Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[C:9]([F:11])[CH:10]=1)[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.O[CH:49]1[CH2:54][CH2:53][N:52]([CH2:55][CH:56]([N:60]2[CH:64]=[C:63]([C:65]3[C:66]4[CH:73]=[CH:72][N:71](COCC[Si](C)(C)C)[C:67]=4[N:68]=[CH:69][N:70]=3)[CH:62]=[N:61]2)[CH2:57][C:58]#[N:59])[CH2:51][CH2:50]1.FC(F)(F)C(O)=O.C(N)CN>C(Cl)Cl.CO>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:8]=[C:9]([F:11])[CH:10]=1)[O:12][CH:49]1[CH2:50][CH2:51][N:52]([CH2:55][CH:56]([N:60]2[CH:64]=[C:63]([C:65]3[C:66]4[CH:73]=[CH:72][NH:71][C:67]=4[N:68]=[CH:69][N:70]=3)[CH:62]=[N:61]2)[CH2:57][C:58]#[N:59])[CH2:53][CH2:54]1)[CH3:1]
Reactant: CN(C)Cc1cc(O)cc(F)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCC(O)CC4)c3)ncnc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)Cc1cc(F)cc(OC2CCN(CC(CC#N)n3cc(-c4ncnc5[nH]ccc45)cn3)CC2)c1
Reaction time: 0.33 h

Procedure:
To a mixture of 3-[(dimethylamino)methyl]-5-fluorophenol (158 mg, 0.934 mmol) in methylene chloride (9 mL) was added Resin of triphenylphosphine (578 mg, 1.37 mmol) and di-tert-butyl azodicarboxylate (229 mg, 0.996 mmol). The mixture was stirred for 20 minutes before adding a solution of 4-(4-hydroxypiperidin-1-yl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile (300 mg, 0.6 mmol) in methylene chloride (2 mL). The reaction was stirred at room temperature overnight. Additional resin of triphenylphosphine (0.5 g), di-tert-butyl azodicarboxylate (0.23 g), and DCM (8 mL) were added and stirred for additional 2 hours. The vial and resin were washed with DCM and filtered. The filtrates were washed with 10% aq. NaOH solution. The organic layer was dried over MgSO4, filtered, and concentrated. The crude was purified by silica gel column (eluted with 0-15% methanol/DCM) to give the SEM protected product. LCMS (M+H)+: 633.5. To the purified product was added methylene chloride (1.5 mL) and trifluoroacetic acid (1.5 mL, 19 mmol) and stirred for 2 hours. The solvents were evaporated before adding methanol (3.5 mL) and ethylenediamine (0.70 mL, 10 mmol). The resulting mixture was stirred for 1 hour then concentrated. The concentrate was taken up in DCM and washed with water, dried over Na2SO4, filtered, and concentrated to give the crude product which was purified by chiral prep-HPLC (Chiralcel OJ-H column, 4.6×250 mm, 5 μ, 60% ethanol/Hex, 0.5 ml/min) to afford 2 enantiomers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=1.Cl.[NH2:19][CH2:20][C:21]1[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=1[CH3:27].ON1C2N=CC=CC=2N=N1.CN1CCOCC1.C(Cl)CCl.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:15]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:17])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:13])[CH3:14])[C:6]=2[N:7]=1
Reactant: Cc1nn(C(C)C)c2nc(Cl)cc(C(=O)O)c12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: On1nnc2cccnc21
Solvent: CS(C)=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2c(C)nn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 17 using 6-chloro-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (486.6 mg, 1.92 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone HCl (489 mg, 2.59 mmol), 1-hydroxy-7-azabenzotriazole (392 mg, 2.88 mmol), N-methylmorpholine (0.84 ml, 7.67 mmol) and EDC (552 mg, 2.88 mmol). An additional 10 mL DMSO was added to the reaction mixture to facilitate stirring, and 10% K2CO3 was used instead of 50% aq. NaOH during the work up. LCMS E-S (M+H)=388.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (d, 6H), 2.12 (s, 3H), 2.22 (s, 3H), 2.40 (s, 3H), 4.34 (d, J=5.05 Hz, 2H), 5.05 (quin, J=6.63 Hz, 1H), 5.88 (s, 1H), 7.16 (s, 1H), 8.78 (t, J=4.93 Hz, 1H), 11.53 (br. s., 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=3)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:25])=[CH:4][CH:3]=1.[C:26](Cl)(=[O:28])[CH3:27]>N1C=CC=CC=1>[CH3:24][C:22]1[NH:21][N:20]=[C:19]([NH:18][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:25])[N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:26](=[O:28])[CH3:27])=[CH:3][CH:4]=3)[N:17]=2)[CH:23]=1
Reactant: Cc1cc(Nc2nn(-c3ccc(N)cc3)c(=O)c3ccccc23)n[nH]1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-n2nc(Nc3cc(C)[nH]n3)c3ccccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(4-Amino-phenyl)-4-(5-methyl-1H-pyrazol-3-ylamino)-2H-phthalazin-1-one (C-2, 0.050 g, 0.15 mmol) was dissolved in pyridine (1 ml) at 0° C. Acetylchloride (0.024 ml, 0.33 mmol) was added and stirring was continued for 30 min at 0° C. before the mixture was allowed to warm to RT. The solvent was evaporated after 2 h stirring at RT. The residue was diluted in MeOH (1 ml) and treated with conc. NH3 (1 ml). The title compound was obtained after stirring at RT for 24 h and evaporation of the solvents in vacuum (0.016 g, 29%). 1H-NMR: (400 MHz, D6-DMSO) 11.93 (1H, s), 10.08 (1H, s), 9.26 (1H, s), 8.49 (1H, d), 8.36 (1H, d), 7.88-7.98 (2H, m), 7.61-7.69 (4H, m), 6.24 (1H, s), 2.19 (3H, s), 2.08 (3H, s); MS (API+)=375 (M+H)+.
Reaction SMILES: C(O)(C)(C)C.CC(C)([O-])C.[Na+].[C:12]1([C@@H:18]([NH:20][C@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1>[C:12]1([C@@H:18]([NH:20][C@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:19])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1N[C@@H](C)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CCCC[C@@H]1N[C@@H](C)c1ccccc1
Temperature: 9 °C
Yield: 97.5 %

