Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[S:21]([CH3:24])(=[O:23])=[O:22])[CH2:6][O:7][CH2:8][C@@H:9]1[CH2:11][C@@H:10]1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:32]1[N:37]=[CH:36][C:35]([O:38][CH2:39][CH3:40])=[CH:34][N:33]=1>CS(C)=O.CCOC(C)=O>[CH2:39]([O:38][C:35]1[CH:34]=[N:33][C:32]([N:15]2[CH2:14][CH2:13][CH:12]([C@H:10]3[CH2:11][C@H:9]3[CH2:8][O:7][CH2:6][C:5]3[CH:18]=[CH:19][C:20]([S:21]([CH3:24])(=[O:22])=[O:23])=[C:3]([F:2])[CH:4]=3)[CH2:17][CH2:16]2)=[N:37][CH:36]=1)[CH3:40]
Reactant: CCOc1cnc(Cl)nc1
Reactant: CS(=O)(=O)c1ccc(COC[C@@H]2C[C@@H]2C2CCNCC2)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(S(C)(=O)=O)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 22.8 %

Procedure:
4-((1R,2R)-2-(((3-fluoro-4-(methylsulfonyl)benzyl)oxy)methyl)cyclopropyl)piperidine hydrochloride (Step D product, 200 mg, 0.53 mmol) was dissolved in DMSO (5 ml) at RT under N2 and Cs2CO3 (517 mg, 1.588 mmol) was added. The mixture was stirred at RT for 5 min and 2-chloro-5-ethoxypyrimidine (101 mg, 0.635 mmol) in DMSO (0.5 mL) was added. The mixture was stirred at 100° C. overnight. The mixture was diluted with EtOAc, washed with sat. NH4Cl, dried over MgSO4, evaporated. The crude material was purified by flash column (25 g SNAP, 15˜50% EtOAc in hexane) to afford 56 mg (23%) of the title compound. 1H NMR (500 MHz, CDCl3) δ 8.10 (s, 2H), 7.90 (m, 1H), 7.30 (m, 2H), 4.60 (m, 4H), 4.00 (t, 2H), 3.60 (m, 2H), 3.20 (s, 3H), 2.93-2.80 (m, 2H), 1.96 (d, 1H), 1.85 (d, 1H), 1.43 (m, 5H), 1.25 (m, 1H), 1.15 (m, 1H), 0.80-0.71 (m, 2H), 0.12-0.08 (m, 1H). MS (ESI) m/z 464 [M+H]+. GPR119 Human EC50: 1.65 nM.
Reaction SMILES: [Na].[C:2]([O:9][CH2:10][CH3:11])(=[O:8])[C:3]([O:5]CC)=O.[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])[CH3:13]>C(O)C>[C:12]([CH2:13][C:3](=[O:5])[C:2]([O:9][CH2:10][CH3:11])=[O:8])(=[O:14])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)c1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
In 560 ml of ethanol was dissolved 25 g (1.08 eq.) of sodium and a mixture of 135.6ml (146 g; 1 mol) of diethyl oxalate and 116.7 ml (120 g; 1 mol) of acetophenone was added thereto dropwise at 40° C. One hour later, reflux was begun and it was continued for 30 minutes. The solvent was distilled off. The residue was neutralized with sulfuric acid (55 g/water 200 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Thereafter, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/hexane 1:1), to give colorless plates. The crystals were recovered by filtration with ethyl acetate/hexane. Yield: 114.6 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](O)=[N:8][C:7]([C:12]1([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]1)=[N:6]2.F[P-](F)(F)(F)(F)F.[N:30]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=N1.C1CCN2C(=NCCC2)CC1.N1C=CC=CC=1CN>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9]([NH:32][CH2:33][C:38]1[CH:37]=[CH:36][CH:35]=[CH:34][N:30]=1)=[N:8][C:7]([C:12]1([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]1)=[N:6]2
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)NC1(c2nc(O)c3c(Cl)ccn3n2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: NCc1ccccn1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)NC1(c2nc(NCc3ccccn3)c3c(Cl)ccn3n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
