7 mmol) and trityl chloride (1.7 g, 6.11 mmol) were added under Argon with stirring. The reaction mixture was irradiated in a microwave reactor at 100° C. for 30 minutes. Upon stirring the mixture the product precipitated and was isolated by filtration at 0° C., washed with cold acetonitrile and dried to yield the title compound (2.37 g, 83%) as white solid; MS (ESI): 557.5(MH+).
Reaction SMILES: [Mg].II.[CH3:4][CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1.C[O:23][B:24]([O:27]C)[O:25]C.S(=O)(=O)(O)O>O1CCCC1>[CH3:4][CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([O:23][B:24]([OH:27])[OH:25])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)CCCC(C)CCOc1cccc(Br)c1
Reactant: COB(OC)OC
Agent: II
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)CCCC(C)CCOc1cccc(OB(O)O)c1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
Under an inert atmosphere, 7.5 g of magnesium and a small amount of iodine were charged in 100 ml of dried tetrahydrofuran in a three-necked flask. Using a dropping funnel, 90 g of the above-mentioned 3-(3,7-dimethyloctyloxy)-bromobenzene was dropped over 50 minutes. After completion of dropping, 200 ml of dried tetrahydrofuran was added, and the mixture was stirred while heating for 2 hours under reflux to prepare a Grignard reagent. After completion of heating, the reagent was left to cool to room temperature. Into a three-necked flask other than the above-mentioned flask was charged 38 g of trimethylboric acid and 300 ml of dried tetrahydrofuran, and the flask was cooled in a dry ice/aceton bath. Using a dropping funnel, the above-mentioned Grignard reagent solution was dropped over 35 minutes. After completion of dropping, the reaction solution was heated up to room temperature. The reaction solution was added to dilute sulfuric acid (sulfuric acid 12 ml/water 360 ml) and the mixture was stirred, then, bisected and the portions were extracted with 150 ml of ethyl acetate and 100 ml ethyl acetate, respectively. The organic layers were combined, then, trisected and respective portions were washed with 100 ml of water. The washed organic layers were combined and the solvent was distilled off by an evaporator, then, 100 ml of hexane was added to suspend a solid component and the suspension was filtrated. Further, the filtrated substance was washed with 100 ml of hexane. 63 g of 3-(3,7-dimethyloctyloxy)-phenylboric acid was obtained in the form of while solid. Under an inert atmosphere, into a three-necked flask was charged 60 g of the above-mentioned 3-(3,7-dimethyloctyloxy)-bromobenzene, 250 ml of toluene, 250 ml of water, 62 g of potassium carbonate and 1.2 g of tetrakis(triphenylphosphine)palladium complex. Argon was bubbled through the solution for 20 minutes to remove oxygen, then, 63 g of the above-mentioned 3-(3,7-dimethyloctyloxy)-phenylboric acid was added and the mixture was heated up to 90° C., and stirred for 8 hours while heating at the same temperature. After completion of heating, the mixture was left to cool to room temperature. The toluene layer was separated, then, a colored component was removed by silica gel column chromatography. The solvent was distilled off to obtain 98 g of an oily product. This is referred to as compound G.
Reaction SMILES: [CH3:1][SH:2].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][CH:5]=1>C(O)C.C[O-].[Na+]>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([S:2][CH3:1])[CH:11]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][CH:5]=1
Reactant: CS
Reactant: CC(C)(C)C(=O)C(=Cc1ccc(Cl)cc1)n1cncn1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CSC(c1ccc(Cl)cc1)C(C(=O)C(C)(C)C)n1cncn1
Yield: 66.6 %

Procedure:
10 g (0.2 mol) of methylmercaptan were introduced into a solution of 0.5 g (9 millimol) of sodium methylate in 300 ml of ethanol. 47 g (0.16 mol) of 1-(4-chloro-phenyl)-4,4-dimethyl-2-(1,2,4-triazol-1-yl)-pent-1-en-3-one (E isomer) were introduced into this solution. The initially clear solution soon changed to a thick crystal slurry. The crystals were filtered off, washed with diisopropyl ether and with ethanol, and dried. 36 g (66.6% of theory) of 1-(4-chlorophenyl)-4,4-dimethyl-1-methylthio-2-(1,2,4-triazol-1-yl)-pentan-3-one of melting point 145° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[C:11](O)=[O:12])=[CH:4][C:3]=1[CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.S(Cl)([Cl:22])=O>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[C:11]([Cl:22])=[O:12])=[CH:4][C:3]=1[CH2:14][CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCc2cc(CC3CCCC3)c(Cl)cc21
Product: O=C(Cl)C1CCc2cc(CC3CCCC3)c(Cl)cc21

