Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=[C:5]([Cl:19])[N:4]=1.[CH3:20][O:21][C:22](=[O:42])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH:30][CH2:31][C:32]2[CH:41]=[CH:40][C:35]3[O:36][CH2:37][CH2:38][O:39][C:34]=3[CH:33]=2)=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:20][O:21][C:22](=[O:42])[C:23]1[CH:24]=[CH:25][C:26]([CH2:29][N:30]([CH2:2][C:3]2[C:8]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:6]=[C:5]([Cl:19])[N:4]=2)[CH2:31][C:32]2[CH:41]=[CH:40][C:35]3[O:36][CH2:37][CH2:38][O:39][C:34]=3[CH:33]=2)=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc(CNCc2ccc3c(c2)OCCO3)cc1
Reactant: CCCCc1c(CBr)nc(Cl)nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCc1c(CN(Cc2ccc(C(=O)OC)cc2)Cc2ccc3c(c2)OCCO3)nc(Cl)nc1-c1ccccc1
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of impure 4-bromomethyl-5-butyl-2-chloro-6-phenyl-pyrimidine (288 mg) and 4-{[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-methyl}-benzoic acid methyl ester (190 mg, 0.606 mmol) in CH3CN containing K2CO3 (300 mg) is stirred at room temperature. The reaction is monitored by TLC until complete consumption of 4-bromomethyl-5-butyl-2-chloro-6-phenyl-pyrimidine (24 hours). The mixture is then diluted with CH2Cl2 and filtered. The filtrate is concentrated, and the resulting residue is purified by flash chromatography on silica gel. Elution with 5:1 hexanes-EtOAc followed by 4:1 hexanes-EtOAc affords 215 mg of pure 4-{[(5-butyl-2-chloro-6-phenyl-pyrimidin-4-ylmethyl)-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δ 7.97 (d, J=8.1 Hz, 2H), 7.44–7.33 (m, 7H), 6.84 (s, 1H), 6.79 (s, 2H), 4.22 (s, 4H), 3.90 (s, 3H), 3.74 (s, 2H), 3.72 (s, 2H), 3.55 (s, 2H), 2.64–2.56 (m, 2H), 1.01 (m, 2H), 0.90 (sext, J=7.2 Hz, 2H), 0.61 (t, J=7.2 Hz, 3H) ppm. MS: m/z 572 [M+1].
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:19]#[N:20])=[C:5]([NH2:18])[C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][O:9][C:10]=1[NH2:11]>[OH-].[Na+].CCO>[NH2:18][C:5]1[C:4]([C:19]#[N:20])=[C:3]([OH:2])[N:11]=[C:10]2[O:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=12
Reactant: COC(=O)C(C#N)=C(N)c1c(-c2ccccc2)noc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1c(O)nc2onc(-c3ccccc3)c2c1N
Reaction time: 3 h

Procedure:
0.5 g (1.76 mmole) of 3-amino-2-cyano-3-(5-amino-3-phenyl-isoxazol-4-yl)-acrylic acid methyl ester [compound (3a)] is dissolved in 7 ml of 2 N NaOH and 10 ml of EtOH, and is heated to boiling for 3 hours. Then the undissolved residue is filtered off. Colorless plates are precipitated during cooling off, which are sucked off (removed) and washed with a small amount of MeOH. Yield: 0.3 g (62 percent) of colorless plates, from crystalline acid, having a melting point of 251° C.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)N)=[CH:14][CH:13]=1.Cl>C(O)C>[CH3:1][N:2]([CH3:10])[CH:3]1[CH2:8][C:7]2[C:21]3[C:20](=[CH:25][CH:24]=[C:23]([F:26])[CH:22]=3)[N:18]([C:15]3[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=3)[C:6]=2[CH2:5][CH2:4]1
Reactant: NN(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CN(C)C1CCC(=O)CC1
Agent: Cl
Solvent: CCO
Product: CN(C)C1CCc2c(c3cc(F)ccc3n2-c2ccc(F)cc2)C1

Procedure:
A solution 7.8 g. of 4-dimethylaminocyclohexanone and 11 g. of 1,1-bis(4-fluorophenyl)hydrazine in 350 ml. of absolute ethyl alcohol and 90 ml. of 5-N hydrogen chloride in absolute ethyl alcohol was heated under reflux for five hours, cooled, and filtered. The solids were suspended in ether and treated with dilute sodium hydroxide solution and the ether extract was separated, dried and evaporated to dryness. The resulting oil was dissolved in ethyl alcohol, treated with hydrogen chloride in ethyl alcohol and the solution was concentrated and cooled. The resulting solids were collected by filtration to give, after recrystallization from ethyl alcohol, 5.6 g. of 3-(dimethylamino)-6-fluoro-9-(4-fluorophenyl)-1,2,3,4-tetrahydrocarbazole hydrochloride, m.p. 283°-285° C.