Procedure:
Tetrahydrofuran (1.25 L) was charged to a reactor followed by t-butanol (150 mL), and sodium t-butoxide (313 g) under nitrogen at ambient temperature. Additional tetrahydrofuran (1.0 L) was added and then the contents were cooled to <10° C. A solution of (1R,2S)-ethyl 2-((S)-1-phenylethylamino)cyclohexane carboxylate (9, 243.9 g) in tetrahydrofuran (300 mL) was added in NLT 30 minutes, while maintaining the temperature between 6-12° C. After the addition was complete, the mixture was warmed to 22° C. in NLT 30 minutes and further mixed for NLT 4 hours under nitrogen. The contents were cooled to <10° C. and the reaction was quenched with a solution of ammonium chloride (269.3 g) and water in NLT 30 minutes, while maintaining the temperature between 6-12° C. The lower aqueous layer was separated and extracted with 750 mL of heptanes. The upper organic layer was concentrated to about 0.8 L volume and extracted with the heptanes solution. The aqueous layer was separated and extracted with fresh heptanes (2×0.75 L) and the combined organic layers were washed with water (2×0.75 L) and 3.5 M aqueous sodium chloride solution (0.75 L), and dried with anhydrous magnesium sulfate. Concentration of the organic layer under vacuum gave 237.9 g of (1S,2S)-ethyl 2-((S)-1-phenylethyl amino)cyclohexane carboxylate (10) as a major isomer.
Reaction SMILES: Br[C:2]1[C:3]([CH3:15])=[C:4]([CH3:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]=1[CH3:13].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1[N:26]1[CH2:27][CH2:28][N:29]([C:2]2[C:3]([CH3:15])=[C:4]([CH3:14])[C:5]3[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=3[C:12]=2[CH3:13])[CH2:30][CH2:31]1
Reactant: Cc1c(C)c2c(c(C)c1Br)CC(C)(C)O2
Reactant: COc1ccc(N2CCNCC2)c(OC)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 55.6 %

