Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](O)([C:12]([S:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)([CH3:14])[CH3:13])[CH2:10][OH:11].CS(Cl)(=O)=O.[OH-].[K+].Cl>N1C=CC=CC=1.O.CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([S:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)([CH3:14])[CH3:13])[CH2:10][O:11]1
Reactant: COc1ccc(CSC(C)(C)C(O)(CO)c2ccc(F)cc2F)cc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Solvent: CO
Product: COc1ccc(CSC(C)(C)C2(c3ccc(F)cc3F)CO2)cc1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
In 580 ml of pyridine was dissolved 70.0 g (0.19 mol) of (+)-2-(2,4-difluorophenyl)-3-((4-methoxy-phenyl)methylthio)-3-methylbutane-1,2-diol, and 25.2 g (0.22 mol) of methanesulfonyl chloride was added dropwise thereto with stirring under ice-cooling. After being stirred for 3 hours, a solution of 32.0 g (0.57 mol) of potassium hydroxide in a mixed solvent of 340 ml of methanol and 340 ml of water was added dropwise to the mixture. After being warmed to room temperature, the mixture was stirred for 12 hours. The mixture was then acidified by slow addition of 850 ml of 4N hydrochloric acid with stirring under ice-cooling, followed by extraction with diethyl ether. The organic layer was washed successively with IN hydrochloric acid, a saturated sodium hydrogencarbonate aqueous solution, and a saturated sodium chloride aqueous solution, and dried. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography using a mixed solvent of hexane and ethyl acetate (100:1). The solvent was removed by distillation under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and diethyl ether to obtain 64.0 g (96%) of (-)-2-(2,4-difluorophenyl)-2-(1-((4-methoxyphenyl)methylthio)-1-methylethyl)oxirane as a colorless crystal.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[CH3:8][N:9]1[CH2:14][C:13]([N+:21]([O-:23])=[O:22])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:11][C:10]1=[O:24].CI>C1COCC1.CCCCCC>[CH3:8][N:9]1[CH2:14][C:13]([N+:21]([O-:23])=[O:22])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH:11]([CH3:1])[C:10]1=[O:24]
Reactant: CC(C)NC(C)C
Reactant: CN1CC(c2ccccc2)([N+](=O)[O-])CCC1=O
Solvent: CI
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1CC(c2ccccc2)([N+](=O)[O-])CN(C)C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.1 %

Procedure:
To a solution of 1.6 ml (11.1 mmol) diisopropylamine in 40 ml THF were added 7 ml (11.1 mmol) of a 1.6M n-Buli solution in hexane at −5° C. The solution was stirred for 15 minutes at 0° C. and then cooled to −70° C. A solution of 2 g (8.538 mmol) rac-1-methyl-5-nitro-5-phenyl-piperidin-2-one (example A9, step 1) in 20 ml THF was added dropwise. The brown solution was stirred at −70° C. for 45 minutes. 639 ul (10.25 mmol) methyliodide in THF (8 ml) were added dropwise at −70° C. The mixture was stirred at −70° C. for 1 hour and then allowed to warm to 0° C. After 30 minutes at 0° C., the mixture was quenched with 30 ml of a 20% NH4Cl solution. Water and ethyl acetate were added. The aqueous layer was extracted once with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 1.72 g (81%) of the title compound as a yellow oil. MS (m/e): 249.2 (M+H)
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH:15][CH2:16][CH:17]([CH2:19]O)[OH:18]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:8]([C:7]1([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[O:18][CH:17]([CH2:16][OH:15])[CH2:19][O:14]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: OCC(O)CO
Reactant: CCCCCCC(=O)CCCCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCCC1(CCCCCC)OCC(CO)O1
Reaction time: 24 h

Procedure:
A reactor equipped with a stirrer, reflux-condenser, thermometer and nitrogen gas inlet pipe was charged with 297 g of 7-tridecanone, 166 g of glycerol and a solvent amount of toluene, and after addition of p-toluenesulfonic acid as a catalyst, the dehydrative condensation reaction was carried out at the reflux temperature for 24 hours. The resulting crude product was washed with an aqueous solution of potassium carbonate and further with 3 portions of distilled water and finally purified by distillation under reduced pressure to provide 2,2-dihexyl-4-hydroxymethyl-1,3-dioxolane.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].NC1C=C(C=CC=1)C([NH:19][C:20]([CH2:26][CH3:27])([CH3:25])[C:21](=[O:24])[CH2:22][Cl:23])=O>[Pd]>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:19][C:20]([CH2:26][CH3:27])([CH3:25])[C:21](=[O:24])[CH2:22][Cl:23])=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CCC(C)(NC(=O)c1cccc(N)c1)C(=O)CCl
Agent: [Pd]
Product: CCC(C)(NC(=O)c1cccc([N+](=O)[O-])c1)C(=O)CCl