Reaction SMILES: [CH3:1][N:2]([CH2:22][CH2:23][NH:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1)=[O:26])[C:3]([C@@H:5]([NH:14]C(=O)OC(C)(C)C)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]>Cl.C(OCC)C>[NH2:14][C@@H:5]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([N:2]([CH3:1])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=1)=[O:26])=[O:4]
Reactant: CN(CCNC(=O)c1ccc(C(F)(F)F)cc1)C(=O)[C@H](CCc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Product: CN(CCNC(=O)c1ccc(C(F)(F)F)cc1)C(=O)[C@@H](N)CCc1ccccc1

Procedure:
A solution of tert-butyl N-[(1S)-1-[methyl(2-{[4-(trifluoromethyl)phenyl]formamido}ethyl)carbamoyl]-3-phenylpropyl]carbamate CXXII (0.65 g, 1.23 mmol) in 1 M HCl in diethyl ether was stirred overnight. The solvent was evaporated under vacuum to give (2S)-2-amino-N-methyl-4-phenyl-N-(2-{[4-(trifluoromethyl)phenyl]formamido}ethyl)butanamide CXXIII as white crystals (0.46 g, 1.14 mmol, 93% yield). 1H NMR (DMSO-d6) 1.87-2.02 (m, 2H), 2.55-2.74 (m, 2H), 3.00 (s, 3H), 3.44-3.59 (m, 2H), 3.88-3.94 (m, 2H), 4.27 (brs, 1H), 7.18-7.28 (m, 6H), 7.71 (d, J=8 Hz, 2H), 7.95 (d, J=8 Hz, 2H), 8.29 (brs, 3H), 8.86-8.88 (m, 1H); ESIMS found for C21H24F3N3O2 m/z 408 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH:9]2[C:14]([OH:16])=[O:15])([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl.[C:23]([O:26][CH2:27][CH3:28])(=[O:25])[CH3:24]>>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH:9]2[C:14]([O:16][C:4]1[CH:13]=[CH:12][C:24]([C:23]([O:26][CH2:27][CH3:28])=[O:25])=[CH:6][CH:5]=1)=[O:15])([O-:3])=[O:2]
Reactant: O=C(O)C1CCCc2c1cccc2[N+](=O)[O-]
Reactant: CCOC(C)=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(OC(=O)C2CCCc3c2cccc3[N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
In 50 ml of ethyl acetate was dissolved 5 g of 5-nitro-1,2,3,4-tetrahydro-1-naphthoic acid. After addition of 4.6 g of phosphorus pentachloride to the resulting solution at room temperature, the mixture was stirred for 30 minutes. The precipitates were removed by filtration and the filtrate was freed from ethyl acetate by distillation under reduced pressure. The residue was dissolved in 100 ml of fresh ethyl acetate. To the solution were added, with cooling, 4.1 g of p-ethoxycarbonylphenol and 2.5 g of triethylamine. The mixture was stirred for 24 hours. The reaction mixture was washed with a cold 5% sodium hydroxide solution and freed from the solvent by distillation to obtain 7.2 g (80% yield) of oily p-ethoxycarbonylphenyl 5-nitro-1,2,3,4-tetrahydro-1-naphthoate.