Procedure:
To the toluene (10 mL) mixture solution of 5-bromo-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran (400 mg, 1.49 mmol) synthesized in Reference example 4, 1-(2,4-dimethoxyphenyl)piperazine (495 mg, 2.23 mmol), palladium acetate (17 mg, 0.0745 mmol) and BINAP (139 mg, 0.224 mmol), sodium t-butoxide (286 mg, 2.98 mmol) was added and stirred for 15 hours under reflux. After cooling to room temperature, water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 95:5-85:15) and crystallized from ethyl acetate-hexane to obtain the title compound 340 mg (yield 56%). Melting point was 154 to 156° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6](/[C:7](=[CH:13]/[C:14]3[NH:18][C:17]([CH3:19])=[C:16]([C:20](O)=[O:21])[C:15]=3[CH3:23])/[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[NH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[NH:60][C:61](=[O:72])[C:62]1[CH:67]=[CH:66][C:65]([NH:68][CH2:69][CH2:70][NH2:71])=[N:64][CH:63]=1>[Cl-].[Na+].O.CN(C=O)C>[NH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[NH:60][C:61](=[O:72])[C:62]1[CH:67]=[CH:66][C:65]([NH:68][CH2:69][CH2:70][NH:71][C:20]([C:16]2[C:15]([CH3:23])=[C:14](/[CH:13]=[C:7]3\[C:8](=[O:12])[NH:9][C:10]4[C:6]\3=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=4)[NH:18][C:17]=2[CH3:19])=[O:21])=[N:64][CH:63]=1
Reactant: COc1ccc2c(c1)NC(=O)/C2=C\c1[nH]c(C)c(C(=O)O)c1C
Reactant: NCCNc1ccc(C(=O)Nc2ccccc2N)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)NC(=O)/C2=C\c1[nH]c(C)c(C(=O)NCCNc2ccc(C(=O)Nc3ccccc3N)cn2)c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.9 %

Procedure:
5-(6-Methoxy-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (312 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and N-(2-aminophenyl)-6-(2-aminoethylamino)nicotinamide (284 mg, 1.05 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (463 mg, 82%) as a yellow solid. LC-MS (m/z) 566 (M+1).
Reaction SMILES: [NH:1]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][CH2:17][C:18]([O:20]CC1C=CC=CC=1)=[O:19])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[Pd].CO>[NH:1]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)NCC(=O)O

Procedure:
7.0 g Boc-Phe-Gly-Gly-OBzl was reduced in the presence of Pd-black as a catalyst in 200 ml MeOH, and this was followed by concentration. The resulting concentrate, after the addition of 1.72 ml CHA, was crystallized with AcOEt and collected by filtration.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([C:15]2[C:16](F)=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:14])[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:23]>>[NH2:23][C:16]1[C:15]([C:13]([C:11]2[N:10]=[CH:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:12]=2)=[O:14])=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: [NH4+]
Reactant: O=C(c1cn(Cc2ccccc2)cn1)c1cccnc1F
Agent: [OH-]
Product: Nc1ncccc1C(=O)c1cn(Cc2ccccc2)cn1
Temperature: 160 °C
Yield: 30 %

Procedure:
A microwave vial was charged with (1-benzyl-1H-imidazol-4-yl)(2-fluoropyridin-3-yl)methanone (50 mg, 0.18 mmol) and a saturated aqueous solution of ammonium hydroxide (1 ml). The reaction mixture was heated under microwave irradiation at 160° C. for 25 minutes. The mixture was evaporated to dryness. The residue was and purified on silica gel by flash column chromatography to give the title compound as a solid (15 mg, 30% yield).
Reaction SMILES: [CH:1]1(/[CH:6]=[CH:7]/[C@H:8]([C@@H:10]2[O:14][C:13](=[O:15])[C@H:12]([O:16][CH3:17])[C@@H:11]2[OH:18])[OH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:20][C@@H:21]1[C:27](=[O:28])[NH:26][C:25]2[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:30][CH:31]=[CH:32][C:24]=2[O:23][CH2:22]1.C(C(CCCC)C([O-])=O)C.[Na+]>C1COCC1>[CH:1]1(/[CH:6]=[CH:7]/[C@@H:8]([OH:9])[C@H:10]([OH:14])[C@@H:11]([OH:18])[C@@H:12]([O:16][CH3:17])[C:13]([NH:20][C@@H:21]2[C:27](=[O:28])[NH:26][C:25]3[C:29]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[CH:30][CH:31]=[CH:32][C:24]=3[O:23][CH2:22]2)=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H]1COc2cccc(-c3ccccc3)c2NC1=O
Reactant: CO[C@H]1C(=O)O[C@@H]([C@H](O)/C=C/C2CCCC2)[C@H]1O
Agent: CCCCC(CC)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H](C(=O)N[C@H]1COc2cccc(-c3ccccc3)c2NC1=O)[C@H](O)[C@@H](O)[C@H](O)/C=C/C1CCCC1
Temperature: 25 °C

