Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:28])[NH:8][C:9](=[O:27])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][C:13]=1[F:26])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:28])[N:8]([CH2:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[C:9](=[O:27])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][C:13]=1[F:26])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CC(=O)C(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 90 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (1.22 g), cesium carbonate (1.73 g), 1-bromo-3,3-dimethylbutan-2-one (0.71 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.86 g, 34%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[NH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].O>ClCCl>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([CH2:12][NH:11][C:8]([C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)=[O:9])[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2cccnc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.4 %

Procedure:
A solution of 3-pyridinecarbonyl chloride hydrochloride (3.87 g) in dichloromethane (100 ml) was added to a suspension of 4-(aminomethyl)-1-tert-butoxycarbonylpiperidine (5.0 g) and potassium carbonate (10 g) in dichloromethane (100 ml), and the mixture stirred at ambient temperature for 2 hours before pouring into water (500 ml). The organic layer was washed with water (250 ml), dried over magnesium sulphate and the solvent was evaporated. The residue was purified by flash chromatography over silica eluting with a 20:1 mixture of dichloromethane and methanol. Appropriate fractions were combined and the solvent removed in vacuo to give N-[(1-tert-butoxycarbonyl-4-piperidyl)methyl]pyridine-3-carboxamide (3.22 g) as an orange oil.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[CH:7]=[C:8]([CH3:10])[O:9][C:4]=2[CH:3]=1.[Na].[C:15]([NH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32]Cl)[CH2:26][CH2:25]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(O)C>[C:15]([NH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][O:1][C:2]2[CH:13]=[CH:12][C:5]3[C:6](=[O:11])[CH:7]=[C:8]([CH3:10])[O:9][C:4]=3[CH:3]=2)[CH2:26][CH2:25]1)(=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cc(=O)c2ccc(O)cc2o1
Reactant: O=C(NC1CCN(CCCCl)CC1)c1ccccc1
Agent: [Na]
Solvent: CC(C)O
Product: Cc1cc(=O)c2ccc(OCCCN3CCC(NC(=O)c4ccccc4)CC3)cc2o1

Procedure:
5.3 g. (0.03 mol) 7-hydroxy-2-methyl-4H-1-benzopyran-4-one are added to a solution of 0.69 g. (0.03 mol) sodium in 75 ml. propan-2-ol and the mixture heated under reflux for 10 minutes. 8.4 g. (0.03 mol) 3-(4-Benzamidopiperidino)-propyl chloride dissolved in 25 ml. propan-2-ol are added thereto, the mixture heated under reflux for 12 hours, evaporated and the residue taken up in dichloromethane and the solution washed with dilute aqueous sodium hydroxide solution. The organic phase is evaporated and the residue recrystallised from propan-2-ol. There are obtained 6.8 g. (54% of theory) 7-[3-(4-benzamidopiperidino)propoxy]-2-methyl-4H-1-benzopyran-2-one; m.p. 173°-175° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:18][C@@H:19]([OH:43])[C@@H:20]([N:28](CC3C=CC=CC=3)CC3C=CC=CC=3)[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:14][CH:15]([CH3:17])[CH3:16])(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.O.[CH3:45][S:46]([OH:49])(=[O:48])=[O:47]>[OH-].[OH-].[Pd+2].C1COCC1>[CH3:45][S:46]([OH:49])(=[O:48])=[O:47].[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:18][C@@H:19]([OH:43])[C@@H:20]([NH2:28])[CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:14][CH:15]([CH3:17])[CH3:16])(=[O:11])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: [Pd+2]
Agent: CS(=O)(=O)O
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CN(C[C@@H](O)[C@@H](N)Cc1ccccc1)S(=O)(=O)c1ccc2c(c1)OCO2
Reaction time: 16 h

