Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][CH2:12][CH:13]([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:8][C:7]([CH3:22])=[CH:6][N:5]2[C:23]=1[C:24](O)=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[NH2:61][CH:62]([CH2:67][CH2:68][CH2:69][C:70]([F:73])([F:72])[F:71])[C:63]([CH3:66])([OH:65])[CH3:64]>CN(C=O)C.O>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][CH2:12][CH:13]([C:14]([F:17])([F:15])[F:16])[C:18]([F:19])([F:20])[F:21])=[CH:8][C:7]([CH3:22])=[CH:6][N:5]2[C:23]=1[C:24]([NH:61][CH:62]([CH2:67][CH2:68][CH2:69][C:70]([F:71])([F:72])[F:73])[C:63]([OH:65])([CH3:64])[CH3:66])=[O:25]
Reactant: Cc1cc(OCCC(C(F)(F)F)C(F)(F)F)c2nc(C)c(C(=O)O)n2c1
Reactant: CC(C)(O)C(N)CCCC(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCCC(C(F)(F)F)C(F)(F)F)c2nc(C)c(C(=O)NC(CCCC(F)(F)F)C(C)(C)O)n2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg (0.390 mmol) of 2,6-dimethyl-8-[4,4,4-trifluoro-3-(trifluoromethyl)butoxy]imidazo[1,2-a]-pyridine-3-carboxylic acid Example 91A and 163 mg (0.429 mmol) of HATU were initially charged in 2 ml of DMF. 0.2 ml (1.17 mmol) of N,N-diisopropylethylamine and 101 mg (0.429 mmol) of rac-3-amino-7,7,7-trifluoro-2-methylheptan-2-ol hydrochloride Example 103A were then added, and the mixture was stirred at RT overnight. 10 ml of water were added, the reaction solution was extracted twice with 20 ml of ethyl acetate and the combined organic phases were washed with 20 ml of water and with 20 ml of sat. aqueous NaCl solution, dried over MgSO4, filtered and concentrated. The residue was purified by preparative RP-HPLC (ACN:water+0.1% HCOOH). The product fractions were combined and concentrated to dryness and the residue was dissolved in a mixture of 1.5 ml of tert-butanol and 2 ml of water and lyophilized overnight. This gave 91 mg of the target compound (98% pure, 40% of theory).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10](=[S:13])([S-:12])[NH2:11].[NH4+]>C(O)C>[CH2:7]([O:6][C:4]([C:3]1[N:11]=[C:10]([SH:13])[S:12][CH:2]=1)=[O:5])[CH3:8]
Reactant: NC(=S)[S-]
Reactant: CCOC(=O)C(=O)CBr
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1csc(S)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 65.9 %

Procedure:
Ethyl bromopyruvate (90%, 100 g) was completely dissolved in ethanol (1000 mL), ammonium dithiocarbamate (55.9 g) was added, and the mixture was stirred at room temperature for 2.5 hrs and heated under reflux for 1 hr. After completion of the reaction, the solvent was evaporated under reduced pressure, water was added to the obtained residue. The solid was collected by filtration, washed with water and isopropyl ether, and dried to give the title compound (63.3 g) as a yellow powder.
Reaction SMILES: [NH2:1][C:2](=[O:16])[CH:3]([CH3:15])[O:4][C:5]1[C:9]([Br:10])=[CH:8][S:7][C:6]=1[C:11]([O:13]C)=[O:12].CO.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:1][C:2](=[O:16])[CH:3]([CH3:15])[O:4][C:5]1[C:9]([Br:10])=[CH:8][S:7][C:6]=1[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1scc(Br)c1OC(C)C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(Oc1c(Br)csc1C(=O)O)C(N)=O
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 73.4 %