To a stirred solution of tert-butyl (1-(5-chloro-4-hydroxypyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropyl)carbamate (500 mg, 1.54 mmol) in acetonitrile (50 mL) was added BOP (1.02 g, 2.31 mmol), DBU (0.464 mL, 3.08 mmol) and the reaction mixture was stirred at RT for 1 h. Pyridin-2-ylmethanamine (166 mg, 1.54 mmol) was added to the reaction mixture and stirred for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed water (2×30 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by CombiFlash ISCO (REDISEP®, SiO2, 12 g, 10% MeOH/CHCl3) to give tert-butyl (1-(5-chloro-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropyl)carbamate (320 mg, 50.1%) as a pale yellow solid. LCMS Condition B-16: retention time 1.06 min, [M+1]=415.2. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.89-0.92 (m, 2H), 1.15-1.17 (m, 2H), 1.38 (s, 9H), 4.75 (d, J=5.7 Hz, 2H), 6.69 (d, J=2.7 Hz, 1H), 7.25-7.33 (m, 3H), 7.52-7.56 (m, 1H), 7.73-7.76 (m, 1H), 7.96-7.98 (m, 1H), 8.53 (d, J=5.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])[CH2:12][O:13][CH3:14])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH3:42][NH:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)Cl>[CH3:42][N:43]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:8]([C:5]1[C:4]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:26])([F:28])[F:27])[CH:19]=2)(=[O:16])=[O:17])[CH2:12][O:13][CH3:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10]
Reactant: CNc1ccccc1
Reactant: COCN(c1cc(Cl)cnc1C(=O)O)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCN(c1cc(Cl)cnc1C(=O)N(C)c1ccccc1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 1 h

Procedure:
To a magnetically stirred solution of 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid (458 mg, 1.00 mmol) in anhydrous methylene chloride (5 mL) was added oxalyl chloride (1.0 mL) at room temperature. The reaction was heated at reflux for 2 h, then concentrated to dryness. The residue was dissolved in methylene chloride (4 mL) and this solution was added dropwise to a magnetically stirred solution of triethylamine (1.0 mL) and N-methylaniline (108 mg, 1.00 mmol) in methylene chloride (2 mL). The reaction mixture was stirred 1 h (the reaction was monitored by LCMS), quenched with saturated aqueous NH4Cl (50 mL), and the aqueous layer was extracted with EtOAc (3×75 mL). The combined extracts were washed with 0.5 M HCl (50 mL), washed with water (50 mL), dried (MgSO4), filtered and concentrated. The residue was purified by chromatography on silica gel using a gradient of ethyl acetate-hexane (0:100 to 100:0) to afford pure 5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid N-methyl-N-phenylamide. MS m/z: 548.2 (M+H), 526.0 (M+H-MeOH).
Reaction SMILES: CS[C:3]([S:15][CH3:16])=[C:4]1[CH2:13][CH2:12][CH:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH2:10]2)[C:5]1=[O:14].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].O>C(#N)C>[CH3:16][S:15][C:3]([N:27]1[CH2:26][CH2:25][N:24]([C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[CH2:29][CH2:28]1)=[C:4]1[CH2:13][CH2:12][CH:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH2:10]2)[C:5]1=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CSC(SC)=C1CCC2CC=CC=C2C1=O
Solvent: CC#N
Solvent: O
Product: CSC(=C1CCC2CC=CC=C2C1=O)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 48.7 %

Procedure:
2-(Bis-methylthiomethylene)-4,5-dihydro-2H-naphthalen 1-one (11.56 g, 46 mmol) and 1-tert-butyloxycarbonylpiperazine (10.3 g, 55 mmol) were refluxed in acetonitrile (300 ml) for 24 h. The mixture was cooled, water (500 ml) added, and extracted with ethyl acetate (3×200 ml). The combined organics were washed with water and brine, dried (MgSO4), evaporated in vacuo, and the resulting oil purified by flash chromatography, eluting with dichloromethane then dichloromethane:methanol (97:3 v/v) to give 2-(methylthio[4-(tert-butyloxycarbonyl)-1-piperazinyl]methylene)-4,5-dihydro-2H-naphthalen-1-one (8.75 g, 49%) as a foam; δ (360 MHz, CDCl3) 1.49 (9H, s, tBu), 3.31 (3H, s, MeS), 2.86-2.94 (4H, m, CCH2CH2C), 3.3-3.5 (8H, m, NCH2CH2N), 7.18 (1H, d, J=7.5 Hz, H-5), 7.30 (1H, t, J=7.5 Hz, H-7), 7.37 (1H, dt, J=1.4 and 7.5 Hz, H-6), 8.10 (1H, dd, J=1.4 and 7.5 Hz, H-8).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:10]([NH2:13])[CH:11]=[CH2:12].C(N(C(C)C)CC)(C)C>C(O)C>[CH2:10]([NH:13][C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=1)[CH:11]=[CH2:12]