Reaction SMILES: [F:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][N:13]([C:16]3[N:23]=[CH:22][CH:21]=[C:20]([C:24]4[N:25]=[C:26]([NH:32][C:33]5[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=5)[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=4)[C:17]=3[CH:18]=[O:19])[C:14](=[O:15])[C:3]=12.[BH4-].[Na+]>CO>[F:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][N:13]([C:16]3[C:17]([CH2:18][OH:19])=[C:20]([C:24]4[N:25]=[C:26]([NH:32][C:33]5[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=5)[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=4)[CH:21]=[CH:22][N:23]=3)[C:14](=[O:15])[C:3]=12
Reactant: Cn1cc(-c2ccnc(N3CCn4c5c(c(F)c4C3=O)CCCC5)c2C=O)nc(Nc2cccnc2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2ccnc(N3CCn4c5c(c(F)c4C3=O)CCCC5)c2CO)nc(Nc2cccnc2)c1=O
Temperature: 20 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
To a solution of 186c (118 mg, 0.23 mmol) in methanol (15 mL) was added NaBH4 (27 mg, 0.70 mmol). The mixture was stirred at 20° C. for 2 h. The reaction was quenched with water and evaporated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 186 (33 mg, 28%) as a white solid. MS-ESI: [M+H]+ 516.3. 1H NMR (500 MHz, DMSO-d6) δ 9.78 (s, 1H), 8.54 (d, J=5.0 Hz, 1H), 8.39-8.37 (m, 2H), 8.06-8.04 (m, 2H), 7.76 (s, 1H), 7.59 (d, J=5.5 Hz, 1H), 4.97 (t, J=5.0 Hz, 1H), 4.68-4.65 (m, 1H), 4.51-4.47 (m, 1H), 4.25-4.19 (m, 2H), 4.10-4.05 (m, 1H), 3.91-3.88 (m, 1H), 3.58 (s, 3H), 2.66-2.60 (m, 1H), 2.57-2.53 (m, 1H), 2.44-2.42 (m, 2H), 1.82-1.75 (m, 2H), 1.71-1.67 (m, 2H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]1[C:14]1[N:18]2[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]2=[N:16][N:15]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:23][C:20]1[CH:21]=[CH:22][C:17]2[N:18]([C:14]([C@H:9]3[CH2:10][O:11][CH2:12][CH2:13][N:8]3[CH3:6])=[N:15][N:16]=2)[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCOC[C@@H]1c1nnc2ccc(F)cn12
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCOC[C@@H]1c1nnc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
To a solution of Intermediate 83b (297 mg, 0.92 mmol) in DCM (8.0 mL) at 0° C. was added TFA (400 μL) and the reaction stirred at RT overnight. Further TFA (600 μL) was added and the reaction stirred for 1 h then partitioned between DCM and sat. aq. NaHCO3 solution. The aqueous layer was then extracted with DCM (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was taken up in DCM (4.0 ml) and MeOH (3 drops) added. Formaldehyde solution (37 wt % in water, 162 μL, 2.00 mmol) was added followed by sodium triacetoxyborohydride (372 mg, 2.40 mmol). The reaction was stirred overnight then loaded onto an SCX-2 cartridge, which was washed with MeOH and eluted with 2M NH3 in MeOH; concentration in vacuo gave the title compound (75.0 mg, 34%). 1H NMR (400 MHz, d4-MeOD): 2.09 (3H, s), 2.49 (1H, td, J 11.4, 3.8), 2.98 (1H, dt, J 11.9, 2.0), 3.79-3.90 (3H, m), 3.94 (1H, m), 4.01 (1H, dd, J 10.1, 4.0), 7.50 (1H, ddd, J 10.0, 7.7, 2.2), 7.81 (1H, ddd, J 10.1, 4.9, 0.8), 8.98 (1H, ddd, J 4.0, 2.3, 0.8).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:40])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][CH2:35]Br)[C:24]=1[CH2:37][CH2:38][CH3:39])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:15]([O:17][C:18](=[O:40])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][CH2:35][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:24]=1[CH2:37][CH2:38][CH3:39])[CH3:16]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2c(C(C)=O)ccc(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Yield: 76.6 %

Procedure:
A mixture of 3.00 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 6.65 g of 4-[4-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]butanoic acid ethyl ester and 4.30 g of anhydrous potassium carbonate in 100 ml of anhydrous acetone and 50 ml of anhydrous dimethylformamide was stirred at reflux for 19 hours. The solvent was removed in vacuo to give a red oil which was purified by high pressure liquid chromatography to yield 6.42 g (76%) of 4-[4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]butanoic acid ethyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=2)=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27]>CN(C=O)C>[CH2:27]([O:14][C:12]1[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=[C:8]([C:5]2[N:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[N:13]=1)[CH:26]=[CH2:25]
Reactant: Nc1ccc(-c2nc(O)cc(C(F)(F)F)n2)nc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(C(F)(F)F)nc(-c2ccc(N)cn2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of compound of example 15 (0.200 g, 0.78 mmol) in DMF (3 mL), was added K2CO3 (0.162 g, 1.170 mmol) and the mixture was stirred at 25° C. for 10 minutes, followed by slow addition of allyl bromide (0.14 g, 1.17 mmol). The reaction mixture was stirred at 25° C. for 45 minutes. DMF was removed under vacuum, and the reaction mass quenched by water, extracted with ethyl acetate (3×20 mL), dried over sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 5% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:20][N:19]([CH:21]4[CH2:24][O:23][CH2:22]4)[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:31]([N:39]2[CH2:50][CH2:49][N:48]3[C:41](=[CH:42][C:43]4[CH2:44][C:45]([CH3:52])([CH3:51])[CH2:46][C:47]=43)[C:40]2=[O:53])=[N:32][CH:33]=[CH:34][C:35]=1B(O)O)(=[O:27])[CH3:26].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[C:25]([O:28][CH2:29][C:30]1[C:31]([N:39]2[CH2:50][CH2:49][N:48]3[C:41](=[CH:42][C:43]4[CH2:44][C:45]([CH3:52])([CH3:51])[CH2:46][C:47]=43)[C:40]2=[O:53])=[N:32][CH:33]=[CH:34][C:35]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:20][N:19]([CH:21]4[CH2:24][O:23][CH2:22]4)[CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:27])[CH3:26]
Reactant: Cn1cc(Br)cc(Nc2ccc(C3CN(C4COC4)C3)cn2)c1=O
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CN(C5COC5)C4)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 49.1 %

Procedure:
A 25-ml round-bottomed flask equipped with a reflux condenser was charged with 272a (140 mg, 0.35 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diaza-tricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (140 mg, 0.35 mmol), Pd(dppf)Cl2 (28 mg, 0.035 mmol), sodium acetate (58 mg, 0.70 mmol), K3PO4 (148 mg, 0.70 mmol), water (6 drops), and acetonitrile (6 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 272b (114 mg, 46%) as a brown solid. MS-ESI: [M+H]+ 664.4
Reaction SMILES: Cl.[CH:2]1([CH:5]([NH2:7])[CH3:6])[CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:32]=[CH:31][C:19]2[N:20]=[C:21](/[CH:25]=[CH:26]/[C:27]([O:29][CH3:30])=[O:28])[O:22][C:23](=[O:24])[C:18]=2[CH:17]=1.O>C(#N)C.C(OCC)(=O)C>[Cl:15][C:16]1[CH:32]=[CH:31][C:19]([NH:20][C:21](=[O:22])/[CH:25]=[CH:26]/[C:27]([O:29][CH3:30])=[O:28])=[C:18]([C:23](=[O:24])[NH:7][CH:5]([CH:2]2[CH2:4][CH2:3]2)[CH3:6])[CH:17]=1
Reactant: COC(=O)/C=C/c1nc2ccc(Cl)cc2c(=O)o1
Reactant: CC(N)C1CC1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/C(=O)Nc1ccc(Cl)cc1C(=O)NC(C)C1CC1

Procedure:
A mixed solution of 0.73 g of 1-cyclopropylethylamine hydrochloride and 0.91 g of triethylamine in 12 ml of acetonitrile was stirred at room temperature for one hour. Then, to the mixed solution, 0.53 g of crude crystals of methyl (E)-3-(6-chloro-4-oxo-4H-benzo[d][1,3]oxazin-2-yl)acrylate were added at room temperature and reacted for 3 hours at room temperature. To the reaction liquid, water was added, and then ethyl acetate was added for extraction. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressed, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1 to 8/2) to obtain 0.22 g of the desired product having a slightly yellow color (melting point: 154.4° C.).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[CH:4]=1)[NH2:2].[CH3:10][C:11](=O)[CH2:12][CH3:13]>C(O)C>[C:11](=[N:2][NH:1][C:3]1[CH:8]=[CH:7][NH:6][C:5](=[O:9])[CH:4]=1)([CH2:12][CH3:13])[CH3:10]