Procedure:
Part B: To the THF solution of crude 1-(N-[(1,3-benzodioxol-5-yl)sulfonyl]-N-(2-methylpropyl)amino]-3(S)-[bis(phenylmethyl)amino]-4-phenyl-2(R)-butanol was added water (500 mL) followed by methane sulfonic acid (531 g, 5.5 moles). The solution was stirred to insure complete mixing and added to a 5 gallon autoclave. Pearlman's catalyst (200 g of 20% Pd(OH)2 on C/50% water) was added to the autoclave with the aid of THF (500 mL). The reactor was purged four times with nitrogen and four times with hydrogen. The reactor was charged with 60 psig of hydrogen and stirring at 450 rpm started. After 16 hours, HPLC analysis indicated that a small amount of the mono-benzyl intermediate was still present. Additional catalyst (50 g) was added and the reaction was allowed to run overnight. The solution was then filtered through celite (500 g) to remove the catalyst and concentrated under vacuum in five portions. To each portion, toluene (500 mL) was added and removed under vacuum to allotropically removed residual water. The resulting solid was divided into three portions and each washed with methyl t-butyl ether (2 L) and filtered. The residual solvent was removed at room temperature in a vacuum oven at less than 1 torr to yield the 2714 g of the expected salt.
Reaction SMILES: Br[C:2]1[C:11]([C@H:12]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:23])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:25])=[N+:7]2[O-:24].[C:26]1(B(O)O)[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]([O:18][C@@H:12]([C:11]1[C:2]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)=[C:3]2[C:8](=[CH:9][C:10]=1[CH3:23])[N+:7]([O-:24])=[C:6]([CH3:25])[CH:5]=[CH:4]2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:22])([CH3:21])[CH3:20]
Reactant: OB(O)C1=CCCCC1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(ccc(C)[n+]2[O-])c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(ccc(C)[n+]2[O-])c1C1=CCCCC1
Temperature: 85 °C
Yield: 82.6 %

Procedure:
Pd(PPh3)4 (6 mg, 0.006 mmol) was added to a mixture (S)-5-bromo-6-(1-tert-butoxy-2-ethoxy-2-oxoethyl)-2,7-dimethylquinoline 1-oxide (compound of Example 20) (20 mg, 0.05 mmol), cyclohexenylboronic acid (12 mg, 0.1 mmol), K2CO3 (0.09 mL 2 M in water, 0.17 mmol) in 1,2-dimethoxyethane (1 mL). The reaction mixture was flushed with nitrogen, heated at 85° C. for overnight, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (30 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by HPLC to provide the desired product (17 mg, 68%). LCMS-ESI+ (m/z): 412.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH3:16])[CH:7]=[C:8]([N+:13]([O-])=O)[C:9]=1[C:10]([OH:12])=[O:11])([O-])=O.[H][H]>CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH3:16])[CH:7]=[C:8]([NH2:13])[C:9]=1[C:10]([OH:12])=[O:11]
Reactant: Cc1cc([N+](=O)[O-])c(C(=O)O)c([N+](=O)[O-])c1
Reactant: [H][H]
Solvent: CO
Product: Cc1cc(N)c(C(=O)O)c(N)c1
Yield: 81 %

Procedure:
3,5-dinitro-p-toluic acid (10.0 gm.) is dissolved in methanol (300 ml.) and 5% palledium on charcoal (1.0 gm.) added. Reduction is carried out in a Parr apparatus for one hour at 40 psi of hydrogen. The product precipitates and the reaction mixture warmed until solution is complete. The catalyst is removed by filtration, washed with a few cc of methanol and the filtrate cooled to 0°. The product precipitates in fine needles and is collected by filtration, washed with a few ml. of methanol and dried (5.95 gm., 81% yield, m.p. 218°-220° dec.). The thin layer chromatogram (Silica gel, 5% methanol in chloroform) shows the material to be homogeneous.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[S:8])[O:5][C:6]=1[CH3:7].S(OC)(O[CH3:13])(=O)=O>[OH-].[Na+]>[CH3:1][C:2]1[N:3]=[C:4]([S:8][CH3:13])[O:5][C:6]=1[CH3:7]
Reactant: COS(=O)(=O)OC
Reactant: Cc1[nH]c(=S)oc1C
Agent: [Na+]
Agent: [OH-]
Product: CSc1nc(C)c(C)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.4 %

Procedure:
4,5-Dimethyl-2(3H)-oxazolethione [Bull. Soc. Chim. Belg. 70, 745, (1961)] (37.5 g, 0.29 m) in 2N aqueous sodium hydroxide (150 ml) was stirred at room temperature during the dropwise addition of dimethyl sulphate (40.0 g, 0.317 m). The mixture was stirred for 4 hours at room temperature and then warmed to 50° C, cooled, and the aqueous phase extracted with diethyl ether. Evaporation of the solvent and distillation of the residue under reduced pressure gave 33.85 g (81%) of the title product as a pale yellow oil, b.p. 82° C./13 mm.
Reaction SMILES: C1N=CN([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[S:7])C=1.[CH3:13][O:14][CH2:15][CH2:16][C@@H](N)C.Cl.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OC)(C)(C)C.C1COCC1>[N:8]([C@@H:9]([CH3:10])[CH2:16][CH2:15][O:14][CH3:13])=[C:6]=[S:7]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COCC[C@H](C)N
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: COCC[C@H](C)N=C=S
Temperature: -5 °C
Reaction time: 0.38 h
Yield: 83.2 %