Procedure:
3.22 g of 6-chloro-5-cyclopentylmethyl-1-indanecarboxylic acid is heated under reflux for one hour with 10.5 ml of thionyl chloride and concentrated, thus yielding 3.45 g of 6-chloro-5-cyclopentylmethyl-1-indanecarboxylic acid chloride as an oil. The acid chloride is reacted with triethyl phosphite as described in Example 2, yielding 3 g of (6-chloro-5-cyclopentylmethyl-1-indanylidene)hydroxymethanephosphonic acid diethyl ester, mp 126° C. The resultant compound is reacted with diethyl phosphite under the conditions mentioned in Example 2, thus obtaining the (6-chloro-5-cyclopentylmethyl-1-indanyl)hydroxymethane-bis(phosphonic acid diethyl ester).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][NH:7][C:8](=[O:26])[C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[NH2:25])[CH3:2].[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.C([SiH](CC)CC)C>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][NH:7][C:8](=[O:26])[C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=2)[CH:12]=[CH:11][C:10]=1[NH:25][CH2:33][C:32]1[CH:35]=[CH:36][C:29]([Cl:28])=[CH:30][CH:31]=1)[CH3:2]
Reactant: CCOC(=O)CCNC(=O)c1cc(OCc2ccc(C#N)cc2)ccc1N
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC[SiH](CC)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCNC(=O)c1cc(OCc2ccc(C#N)cc2)ccc1NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.5 %

Procedure:
A solution of 1.03 g (2.80 mmol) of N-(5-(4-cyanobenzyloxy)-2-aminobenzoyl)-b-alanine ethyl ester, 394 mg (2.80 mmol) of p-chlorobenzaldehyde, and 20 mg of p-toluenesulfonic acid in 30 mL of toluene was heated at reflux through a Dean-Stark trap for 45 min. The solvent was removed in vacuo and the residue was dissolved in 15 mL of trifluoroacetic acid. Triethylsilane (1.34 mL, 8.40 mmol) was added and the mixture was stirred at room temperature for 12 h, concentrated in vacuo, and partitioned between 1N aqueous sodium bicarbonate and ethyl acetate. The organic phase was washed with water, brine, dried over anhydrous magnesium sulfate, and concentrated. Chromatography (silica gel-60, 2:3 ethyl acetate/hexane) gave 820 mg (59%) of N-(5-(4-cyanobenzyloxy)-2-(4-chlorobenzylamino)benzoyl)-b-alanine ethyl ester as a colorless solid. 1H NMR (300 MHz, CDCl3) d 7.66 (2H, d, J=7.8 Hz, NC--Ar--H2), 7.51 (2H, d, J=7.8 Hz, NC--Ar--H2), 7.27 (4H, s, ClArH4), 6.98 (1H, d, J=2.0 Hz, O--Ar--H), 6.89 (1H, dd, J=2.0, 9.3 Hz, O--Ar--H), 6.78 (1H, b, N--H), 6.66 (1H, d, J=9.3 Hz, O--Ar--H), 5.03 (2H, s, ArCH2O), 4.32 (2H, s, ClArCH2), 4.17 (2H, q, J=7.3 Hz, OCH2CH3), 3.65 (2H, bq, J=5.7 Hz, NHCH2CH2), 2.62 (2H, t, J=5.7 Hz, NHCH2CH2), 1.28 (3H, t, J=7.3 Hz, OCH2CH3); Exact mass (FAB, M+H+) calcd for C27H27ClN3O4 : 492.1690; Found: 492.1681.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:23]=[CH:22][C:11]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:10][CH:9]=2)[CH2:3]1.[CH:24]1([CH:30]=O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[BH4-].[Na+]>>[CH:24]1([CH2:30][N:2]2[CH2:7][CH2:6][CH2:5][CH:4]([C:8]3[CH:9]=[CH:10][C:11]([O:12][C:13]4[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=4)=[CH:22][CH:23]=3)[CH2:3]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=CC1CCCCC1
Reactant: NC(=O)c1ccc(Oc2ccc(C3CCCNC3)cc2)nc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2ccc(C3CCCN(CC4CCCCC4)C3)cc2)nc1
Yield: 18.6 %