Procedure:
To a mixture of methyl 3-(2-amino-1-methyl-2-oxoethoxy)-4-bromothiophene-2-carboxylate (634 mg), MeOH (20 mL) and water (0.074 ml) was added potassium carbonate (853 mg), and the mixture was stirred at 65° C. for 1.5 hr. The reaction mixture was concentrated under reduced pressure, the residue was acidified (pH 1) with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of Et2O and hexane to give the title compound (444 mg, 73%) as colorless crystals.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=1)[NH2:3].CN(C)/[CH:14]=[CH:15]/[C:16]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)=O>>[CH3:27][S:24]([C:21]1[CH:22]=[CH:23][C:18]([C:16]2[N:2]([C:4]3[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=3)[N:3]=[CH:14][CH:15]=2)=[CH:19][CH:20]=1)(=[O:25])=[O:26]
Reactant: CN(C)/C=C/C(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: N#Cc1ccnc(NN)c1
Agent: Cl
Product: CS(=O)(=O)c1ccc(-c2ccnn2-c2cc(C#N)ccn2)cc1
Yield: 100 %

Procedure:
The title compound was prepared in 100% yield from 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3) and (2E)-3-(dimethylamino)-1-[4-(methylsulfonyl)phenyl]prop-2-en-1-one according to the procedure for the preparation of Example 12, part B. 1H NMR (400 MHz, CDCl3): δ 3.10 (3H, s), 6.58 (1H, d, J=1.6 Hz), 7.39 (1H, dd, J=5.2, 1.2 Hz), 7.51 (2H, d, J=8.4 Hz), 7.81 (1H, d, J=1.6 Hz), 7.93 (2H, d, J=8.4 Hz), 8.20 (1H, s), 8.29 (1H, d, J=5.2 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([N:18]=C(C1C=CC=CC=1)C1C=CC=CC=1)[C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[N:7]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.Cl>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH2:18])[C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[N:7]=1)[CH3:2]
Reactant: CCOC(=O)C(N=C(c1ccccc1)c1ccccc1)c1cc(C)nc(-n2ccnc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(N)c1cc(C)nc(-n2ccnc2)n1
Yield: 69.6 %

Procedure:
A solution of (benzhydrylidene-amino)-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-acetic acid ethyl ester (460 mg, 1.10 mmol) in THF (4 mL), water (3 mL) and hydrochloride acid (1 mL, 37%) was stirred at r.t for 0.5 h. The saturated K2CO3 solution was added to make the solution basic (pH 9). The mixture was extracted with ethyl acetate (2×100 mL), washed with brine and dried over Na2SO4. Evaporation of the solvent and purification by column chromatography gave 200 mg (70%) of amino-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-acetic acid ethyl ester. [M+H]+ 262.64.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:4]1[C@@H:7]([CH2:8][C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])[N:6]([C:18]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[O:23])=[C:19]([CH3:21])[CH3:20])[C:5]1=[O:35])[CH3:3].[N+:36]([C:39]1[CH:49]=[CH:48][C:42]([CH2:43][O:44][C:45](Cl)=[O:46])=[CH:41][CH:40]=1)([O-:38])=[O:37].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:20][C:19]([CH3:21])=[C:18]([N:6]1[C@H:7]([CH2:8][C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])[C@@H:4]([C@H:2]([O:1][C:45]([O:44][CH2:43][C:42]2[CH:41]=[CH:40][C:39]([N+:36]([O-:38])=[O:37])=[CH:49][CH:48]=2)=[O:46])[CH3:3])[C:5]1=[O:35])[C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=1)=[O:23]
Reactant: CC(C)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@H]([C@@H](C)O)[C@H]1CC(=O)Sc1ccccc1
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@H]([C@@H](C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)[C@H]1CC(=O)Sc1ccccc1
Temperature: 0 °C
Yield: 35.2 %

Procedure:
44 mg (0.088 mmole) of (3S, 4R)-3-[(R)-1-hydroxyethyl]-1-[2-methyl-1-(p-nitrobenzyloxycarbonyl)prop-1-enyl]-4-[(phenylthio)carbonylmethyl]-2-azetidinone were dissolved in 2 ml of methylene chloride. To the solution were added 32 mg (0.26 mmole) of 4-(N,N-dimethylamino)pyridine and 57 mg (0.26 mmole) of p-nitrobenzyloxycarbonyl chloride, with stirring at 0° C. The mixture was stirred at that temperature for 3 hours, after which it was poured into a dilute aqueous solution of sodium bicarbonate and extracted with chloroform. The chloroform extract was washed successively with dilute hydrochloric acid and a dilute aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulphate. The solvent was then distilled off. The residue was subjected to thin layer chromatography using silica gel developed with a 3:1 by volume mixture of benzene and ethyl acetate, to afford 21 mg (yield 35%) of the title product as an oil.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[C:5](=[C:10]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>C(O)C>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:25])=[O:2])[C:5]=2[C:6]([OH:8])=[O:7])[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COC(=O)c1cccc(Nc2ccc(OC)c(OC)c2)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(Nc2cccc(C(=O)O)c2C(=O)O)cc1OC
Yield: 80.8 %

