Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([CH2:16]O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:21](C(C)C)CC)(C)C.CS(Cl)(=O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:21])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CO)C1
Reactant: CCN(C(C)C)C(C)C
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: NCC1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.3 %

Procedure:
To a 0° C. solution of 350 mg of 1-benzyloxycarbonyl-3-hydroxymethylpyrrolidine in 10 mL of CH2Cl2 was added 288 mg of diisopropylethylamine, then 204 mg of methanesulfonyl chloride. After 10 min, the cooling bath was removed and the mixture was stirred for 30 min at room temperature. The mixture was diluted with 25 mL of EtOAc and washed with 10 mL of saturated NaHCO3, 2×10 mL of 1 N HCl and 10 mL of brine. The organic phase was dried over MgSO4 and concentrated. The residue was dissolved in 10 mL of DMF and 145 mg of sodium azide was added. The mixture was heated to 100° C. and stirred overnight at this temperature, then cooled, diluted with 25 mL of EtOAc, and washed with 2×10 mL of water and 10 ml of brine. The organic phase was dried over MgSO4 and concentrated. The residue was dissolved in 10 mL of 9:1 THF-water and 586 mg of triphenylphosphine was added. The mixture was heated to 50° C. and stirred at this temperature for 3 h, then cooled, poured into 20 mL of 1 N HCl, and extracted with 2×10 mL of EtOAc. The aqueous phase was made very basic (pH>12) by addition of 5 N NaOH, then extracted with 4×10 mL of EtOAc. The combined organic extracts were washed with 10 mL of brine, dried over MgSO4, and concentrated. The residue was purified by flash chromatography, eluting with 20:1 CH2Cl2-2M NH3 in MeOH, to yield 273 mg of the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.28-7.40 (m, 5H), 5.13 (m, 2H), 3.47-3.67 (m, 2H), 3.38 (dt J=9.8, 16.7 Hz, 1H), 3.09 (ddd, J=7.6, 10.5, 15.1 Hz, 1H), 2.64-2.78 (m, 2H), 2.23 (dt, J=7.8, 15.3 Hz, 1H), 1.96-2.08 (m, 1H), 1.52-1.67 (m, 1H), 1.25 (br s, 2H).
Reaction SMILES: C1COCC1.[C:6](/[C:8](=[CH:13]\[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]2[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=2[Cl:32])=[CH:16][CH:15]=1)/[C:9]([O:11]C)=[O:10])#[N:7].[OH-].[Na+]>CO>[C:6](/[C:8](=[CH:13]\[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]2[C:25]([Cl:32])=[CH:26][C:27]([CH3:31])=[CH:28][C:29]=2[Cl:30])=[CH:18][CH:19]=1)/[C:9]([OH:11])=[O:10])#[N:7]
Reactant: COC(=O)/C(C#N)=C/c1ccc(OCCOc2c(Cl)cc(C)cc2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Cl)c(OCCOc2ccc(/C=C(\C#N)C(=O)O)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 2:1 (v/v) THF:MeOH solution (0.1 M) of methyl (2E)-2-cyano-3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}acrylate from Example 9, Step 1 (1 eq.) was added sodium hydroxide (1.0 M aq. solution, 3 eq.). The resulting solution was stirred at RT for 18 h before the volatiles were removed in vacuo. Following careful acidification of the resulting mixture to pH ˜1 with 10% aq. HCl, the solution was extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a yellow semi-solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:29])[CH2:15][CH:16]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:31]1[S:32][C:33]2[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:34]=2[N:35]=1>>[Cl:40][C:38]1[CH:37]=[CH:36][C:34]2[N:35]=[C:31]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14](=[O:29])[CH2:15][CH:16]([CH2:21][CH2:22][C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)[S:32][C:33]=2[CH:39]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: COC(=O)C(CCc1ccccc1)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Product: O=C(CC(CCc1ccccc1)C(=O)O)c1ccc(-c2ccc(Nc3nc4ccc(Cl)cc4s3)cc2)cc1
Yield: 24.7 %