Reactant: CCC(C)=O
Reactant: NNc1cc[nH]c(=O)c1
Solvent: CCO
Product: CCC(C)=NNc1cc[nH]c(=O)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
4-hydrazino-1H-pyridin-2-one (20.1 g, 161.0 mmol) prepared in Step 1 and 2-butanone (21.6 ml, 241.0 mmol) were added to ethanol (400 ml). The reaction mixture was refluxed under stirring for 4 hours and cooled to 0° C. The resulting precipitate was filtered and then washed with cooled ethanol to give the titled compound as a white solid. (Yield: 75.0%)
Reaction SMILES: [OH:1][C@H:2]([C:9]1[N:10]=[C:11]([C:14](=O)[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6].[C:17]([NH:20][NH2:21])(=[O:19])[CH3:18]>CO.O.Cl.O1CCCC1>[OH:1][C@H:2]([C:9]1[N:10]=[C:11]([C:14](=[N:21][NH:20][C:17](=[O:19])[CH3:18])[CH3:15])[NH:12][CH:13]=1)[C@H:3]([OH:8])[C@H:4]([OH:7])[CH2:5][OH:6]
Reactant: CC(=O)NN
Reactant: CC(=O)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)NN=C(C)c1nc([C@@H](O)[C@H](O)[C@H](O)CO)c[nH]1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
1-[4-((1R,2S,3R)-1,2,3,4-Tetrahydroxy-butyl)-1H-imidazol-2-yl]-ethanone (160 mg, 0.70 mmol) was suspended in methanol (3 ml) and water (1 ml). Acetic hydrazide (56 mg, 0.75 mmol, 1.2 eq.) and hydrochloric acid (one drop, 12 N) were added, and the suspension was stirred at 50° C. for 48 hours. LCMS analysis indicated the formation of the product and the absence of starting material. The reaction mixture was cooled to room temperature and diluted with tetrahydrofuran. The resulting white precipitate was collected and washed with tetrahydrofuran to yield the product, a mixture of approximately 3:1 E:Z isomers, as a white solid: 129 mg (65%).
Reaction SMILES: [NH:1]1[C:5]2[N:6]=[CH:7][CH:8]=[C:9]([C:10]#[N:11])[C:4]=2[CH:3]=[N:2]1.CCO>[NH4+].[OH-].[Ni]>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([CH2:10][NH2:11])=[C:4]2[CH:3]=[N:2]1
Reactant: N#Cc1ccnc2[nH]ncc12
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: NCc1ccnc2[nH]ncc12
Reaction time: 18 h

Procedure:
1H-Pyrazolo[3,4-b]pyridine-4-carbonitrile (290 mg, 2.01 mmol) was dissolved in aqueous NH4OH (4 mL) and EtOH (4 mL) then added wet Raney Nickel (2 mL). The reaction was put under a balloon of H2 gas and stirred for 18 h. The mixture was filtered through a pad of Celite®, washing with MeOH. The filtrate was concentrated in vacuo to yield C-(1H-pyrazolo[3,4-b]pyridin-4-yl)-methylamine as a tan solid.
Reaction SMILES: [CH2:1](N)C(C)C.[CH2:6]([N:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[CH3:22])C1=S)[CH:7]=[CH2:8]>ClCCl>[Cl:21][C:19]1[CH:18]=[CH:17][C:16]([CH3:22])=[C:15]([NH:11][CH2:12][CH2:13][CH2:14][NH:9][CH2:6][CH:7]([CH3:8])[CH3:1])[CH:20]=1
Reactant: C=CCN1CCCN(c2cc(Cl)ccc2C)C1=S
Reactant: CC(C)CN
Solvent: ClCCl
Product: Cc1ccc(Cl)cc1NCCCNCC(C)C
Yield: 85.9 %

Procedure:
A mixture of isobutylamine (27.2 mL) and the hydrobromide salt of Example 8, Step B (9.4 g) was heated at 90° C. under nitrogen for 1 hour. The reaction was cooled and partitioned between dichloromethane and 1N sodium hydroxide. The aqueous layer was extracted with dichloromethane, and the combined extracts were dried over sodium sulfate and concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with 25% ethyl acetate in hexane followed by 80:20 dichloromethane-methanol containing 0.2% ammonium hydroxide gave the title compound (6.0 g, 85.9%) as a brown oil, which was used as such in the next step.