Procedure:
A mixture of 3-(3,4-dimethoxyphenylamino)phthalic acid dimethyl ester (0.80 g, 2.3 mmol) and 3N NaOH (50 mL) in ethanol (100 mL) was heated to reflux for 90 minutes. The mixture was cooled, and the solvent was removed under vacuum. The residue was dissolved in water (100 mL), washed with ethyl acetate (3×75 mL), acidified (HCl) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were washed with water (3×75 mL), dried (MgSO4), and evaporated, providing 0.59 g of the product in 81% yield: 1H NMR (DMSO-d6) δ 3.72 (s, 6H), 6.68 (dd, J=8.6 Hz, J=2.4 Hz, 1H), 6.81 (d, J=2.4 Hz, 1H), 6.90 (d, J=8.6 Hz, 1H), 7.00 (d, J=7.3 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.30 (t, J=7.9 Hz, 1H), 7.98 (br, 1H).
Reaction SMILES: C([O:5][C@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[C:19]([F:20])=[CH:18][N:17]=[C:16]([NH:21][C@H:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([O:37][C:38]([F:41])([F:40])[F:39])[CH:31]=3)[CH2:26][CH2:25]2)[CH3:23])[N:15]=1)[CH3:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([N:27]2[CH2:28][CH2:29][CH:24]([C@@H:22]([NH:21][C:16]3[N:15]=[C:14]([N:9]4[C@@H:8]([C@@H:6]([OH:5])[CH3:7])[CH2:12][O:11][C:10]4=[O:13])[C:19]([F:20])=[CH:18][N:17]=3)[CH3:23])[CH2:25][CH2:26]2)=[CH:31][C:32]=1[O:37][C:38]([F:39])([F:40])[F:41]
Reactant: C[C@H](Nc1ncc(F)c(N2C(=O)OC[C@@H]2[C@H](C)OC(C)(C)C)n1)C1CCN(c2ccc(Cl)c(OC(F)(F)F)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](Nc1ncc(F)c(N2C(=O)OC[C@@H]2[C@H](C)O)n1)C1CCN(c2ccc(Cl)c(OC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
(R)-4-((S)-1-(tert-butoxy)ethyl)-3-(2-(((S)-1-(1-(4-chloro-3-(trifluoromethoxy)phenyl)piperidin-4-yl)ethyl)amino)-5-fluoropyrimidin-4-yl)oxazolidin-2-one (34 mg, 0.058 mmole) was dissolved in DCM (1 mL), TFA (1 mL) was added. The reaction solution was stirred for 2 hour at room temperature and was concentrated by rotary evaporation. The resulting residue was dissolved in DCM (2 mL) and water 2 mL) and the pH was adjusted to ˜9 with NH4OH. The DCM layer was separated and concentrated by rotary evaporation to afford 28 mg of the title product as a yellow oil (ratio of two peaks with same MS: 96/4% by LC-MS). (400 MHz, CD2Cl2) δ 8.22 (d, J=2.27 Hz, 1H), 7.31 (d, J=8.85 Hz, 1H), 6.88-6.79 (m, 2H), 5.12 (br s, 1H), 4.61-4.50 (m, 2H), 4.46-4.37 (m, 1H), 4.26-4.15 (m, 1H), 3.93 (br s, 1H), 3.77-3.68 (m, 2H), 3.20 (br s, 1H), 2.79-2.67 (m, 2H), 1.96-1.78 (m, 2H), 1.70-1.58 (m, 1H), 1.55-1.28 (m, 2H), 1.23 (d, J=6.63 Hz, 3H), 1.19 (d, J=7.19 Hz, 3H), HRMS(C) tR=4.47 min; MS m/z 548.1689 (M+H)+
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]=[C:18](/[CH:20]=[CH:21]/[CH2:22][O:23][CH3:24])[CH:19]=1)[CH2:12][NH:13][CH:14]1[CH2:16][CH2:15]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]=[C:18]([CH2:20][CH2:21][CH2:22][O:23][CH3:24])[CH:19]=1)[CH2:12][NH:13][CH:14]1[CH2:16][CH2:15]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COC/C=C/c1cc(CNC2CC2)cc(O[Si](C)(C)C(C)(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCCc1cc(CNC2CC2)cc(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 1.5 h