Procedure:
53 mg of 32 (207 μmol), 60 mg of 44 (207 μmol), 86 mg of sodium 2-ethylhexanoate (0.52 mmol) in 1 mL of THF are successively introduced into a Wheaton tube, with stirring and under an argon atmosphere. The stirring is maintained at RT for 24 h. The reaction medium is concentrated to dryness. The residues are chromatographed on a silica cartridge (4 g, eluent AcOEt). 45 mg of expected product Ex17 (cream-coloured solid) are recovered.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[N:22]1[CH:27]=[CH:26][C:25]([S:28]([C:31]2[S:35][C:34]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[N:33][CH:32]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:39]2[CH2:38][CH2:37][N:36]([C:34]3[S:35][C:31]([S:28]([C:25]4[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=4)(=[O:29])=[O:30])=[CH:32][N:33]=3)[CH2:41][CH2:40]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Reactant: O=S(=O)(c1ccncc1)c1cnc(N2CCNCC2)s1
Agent: Cl
Product: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(S(=O)(=O)c3ccncc3)s2)CC1)C(F)(F)F
Yield: 32 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-[5-(pyridine-4-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride (Example 52(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as a light yellow crystalline solid (yield 32%). MS (m/e): 551.2 (M+H+, 100%).
Reaction SMILES: C1(C)C=CC=CC=1.C[Al](C)C.C1C[O:15][CH2:14]C1.Cl.CNOC.C([C@@H]1CO[C:31](=O)[N:30]1[C:35](=[O:42])[C@H:36]([CH3:41])[C@@H:37]([OH:40])[CH2:38][CH3:39])C1C=CC=CC=1>ClCCl.C1COCC1.ClCCl>[OH:40][C@@H:37]([CH2:38][CH3:39])[C@@H:36]([CH3:41])[C:35]([N:30]([O:15][CH3:14])[CH3:31])=[O:42]
Reactant: CC[C@H](O)[C@@H](C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: C1CCOC1
Agent: CNOC
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC[C@H](O)[C@@H](C)C(=O)N(C)OC
Temperature: 0 °C

Procedure:
2M trimethylaluminum toluene solution (90 ml, 180 mmol) was added to a THF (180 ml) solution of N,O-dimethylhydroxyamine hydrochloride (18.3 g, 187.6 mmol) at −10° C. under stirring. After the reaction solution was warmed to 0° C. and stirred for 10 minutes, it was warmed to room temperature and further stirred for 30 minutes. The reaction solution was cooled to −10° C. again, and a THF-dichloromethane solution (4:5, 180 ml) of (4R)-4-benzyl-3-[(2R,3S)-3-hydroxy-2-methylpentanoyl]-1,3-oxazolidin-2-one (21.85 g, 75 mmol) was added dropwise to the reaction solution. After the reaction solution was warmed to 0° C. and stirred for two hours, a mixed solution of dichloromethane −0.5N hydrochloric acid (1:1, 80 ml) was added slowly, and the mixture was stirred for one hour at 0° C. The reaction solution was filtered through celite and the filtrate was dried over anhydrous sodium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Merck, commercial name Silica Gel 60; heptane:ethyl acetate=1.5:1) to obtain (2R,3S)-3-hydroxy-N-methoxy-N,2-dimethylpentanamide (13.0 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[OH:15].Br[CH:17]([CH3:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([Cl:14])[C:3]=1[O:15][CH:18]([CH2:17][CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: CCOC(=O)CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC)Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
A reaction vessel was charged with 2.02 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 1.56 g of ethyl 3-bromobutyrate, 1.11 g of potassium carbonate and 20 ml of N,N-dimethylformamide. After stirring at room temperature for 12 hours, the reaction mixture was poured into water and extracted twice with 50 ml of diethyl ether. The ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 2.54 g of ethyl 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxybutyrate (90% yield).
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[CH2:21][CH2:20]1>>[CH:19]1([NH:22][C:23]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([C:2]3[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]4[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=4)=[O:7])=[CH:4][N:3]=3)[CH:25]=2)=[O:40])[CH2:20][CH2:21]1
Reactant: COc1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Product: COc1ccc(NC(=O)c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)nc2)cc1

