Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:14])[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[C@H:3]1[C:15]([OH:17])=[O:16].[CH3:19][C@@H:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:18])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:14])[O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[C@H:3]1[C:15]([O:17][C@H:20]([CH3:19])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)=[O:16]
Reactant: C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C\C(=O)OCC(F)(F)F
Solvent: ClC(Cl)Cl
Product: C[C@@H](OC(=O)[C@@H]1[C@H](/C=C\C(=O)OCC(F)(F)F)C1(C)C)c1cccc(Oc2ccccc2)c1

Procedure:
Using the procedure of Step F of Example 9, the acid of Step D of Example 1 and (R)α-methyl-3-phenoxy-benzyl alcohol were reacted to obtain (R)α-methyl-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-(2,2,2-trifluoroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+108.5°±2° (c=1% in CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14].[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: COC(=O)CCCCc1ccc(O)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCc1ccc(O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.3 %

Procedure:
To a solution of methyl 5-(2-chloro-4-hydroxyphenyl)pentanoate (2.28 g) in methanol (20.0 mL) was added a 1 M aqueous sodium hydroxide solution (28.2 mL), followed by stirring at room temperature for 1 hour. To a reaction solution was added 1 M hydrochloric acid (28.2 mL), followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 5-(2-chloro-4-hydroxyphenyl)pentanoic acid (2.22 g) as a mixture.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:15]S(=O)O[CH2:12][C:11]([CH3:18])([CH3:17])[C:10]=2[CH:19]=1)(=[O:4])=[O:3].[Cl-].[Na+].O>CN(C)C=O>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:15][CH2:12][C:11]([CH3:18])([CH3:17])[C:10]=2[CH:19]=1)(=[O:4])=[O:3]
Reactant: CC1(C)COS(=O)Oc2ccc(OS(C)(=O)=O)cc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)COc2ccc(OS(C)(=O)=O)cc21
Yield: 84 %

Procedure:
A mixture of 4,5-dihydro-5,5-dimethyl-2-oxido-1,3,2-benzodioxathiepin-7-yl methanesulphonate (24 parts) (from Example 20) and sodium chloride (1 part) in dimethyl formamide (400 parts) was boiled under reflux for 3 hours. The mixture was then added to water and the product extracted with ether to give 2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (16 parts, 84% yield), identical with the product of Example 37(a) above.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([Br:13])[CH:12]=2)[C:5]([C:14]#[N:15])=[C:4](S(C)=O)[N:3]=1.Cl.Cl.[CH3:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][NH2:29])=[N:26][CH:27]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[C:11]([Br:13])[CH:12]=2)[C:5]([C:14]#[N:15])=[C:4]([NH:29][CH2:28][C:25]2[CH:24]=[CH:23][C:22]([CH3:21])=[CH:27][N:26]=2)[N:3]=1
Reactant: Cc1ccc(CN)nc1
Reactant: CS(=O)c1nc(N)nc(-c2cc(Br)co2)c1C#N
Agent: Cl
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(CNc2nc(N)nc(-c3cc(Br)co3)c2C#N)nc1

Procedure:
From 2-amino-4-(4-bromo-furan-2-yl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, C-(5-methyl-pyridin-2-yl)-methylamine dihydrochloride and DBU in DME. 387 (M{81Br}+H+, 100), 385 (M{79Br}+H+, 95).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([OH:18])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]2[CH3:19])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>>[CH3:27][O:26][C:24](=[O:25])[CH2:23][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH:11]=[C:10]([CH3:19])[N:9]2[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1
Reactant: COC(=O)CBr
Reactant: Cc1cc2c(O)cccc2n1Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)COc1cccc2c1cc(C)n2Cc1ccc(F)cc1
Yield: 80.9 %

Procedure:
Using the procedure described in Example 1, Part E, 1-[(4-fluorophenyl)methyl]-4-hydroxy-2-methyl-1H-indole (881 mg, 3.45 mmol) was treated with 138 mg (3.45 mmol) of 60% NaH/mineral oil and then 0.33 mL (3.45 mmol) of methyl bromoacetate. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 914 mg (81% yield) of [[1-[(4-fluorophenyl)methyl]-2-methyl-1H-indol-4-yl]oxy]acetic acid methyl ester, mp, 92°-98° C.
Reaction SMILES: CC[C:3](C1C=CC=CC=1)=[S:4].Br[CH2:12][C:13]([C:15]1[CH:25]=[CH:24][C:18]2[O:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=2[CH:16]=1)=[O:14].C[S-].[Na+]>CO>[CH3:22][C:20]1([CH3:23])[O:19][C:18]2[CH:24]=[CH:25][C:15]([C:13](=[O:14])[CH2:12][S:4][CH3:3])=[CH:16][C:17]=2[O:21]1
Reactant: CCC(=S)c1ccccc1
Reactant: CC1(C)Oc2ccc(C(=O)CBr)cc2O1
Agent: C[S-]
Agent: [Na+]
Solvent: CO
Product: CSCC(=O)c1ccc2c(c1)OC(C)(C)O2
Reaction time: 15 h