Procedure:
To a solution of N-{3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(1E)-3-methoxyprop-1-en-1-yl]benzyl}cyclopropanamine from the previous step (1 eq.) in EtOAc (0.04 M) was added 10% palladium on activated carbon (10 mol %). The vessel was evacuated and back filled with hydrogen. The reaction suspension was then stirred under a balloon atmosphere of hydrogen for 1.5 h. The reaction was diluted with DCM and filtered through a bed of celite. The insolubles were further washed with EtOAc and methanol. Concentration of the filtrate in vacuo afforded the title compound amine 1 as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.[Li]CCCC.[B:17](OCCCC)([O:23]CCCC)[O:18]CCCC>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([B:17]([OH:23])[OH:18])=[CH:8][C:7]=2[CH:11]=1
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: COc1ccc2occc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2oc(B(O)O)cc2c1
Temperature: -30 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
5-Methoxybenzofuran (5.3 g, 35.8 mmol) was dissolved in anhydrous THF (120 mL) and cooled to −30° C. The solution was treated with n-BuLi (18 mL, 45 mmol, 2.5 M in hexanes) over 30 min, maintaining the internal temperature at −30° C. during the addition to give a yellow solution. After 1 h at −30° C., tributyl borate (12.2 mL, 45.1 mmol) was added over 10 min and the solution became pale yellow. The resulting solution was allowed to warm slowly to 14° C. over 12 h, then was quenched with 6 M HCl (50 mL) and extracted with EtOAc (150 mL). The organics were washed with water, then brine and dried over MgSO4. After filtration, the organic solution was concentrated and the boronic acid precipitated by the addition of hexanes. The solid was filtered and washed with hexanes to give an off-white solid (3.95 g, 48%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[OH:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=2)[N:17]=[CH:16][C:15]=1[C:28]([OH:30])=O.[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1>O1CCCC1>[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH:37][C:28]([C:15]2[CH:16]=[N:17][C:18]3[C:23]([C:14]=2[OH:13])=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=3)=[O:30])=[CH:34][CH:33]=1
Reactant: O=C(O)c1cnc2cc(C(F)(F)F)ccc2c1O
Reactant: NCc1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2cc(C(F)(F)F)ccc2c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.892 g 1,1'-carbonyldiimidazole in 30 mL of tetrahydrofuran is added 1.29 g 4-hydroxy-7-trifluoromethyl-3-quinolinecarboxylic acid. The reaction is stirred at room temperature for 1 h. A solution of 0.91 mL of 4-chlorobenzylamine in 10 mL of tetrahydrofuran is added dropwise. The reaction is allowed to warm slowly to room temperature and stirred for 18 h. The reaction mixture is concentrated in vacuo. The residue is taken up in 100 mL of dichloromethane and filtered. The filtrate is chromatographed twice, eluting with 5% methanol/dichloromethane. Fractions homogeneous by TLC are combined and concentrated in vacuo to yield a pale yellow solid. The solid is recrystallized from ethyl acetate to yield 0.298 g of the title compound as a white crystalline solid.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][S:9][CH:10]([CH:23]1[CH2:27][CH2:26][CH2:25][NH:24]1)[CH2:11][C:12]([NH:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13].[CH3:28][N:29]([CH3:57])[C@H:30]([C:34]([NH:36][C@H:37]([C:41]([N:43]([C@@H:45]([C@@H:53]([CH3:56])[CH2:54][CH3:55])[C@H:46]([O:51][CH3:52])[CH2:47][C:48](O)=[O:49])[CH3:44])=[O:42])[CH:38]([CH3:40])[CH3:39])=[O:35])[CH:31]([CH3:33])[CH3:32].C(O)(C(F)(F)F)=O.P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[CH:53]([CH:45]([N:43]([CH3:44])[C:41]([CH:37]([NH:36][C:34](=[O:35])[CH:30]([N:29]([CH3:57])[CH3:28])[CH:31]([CH3:32])[CH3:33])[CH:38]([CH3:39])[CH3:40])=[O:42])[CH:46]([O:51][CH3:52])[CH2:47][C:48]([N:24]1[CH2:25][CH2:26][CH2:27][CH:23]1[CH:10]([S:9][CH3:8])[CH2:11][C:12](=[O:13])[NH:14][CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:49])([CH2:54][CH3:55])[CH3:56]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C)C(C)C
Reactant: CSC(CC(=O)NCCc1ccccc1)C1CCCN1
Agent: CCOP(=O)(C#N)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCC(C)C(C(CC(=O)N1CCCC1C(CC(=O)NCCc1ccccc1)SC)OC)N(C)C(=O)C(NC(=O)C(C(C)C)N(C)C)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
After the crude 3-methylsulfanyl-N-phenethyl-3-pyrrolidin-2-yl-propionamide TFA salt obtained above was dissolved in DMF(2 ml), the solution was added at 0° C. to (3R*,4S*,5S*)-4-[N,N-dimethyl-L-valyl-(N-methyl-L-valinamido)]-3-methoxy-5-methylheptanoic acid which was prepared from (3R*,4S*,5S*)-4-[N,N-dimethyl-L-valyl-(N-methyl-L-valinamido)]-3-methoxy-5-methylheptanoic acid t-Bu ester (34 mg, 0.0700 mmol) by treating with TFA in CH2Cl2 according to the literature method (Chem. Pharm. Bull., 43(10), 1706-1718, 1995). To the solution were added diethyl phosphorocyanidate (95%: 12 μl, 0.0751 mmol) and triethylamine (49 μl, 0.352 mmol) at 0° C. After being stirred at 0° C. for 1 hr, the mixture was allowed to warm to room temperature and stirred for 20 hr. The mixture was quenched with saturated aqueous NaHCO3, extracted with AcOET, washed with saturated aqueous NaCl, dried (MgSO4), and concentrated in vacuo to give the crude oil (90 mg), which was purified by preparative HPLC (column: ODS-80Ts, eluent: 39/31 H2O:CH3CN/0.05% TFA). The appropriate fractions were lyophilized to obtain the title compound as a white amorphous powder (30 mg, 47%).
Reaction SMILES: [OH:1][C@H:2]([CH3:14])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH:6]=[N:5]1.[Br:15]N1C(=O)CCC1=O>O1CCCC1>[Br:15][C:11]1[C:10]([OH:13])=[CH:9][CH:8]=[C:7]2[C:12]=1[N:4]([CH2:3][C@H:2]([OH:1])[CH3:14])[N:5]=[CH:6]2
Reactant: O=C1CCC(=O)N1Br
Reactant: C[C@@H](O)Cn1ncc2ccc(O)cc21
Solvent: C1CCOC1
Product: C[C@@H](O)Cn1ncc2ccc(O)c(Br)c21
Temperature: 25 °C