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: C=CCN
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: C=CCNc1nc(Cl)ncc1Br
Yield: 89 %

Procedure:
A solution of 5-bromo-2,4-dichloropyrimidine (5.0 g, 22 mmol), allylamine (1.98 mL, 26.4 mmol), and diisopropylethylamine (5.6 mL, 33.0 mmol) are stirred in ethanol (100 mL) at 50° C. overnight. The solvent is removed in vacuo and the residue is partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The organic layer is washed with brine, dried over anhydrous sodium sulfate and evaporated to provide Allyl-(5-bromo-2-chloro-pyrimidin-4-yl)-amine as a white crystalline solid (89%), which is used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:39])[NH:15][CH2:16][C:17]([C:20]2[O:21][C:22]([C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([OH:32])[CH:26]=3)[CH:24]=2)([CH3:19])[CH3:18])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[CH:24]=[C:20]([C:17]([CH3:18])([CH3:19])[CH2:16][NH:15][C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:39])[O:21][C:22]=2[C:33]2[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=2)=[CH:26][C:27]=1[OH:32]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCC(C)(C)c2cc(-c3ccc(Cl)c(O)c3)c(-c3ccncc3)o2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)C1CCNCC1)c1cc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)o1
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A solution of the product of Example 12 Step 1 (110 mg, 0.19 mmol) in dichloromethane (5 ml) was treated with trifluoroacetic acid (1 ml). After stirring for 2 h, the mixture was concentrated, re-dissolved in dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution. The organic solution was dried and concentrated in vacuo to yield the title compound (80 mg, 93%); MS (ES+) m/e 454, 456 [M+H]+.
Reaction SMILES: [S:1](=[O:37])(=[O:36])([O:3][CH2:4][C@@H:5]1[C@@H:9]([O:10][Si](C(C)(C)C)(C)C)[CH2:8][C@H:7]([N:18]2[C:22]3[N:23]=[CH:24][N:25]=[C:26]([NH:27][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:21]=3[CH:20]=[CH:19]2)[O:6]1)[NH2:2]>N1C=CC=CC=1.C1COCC1.N1C=CC=CC=1>[S:1](=[O:36])(=[O:37])([O:3][CH2:4][C@@H:5]1[C@@H:9]([OH:10])[CH2:8][C@H:7]([N:18]2[C:22]3[N:23]=[CH:24][N:25]=[C:26]([NH:27][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:21]=3[CH:20]=[CH:19]2)[O:6]1)[NH2:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1COS(N)(=O)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: NS(=O)(=O)OC[C@H]1O[C@@H](n2ccc3c(NC(=O)c4ccccc4)ncnc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of ((2R,3S,5R)-5-[4-(benzoylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-{[tert-butyl(dimethyl)silyl]oxy}tetrahydrofuran-2-yl)methyl sulfamate (0.292 g, 0.533 mmol) in 5.4 mL pyridine/THF (1:1) was added approximately 5 drops of hydrofluoridic acid in pyridine. The solution was stirred at r.t. overnight, quenched by slowly adding saturated aq NaHCO3 (20 mL) and extracted with DCM (2×25 mL) and EtOAc (25 mL). The organics were combined, dried (Na2SO4), filtered, and concentrated. The crude material was purified by flash chromatography (1 to 10% MeOH/DCM) to afford the final compound (0.177 g, 77%).