Procedure:
This compound was prepared from methyl 4-(4′-amino-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate (78 mg, 0.20 mmol), 2,6-dichloro-1,3-benzothiazole (61.6 mg, 0.30 mmol) in a similar manner to the method described for 4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenylyl-4-yl]-2,2-dimethyl-4-oxobutanoic acid, providing 26.7 mg (25%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 10.80 (br s, 1H), 7.75-8.05 (m, 9H), 7.60 (d, 1H), 7.10-7.40 (m, 6H), 3.50 (q, 1H), 3.10 (m, 1H), 2.85 (m, 1H), 2.65 (m, 2H), 1.80 (m, 2H). LC-MS m/z 541.3 (MH+), ret. time 4.07 min.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:16])[C:7]=2[N:17]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[O:28]1[CH2:29][CH2:30][N:25]([CH2:3][C:4]2[N:5]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=[C:8]([NH2:16])[C:7]=3[N:17]=2)[CH2:26][CH2:27]1
Reactant: C1COCCN1
Reactant: Nc1nc2ccccc2c2c1nc(CCl)n2Cc1ccccc1
Agent: Cl
Product: Nc1nc2ccccc2c2c1nc(CN1CCOCC1)n2Cc1ccccc1
Temperature: 25 °C

Procedure:
2-Chloromethyl-1-phenylmethyl-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride (Example 28, prepared from 2.0 g of the alcohol) was added to morpholine (5.0 mL) and the mixture was refluxed for 4 hr. The mixture was then cooled to room temperature and the solid was filtered from the mixture. The solid was slurried in aqueous sodium bicarbonate solution, filtered from the mixture, and dried. A crude yield of 2.0 g of product as a white solid was obtained. The crude product was recrystallized from methanol/dichloromethane. m.p. >300° C. Analysis: Calculated: C, 70.7; H, 6.2; N, 18.8. Found: C, 70.4; H, 6.2; N, 18.6.
Reaction SMILES: [I:1][C:2]1[C:3]2[CH:4]=[CH:5][C:6]([CH3:13])=[N:7][C:8]=2[C:9](=O)[NH:10][CH:11]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:9]1[N:10]=[CH:11][C:2]([I:1])=[C:3]2[C:8]=1[N:7]=[C:6]([CH3:13])[CH:5]=[CH:4]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2c(I)c[nH]c(=O)c2n1
Product: Cc1ccc2c(I)cnc(Cl)c2n1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
5-Iodo-2-methyl-7H-[1,7]naphthyridin-8-one (14.2 g, 49.8 mmol) was suspended in phosphorus oxychloride (68 ml, 750 mmol) and stirred for 5 hours at 90° C. The reaction mixture was cooled to room temperature and evaporated to dryness. The residue was taken up in dichloromethane and extracted carefully with saturated NaHCO3-Solution. The aqueous layer was washed two times with dichloromethane. The organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (ethyl acetate/heptane 10:90->100:0 gradient). The desired compound was obtained as a light red solid (4.8 g, 32%), MS: m/e=305.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH:16]([OH:21])[CH2:15]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].S(OC)(O[CH3:28])(=O)=O>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH:16]([O:21][CH3:28])[CH2:15]2)(=[O:12])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(S(=O)(=O)N2CCC(O)C(O)C2)ccc1Cl
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC1CN(S(=O)(=O)c2ccc(Cl)c(C(=O)O)c2)CCC1O
Temperature: 25 °C

Procedure:
2-Chloro-5-(3,4-dihydroxypiperidinosulfonyl)benzoic acid (4.0 g.) is heated for 16 hours at 90° C. with water (15 ml.), NaOH (1.0 g.) and dimethyl sulfate (0.5 ml.). Dimethyl sulfate and NaOH are added during the course of the reaction to maintain basicity. After cooling to room temperature, the reaction mixture is washed with ether and the aqueous phase is acidified with concentrated hydrochloric acid and decanted from the precipitated gum. The gum is dissolved in ethyl acetate and chromatographed on a silica gel column. The product fractions in the column effluent are identified by paper chromatography, with development in a solvent system of ethyl acetateacetic acid. Concentration of the column fraction yields the product, m.p. 170°-174° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]([O:7][C:8]([C:10]1[N:11]=[CH:12][C:13]2[NH:14][C:15]3[C:20]([C:21]=2[CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:9])[CH3:6].O.[C:24](Cl)(=[O:26])[CH3:25]>>[CH2:5]([O:7][C:8]([C:10]1[N:11]=[CH:12][C:13]2[NH:14][C:15]3[C:20]([C:21]=2[CH:22]=1)=[CH:19][C:18]([C:24](=[O:26])[CH3:25])=[CH:17][CH:16]=3)=[O:9])[CH3:6]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(C(C)=O)cc12
Reaction time: 0.08 h