Procedure:
A solution of 1-[(R)-2-hydroxypropyl]-1H-indazol-6-ol (4.76 g, 24.8 mmol) in tetrahydrofuran (50 mL), cooled in an ice bath, added small portions of N-bromosuccinimide (4.41 g, 24.8 mmol) and stirred while the reaction warmed to room temperature. The reaction was quenched with aqueous saturated sodium sulfite (100 mL) and extracted with ethyl acetate (100 mL). The combined extracts were dried (magnesium sulfate), filtered and evaporated to a yellow solid (7 g): mp 134–136° C.; LC/MS m/z 271/273.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[N:10]=[C:9]([C:11]2[N:16]=[CH:15][C:14]3[CH:17]=[N:18][N:19]([C:20]4[N:25]=[C:24]([N:26]5[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]5)[CH:23]=[CH:22][CH:21]=4)[C:13]=3[CH:12]=2)[CH:8]=[N:7][CH:6]=1)=[O:4]>CO>[OH:4][CH2:3][C:5]1[N:10]=[C:9]([C:11]2[N:16]=[CH:15][C:14]3[CH:17]=[N:18][N:19]([C:20]4[N:25]=[C:24]([N:26]5[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]5)[CH:23]=[CH:22][CH:21]=4)[C:13]=3[CH:12]=2)[CH:8]=[N:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-n3ncc4cnc(-c5cncc(C=O)n5)cc43)n2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-n3ncc4cnc(-c5cncc(CO)n5)cc43)n2)CC1
Reaction time: 1 h

