Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[N:16][C:7]=3[NH:6][C:5]=2[C:4]([CH3:17])=[N:3]1.[H-].[Na+].[CH3:20]I.O>CN(C)C=O>[CH3:1][N:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:20])[C:8]3[CH:13]=[CH:14][CH:15]=[N:16][C:7]=3[NH:6][C:5]=2[C:4]([CH3:17])=[N:3]1
Reactant: CI
Reactant: Cc1nn(C)c2c1Nc1ncccc1NC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(C)c2c1Nc1ncccc1N(C)C2=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
An amount of 5.25 gm (0.025 mol) of 1,3-dimethyl-1,4,9,10-tetrahydro-pyrazolo[4,3-e]pyrido[3,2-b][1,4]diazepin-10-one was dissolved in 25 ml of N,N-dimethylformamide and mixed with 1.2 gm of a 55% sodium hydride dispersion in mineral oil. After stirring for 2 hours at 60° C., the solution was cooled to 40° C., and 2.2 ml of methyl iodide were added dropwise. Subsequently the mixture was stirred for 3 hours at 40° C., and after addition of 50 ml of water and cooling in the ice-bath, the desired compound was obtained in crystals. The crystals were recovered by suction filtration, and the mineral oil was washed out by means of petroleum ether.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH:10]([C:22]2([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH2:29]=O.O.[OH-].[Na+]>C(O)=O>[CH3:29][N:6]1[CH2:7][CH2:8][N:3]([CH2:9][CH:10]([C:22]2([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=2)[CH2:4][CH2:5]1
Reactant: OC1(C(CN2CCNCC2)c2cccc(OC(F)(F)F)c2)CCCCC1
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: CN1CCN(CC(c2cccc(OC(F)(F)F)c2)C2(O)CCCCC2)CC1
Temperature: 70 °C
Yield: 71.9 %

Procedure:
A solution of 1-{2-piperazin-1-yl-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol (590 mg, 1.59 mmol) (see Example 23), in formic acid (3.1 mL) at 50° C., was treated with an aqueous solution of formaldehyde (37% in water, 1.3 mL, 1.94 mmol). The reaction was heated at 70° C. for 1.5 h, after which time the reaction was poured into water (50 mL) and basified to pH=10 with the addition of a 2 N aqueous solution of sodium hydroxide. The product was then extracted with ethyl acetate (3×20 mL), and the combined organic extracts were dried over magnesium sulfate and concentrated to yield 442 mg (72%) 1-{2-(4-methylpiperazin-1-yl)-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol as a colorless oil. The product was dissolved in methanol (0.5 mL) and the resulting solution was treated with a saturated methanolic solution of hydrochloric acid (0.5 mL) followed by diethyl ether (2 mL). The solution was stored in the refrigerator for 16 h. The resulting precipitate was filtered and washed with diethyl ether to yield 299 mg (57%) 1-{2-(4-methylpiperazin-1-yl)-1-[3-(trifluoromethoxy)phenyl]ethyl}cyclohexanol dihydrochloride as a white solid. HRMS: calcd for C20H29F3N2O2.2.00 HCl, 458.1715. found (ESI), 387.2263.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:6]
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-Iodobenzoic acid (12.4 g) was dissolved in DMF (100 mL) and potassium carbonate (7.6 g) was added. Benzyl bromide (6.5 mL) was then added dropwise over approximately 10 minutes causing a slight exotherm to 24° C. The suspension was stirred at room temperature for 1.5 hours. The suspension was then poured into water (approximately 300 mL) and was extracted with diethyl ether. The combined organic phase was back washed with water and brine and dried over sodium sulfate. The solvent was stripped to yield a crude product as a colourless oil (17.0 g). The crude product was applied to a silica gel column and was eluted with cyclohexane-ethyl acetate (95:5) to give a colourless oil (13.08 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]2[S:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:18][CH2:19][CH2:20][N:21]1[C:25]([CH3:27])([CH3:26])[C:24](=[O:28])[NH:23][C:22]1=[O:29].C(N(C(C)C)CC)(C)C>C(O)(C)C>[Br:1][C:2]1[C:3]([C:9]2[S:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=[N:4][C:5]([NH:18][CH2:19][CH2:20][N:21]2[C:25]([CH3:26])([CH3:27])[C:24](=[O:28])[NH:23][C:22]2=[O:29])=[N:6][CH:7]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCN
Reactant: Clc1ncc(Br)c(-c2cc3ccncc3s2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cc3ccncc3s2)n1
Temperature: 170 °C