Procedure:
The procedure is as in Example 4 for the preparation of α-methylthioacetophenone, starting with a stirred solution of 5-(2-bromoacetyl)-2,2-dimethyl-1,3-benzodioxole (14.9 g) in methanol (150 cc). Sodium methanethiolate (3.8 g) is added in the course of 5 minutes at a temperature in the region of 20° C., and the mixture is left with stirring for 15 hours at the same temperature. 2,2-Dimethyl-5-[2-(methylthio)acetyl]-1,3-benzodioxole (11 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [CH3:1][C:2]([CH3:48])([CH3:47])[Si:3]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[O:4][CH2:5][CH:6]([C:31]([F:34])([F:33])[F:32])[NH:7]/[C:8](=[N:20]/C(=O)OCC1C=CC=CC=1)/[NH:9]C(=O)OCC1C=CC=CC=1.[H][H]>CCO.C1COCC1.[OH-].[OH-].[Pd+2]>[Si:3]([O:4][CH2:5][CH:6]([NH:7][C:8]([NH2:20])=[NH:9])[C:31]([F:34])([F:33])[F:32])([C:2]([CH3:1])([CH3:47])[CH3:48])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)[Si](OCC(N/C(=N/C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)C(F)(F)F)(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)[Si](OCC(NC(=N)N)C(F)(F)F)(c1ccccc1)c1ccccc1
Yield: 100 %

Procedure:
To a stirred solution of 346 (210 mg, 0.310 mmol) in 95% EtOH/THF (5 mL, 1:1) was added Pearlman's Catalyst (21.8 mg, 0.0310 mmol). The suspension was put through a vacuum/purge cycle three times with hydrogen gas and then maintained under 1 atmosphere of hydrogen pressure overnight. The mixture was then filtered through GF/F filter paper with 95% ethanol and the filtrate was concentrated to afford 127 mg (100%) of 1-(3-(tert-butyldiphenylsilyloxy)-1,1,1-trifluoropropan-2-yl)guanidine (348) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][O:17][CH2:18][CH2:19][OH:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32].C(=O)([O-])O.[Na+]>CCCCCC.C(Cl)Cl>[C:31]([O:20][CH2:19][CH2:18][O:17][CH2:16][C:13]1[N:14]([CH3:15])[C:10]([S:9][C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)=[C:11]([CH:21]([CH3:23])[CH3:22])[N:12]=1)(=[O:33])[CH3:32]
Reactant: CC(C)c1nc(COCCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(=O)OCCOCc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1C
Reaction time: 0.25 h
Yield: 95.8 %

Procedure:
To dry methylene chloride solution (5 ml)of 200 mg (0.5 mmol)of 2-{[5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol-2-yl]methoxy}ethanol (25a), 161 mg (1.60 mmol)of triethylamine was added under ice-cooling, 63 mg (0.8 mmol)of acetyl chloride was added, and the mixture was stirred at the same temperature for 15 minutes. To the reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate was added, neutralized, and extracted with methylene chloride. The extract was washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate:n-hexane=1:1)to obtain 200 mg of 2-[5-(3,5-dichlorophenylthio)-4-isopropyl-1-methylimidazol-2-ylmethoxy]ethyl acetate (Compound I-60)as oil (yield 90%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:20](=O)[C:21]1[C:22]([O:27][CH3:28])=[CH:23][CH:24]=[CH:25][CH:26]=1>[OH-].[K+].CCO.O>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[C:14](=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccccc1C=O
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccccc1C=C1CCc2cc(OCCn3ccnc3)ccc2C1=O
Yield: 85.3 %

Procedure:
6-(2-Imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.200 g, 0.78 mmol) was reacted with o-anisaldehyde (0.117 g, 0.87 mmol) in 2 mL of 4% KOH in EtOH at room temperature overnight. The reaction was diluted with water to induce the precipitation of a red gum. The aqueous layer was decanted, and the remaining residue was concentrated several times from EtOH and then chromatographed (SiO2, 30 g, 8% MeOH in DCM) to afford 0.249 g (84%) of the title compound as a yellow foam: APCI-MS m/e 375.3 M++1).
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=2)[C:13]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:12]1[C:30]1[C:31]([O:36]CC2C=CC=CC=2)=[N:32][CH:33]=[CH:34][CH:35]=1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[CH:24]1([C:13]2[C:14]3[C:19](=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=3)[N:11]([CH2:10][CH2:9][OH:8])[C:12]=2[C:30]2[C:31]([OH:36])=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccnc3OCc3ccccc3)n(CCOCc3ccccc3)c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccnc3O)n(CCO)c2c1
Reaction time: 72 h
Yield: 89.6 %