Reaction SMILES: P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[NH2:9][CH2:10][CH:11]1[O:15][CH2:14][CH:13]([S:16][C:17]2[CH:23]([CH3:24])[CH:22]3[N:19]([C:20](=[O:28])[CH:21]3[CH:25]([OH:27])[CH3:26])[C:18]=2[C:29]([OH:31])=[O:30])[CH2:12]1.C(O[CH:36](OC(C)C)[N:37]([CH3:39])[CH3:38])(C)C>>[CH3:36][N:37]([CH:39]=[N:9][CH2:10][CH:11]1[O:15][CH2:14][CH:13]([S:16][C:17]2[CH:23]([CH3:24])[CH:22]3[N:19]([C:20](=[O:28])[CH:21]3[CH:25]([OH:27])[CH3:26])[C:18]=2[C:29]([OH:31])=[O:30])[CH2:12]1)[CH3:38]
Reactant: CC(O)C1C(=O)N2C(C(=O)O)=C(SC3COC(CN)C3)C(C)C12
Reactant: CC(C)OC(OC(C)C)N(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: CC(O)C1C(=O)N2C(C(=O)O)=C(SC3COC(CN=CN(C)C)C3)C(C)C12
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
Three ml of sodium phosphate buffer, pH 7, is cooled to 0° C. and 0.052 g of product from Example 46 is added. To this cooled solution is added, dropwise, 159 μl of N,N-dimethylformamide diisopropyl acetal, while maintaining the pH below 8.5. The reaction mixture is stirred at 0° C. for 35 minutes, pH adjusted to 7.0 and freeze-dried. The residue is purified by chromatography (C18 reverse phase tlc plates: 75% aqueous ethyl alcohol) to give 0.031 g of the desired product.
Reaction SMILES: [OH-].[Li+].[F:3][CH:4]([F:29])[C:5]1[N:6]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH2:27][CH3:28])=[CH:19][CH:18]=2)[C:7]([S:10][CH2:11][C:12]([O:14]CC)=[O:13])=[N:8][N:9]=1>C1COCC1.O>[F:29][CH:4]([F:3])[C:5]1[N:6]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH2:27][CH3:28])=[CH:19][CH:18]=2)[C:7]([S:10][CH2:11][C:12]([OH:14])=[O:13])=[N:8][N:9]=1
Reactant: CCOC(=O)CSc1nnc(C(F)F)n1-c1ccc(CC)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(-n2c(SCC(=O)O)nnc2C(F)F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
Lithium hydroxide solution (1M aqueous, 0.77 mL, 0.77 mmol) was added to a solution of ethyl 2-(5-(difluoromethyl)-4-(4-ethylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetate (0.15 g, 0.38 mmol) in THF/water (3:1, 1.5 mL) and the mixture stirred for 8 h at room temperature. The crude reaction mixture was then concentrated and acidified with HCl (1N, 3 mL) and extracted with ethyl acetate (3×2 mL). The combined organic extracts were concentrated to afford 2-(5-(difluoromethyl)-4-(4-ethylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid as an off-white foam (0.136 g, 99%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:22])=O)=[CH:16][CH:15]=1)[C:6]([C:23](=[O:26])[CH2:24][CH3:25])=[C:5]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.BrC[O:35][C:36](=[O:38])[CH3:37]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][CH2:22][O:38][C:36](=[O:35])[CH3:37])=[CH:16][CH:15]=1)[C:6]([C:23](=[O:26])[CH2:24][CH3:25])=[C:5]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(C)=O)cc1
Reactant: CC(=O)OCBr
Product: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(SCOC(C)=O)cc1
Yield: 69 %

Procedure:
In the same manner as in Example 552, the title compound (190 mg, 69%) was obtained from 6-bromo-2-(4-methanesulfinylbenzyl)-4-phenyl-3-propionyl-2H-isoquinolin-1-one and acetic acid bromomethyl ester.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:42])[CH:13]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][O:31][Si](C(C)C)(C(C)C)C(C)C)=[CH:26][CH:25]=3)[CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O>C1COCC1>[OH:31][CH2:30][C:27]1[CH:26]=[CH:25][C:24]([CH:13]([C:12]([NH:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH:1]=[N:2][CH:3]=[CH:4]3)=[O:42])[CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:29][CH:28]=1