Reaction SMILES: [C:1]([NH:4][C@:5]([CH3:15])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH:7]([CH3:9])[CH3:8])(=[O:3])[CH3:2]>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[C:1]([NH:4][C@@:5]([CH3:15])([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH:7]([CH3:9])[CH3:8])(=[O:3])[CH3:2]
Reactant: CCOC(=O)[C@](C)(CC(C)C)NC(C)=O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)[C@@](C)(CC(C)C)NC(C)=O
Reaction time: 120 h
Yield: 48 %

Procedure:
To a solution of ethyl N-acetyl-(±)-α-methylleucinate (250.0 mg, 1.16 mmol) in 70 mL of 50 mM sodium phosphate buffer pH 7.5 is added carboxypeptidase Y from Bakers Yeast (10.4 mg of protein). After 120 h, 50% conversion is observed by HPLC (C18 column, 210 nm detection, amido acid tR =8.1 rain and amido ester tR =10.7 min). The reaction is extracted with 3×25 mL chloroform. The combined extracts are dried with magnesium sulfate and concentrated in vacuo to yield ethyl (R)-N-acetyl-α-methylleucinate (120 mg, 0.557 mmol, 48%). A portion of this (R)-α-methyl amido ester (70 mg, 0.325 mmol) is refluxed in 50 mL 6N HCl for 2 h then concentrated in vacuo to afford (R)-α-methylleucine hydrochloride (70 mg). The enantiomeric excess of the amino acid is determined by HPLC analysis ((D)-Penicillinamine column from Phenomonex, detection 254 nm, (S)-enantiomer tR =4.6 min and (R)-enantiomer tR =7.4 min) to be >98% (R)-enantiomer.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[C:9]([CH2:11][S:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:10]=2)[CH:7]=1.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)#[CH:21].C(N(CC)CC)C>CN(C=O)C.[Cu](I)I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:21]#[C:20][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=3)=[C:9]([CH2:11][S:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:10]=2)[CH:7]=1
Reactant: CCOC(=O)CSCc1nc2ccc(Cl)cn2c1I
Reactant: C#Cc1cccc(C(F)(F)F)c1
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CSCc1nc2ccc(Cl)cn2c1C#Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
In an argon atmosphere, 27 g (59.8 mmol) of ethyl 2-((6-chloro-3-iodoimidazo[1,2-a]-pyridin-2-yl)methylthio)acetate, 9.51 ml (65.8 mmol) of 1-ethynyl-3-(trifluoromethyl)benzene, 1.139 g (5.98 mmol) of copper iodide and 125 ml (897 mmol) of triethylamine are loaded in 100 ml of DMF. Argon was bubbled in the solution for 10 min, and then 2.74 g (2.99 mmol) of Pd2(dba)3 were added. The mixture was stirred for 1 h at r.t. The catalyst was filtered on folded paper, the solution was poured onto 300 ml of water, extracted with 2×200 ml of ethyl acetate, the collected organic phases were washed with 3×150 ml of water and once with 150 ml of brine, dried on Na2SO4 which was then removed by filtration and the obtained filtrate was concentrated in vacuo. The residue was purified on a silica cake, and eluted with a heptane/ethyl acetate mixture. 23.21 g (yield=85%) of ethyl 2-((6-chloro-3-((3-(trifluoromethyl)phenyl)ethynyl)-imidazo[1,2-a]pyridin-2-yl)methylthio)acetate were obtained as a yellow solid. LC-MS: m/z=453 (MH+) UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.91 (dd, J=1.9, 0.6 Hz, 1H), 8.14 (s, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.71 (ddd, J=14.3, 9.4, 4.3 Hz, 3H), 7.47 (dd, J=9.5, 2.0 Hz, 1H), 4.18-3.93 (m, 4H), 3.46 (s, 2H), 1.11 (t, J=7.1 Hz, 3H).