Procedure:
Combine 6-(4-Piperidin-3-yl-phenoxy)-nicotinamide (free base of compound of example 322) (0.96 mL of 0.12 M stock solution in methanol, 0.0344 g, 0.116 mmol) and cyclohexanecarboxaldehyde (0.021 mL, 0.173 mmol), and stir overnight. Add sodium borohydride (0.0108 g, 0.285 mmol), stir for 4.5 h, then concentrate and purify by silica gel chromatography (20:1→10:1 ethyl acetate:methanol) to provide 0.0085 g (19%) of the title compound as a white solid: high resolution mass spectrum (electrospray): m/z calc for C24H32N3O2 394.2495, found 394.2488; 1H NMR (CDCl3): 8.58 (s, 1H), 8.14 (d, 1H, J=7.8 Hz), 7.27 (d, 2H, J=8.3 Hz), 7.05 (d, 2H, J=7.8 Hz), 6.93 (d, 1H, J=8.8 Hz), 5.89 (s br, 2H), 2.99-2.77 (m, 3H), 2.16-2.06 (m, 2H), 1.97-1.83 (m, 3H), 1.80-1.59 (m, 7H), 1.54-1.34 (m, 2H), 1.29-1.03 (m, 5H), 0.93-0.77 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][C:9](=[O:11])[N:8]2[CH:12]([C:15]([OH:17])=O)[CH2:13][CH2:14][CH:7]2[CH2:6]1)=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.Cl.[NH2:50][CH2:51][C:52]([C:54]1[CH:59]=[CH:58][C:57]([Br:60])=[CH:56][CH:55]=1)=[O:53]>CN(C)C=O>[CH3:1][O:2][C:3]([N:5]1[CH2:10][C:9](=[O:11])[N:8]2[CH:12]([C:15](=[O:17])[NH:50][CH2:51][C:52]([C:54]3[CH:59]=[CH:58][C:57]([Br:60])=[CH:56][CH:55]=3)=[O:53])[CH2:13][CH2:14][CH:7]2[CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC(=O)N2C(CCC2C(=O)O)C1
Reactant: NCC(=O)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)N1CC(=O)N2C(CCC2C(=O)NCC(=O)c2ccc(Br)cc2)C1
Yield: 75.8 %

Procedure:
A solution of 4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2,6-dicarboxylic acid 2-methyl ester (81 mg, 0.33 mmol), HATU (152 mg, 0.40 mmol), and 4-methyl morpholine (146 μL, 1.33 mmol) in dimethylformamide (4 mL) was stirred at ambient temperature for 5 minutes. 2-Amino-1-(4-bromo-phenyl)-ethanone hydrochloride (91 mg, 0.37 mmol) was added to the reaction mixture. After 1 hour the solvent was removed under reduced pressure and the resulting residue was taken up in ethyl acetate (10 mL). The resulting mixture contained a solid and was filtered. The solvent was removed under reduced pressure from the filtrate. The resulting residue was subjected to flash chromatography with eluent of (10% methanol in ethyl acetate) and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to provide 6-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylic acid methyl ester (110 mg, 0.25 mmol, 75%). C18H20BrN3O5 calculated 437.1 observed [M+1]+ 438.1; rt=1.82 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19](/[CH:24]=[CH:25]/[S:26]([CH3:29])(=[O:28])=[O:27])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)([CH2:13][CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:15]2[C:23]3[C:18](=[C:19]([CH2:24][CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)([CH2:13][CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(/C=C/S(C)(=O)=O)cccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(CCS(C)(=O)=O)cccc21
Reaction time: 0.5 h

Procedure:
To a solution of (E)-methyl 2-(4-chlorophenyl)-2-(4-(2-(methylsulfonyl)vinyl)-1H-indol-1-yl)butanoate (1.18 g, 2.73 mmol) in EtOAc (50 mL) was added Pd/C (10% on carbon, 0.2 g). The mixture was stirred under H2 atmosphere for 30 min. Then the reaction mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo. The residue was purified via column chromatography (0-30% EtOAc/hexanes) to provide the title compound. LC/MS m/z=434.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C([Sn](CCCC)(CCCC)[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1)CCC.C(OCC)C.[F-].[K+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[O:5])[CH2:16][O:17][CH2:18][C:19]1[CH:20]=[C:21]([C:29]([F:30])([F:31])[F:32])[CH:22]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:24]=1
Reactant: CCCC[Sn](CCCC)(CCCC)COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: [F-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: O=C(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1Cl
Temperature: 70 °C