Reactant: CC(C)[Si](OCc1ccc(C(CN(C)C(=O)OC(C)(C)C)C(=O)Nc2ccc3cnccc3c2)cc1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(CC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)cc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-2-(4-((triisopropylsilyloxy)methyl)phenyl)propyl(methyl)carbamate (E205) in THF under N2 at 0° C. was added TBAF, and the solution was stirred for 30 min at 0° C. The reaction was warmed to room temperature and stirred another 4.5 h. The compound was poured into EtOAc and washed with NH4Cl(sat), dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-20% MeOH/CH2Cl2 gradient) gave pure tert-butyl 2-(4-(hydroxymethyl)phenyl)-3-(isoquinolin-6-ylamino)-3-oxopropyl(methyl)carbamate (E205-1)
Reaction SMILES: C(OC([N:8]([CH3:84])[C@@H:9]([CH3:83])[C:10]([NH:12][C@@H:13]([C:79]([CH3:82])([CH3:81])[CH3:80])[C:14]([N:16]1[C@H:25]([C:26]([NH:28][C@@H:29]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:30](O)=[O:31])=[O:27])[CH2:24][C:23]2[C:18](=[CH:19][C:20]([C@H:40]3[CH2:44][C@@H:43]([C:45](=[O:57])[NH:46][C@H:47]4[C:56]5[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=5)[CH2:50][CH2:49][CH2:48]4)[N:42]([C:58](=[O:78])[C@@H:59]([NH:64][C:65](=[O:77])[C@@H:66]([N:68]([C:70](OC(C)(C)C)=O)C)[CH3:67])[C:60]([CH3:63])([CH3:62])[CH3:61])[CH2:41]3)=[CH:21][CH:22]=2)[CH2:17]1)=[O:15])=[O:11])=O)(C)(C)C.[NH:85]1[CH2:90][CH2:89][O:88][CH2:87][CH2:86]1>>[CH3:82][C:79]([CH3:80])([CH3:81])[C@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][CH3:84])[CH3:83])[C:14]([N:16]1[C@H:25]([C:26]([NH:28][C@@H:29]([CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:30]([N:85]2[CH2:90][CH2:89][O:88][CH2:87][CH2:86]2)=[O:31])=[O:27])[CH2:24][C:23]2[C:18](=[CH:19][C:20]([C@H:40]3[CH2:44][C@@H:43]([C:45](=[O:57])[NH:46][C@H:47]4[C:56]5[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=5)[CH2:50][CH2:49][CH2:48]4)[N:42]([C:58](=[O:78])[C@@H:59]([NH:64][C:65](=[O:77])[C@@H:66]([NH:68][CH3:70])[CH3:67])[C:60]([CH3:63])([CH3:62])[CH3:61])[CH2:41]3)=[CH:21][CH:22]=2)[CH2:17]1)=[O:15]
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1Cc2cc([C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)(C)C)C3)ccc2C[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Reactant: C1COCCN1
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1Cc2cc([C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)(C)C)C3)ccc2C[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCOCC1)C(C)(C)C
Yield: 36.9 %

Procedure:
Following procedures analogous to those described for the preparation of Example 42, (S)-2-((S)-2-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-7-((3R,5S)-1-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamido)-3-phenylpropanoic acid (Compound B of Example 41, 25 mg, 0.021 mmol) and morpholine (Aldrich, 3 mg, 0.032 mmol) were converted to the title compound (8 mg, 37% over 2 steps). MS (ESI+) m/z 1032.7 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.C[O:16][B:17](OC)[O:18]C.[OH-].[Na+]>C1COCC1.CCCCCC>[CH3:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([B:17]([OH:18])[OH:16])=[CH:3][CH:4]=1
Reactant: COB(OC)OC
Reactant: CSc1ccc(Br)cc1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
Under nitrogen, a stirred solution of 30 g (150 mmol of 4-bromothioanisole (Aldrich) in 1500 mL of anhydrous THF at -78° C. was treated with 180 mmol of n-butyllithium in hexane. After 30 minutes, 51 mL (450 mmol) of trimethylborate was added neat and the reaction was allowed to warm to ambient temperature overnight. A solution of 300 mL of 10% NaOH was added and the mixture stirred vigorously for 1 hour. The solvent was removed in vacuo, the pH adjusted to 4-5, and the product collected by filtration. Repeated washings with hexane and water provided 21 g (83%) of 4-methylthiophenylboronic acid (21 in Synthetic Scheme VII when R5 =SCH3 and R3, R4, R6, and R7 =H) as a colorless solid: NMR (DHSO-d6) δ 2.47 (s, 3H), 7.20 (d, J=8 Hz, 2H), 7.71 (d, J=8 Hz, 2H), 7.96 (br s, 2H).