Procedure:
Under a nitrogen atmosphere N,N-thiocarbonyldiimidazole (97.0 g, 0.55 mol) and THF (470 mL) are added and the mixture is stirred for 15-30 min. The mixture is cooled to −10 to 0° C., a solution of (S)-4-methoxybutan-2-amine (46.9 g, 0.455 mol) in methyl tert-butyl ether (389 mL) is added, and the reaction mixture is warmed to 10-20° C. The reaction mixture is stirred at this temperature for 15-20 h, and then is cooled to 0-10° C. Hydrochloric acid (275 mL, 4 N in water) is added to arrive at a pH of 1 to 2. The reaction mixture is warmed to RT and the layers are separated. The aqueous layer is extracted with ethyl acetate (235 mL) and the organic layers are combined and washed with water (140 mL). The organic solution is concentrated under reduced pressure below 45° C., ethyl acetate (211.5 mL) is added, and the solution is concentrated under reduced pressure below 45° C. twice, and ethyl acetate (235 mL) is added. Sodium thiosulfate (32.3 g, 227.0 mmol) is added, the solution is filtered, and the filtercake is washed with ethyl acetate (104 mL). The filtrate is concentrated under reduced pressure below 45° C. to furnish the title compound as a yellow oil (55.0 g, 77%).
Reaction SMILES: [OH-].[Na+].[C:3]1([CH3:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[NH:11][NH2:12]>O>[NH:11]1[CH:9]=[CH:3][CH:4]=[N:12]1.[C:3]1([CH3:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: c1cn[nH]c1
Temperature: -10 °C

Procedure:
A 2000-ml three-neck flask was equipped with a dropping funnel and a thermometer and sealed under a nitrogen balloon. Into this flask, 36.0 g of water, 6.4 g of sodium hydroxide, 400 ml of toluene and 24.0 g (0.52 mol) of monomethylhydrazine were placed. The resulting solution was cooled, with stirring, to −10° C. or lower in a low-temperature thermostat whose temperature was set to −15° C. Then, 375 g of the water-washed DFAAE-toluene solution (DFAAE: 0.11 mol) was gradually dropped into the flask through the dropping funnel in such a manner that the inside temperature of the flask did not exceed −10° C. After completion of the dropping, the solution was kept stirred for 1 hour at −12° C. The inside temperature of the flask was then raised to 0° C. The thus-obtained solution was separated with the addition of 400 ml of water. The organic phase was recovered by a separatory funnel and washed with 400 ml of water, thereby yielding 702 g of 9.7 mass % pyrazole-toluene solution.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:23](O)[CH3:24]>>[CH2:23]([O:17][C:16](=[O:18])[C@@H:12]([CH:13]([CH3:15])[CH3:14])[NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])[CH3:24]
Reactant: CCO
Reactant: CC(C)[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H](NS(=O)(=O)c1ccc(F)cc1)C(C)C
Temperature: 25 °C
Reaction time: 28 h