Procedure:
To a solution of methyl 1-(2-(benzyloxy)ethyl)-2-(2-(benzyloxy)pyridin-3-yl)-3-cyclohexyl-1H-indole-6-carboxylate (57 mg, 0.099 mmol) in ethyl acetate (10 mL), 10% Pd on carbon (10 mg) was added. The reaction mixture was stirred under an hydrogen atmosphere (1 atmos.) for three days. It was filtered through celite, and the filtrate concentrated to give the title compounds as an off-white solid, (35 mg, 90% yield). MS m/z 395(MH+); 1H NMR (300 MHz, CD3OD) □ ppm 1.24–1.40 (m, 3 H) 1.70–1.98 (m, 7 H) 2.58 (m, 1 H) 3.71 (t, J=6.04 Hz, 2 H) 3.94 (s, 3 H) 4.11 (m, 1 H) 4.22 (m, 1 H) 6.58 (t, J=6.59 Hz, 1 H) 7.58–7.76 (m, 3 H) 7.82 (d, J=8.78 Hz 1 H) 8.19 (s, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][CH3:38])[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][CH3:38])[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCCOc1cccc(Br)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCCOc1cccc(Nc2c(C)noc2-c2ccc(-c3ccc(C4(C(=O)OCC)CC4)cc3)cc2)n1

Procedure:
Prepared according to the procedure described in Example 290, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-propoxy-pyridine.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.C(N(CC)C(C)C)(C)C.[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][C:40]=2B(O)O)[CH:35]=[CH:34][CH:33]=1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([C:40]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:41]=2[N:32]=[CH:33][CH:34]=[CH:35]3)[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:5]=1
Reactant: OB(O)c1cccc2cccnc12
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1Cl
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1cccc2cccnc12
Yield: 54.5 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate (0.081 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 g; 0.025 mmol), N,N-diisopropylethylamine (0.172 mL; 1.00 mmol) and quinolin-8-ylboronic acid (0.086 g; 0.500 mmol) in DME-water (1 mL) for 20 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (5-40%) in heptane furnished 0.057 g (52%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9]CC)=O.[CH3:12][NH:13][CH3:14]>C(O)C>[CH3:12][N:13]([CH3:14])[C:7]([CH:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])=[O:9]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CNC
Solvent: CCO
Product: CN(C)C(=O)C1CCCC1=O

Procedure:
0.337 mol (50 ml) of ethyl 2-oxocyclopentanecarboxylate and 152 ml 33% dimethylamine solution in ethanol were stirred in a pressure reactor for 4 h at 110° C. The reaction mixture was then evaporated to dryness and the crude product was purified over 400 g silica gel with ethyl acetate/hexane 1/1. 17.7 g of the title compound were obtained.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[CH2:11](Br)[CH:12]=[CH2:13]>C(OCC)C>[CH2:13]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)[CH:12]=[CH2:11]
Reactant: C=CCBr
Reactant: c1ccc2c(c1)CCNC2
Solvent: CCOCC
Product: C=CCN1CCc2ccccc2C1
Temperature: 0 °C
Yield: 98.4 %