Reaction SMILES: ClC12[O:8]C1CCC(Cl)(F)C2.[CH:11]([C:13]1(O)[C:18]([Cl:20])([Cl:19])[CH2:17][CH2:16][CH2:15][C:14]1([Cl:22])Cl)=[CH2:12].[OH-].[Na+]>O>[Cl:22][C:14]12[O:8][CH:15]1[CH2:16][CH2:17][C:18]([Cl:20])([Cl:19])[CH:13]2[CH:11]=[CH2:12]
Reactant: FC1(Cl)CCC2OC2(Cl)C1
Reactant: C=CC1(O)C(Cl)(Cl)CCCC1(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CC1C(Cl)(Cl)CCC2OC21Cl
Reaction time: 0.25 h
Yield: 90 %

Procedure:
The same procedure was employed as for the preparation of 2e in Example 17: it was performed with 1.14 g (4.32 mmol) of pure alcohol 1k, 12 cm3 of distilled water and 0.5 g (12.5 mmol) of sodium hydroxide; reaction time was 1 h 15 min; ether extraction (4×25 cm3); the crude product was employed as such (crude yld=90.5%) or purified by flash chromatography on silica (eluent: ether/petroleum ether=3/97): 0.88 g of epoxide 2i were obtained, that was a 90% yield (macrobore GC purity>98.6%)
Reaction SMILES: [CH:1]([C:3]1[C:8]2[C:9]([CH3:12])=[CH:10][S:11][C:7]=2[CH:6]=[CH:5][C:4]=1[OH:13])=[O:2].[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[N:19]=[C:18](S(C)(=O)=O)[N:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[N:19]=[C:18]([O:13][C:4]2[CH:5]=[CH:6][C:7]3[S:11][CH:10]=[C:9]([CH3:12])[C:8]=3[C:3]=2[CH:1]=[O:2])[N:17]=1
Reactant: Cc1csc2ccc(O)c(C=O)c12
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Oc2ccc3scc(C)c3c2C=O)n1
Temperature: 70 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
A mixture comprising 2.1 g of 4-formyl-5-hydroxy-3-methylbenzothiophene, 2.4 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 1.8 g of potassium carbonate in 30 ml of N,N-dimethylformamide, was heated and stirred at 70° C. for 3 hours. The mixture was returned to room temperature, then poured into water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. Then, it was concentrated under reduced pressure, and the oily substance thereby obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/1) to obtain 3.1 g (yield: 86%) of the desired compound.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[OH:10])[CH:3]=[CH:2]1.[Br:11]Br>C(O)(=O)C>[Br:11][C:7]1[C:8]([OH:10])=[C:9]2[S:1][CH:2]=[CH:3][C:4]2=[N:5][CH:6]=1
Reactant: Oc1ccnc2ccsc12
Reactant: BrBr
Solvent: CC(=O)O
Product: Oc1c(Br)cnc2ccsc12
Temperature: 110 °C
Yield: 115.2 %

Procedure:
To a solution of thieno[3,2-b]pyridin-7-ol (1, 2.55 g, 16.87 mmol) in acetic acid (50 mL) was added bromine (1.7 mL, 32.72 mmol). The mixture was heated at 110° C. for 1 h, cooled and the resultant precipitate was separated by filtration, to afford the title compound 270 (4.47 g, crude) as a dark brown powder, which was used in next step without further purification. M/S (m/z): 231.9(M+H) (found).