Procedure:
400 mg of AlCl3 was suspended in 10 ml of acetyl chloride at 0° C. and 600 mg of beta-carboline-3-carboxylic acid ethyl ester was added. After 5 minutes, 600 mg of AlCl3 was added and the mixture was stirred for 1 hour. Alcohol was added and the pH adjusted to 7-8. 50 ml of water was added and the filtered mixture yielded 450 mg of raw product, which was recrystallized from ethanol/water (1:1). Mp: 290°-305° C.
Reaction SMILES: Cl.[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH:13]=[C:12](/[CH:14]=[C:15]2\[CH2:16][N:17]([CH:22]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[C:23]([CH:25]3[CH2:27][CH2:26]3)=[O:24])[CH2:18][CH2:19][CH:20]\2[SH:21])[N:11]=[N:10]1)([OH:4])=[O:3].[C:35](OC(=O)C)(=[O:37])[CH3:36]>>[C:35]([S:21][CH:20]1[CH2:19][CH2:18][N:17]([CH:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[C:23]([CH:25]2[CH2:26][CH2:27]2)=[O:24])[CH2:16]/[C:15]/1=[CH:14]\[C:12]1[N:11]=[N:10][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])[CH:13]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CCCCn1cc(/C=C2\CN(C(C(=O)C3CC3)c3ccccc3F)CCC2S)nn1
Agent: Cl
Product: CC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1cn(CCCCC(=O)O)nn1
Yield: 99 %

Procedure:
In a similar manner to that described in Example 183, (E)-3-{[1-(4-carboxybutyl)-1H-1,2,3-triazol-4-yl]methylidene}-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-sulfanylpiperidine hydrochloride (190 mg) was treated with acetic anhydride. The crude product extracted using conventional procedures was purified by chromatography on silica gel using a mixture of methanol and dichloromethane (1:99 to 7:93) as the eluent to afford the title compound as a colourless oil (190 mg, yield: 99%).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1I>>[NH2:15][C:7]1[C:6]([C:4]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[F:17])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: Fc1ccccc1I
Product: CCSc1ncc(C(=O)c2ccccc2F)c(N)n1

Procedure:
The same procedure was used as described in Example 2, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methylamide (from Example 1) and a solution of 2-fluorophenylilithium (˜3 equiv, freshly prepared from 1-fluoro-2-iodobenzene as in Example 2A), to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2-fluoro-phenyl)-methanone. MS (M+H)+: 278.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])=[C:5]([NH2:13])[NH:4][N:3]=1.O.C(N(C(C)C)[CH:19]=[C:20]([F:23])[CH:21]=O)(C)C>CS(C)=O>[NH2:13][C:5]1[C:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])=[C:2]2[N:1]=[CH:19][C:20]([F:23])=[CH:21][N:3]2[N:4]=1
Reactant: CC(C)N(C=C(F)C=O)C(C)C
Reactant: C=CCOC(=O)c1c(N)n[nH]c1N
Solvent: CS(C)=O
Solvent: O
Product: C=CCOC(=O)c1c(N)nn2cc(F)cnc12
Temperature: 100 °C

Procedure:
To a suspension of allyl 3,5-diamino-1H-pyrazole-4-carboxylate 3 (42.72 g, 234.5 mmol) in DMSO (270.8 mL)/Water (270.8 mL), was added p-TsOH hydrate (46.72 g, 245.6 mmol) and 3-(diisopropylamino)-2-fluoro-prop-2-enal (described in Tetrahedron Letters, 33(3), 357-60; 1992) (38.69 g, 223.3 mmol). The reaction mixture was heated to 100° C. for 3 h during which time a solid slowly precipitated out of solution. The orange suspension was allowed to cool down to RT overnight. The solid was filtered, washed with water and dried under vacuum to give allyl 2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylate 4a as a sand solid (45.05 g, 85% yield).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[N:17]([CH2:24][CH3:25])[C:16]2=[O:26])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCO.[C].[Pd]>[CH2:24]([N:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[N:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[C:16]1=[O:26])[CH3:25]
Reactant: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncccc21
Agent: [Pd]
Solvent: CCO
Product: CCn1c(=O)n(-c2ccc(O)cc2)c2ncccc21
Reaction time: 3 h
Yield: 71.2 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.70 g) and 10% palladium-carbon (0.832 g) in EtOH (250 mL) was hydrogenated under balloon pressure at room temperature for 3 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.42 g) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16](F)=[CH:15][CH:14]=2)[CH:3]=1.[NH:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1>C(O)C>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:3]=[C:2]2[N:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1
Reactant: NC(=O)C1CCNCC1
Reactant: Fc1ccc(-c2cc(Cl)c3cc(Cl)ccc3n2)cc1
Solvent: CCO
Product: NC(=O)C1CCN(c2cc(-c3ccccc3)nc3ccc(Cl)cc23)CC1