Procedure:
Sodium borohydride (25 mg, 0.66 mmol) was added portionwise to a solution of tert-butyl 4-[6-[6-(6-formylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]piperazine-1-carboxylate (162 mg, 0.33 mmol) in 6 ml of methanol. The mixture was stirred for 1 hour, concentrated in vacuum, the residue partitioned between ethyl acetate and water. The organic extracts were washed with water, 1% aq. citric acid, water, and brine, dried over sodium sulfate and concentrated. The residue was purified on a 12 g silica gel column eluting with 0-7% gradient of methanol in DCM to afford 125 mg (77%). MS (ESI) m/z: 489.2 [M+H]+
Reaction SMILES: [OH-].[K+].Br[CH:4]1[CH:8]([Br:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[O:5]1>C(O)C>[Br:9][C:8]1[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[O:5][CH:4]=1
Reactant: BrC1Oc2ccccc2C1Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Brc1coc2ccccc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 108 %

Procedure:
To 11.3 g KOH (176 mmol) in 100 mL ethanol at 0° C. was added in small portions 22.2 g of 2,3-dibromo-2,3-dihydrobenzofuran, and the resulting reaction mixture was stirred at 0° C. for an additional 3 h. Most of the solvent was then removed in vacuo. Water and ether were added to the residue. The aq layer was separated and extracted with ether. The combined ether layers were washed with water and brine, dried (MgSO4), and concentrated to give 17 g of 3-bromobenzofuran.
Reaction SMILES: [CH3:1][C:2](=[N:6][OH:7])[C:3](=[O:5])[CH3:4].C(N(CC)CC)C.[C:15](Cl)(=[O:19])[C:16]([CH3:18])=[CH2:17].O>CCOCC>[C:15]([OH:19])(=[O:5])[C:16]([CH3:18])=[CH2:17].[N:6](=[C:2]([CH3:1])[C:3](=[O:5])[CH3:4])[OH:7]
Reactant: C=C(C)C(=O)Cl
Agent: CC(=O)C(C)=NO
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: C=C(C)C(=O)O

Procedure:
The monomer 3-oximino-2-butanone methacrylate (OBM) was prepared. This preparation began by cooling to a temperature of 0 degree C. with an ice water bath, a solution of butanedione monoxime (54.5 g) and triethylamine (120 ml) in ether (1000 ml). Approximately 56 ml of methacryloyl chloride in 250 ml of ether was added dropwise under a nitrogen atmosphere over the course of 1 hour. The solution was stirred during this addition and the stirring was continued under nitrogen at 0 degree C. for 3 hours after the addition was completed. The resulting mixture was filtered to remove the solid residues. The solid residues were discarded, and the liquid obtained was transferred to a separatory funnel. Approximately 300 ml of water was added to the separatory funnel and the liquid was agitated. The water and ether phases were separated, the water phase was discarded, and the ether phase was dried over magnesium sulfate for 1 hour. The magnesium sulfate was removed by filtration and the ether solution was evaporated to dryness on a rotary evaporator using water aspirator vacuum. The resulting solid was recrystallized from cyclohexane to yield 45 g of OBM. (The material obtained melted between 38.5 and 39 degrees C.)
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[C:10](=O)(O)[O-:11].[Na+].C(Cl)(Cl)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[N:7]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=1)=[C:10]=[O:11]
Reactant: Cc1ccc(CN)cc1
Reactant: O=C([O-])O
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccc(CN=C=O)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of p-methyl benzylamine (25 g, 0.21 mol) in CH2Cl2 (200 mL) and aqueous saturated solution of sodium bicarbonate (200 mL) was cooled to 0° C. and then treated dropwise with a 20% solution of phosgene in toluene (100 mL). The reaction was stirred at room temperature for 20 minutes and then the organic layer removed and the aqueous layer back-extracted with CH2Cl2. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to give 20.6 g 1-isocyanatomethyl-4-methyl-benzene that was utilized directly in the next reaction without purification.