Procedure:
2-(5-Bromo-2-chloropyrimidin-4-yl)thieno[2,3-c]pyridine (0.38 g, 1.16 mmol), 1-(2-aminoethyl)-5,5-dimethylimidazolidine-2,4-dione (0.393 g, 2.3 mmol), diisopropylethyl-amine (0.4 mL, 2.3 mmol) and isopropyl alcohol (2 mL) were all placed in a microwave tube and heated to 170° C. for 20 min. The volatiles were removed in vacuo and the residue dissolved in 9:1 mixture of dichloromethane, preadsorbed onto silica gel and purified by flash chromatography using a gradient of 0 to 10% methanol in dichloromethane to obtain a yellow solid. Yield=0.4 g. MS (M+H)+ 461/463.
Reaction SMILES: [CH3:1][SiH:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH2:8])=[CH:5][CH:4]=1.[CH3:12][SiH:13]([O:16][CH3:17])[O:14][CH3:15].C1(C)C=CC=CC=1>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.C(O)(C)C>[CH3:11][SiH:2]([CH3:1])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][CH2:8][CH2:12][SiH:13]([O:16][CH3:17])[O:14][CH3:15])=[CH:5][CH:4]=1
Reactant: CO[SiH](C)OC
Reactant: C=Cc1ccc([SiH](C)C)cc1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CO[SiH](CCCc1ccc([SiH](C)C)cc1)OC
Temperature: 50 °C
Yield: 4.1 %

Procedure:
325 mg Of 4-dimethylsilylstyrene, 212 mg of methyldimethoxysilane, and 83 mg of toluene were placed in a glass reaction vessel and 0.001 ml of an isopropyl alcohol solution of chloroplatinic acid (platinum content: 0.39 Wt. %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 0.5 hours in an oil bath at 50° C. When the tube contents were analyzed by GC-MS following cooling, the conversion rate of 4-dimethylsilylstyrene was 12.7% and (4-(dimethylsilyl) phenethyl)methyldimethoxysilane was produced at a yield of 4.1%. The yield of (α-(4-(dimethylsilyl)phenyl)ethyl)methyldimethoxysilane was 3.3%.
Reaction SMILES: [NH3:1].CO.[C:4]1([C:10]2[N:11]=[C:12]([C:21]3[CH:22]([CH2:27][C:28]4[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=4)[CH2:23][CH2:24][CH2:25][CH:26]=3)[O:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1.CCOC(C)=O>[C:4]1([C:10]2[N:11]=[C:12]([C:21]3[CH:22]([CH2:27][C:28]4[CH:29]=[C:30]([S:34]([NH2:1])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=4)[CH2:23][CH2:24][CH2:25][CH:26]=3)[O:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=S(=O)(Cl)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Reactant: N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: NS(=O)(=O)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
To a mixture of 28% ammonia solution (0.7 ml) and MeOH (1.0 ml) was added a solution of crude 3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}-benzenesulfonyl chloride (253 mg, 0.52 mmol) in tetrahydrofuran (3 ml) at 5° C. After stirring at room temperature for 30 min, the reaction mixture was diluted with EtOAc, washed with 1N hydrochloric acid, water, saturated sodium hydrogencarbonate solution, water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:EtOAc, 2:1 elution) to give 3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzenesulfonamide (41.3 mg, 17%).
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:11])([F:10])[F:9])(=O)=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:24]2[N:29]=[C:28]([O:30][C@@H:31]([C@H:33]3[CH2:37][NH:36][C:35](=[O:38])[CH2:34]3)[CH3:32])[C:27]3[NH:39][CH:40]=[N:41][C:26]=3[CH:25]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:24]2[N:29]=[C:28]([O:30][C@@H:31]([C@H:33]3[CH2:37][NH:36][C:35](=[O:38])[CH2:34]3)[CH3:32])[C:27]3[N:39]([CH2:7][C:8]([F:11])([F:10])[F:9])[CH:40]=[N:41][C:26]=3[CH:25]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:24]2[N:29]=[C:28]([O:30][C@@H:31]([C@H:33]3[CH2:37][NH:36][C:35](=[O:38])[CH2:34]3)[CH3:32])[C:27]3[N:39]=[CH:40][N:41]([CH2:7][C:8]([F:11])([F:10])[F:9])[C:26]=3[CH:25]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(-c2cc3nc[nH]c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc3c(ncn3CC(F)(F)F)c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC
Product: COc1ccc(-c2cc3ncn(CC(F)(F)F)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC
Reaction time: 1 h