Procedure:
The named compound was made in a manner analogous to that of Example 4(c) using 4,6-dichloro-2-(4-fluorophenyl)quinoline and isonipecotamide as starting materials. It was obtained as white needles, mp 253°-255° dec on recrystallization from ethanol.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:16][CH:17]1[CH2:19][CH2:18]1)[C:12](OC)=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].O>CO>[CH:17]1([CH2:16][C@H:11]([NH:10][C:8](=[O:9])[O:7][C:3]([CH3:5])([CH3:4])[CH3:6])[CH2:12][OH:13])[CH2:19][CH2:18]1
Reactant: COC(=O)[C@H](CC1CC1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CO)CC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
NaBH4 (1.5 g, 39 mmol) was added in portions to a solution of (S)-methyl 2-(tert-butoxycarbonylamino)-3-cyclopropylpropanoate (Example 135 a, 3.15 g, 13 mmol) in MeOH (30 mL) at room temperature. The mixture was stirred at room temperature for 2 h. H2O (50 mL) was added and a white precipitate formed. The precipitate was collected by filtration and dried to give the title product (1.84 g, 66%) as white solid which was used in the next step without further purification; MS (EI): m/e=238.1 [M+Na]+.
Reaction SMILES: C([O:3][C:4](=O)/[CH:5]=[C:6](/[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)\[CH3:7])C.CC(C[AlH]CC(C)C)C>>[Br:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8](/[C:6](/[CH3:7])=[CH:5]/[CH2:4][OH:3])=[CH:9][CH:10]=2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(-c2ccc(Br)cc2)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: C/C(=C\CO)c1ccc(-c2ccc(Br)cc2)cc1

Procedure:
(E)-3-(4′-bromo-biphenyl-4-yl)-but-2-en-1-ol was prepared from (E)-3-(4′-bromo-biphenyl-4-yl)-but-2-enoic acid ethyl ester (3.45 g, 10.0 mmol) and DIBAL-H (1M in toluene, 40 mL, 40 mmol) by a procedure analogous to that described in example 11 step B, yielding 1.68 g (55%).
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH2:5][C@@:6]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4].Br[C:38]1[S:39][C:40]([C:43]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[CH:41][N:42]=1>>[C:46]([NH:45][C:43]([C:40]1[S:39][C:38]([C:18]2[CH:19]=[CH:20][C:15]([C@@H:13]([N:9]3[CH2:8][CH2:7][C@:6]([CH2:5][C:2]([C:3]#[N:4])([CH3:36])[CH3:1])([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[O:11][C:10]3=[O:12])[CH3:14])=[CH:16][CH:17]=2)=[N:42][CH:41]=1)=[O:44])([CH3:49])([CH3:47])[CH3:48]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Reactant: CC(C)(C)NC(=O)c1cnc(Br)s1
Product: C[C@@H](c1ccc(-c2ncc(C(=O)NC(C)(C)C)s2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrile and 2-bromo-N-tert-butylthiazole-5-carboxamide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.292 min, m/z=545.4; 1H NMR (CDCl3) 1.25 (s, 3H), 1.40 (s, 3H), 1.49 (d, 3H), 2.11 (s, 2H), 2.26 (m, 1H), 2.42 (m, 2H), 2.88 (m, 1H), 5.61 (m, 1H), 5.73 (s, 1H), 6.85 (m, 2H), 7.31 (m, 5H), 7.60 (m, 2H), 8.00 (m, 1H).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([O:11][C@@H:12]1[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:16]([O:22][C:23](=[O:25])[CH3:24])[CH2:15][S:14][C@@H:13]1Br)(=[O:10])[CH3:9]>[O-2].[Zn+2]>[C:8]([O:11][C@@H:12]1[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:16]([O:22][C:23](=[O:25])[CH3:24])[CH2:15][S:14][C@H:13]1[S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:10])[CH3:9]
Reactant: Sc1ccccc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Agent: [O-2]
Agent: [Zn+2]
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccccc2)SC[C@H]1OC(C)=O
Yield: 32.2 %

Procedure:
If the procedure described in Preparation IV is followed starting from 4 g (36.3.10-3 mol) of benzenethiol, 15 g (42.3.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 3 g (36.8.10-3 mol) of zinc oxide (ZnO), 4.5 g (yield: 32.29%) of the expected product are obtained after crystallization from ether.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Br:16]N1C(=O)CCC1=O.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Br:16][CH:5]1[CH2:6][N:7]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[CH2:8][CH2:9][N:4]1[CH:1]([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)N1CCN(c2cnccn2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)N1CCN(c2cnccn2)CC1Br
Reaction time: 8 h