Procedure:
To a 1L 3-necked round-bottomed flask, was added 100.0 g of 1,2,3,4-tetrahydroisoquinoline dissolved in 150 mL diethyl ether. The reaction mixture was cooled to 5° C. with an ice. While stirring, 45.4 g of allyl bromide in 60 mL diethyl ether was added slowly to the amine solution. After addition was complete, the reaction mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was diluted with 300 mL diethyl ether, and the white precipitate was removed by filtration. Ether was removed from the filtrate under reduced pressure using a rotary evaporator yielding 64.0 g of N-allyl 1,2,3,4-tetrahydroisoquinoline as a viscous liquid. To a 500 mL 3-necked round-bottomed flask was added 61 g of N-allyl 1,2,3,4-tetrahydroisoquinoline dissolved in 100 mL diethyl ether. After cooling to 5° C. with an ice bath, 42.6 g of allyl bromide in 60 mL diethyl ether was added slowly. After completion of addition of allyl bromide, the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 24 hours. The solid residue thus formed was collected by filtration and was washed with diethyl ether (2×500 mL). The washed solid was recrystallized from acetonitrile. After removal of acetonitrile by filtration, the residue was dried under vacuum yielding 55.0 g of N,N-diallyl 1,2,3,4-tetrahydroisoquinolinium bromide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:20])[C:9]([NH:11][C:12]2[CH:16]=[C:15]([CH:17]3[CH2:19][CH2:18]3)[NH:14][N:13]=2)=[O:10])=[CH:4][CH:3]=1.[Cl:21][CH2:22][CH2:23][O:24][C:25](Cl)=[O:26]>N1C=CC=CC=1>[Cl:21][CH2:22][CH2:23][O:24][C:25]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:20])[C:9]([NH:11][C:12]2[N:13]([C:25]([O:24][CH2:23][CH2:22][Cl:21])=[O:26])[N:14]=[C:15]([CH:17]3[CH2:19][CH2:18]3)[CH:16]=2)=[O:10])=[CH:6][CH:7]=1)=[O:26]
Reactant: CC(C(=O)Nc1cc(C2CC2)[nH]n1)c1ccc(N)cc1
Reactant: O=C(Cl)OCCCl
Solvent: c1ccncc1
Product: CC(C(=O)Nc1cc(C2CC2)nn1C(=O)OCCCl)c1ccc(NC(=O)OCCCl)cc1
Yield: 81.7 %

Procedure:
154 mg (0.57 mmol) of 2-(4-aminophenyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)propanamide were dissolved in 1.9 ml of dry pyridine at 4° C. under argon atmosphere and 0.12 ml (1.148 mmol) of 2-chloroethylchloroformate were added dropwise. After 2.5 hours the reaction mixture was poured into ice and the precipitate solid collected by filtration, affording 225 mg (82% yield) of the title compound.
Reaction SMILES: ClC(OCC)=O.[C:7]([NH:10][C@H:11]([C:17]([OH:19])=O)[C@:12]([SH:16])([CH2:14][CH3:15])[CH3:13])(=[O:9])[CH3:8].C(N(CC)CC)C>ClCCl>[C:7]([NH:10][CH:11]1[C:12]([CH2:14][CH3:15])([CH3:13])[S:16][C:17]1=[O:19])(=[O:9])[CH3:8]
Reactant: CC[C@@](C)(S)[C@H](NC(C)=O)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1(C)SC(=O)C1NC(C)=O
Temperature: 25 °C

Procedure:
Ethyl chloroformate (0.12 ml) was added to a stirred solution of DL-N-acetyl-3-mercaptoisoleucine (0.20 g) in dichloromethane (10 ml) and triethylamine (0.28 ml) at -10° C. The solution was allowed to warm to room temperature, washed with dilute hydrochloric acid and then with sodium bicarbonate solution, dried and evaporated to give 3-acetamido-4-ethyl-4-methyl-2-thietanone as a pale oil.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:16]=[C:15]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[O:14][N:13]=2)[C:9]([C:23]([OH:25])=O)=[CH:8][N:7]=1)=[O:5].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C.[CH:57]([N:60]1[CH2:65][CH2:64][CH:63]([NH2:66])[CH2:62][CH2:61]1)([CH3:59])[CH3:58]>CN(C=O)C.C(Cl)Cl>[CH2:2]([O:3][C:4]([C:6]1[N:10]([CH2:11][C:12]2[CH:16]=[C:15]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[O:14][N:13]=2)[C:9]([C:23](=[O:25])[NH:66][CH:63]2[CH2:64][CH2:65][N:60]([CH:57]([CH3:59])[CH3:58])[CH2:61][CH2:62]2)=[CH:8][N:7]=1)=[O:5])[CH3:1]
Reactant: CC(C)N1CCC(N)CC1
Reactant: CCOC(=O)c1ncc(C(=O)O)n1Cc1cc(-c2ccc(Cl)s2)on1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncc(C(=O)NC2CCN(C(C)C)CC2)n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.4 %