Procedure:
To a solution of 15.0 g (54 mmol) of N-[(4-fluorophenyl)sulfonyl]-D-valine from Example 1a in 55 mL of anhydrous ethanol cooled in an ice bath, was slowly added 5.0 mL (8.1 g, 68 mmol) of thionyl chloride over 5 minutes. The reaction mixture was then stirred at room temperature for 28 hours, the solvents removed under reduced pressure and the residue dissolved in ethyl acetate. This was then washed with saturated sodium bicarbonate, 5% potassium hydrogen sulfate and brine, dried over sodium sulfate, filtered and concentrated to afford crude product, which was chromatographed on silica gel using 10-20% ethyl acetate/hexane to yield 12.8 g of pure N-[(4-fluorophenyl)sulfonyl]-D-valine ethyl ester, m/e=304 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:10]=[C:6]2[N:5]=[C:4]([CH3:17])[C:3]=1[F:18]>CC(O)=O.[Zn]>[F:18][C:3]1[C:4]([CH3:17])=[N:5][C:6]2[N:7]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:10]=2)[CH:2]=1
Reactant: Cc1nc2cc(-c3ccccc3)nn2c(Cl)c1F
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1nc2cc(-c3ccccc3)nn2cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 7-chloro-6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine x136 (22.9 mmol, 1 eq, 6 g) in 150 ml of AcOH at 0° C., is added zinc dust (68 mmol, 3 eq, 4.5 g). The mixture is stirred at 25° C. overnight. After evaporation of the solvent under reduced pressure, the crude product is poured on ice and quenched with a saturated aqueous NaHCO3 solution and extracted with AcOEt. The cumulated organic layers are washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure to yield 6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine x139.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:72][Si:73]([C:76]([CH3:79])([CH3:78])[CH3:77])([CH3:75])[CH3:74])[CH2:21][NH:22][C@H:23]([CH3:71])[CH2:24][C:25]2[CH:26]=[C:27]([CH2:31][CH2:32][NH:33][C:34]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([CH2:43][NH:44][C:45]([CH2:47][CH2:48][N:49]4[CH2:54][CH2:53][CH:52]([O:55][C:56](=[O:70])[NH:57][C:58]5[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=5[C:64]5[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=5)[CH2:51][CH2:50]4)=[O:46])=[CH:39][CH:38]=3)=[O:35])[CH:28]=[CH:29][CH:30]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)C1C=CC=CC=1>CCO.[Pd]>[Si:73]([O:72][C@H:20]([C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:19])[NH:17]2)[CH2:21][NH:22][C@H:23]([CH3:71])[CH2:24][C:25]1[CH:26]=[C:27]([CH2:31][CH2:32][NH:33][C:34]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([CH2:43][NH:44][C:45]([CH2:47][CH2:48][N:49]3[CH2:50][CH2:51][CH:52]([O:55][C:56](=[O:70])[NH:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=4[C:64]4[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=4)[CH2:53][CH2:54]3)=[O:46])=[CH:41][CH:42]=2)=[O:35])[CH:28]=[CH:29][CH:30]=1)([C:76]([CH3:77])([CH3:78])[CH3:79])([CH3:74])[CH3:75]
Reactant: C[C@H](Cc1cccc(CCNC(=O)Cc2ccc(CNC(=O)CCN3CCC(OC(=O)Nc4ccccc4-c4ccccc4)CC3)cc2)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: [Pd]
Solvent: CCO
Product: C[C@H](Cc1cccc(CCNC(=O)Cc2ccc(CNC(=O)CCN3CCC(OC(=O)Nc4ccccc4-c4ccccc4)CC3)cc2)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c2[nH]c(=O)ccc12
Reaction time: 1 h

Procedure:
Dry nitrogen was bubbled into a stirred solution of biphenyl-2-ylcarbamic acid 1-{2-[(4-{[2-(3-{(R)-2-[(R)-2-(8-benzyloxy-2-oxo-1,2-dihydroquinolin-5-yl)-2-(tert-butyldimethylsilanyloxy)-ethylamino]propyl} phenyl)ethylcarbamoyl]-methyl}phenyl)methylcarbamoyl]ethyl}-piperidin-4-yl ester (0.704 g, 0.650 mmol) in EtOH (5.00 mL) for 3 min and then palladium on carbon (10 wt. %, ˜50% water; 0.289 g, 0.130 mmol) was added. Hydrogen was bubbled into the reaction mixture for 3 min and then the mixture was stirred under an atmosphere of hydrogen (balloon) for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound, which was used without further purification in the next reaction.
Reaction SMILES: [N:1]([CH:4]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[N:25]([CH:26]([CH3:28])[CH3:27])[C:24]([CH3:29])=[N:23][CH:22]=4)[C:18]([F:30])=[CH:17][N:16]=3)=[CH:10][CH:9]=2)[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.Cl>C1COCC1>[NH2:1][CH:4]1[CH2:5][N:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[N:25]([CH:26]([CH3:27])[CH3:28])[C:24]([CH3:29])=[N:23][CH:22]=4)[C:18]([F:30])=[CH:17][N:16]=3)=[CH:12][CH:13]=2)[CH2:7]1
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CC(N=[N+]=[N-])C4)cc3)ncc2F)n1C(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ncc(-c2nc(Nc3ccc(N4CC(N)C4)cc3)ncc2F)n1C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.6 %