Procedure:
4-Isopropyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (1.0 g, 4.8 mmol) was dissolved in dichloromethane (30 mL) and the solution was placed on an ice-bath and brominated according to literature (Tetrahedron 44, 10, 1988, 2977-2984) in very bad yield. N-Bromosuccinimide (3.45 g, 19.4 mmol) was added slowly at 0° C. and then left overnight at rt. No reaction was observed. An additional 3.45 g of N-bromosuccinimide was added during 8 h, and then the reaction mixture was left at rt for 2 days. Aqueous concentrated Na2CO3 was added and the mixture was extracted with dichloromethane (3×75 mL). The combined organic extracts were dried (MgSO4), filtered and evaporated. The oily residue was purified on a silica gel column with dichloromethane/MeOH (9:1) as eluent. Yield: 196 mg (28%) of 5-bromo-4-isopropyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl as an oil.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:15]([CH3:17])[N:16]=1>CN(C=O)C>[CH2:1]([NH:8][C:9](=[O:10])[NH:11][C:12]1[S:13][C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:15]([CH3:17])[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(N)nc1C
Reactant: O=C=NCc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(NC(=O)NCc2ccccc2)nc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.05 ml of benzyl isocyanate are added to a solution of 5.0 g of ethyl 2-amino-4-methyl-thiazole-5-carboxylate in 50 ml of DMF. The reaction mixture is stirred at RT overnight, evaporated on a rotary evaporator and the residue is suspended in methylene chloride:methanol 1:1. The insoluble material is filtered off and dried. There are obtained 4.6 g of colorless ethyl 2-(3-benzyl-ureido)-4-methyl-thiazole-5-carboxylate, MS: 320 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([N:16]1[C@@H:23]([C:24]#[CH:25])[CH2:22][CH2:21][C@H:17]1[C:18](O)=[O:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:27]1CCOCC1.ClC(OCC(C)C)=O.N.Cl>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([N:16]1[C@@H:23]([C:24]#[CH:25])[CH2:22][CH2:21][C@H:17]1[C:18]([NH2:27])=[O:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CN1CCOCC1
Reactant: C#C[C@H]1CC[C@@H](C(=O)O)N1C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: N
Solvent: C1CCOC1
Product: C#C[C@H]1CC[C@@H](C(N)=O)N1C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of N-(tert-butoxycarbonyl)-L-leucyl-(5R)-5-ethynyl-L-proline (2.83 mmol) and N-methyl morpholine (0.39 mL, 3.50 mmol) in THF (15 mL) was added isobutyl chloroformate (0.42 mL, 3.25 mmol). The resulting cloudy white mixture was stirred at 0° C. for 30 minutes followed by the addition of a solution of ammonia (0.5 M in dioxane, 10.0 mL, 5.0 mmol). The solution was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was diluted by the addition of 1 M HCl (100 mL), and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated to provide the titled compound.
Reaction SMILES: [C-]#N.[Na+].O.[N:5]12CCN(CC1)C[CH2:6]2.[N:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:24]=[C:23](SC)[N:22]([CH3:27])[C:21](=[O:28])[C:20]=2[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[CH:15][CH:14]=1>CN1CCCC1=O>[CH3:27][N:22]1[C:21](=[O:28])[C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=[C:19]([C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)[N:24]=[C:23]1[C:6]#[N:5]
Reactant: CSc1nc(-c2ccncc2)c(-c2cccc(C(F)(F)F)c2)c(=O)n1C
Reactant: C1CN2CCN1CC2
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cn1c(C#N)nc(-c2ccncc2)c(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of NaCN (55 mg), water (0.1 ml) in 1-methyl-2-pyrrolidone (50 mL) was added 1,4-diazabicyclo[2,2,2]octane (220 mg, 2 mmole) and a solution of 365 mg of 6-(4-pyridyl)-3-methyl-2-methylthio-5-(3-(trifluoromethyl)phenyl)-(3H)-pyrimidin-4-one in 1-methyl-2-pyrrolidone (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 5 minutes. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over Na2SO4 and then concentrated. The residue was purified by flash chromatography (20% EtOAc:Hexanes) to provide the product as a colorless oil; MS (m/z) 357 (M+H)+; C18H11F3N4O requir. 356.3.