Procedure:
2,2,2-trifluoroethyl trifluoromethanesulfonate (13 mg, 0.056 mmol) was added to a solution of (R)-4-((R)-1-(6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.09 (20 mg, 0.052 mmol) and cesium carbonate (43 mg, 0.132 mmol) in 5 mL of DMF at room temperature. After 1 h, reaction mixture was taken up in ethyl acetate (100 mL) and washed with saturated NaHCO3 (aq) (2×100 mL) and brine. The separated organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield (R)-4-((R)-1-(6-(3,4-dimethoxyphenyl)-3-(2,2,2-trifluoroethyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.10 and (R)-4-((R)-1-(6-(3,4-dimethoxyphenyl)-1-(2,2,2-trifluoroethyl)-1H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.11.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH2:4]([Si:10]([CH3:13])(Cl)Cl)[CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7].CCCCCC.[CH3:20][OH:21]>>[CH2:4]([Si:10]([CH3:13])([O:21][CH3:20])[O:2][CH3:1])[CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)CC[Si](C)(Cl)Cl
Reactant: C[O-]
Reactant: CO
Agent: [Na+]
Solvent: CCCCCC
Product: CO[Si](C)(CCC(C)(C)C)OC
Temperature: 25 °C
Yield: 70 %

Procedure:
A 3-liter, 4-necked flask equipped with an overhead stirrer, condenser, pot thermometer and additional funnel was charged with 970 g (4.49 mol) of 25% sodium methoxide in methanol. To this was added 401 g (2.01 mol) of neohexylmethyldichlorosilane at a rate such as to maintain reflux. Upon completion of the reaction, additional sodium methoxide solution was added to bring the pH to 10. The reaction mixture was cooled to room temperature and 500 ml of hexane was added. The reaction mixture was then filtered and the volatiles removed at 60° C. and 150 mm pressure. The volatiles consisted of two layers. The lower methanol layer was extracted with hexane (2×200 ml) and combined with the original top layer of hexane. The combined hexane layers were distilled through an 18" glass packed column to give 268 g (70% of theory) of neohexylmethyldimethoxysilane. Neohexylmethyldiethoxysilane was prepared following an analogous procedure.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([O:17]S(C4C=CC(C)=CC=4)(=O)=O)[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4](S(C2C=CC(C)=CC=2)(=O)=O)[CH:3]=1.[O:38]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39]1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>O.CN(C=O)C.Cl[Pd-2](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:38]1[CH:42]=[CH:41][C:40]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=4)[CH:9]=3)[NH:4][CH:3]=2)=[CH:39]1
Reactant: OB(O)c1ccoc1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc(-c3cnc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)c2)cc1
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: Oc1cccc(-c2cnc3[nH]cc(-c4ccoc4)c3c2)c1
Reaction time: 0.33 h
Yield: 28.2 %

Procedure:
To toluene-4-sulfonic acid 3-[3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenyl ester (50 mg, 0.077 mmol, prepared method 6), furan-3-boronic acid (11 mg, 0.1 mmol) and dichlorobis (triphenylphosphino)palladium (ii) (3 mg, 0.0046 mmol) in a Smith process vial was added 0.6 mL of a 1:1 mixture of acetonitrile, and a 2 M solution of sodium carbonate in water. The reaction was run in a Personal Chemistry® microwave reactor at 165° C. for 1200 s. The mixture was diluted with DMF (ca. 5 mL) and filtered with a syringe filter (0.45 micron). The filtrate was concentrated in vacuo and redissolved in DMSO. Purification by reverse phase chromatography using a gradient of H2O and acetonitrile (with 0.1% formic acid as a modifier) afforded 3-(3-furan-3-yl-1H-pyrrolo[2,3-b]pyridine-5-yl)-phenol as an off-white solid (6 mg, 56% yield). 1H NMR (500 MHz, DMSO-d6) δ 6.70 (dd, J=2.5, 8.0 Hz, 1H), 6.92 (d, J=2.0 Hz, 1H), 7.07 (t, J=2.0 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.21 (t, J=8.0 Hz, 1H), 7.67 (t, J=1.5 Hz, 1H), 7.77 (d, J=2.5 Hz, 1H), 8.25 (d, J=2.0 Hz, 1H), 8.27 (s, 1H), 8.41 (d, J=2.0 Hz, 1H), 9.5 (broad s, 1H), 11.8 (s, 1H). MS: m/z 277 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:11][C:12]1[CH:13]=[CH:14][C:15](S(O)(=O)=O)=[CH:16][CH:17]=1.[CH3:22][N:23]([CH:25]=[O:26])C>CCOC(C)=O>[NH2:2][C:3]1[C:13]2[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11]([O:26][C:25]2[N:23]=[CH:22][N:1]=[C:9]([NH:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][N:2]=[CH:3]4)[CH:8]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CN(C)C=O
Reactant: Nc1ccc2[nH]ncc2c1
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2cc(Nc3ccc4[nH]ncc4c3)ncn2)c2ccccc12
Temperature: 60 °C