Procedure:
6-[5-Cyclopropylcarbamoyl-2-methyl-phenyl]-N-(4-methoxyphenyl)-nicotinamide was prepared from 6-chloro-N-(4-methoxyphenyl)nicotinamide (Intermediate 2) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 8) using General Method B. LCMS: retention time 2.96 min, MH+ 402.
Reaction SMILES: C([O:4][C@H:5]([CH3:29])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[N:16]3[CH2:20][CH2:21][N:22]([CH2:23][O:24][CH2:25][CH3:26])[C:15]3=[N:14][C:13]=2[N:12]([CH3:27])[C:11]1=[O:28])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:25]([O:24][CH2:23][N:22]1[C:15]2=[N:14][C:13]3[N:12]([CH3:27])[C:11](=[O:28])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]([OH:4])[CH3:29])[C:18](=[O:19])[C:17]=3[N:16]2[CH2:20][CH2:21]1)[CH3:26]
Reactant: CCOCN1CCn2c1nc1c2c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCOCN1CCn2c1nc1c2c(=O)n(CCCC[C@@H](C)O)c(=O)n1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
A mixture of (R)-3-(5-acetoxyhexyl)-7,8-dihydro-8-ethoxymethyl-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (100 mg, 0.245 mmol) and potassium carbonate (51 mg, 0.368 mmol) in methanol (12 ml) was stirred at room temperature for 16 hours. After concentration under reduced pressure, the residue was treated with 1.0 M aqueous ammonium chloride solution (10 ml) and stirred for 1 hour. The solid was filtered, washed with water, and dried under vacuum to provide (R)-7,8-dihydro-8-ethoxymethyl-3-(5-hydroxyhexyl)-1-methyl-1H-imidazo[2,1-f]-purine-2,4(3H,6H)-dione (60 mg, 67% yield) as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[CH3:17][N:18]1[CH2:23][CH:22]=[C:21](O[Si](C)(C)C)[CH2:20][CH2:19]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClC(Cl)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][CH:21]1[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1)=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Reactant: CN1CC=C(O[Si](C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1sc(-c2ccccc2)cc1NC1CCN(C)CC1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
To a stirred solution of methyl-3-amino-5-phenylthiophene-carboxylate (233 mg, 1.0 mmol) and 1-methyl-4-trimethylsilanyloxy-1,2,3,6-tetrahydro-pyridine (370 mg, 2.0 mmol) in dichloroethane (3.0 mL) was added AcOH (0.114 mL, 2.0 eq) and followed addition of NaBH(OAc)3 (424 mg, 2.0 mmol) in one portion. The resultant reaction mixture was stirred at RT for weekend, aq. 10% NaOH (until basic) was added, after 30 min, reaction mixture was extracted with dichloromethane. The organic extract was washed with brine and dried. The crude product was purified on silica gel column using 20% EtOAc/hexane for unreacted starting material followed by CHCl3/MeOH/Et3N (180/16/1) furnished the 3-(1-methyl-piperidin-4-ylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester (240 mg, 73%). NMR 1H (CDCl3, 400 MHz): 7.64-7.6 (m, 2H), 7.43-7.34 (m, 3H), 6.83 (brs, 2H), 3.83 (s, 3H), 3.46-3.4 (m, 1H), 2.82-2.74 (m, 1H), 2.3 (s, 3H), 2.26-2.2 (m, 4H), 1.72-1.62 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([Cl:20])[CH:3]=1.[CH:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:20][C:4]1[CH:3]=[C:2]([NH:27][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=1
Reactant: NC1CCCCC1
Reactant: O=C(Nc1nc2cc(Cl)cc(Cl)n2n1)c1cccnc1
Product: O=C(Nc1nc2cc(Cl)cc(NC3CCCCC3)n2n1)c1cccnc1
Yield: 21.9 %

Procedure:
The title compound was prepared following procedure and work up described for example 118, but starting from N-(5,7-dichloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B10), 100 mg; 0.32 mmol; 1.0 eq) and cyclohexylamine (187 μL; 1.62 mmol; 5.0 eq) to give the title compound as a white solid (26 mg, 22%). HPLC, Rt: 3.48 min. (purity 98.5%). LC/MS, M+(ESI): 370.9, M−(ESI): 368.9.