Procedure:
To a solution of 12 mg of 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3H-imidazole-2,4-dicarboxylic acid 2-ethyl ester (ii) in DMF (0.5 mL) and DCM (0.5 mL) was added successively 1-Hydroxy-7-azabenzotriazole (5 mg), N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (7 mg) and diisopropyl ethylamine (26 μL). The mixture was stirred for 15 min at RT. 7 mg of 1-Isopropyl-piperidin-4-ylamine (dihydrochloride) were added and stirring was continued at RT. After 2 h the mixture was concentrated in vacuo and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated to provide 8.5 mg of the title compound as its trifluoroacetate salt. Yield: 8.5 mg; MS (ESI+): m/e=505, chloro pattern.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:9][C:10]([C:13]2[CH:18]=[C:17]([C:19](=[O:24])[NH:20][CH:21]3[CH2:23][CH2:22]3)[CH:16]=[CH:15][C:14]=2[CH3:25])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C[O:29][CH2:28]C1.C([Li])CCC.CN(C=O)C>CCOC(C)=O>[C:1]([NH:5][C:6]([C:8]1[S:9][C:10]([C:13]2[CH:18]=[C:17]([C:19](=[O:24])[NH:20][CH:21]3[CH2:23][CH2:22]3)[CH:16]=[CH:15][C:14]=2[CH3:25])=[CH:11][C:12]=1[CH:28]=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NC(C)(C)C)s1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cc(C=O)c(C(=O)NC(C)(C)C)s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In 150 mL round-bottom flask equipped with a stir bar, under N2, was added N-tert-butyl-5-(5-(cyclopropylcarbamoyl)-2-methylphenyl)thiophene-2-carboxamide (1.2 g, 3.4 mmol) followed by anhydrous THF (100 mL). The solution was cooled down to −78° C. and butyllithium, (2.2 ml, 30 mmol) was added dropwise over 5 min. The mixture was stirred at −78° C. for 0.5 hrs and was added DMF (0.780 ml, 10 mmol). The mixture was stirred at −78° C. for 0.5 hr, quenched with saturated solution of NH4Cl and then allowed to warm up to room temperature. The reaction then diluted with EtOAc (100 ml) and the layers were separated and the aqueous layer was extracted with EtOAc (3×50 ml) and the combined organic solution was washed with brine, water and dried over MgSO4. The organic solutions were evaporated under reduced pressure and the crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 5% to 95% MeOH in DCM to provide N-tert-butyl-5-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-3-formylthiophene-2-carboxamide (1.01 g). MS (ES+): 385 (M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:25])[CH:3]=1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31]>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:28]4[CH2:29][CH2:30][O:26][C:27]4=[O:31])=[CH:3][C:4]=3[CH3:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Reactant: O=C1NCCO1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3C)CC2)c(C)c1
Yield: 79.6 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methylphenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (350 mg) described in Preparation Example 129 and oxazolidin-2-one (114 mg), the title compound (283 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[NH:15][N:14]=[C:13]([CH:16]3[CH2:18][CH2:17]3)[CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C([O:22][CH2:23][C:24]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=[CH:26][C:25]=1[N:39]1[CH2:47][C:46]2[C:41](=[CH:42][CH:43]=[C:44]([C:48]([CH3:51])([CH3:50])[CH3:49])[CH:45]=2)[C:40]1=[O:52])(=O)C>>[C:48]([C:44]1[CH:45]=[C:46]2[C:41](=[CH:42][CH:43]=1)[C:40](=[O:52])[N:39]([C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[NH:15][N:14]=[C:13]([CH:16]5[CH2:18][CH2:17]5)[CH:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=3)[C:24]=1[CH2:23][OH:22])[CH2:47]2)([CH3:51])([CH3:49])[CH3:50]
Reactant: Cn1cc(Br)cc(Nc2cc(C3CC3)n[nH]2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Product: Cn1cc(-c2cccc(N3Cc4cc(C(C)(C)C)ccc4C3=O)c2CO)cc(Nc2cc(C3CC3)n[nH]2)c1=O
Yield: 32.7 %

Procedure:
Using the same general procedure as Example 105, reaction of 110a (260 mg, 0.841 mmol) and 103f (429 mg, 0.926 mmol) afforded a 33% yield (144 mg) of 110 as an off-white solid: mp 178-180° C.; 1H NMR (500 MHz, DMSO-d6) δ 11.76 (d, 1H, J=2.0 Hz), 7.98 (d, 1H, J=2.0 Hz), 7.92 (s, 1H), 7.71 (m, 2H), 7.61 (dd, 1H, J=7.9, 1.6 Hz), 7.48 (m, 1H), 7.42 (dd, 1H, J=7.6, 1.1 Hz), 7.35 (dd, 1H, J=7.6, 1.1 Hz), 7.23 (d, 1H, J=2.1 Hz), 5.79 (d, 1H, J=2.2 Hz), 4.93 (s, 2H), 4.90 (t, 1H, J=4.9 Hz), 4.35 (d, 2H, J=4.6 Hz), 3.57 (s, 3H), 1.81 (m, 1H), 1.37 (s, 9H), 0.89 (m, 2H), 0.64 (m, 2H); MS (ESI+) m/z 524.2 (M+H).