Procedure:
A solution of Intermediate E3 (1.50 g, 5.50 mmol), 1H-indazol-5-amine (735 mg, 5.52 mmol) and p-TSA (525 mg, 2.76 mmol) in DMF (14.0 mL) was degassed with nitrogen and was then heated to 60° C. for 16 hr. Additional p-TSA (525 mg, 2.76 mmol) and 1H-indazol-5-amine (368 mg, 2.76 mmol) was added and the reaction maintained at 60° C. for a further 3 hr and then cooled to RT. The resulting mixture was diluted with EtOAc (250 mL) and was washed sequentially with saturated aq. NaHCO3 (2×50 mL), water (2×50 mL) and brine (2×50 mL) and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 120 g, 0-10% [1% NH3 in MeOH] in DCM, gradient elution) to afford the title compound, Intermediate B14, as a dark purple solid (536 mg, 26%); Rt 1.59 min (Method 2, acidic); m/z 369 (M+H)+, (ES+).
Reaction SMILES: [P:1]([O:8]CC)([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[Br:11][CH2:12]Br>>[CH2:3]([O:2][P:1]([CH2:12][Br:11])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:4]
Reactant: CCOP(OCC)OCC
Reactant: BrCBr
Product: CCOP(=O)(CBr)OCC

Procedure:
(according to P. C. Crofts, G. M. Kosolapoff J. Am. Chem. Soc. 1953, 75, 5738-40) 126 g of triethyl phosphite and 162 g of dibromomethane are heated to 170° C. in an autoclave for 4 hours. Bromomethylphosphonic acid diethyl ester may be isolated in moderate yield from the reaction mixture by distillation (b.p.: approx. 50° C., 7 Pa (0.05 Torr)). A second fractional distillation was then performed.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:16])=[O:6]
Reactant: Cc1c(O)cccc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(O)c1C
Temperature: 25 °C
Yield: 84 %

Procedure:
To a solution of 3-hydroxy-2-methylbenzoic acid (3.80 g, 25.0 mmol) in methanol (3.0 mL) at 0° C. was added thionyl chloride (3.00 mL, 41.2 mmol) dropwise. The reaction was allowed to warm to room temperature and was then heated at 50° C. for 2 hours. The solvent was removed under vacuum and the resulting solids were dissolved in ethyl acetate and washed with NaHCO3 (sat. aq.). The ethyl acetate layer was dried over Na2SO4, filtered, and concentrated under vacuum to give methyl 3-hydroxy-2-methylbenzoate (114a, 3.49 g, 84% yield) as a light tan solid.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][C:7](=[O:9])[CH:6]([C:10](=[O:13])[CH2:11][CH3:12])[C:5](=[O:14])[CH2:4]1)=O.[NH2:15]OS(O)(=O)=O>O>[O:14]=[C:5]1[CH:6]([C:10](=[O:13])[CH2:11][CH3:12])[C:7](=[O:9])[CH2:8][CH:3]([C:1]#[N:15])[CH2:4]1
Reactant: NOS(=O)(=O)O
Reactant: CCC(=O)C1C(=O)CC(C=O)CC1=O
Solvent: O
Product: CCC(=O)C1C(=O)CC(C#N)CC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
30.7 g (0.16 mol) of 5-formyl-2-propionylcyclohexane-1,3-dione were introduced into 150 ml of distilled water and, at room temperature, 21.0 g (0.19 mol) of hydroxylamine-O-sulfonic acid were added. The mixture was then stirred at room temperature overnight. The precipitate was filtered off with suction, washed with water and dried. 23.8 g (71% of theory) of 3,5-dioxo-4-propionylcyclohexanecarbonitrile were obtained (melting point 70° to 74° C).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[OH:31].CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:24][C@@H:25]5[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]5[OH:31])[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(F)cnc43)cc2o1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2o1
Temperature: 135 °C
Yield: 26.6 %