Procedure:
To a solution N-[4-(3-azidoazetidin-1-yl)phenyl]-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-amine (Example 139; 382 mg, 938 mM) in THF (10 ml), triphenylphosphine (260 mg, 0.984 mM) was added. The reaction was stirred at room temperature under nitrogen for 24 hours. Water (2.0 ml) was then added and the mixture stirred and heated at 65° C. for 3 hours. Hydrochloric acid (1M, 1.5 ml) was added and the THF removed in vacuo. More water was then added and the solution extracted with EtOAc. Sodium hydroxide (1M, 1.5 ml) was added to the water layer and the solution was extracted with EtOAc. The organic layers were combined, dried with anhydrous sodium sulphate, filtered and evaporated to give the title compound as a yellow foam (324 mg, 91%). NMR (DMSO-d6+d4-acetic acid) 1.38 (d, 6H), 2.5 (s, 3H), 3.73 (m, 2H), 4.05 (m, 3H), 5.43 (m, 1H), 6.45 (d, 2H), 7.33 (s, 1H), 7.4 (d, 2H), 8.4 (d, 1H); m/z 382.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C:5]=12.C1C(=O)N([Br:24])C(=O)C1>C1C=CC=CC=1>[Br:24][C:3]1[N:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C:5]2=[N:1][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCn2ccnc2C1
Reactant: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCn2c(Br)cnc2C1

Procedure:
A mixture of tert-butyl 5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (2.23 g, 10 mmol) and NBS (1.78 g, 10 mmol) in benzene (10 mL) is heated at reflux for one hr. The solvent is evaporated and the residue is purified by column with 5% MeOH in DCM to give the title compound. 1H NMR (CDCl3) δ 6.98 (s, 1H), 4.65 (s, 2H), 3.86 (s, 4H), 1.47 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[C:20]([F:21])=[CH:19][CH:18]=[C:17]([O:22][CH2:23][CH3:24])[C:16]=2[F:25])=[CH:11][C:10]1=[O:26])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1>[CH2:23]([O:22][C:17]1[C:16]([F:25])=[C:15]([C:20]([F:21])=[CH:19][CH:18]=1)[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:27])=[O:2])[C:10](=[O:26])[CH:11]=1)[CH3:24]
Reactant: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)OC)C2)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1F
Temperature: 5 °C
Reaction time: 3 h
Yield: 105.6 %

Procedure:
To a solution containing (S)-2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (1.68 g, 0.004 mol) in tetrahydrofuran (60 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 18 mL, 0.009 mol). The mixture was stirred at 5° C. for 3 h, and the solvents evaporated. The residue was dissolved in water and washed with diethyl ether, and the diethyl ether layer discarded. The aqueous phase was acidified with dilute hydrochloric acid (pH <2), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford (S)-2-[4-(3-ethoxy-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid, (1.56 g, 96%), as a pale brown solid.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][C:8]([C:11]([OH:13])=O)=[C:7]([CH3:14])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][CH2:17][CH2:18][N:19]([CH3:27])[C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][N:21]=1>>[CH3:15][O:16][CH2:17][CH2:18][N:19]([CH3:27])[C:20]1[N:21]=[CH:22][C:23]([NH:26][C:11]([C:8]2[O:9][C:10]3[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=3[C:7]=2[CH3:14])=[O:13])=[CH:24][CH:25]=1
Reactant: COCCN(C)c1ccc(N)cn1
Reactant: Cc1c(C(=O)O)oc2c(F)cccc12
Product: COCCN(C)c1ccc(NC(=O)c2oc3c(F)cccc3c2C)cn1

Procedure:
With a procedure similar to the example above, 7-fluoro-3-methyl-benzofuran-2-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 7-fluoro-3-methyl-benzofuran-2-carboxylic acid and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C19H20FN3O3 (m/e) 357, obsd 358 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:10]2[N:14]=[CH:13][CH:12]=[N:11]2)=[C:4]([N+:7]([O-])=O)[S:5][CH:6]=1.C(O)(=O)C>[Fe].O>[Br:1][C:2]1[C:3]([N:10]2[N:14]=[CH:13][CH:12]=[N:11]2)=[C:4]([NH2:7])[S:5][CH:6]=1
Reactant: O=[N+]([O-])c1scc(Br)c1-n1nccn1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1scc(Br)c1-n1nccn1
Reaction time: 1 h
Yield: 66.4 %

Procedure:
A mixture of 2-(4-bromo-2-nitrothiophen-3-yl)-2H-1,2,3-triazole (0.59 g, 2.15 mmol), iron powder (0.75 g, 13.38 mmol), glacial acetic acid (8.4 mL) and H2O (1.2 mL) was heated in an oil bath set at 70° C. under condenser with N2 (g) inlet for 1 h. Purification by flash chromatography (silica, 40:60 ethyl acetate/hexane) gave 4-bromo-3-(2H-1,2,3-triazol-2-yl)thiophene-2-amine (0.35 g, 66%). Retention time (min)=1.540, method [4], MS(ESI) 246.9 (M+H).