Procedure:
2-Chlorobenzoyl chloride (1.27 ml), tri-n-butyl-((3,5-bis(trifluoromethyl)phenyl)methyloxymethyl)tin (part (a), 6.2 g) and benzylchlorobis(triphenylphosphine)palladium (II) (80 mg) were dissolved in chloroform (10 ml) and the solution heated to 70° C. for 36 hours. On cooling diethyl ether and saturated aqueous potassium fluoride were added and this solution filtered through a pad of Hyflo. The organic layer was washed with water, dried (MgSO4) and reduced in vacuo giving a residue which was purified by chromatography on silica gel to give 2'-chloro-2-((3,5-bis(trifluoromethyl)phenyl) methyloxy)acetophenone, 1H NMR (360MHz, CDCl3) δ 7.79 (3H, bs, bis(CF3) aryl CH2,4,6), 7.54-7.26 (4H, m, aryl), 4.75 (2H, s), 4.76 (2H, s).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:9]=2[CH3:17])[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[CH3:17])[CH2:6][CH2:7]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N1CCN(C)CC1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)ccc1N1CCN(C)CC1
Yield: 86 %

Procedure:
A heterogeneous mixture of 4-(4-methylpiperazinyl)-3-methylnitrobenzene 5 (20 g, 85 mmol), 10% Pd/C (1.3 g) in methanol (1.2 liter) was hydrogenated [H2] at 40 PSI for 3 hours. The palladium catalyst was filtered through a pad of celite, washed with methanol (3×50 mL) and the combined filtrate was concentrated to afford 4-(4-methylpiperazinyl)-3-methylaniline 7 (15 g, 86%). 1H NMR (CD3OD): δ 6.83 (d, 1H, J=8.7 Hz), 6.59 (d, 1H, J=2.7 Hz), 6.54 (dd, 1H, J=8.4 and 2.7 Hz), 2.84 (t, 4H, J=4.8 Hz), 2.60 (bm, 4H), 2.34 (s, 3H), 2.20 (s, 3H); LCMS: purity: 99.9%, MS (m/e): 206 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@H:21]([CH3:29])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:28])[CH:26]=[CH2:27])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([OH:20])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([O:41][CH3:42])=[CH:33][N:32]=1.CC([O-])(C)C.[K+]>CS(C)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:21]([CH3:29])[CH2:22][CH2:23][CH2:24][CH:25]([CH3:28])[CH:26]=[CH2:27])[C:10]([N:12]1[CH2:16][C@H:15]([O:17][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]([O:41][CH3:42])=[CH:33][N:32]=2)[CH2:14][C@H:13]1[C:18]([OH:20])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cnc(Cl)c2ccccc12
Reactant: C=CC(C)CCC[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=CC(C)CCC[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc2ncc(OC)c3ccccc23)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
To a solution of (2S,4R)-1-((3R)-2-((tert-butoxycarbonyl)amino)-3,7-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.5 g, 3.6 mmol) in DMSO was added 1-chloro-4-methoxyisoquinoline (840 mg, 4.4 mmol) followed by t-BuOK (1M sol. in THF, 18 mL) at room temperature under nitrogen atmosphere. The reaction mass was stirred at room temperature for 4 h. The reaction mass was quenched with aqueous citric acid solution and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get crude compound. The crude compound was purified by combiflash to get desired product (800 mg, 40%) as off-white solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.11-8.09 (m, 2H), 7.70-7.66 (t, J=7.4 Hz, 1H), 7.56-7.51 (t, J=8.0 Hz, 1H), 7.47 (s, 1H), 5.78 (bs, 1H), 5.69-5.65 (m, 1H), 5.14-5.11 (m, 1H), 4.96-4.88 (m, 3H), 4.43-4.41 (m, 1H), 4.27-4.24 (m, 1H), 3.99 (s, 4H), 2.75-2.73 (m, 1H), 2.67-2.65 (m, 1H), 2.10 (bs, 1H), 1.88-1.85 (m, 2H), 1.31 (s, 9H), 1.24 (s, 2H), 0.98-0.96 (m, 4H), 0.91-0.86 (m, 4H) MS: MS m/z 568.2 (M++1).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH2:24][C:25]#[N:26])=[CH:4][CH:3]=1.[CH2:27](I)[CH3:28].CC(C)([O-])C.[K+]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH2:27][CH3:28])[C:25]#[N:26])=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(CC#N)c23)c(C)n1
Reactant: CCI
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(C#N)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a solution of [9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]acetonitrile (176.0 mg, 0.478 mmol) in tetrahydrofuran (4.5 mL) was added ethyl iodide (57.3 μL, 0.717 mmol) and potassium tert-butoxide (75.8 mg, 0.574 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hr under nitrogen atmosphere. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-60% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless powder (154.3 mg, 0.390 mmol, 82%).