Procedure:
A stirred mixture of 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (220 mg, 0.67 mmol) from the previous step, (1R,2R)-2-amino-cyclohexanol (152 mg, 1 mmol), and DIEA (259 mg, 2.01 mmol) in DMA (5 mL) was heated at 135° C. for 2 h. The reaction mixture was cooled to rt, poured into water (30 mL), and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed sequentially with water and brine. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified directly by preparative reverse-phase HPLC to afford (1R,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol (68 mg, 27%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 8.67 (s, 1H), 8.41 (m, 1H), 8.06 (m, 1H), 7.79 (m, 1H), 7.39 (s, 1H), 7.13-7.15 (m, 2H), 5.48 (s, 2H), 4.67 (d, J=3.9 Hz, 1H), 3.30-3.35 (m, 2H), 1.86-1.95 (m, 2H), 1.60-1.65 (m, 2H), 1.15-1.35 (m, 4H); LCMS (ESI) m/z 382 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=[O:7])=C.[O:12]=[O+][O-].CSC>CO.C(Cl)Cl>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=[O:7])=[O:12]
Reactant: C=Cc1cc(C(=O)O)ccn1
Reactant: O=[O+][O-]
Solvent: CSC
Solvent: CO
Solvent: ClCCl
Product: O=Cc1cc(C(=O)O)ccn1
Temperature: 25 °C

Procedure:
A solution of 2-vinyl-isonicotinic acid in methanol/DCM 1/1 was cooled to −78° C. and ozone bubbled through it until the solution becomes blue. A stream of nitrogen is then passed through to remove the ozone excess and 1.5 equivalent of methyl sulfide added. The solution was allowed to warm up to room temperature and was concentrated. The product (iic) was then purified by silica flash chromatography.
Reaction SMILES: CO.[BH4-].[Na+].[Cl:5][C:6]1[C:15]([N+:16]([O-])=O)=[C:14]([NH:19][CH2:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.O>O1CCCC1.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:16][C:15]1[C:6]([Cl:5])=[N:7][C:8]2[C:13]([C:14]=1[NH:19][CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:24][CH2:23]1)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Nc1c(Cl)nc2ccccc2c1NCCC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
To a solution of 6.56 g of nickel chloride hexahydrate and 22.3 ml of methanol in 100 ml of tetrahydrofuran, 2.09 g of sodium borohydride was added portionwise under ice-cooling, and then a suspension of 31.9 g of 2-chloro-3-nitro-4-[2-(N-triphenylmethyl-4-piperidyl)ethylamino]quinoline in 300 ml of tetrahydrofuran was added to the mixture. Successively, 8.35 g of sodium borohydride divided in four portions was added portionwise, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added with 50 ml of water and an insoluble matter was filtered off, and then the extract was concentrated. The residue was added with water and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried, and then the solvent was evaporated. The resulting pale green liquid was solidified with a mixture of ethyl acetate and diisopropyl ether, and the solid was washed successively with isopropanol and diisopropyl ether to give 20.1 g of pale green crystals. Recrystallization from isopropanol gave pale green crystals having the melting point of from 116 to 121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([NH2:15])=[O:14])=[CH:4][CH:3]=1.Br[CH2:23][CH:24]=[CH:25][CH2:26]C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH2:20][CH:23]=[CH:24][CH2:25][CH3:26])[C:13]([NH2:15])=[O:14])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Cl)cc1
Reactant: CCC=CCBr
Product: CCC=CCOc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Cl)cc1

Procedure:
The captioned compound was synthesized from 3-N-(4-chlorophenyl)-4-methoxyisophthalamide and 1-bromo-2-pentene by the same procedure as in the manufacturing method described in Example 1-1-2.
Reaction SMILES: [F:1][C:2]1[C:3](=[N:17][NH2:18])[N:4]=[C:5]([CH3:16])[NH:6][C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[CH:19]1([CH2:24][C@H:25]([CH2:29][N:30]([CH:39]=[O:40])[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:26](O)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1.CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH:19]1([CH2:24][C@@H:25]([C:26]([NH:18][NH:17][C:3]2[C:2]([F:1])=[C:7]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[N:6]=[C:5]([CH3:16])[N:4]=2)=[O:27])[CH2:29][N:30]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:39]=[O:40])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: Cc1nc(=NN)c(F)c(NCc2ccccn2)[nH]1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1nc(NCc2ccccn2)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)n1
Reaction time: 8 h
Yield: 48.5 %

Procedure:
5-Fluoro-2-methyl-6-[(2-pyridinylmethyl)amino]-4(1H)-pyrimidinone hydrazone (0.0954 g, 0.3846 mmol) and (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (0.141 g, 0.4622 mmol) were dissolved in DMF (3 mL). NMM (0.13 mL, 1.1824 mmol) was added, followed by HOAt (0.063 g, 0.4632 mmol) and EDC (0.088 g, 0.459 mmol). After stirring overnight the reaction mixture was purified by RP-HPLC to provide [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-2-methyl-6-[(2-pyridinylmethyl)amino]-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide as a white solid (0.0999 g, 48%). LCMS: (M+H)+=536.3.