Procedure:
3-Nitro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)benzamide was prepared by reaction of 3-nitrobenzoylchloride with VIII as in scheme A (above), then converted to 3-amino-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)benzamide by catalytic hydrogenation using palladium as the catalyst.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.OO.NC(N)=[O:13].FC(F)(F)C(O)=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl>ClCCl>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:13]
Reactant: Cc1cccnc1Cl
Reactant: NC(N)=O
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc[n+]([O-])c1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 2-chloro-3-methylpyridine (12.8 g, 100 mmol), urea hydrogen peroxide (19.8 g, 210 mmol) and dichloromethane (130 mL) was added dropwise anhydrous trifluoroacetic acid (28.2 mL, 200 mmol) at 0° C. The reaction was stirred for a further 1.5 hours, warmed to room temperature and then treated with 9% w/w aqueous sodium hydrosulfite (200 mL). The mixture was stirred for a further 15 minutes then 2N hydrochloric acid (50 ml) was added and the mixture was extracted with dichloromethane (2×120 mL). The combined extracts were washed with saturated aqueous sodium hydrogen carbonate (2×100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 2-chloro-3-methylpyridine 1-oxide as a yellow solid (11.45 g; 89% purity by UV).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:10][CH2:11][O:12][CH2:13][CH2:14]O)[CH:6]=[CH:7][CH:8]=1.C([Li])CCC.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH:39]1[CH2:44][CH2:43][CH2:42][C@@H:41]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:40]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C1(C)C=CC=CC=1.CC(C)=O>[CH2:48]([O:47][C:45]([C@@H:41]1[CH2:42][CH2:43][CH2:44][N:39]([CH2:14][CH2:13][O:12][CH2:11][CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:40]1)=[O:46])[CH3:49]
Reactant: COc1cccc(C(=CCOCCO)c2ccccc2C)c1
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CCOC(=O)[C@@H]1CCCN(CCOCC=C(c2cccc(OC)c2)c2ccccc2C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
A solution of 2-(3-(3-methoxyphenyl)-3-(2-methylphenyl)-2-propen-1-yloxy)ethanol (7.6 g, 25.4 mmol) in dry toluene (150 ml) was cooled on an ice-bath and a solution of n-butyllithium in hexanes (11.2 ml, 2.5 M) was added dropwise. The reaction mixture was stirred for 0.5 h at room temperature and p-toluenesulphonyl chloride (5.3 g, 28 mmol) was added. The mixture was stirred at room temperature for 1.5 h. Ethyl (R)-3-piperidinecarboxylate (8.8 g, 50 mmol) and potassium carbonate (7.7 g, 50 mmol) were added and the mixture was stirred at room temperature for 4 h. Toluene (100 ml), acetone (50 ml) and potassium iodide (1.7 g) were added and the reaction mixture was heated at 75° C. for 84 h. The cooled reaction mixture was filtered and the solvent evaporated in vacuo. The residue was submitted to flash chromatography on silica gel (250 g) using a mixture of n-heptane and ethyl acetate (4:1) as eluent to give 7.5 g (68%) of (R)-N-(2-(3-(3-methoxyphenyl)-3-(2-methylphenyl)-2-propen-1-yloxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil. TLC: rf=0.20 (SiO2 ; ethyl acetate).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[C:15]([Cl:16])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([C:17]2[NH:18][C:19](=[O:26])[C:20]3[S:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[CH:8]=1.CO.O1CCOC[CH2:30]1>>[Cl:6][C:7]1[C:15]([Cl:16])=[CH:14][C:10]([C:11]([O:13][CH3:30])=[O:12])=[C:9]([C:17]2[NH:18][C:19](=[O:26])[C:20]3[S:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[CH:8]=1
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1-c1nc2ccsc2c(=O)[nH]1
Reactant: C1COCCO1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cc(Cl)c(Cl)cc1-c1nc2ccsc2c(=O)[nH]1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
3-aminothiophene-2-carboxamide was added to an acetic acid solution of 4,5-dichlorophthalic anhydride and stirred all night heated to reflux to give 3-(5,6-dichloro-1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)thiophene-2-carboxamide. 1M NaOH aq was added to THF-MeOH solution of the obtained 3-(5,6-dichloro-1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)thiophene-2-carboxamide and stirred for 2.5 hours at 80° C. to give 4,5-dichloro-2-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)benzoic acid. Sulfuric acid was added to a MeOH-1,4-dioxane solution of the obtained 4,5-dichloro-2-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)benzoic acid and stirred for three days at 70° C. to give methyl 4,5-dichloro-2-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)benzoate.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][C:8]2[N:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N+:18]([CH3:21])([O-:20])=[O:19].C([O-])(=O)C.[NH4+].[BH4-].[Na+]>O.C(O)(=O)C.CS(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:21][N+:18]([O-:20])=[O:19])=[CH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(COc2ccc(F)cc2)nc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])CCc1ccc(COc2ccc(F)cc2)nc1
Temperature: 105 °C
Reaction time: 2 h
Yield: 13.9 %

Procedure:
To an acetic acid (5.00 mL) solution of 6-(4-fluoro-phenoxymethyl)-pyridine-3-carbaldehyde (500 mg, 1.30 mmol) described in Manufacturing Example 72-1-2 were added nitromethane (923 mg, 15.1 mmol) and ammonium acetate (333 mg, 4.32 mmol) under nitrogen atmosphere, which was stirred for 2 hours at 105° C. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated from the filtrate under a reduced pressure. Dimethyl sulfoxide (10.0 mL) and acetic acid (600 μL) were added to the residue, and sodium borohydride (131 mg, 3.46 mmol) was then added at room temperature while cooling appropriately. Following 20 minutes of stirring, water was added dropwise at room temperature while cooling appropriately. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1) to obtain the title compound (50 mg, 8.38%).
Reaction SMILES: C([N:5]1[C:9]2=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]2[C:7]([C:15]2[CH:16]=[CH:17][C:18]3[O:22][CH2:21][O:20][C:19]=3[CH:23]=2)=[N:6]1)(C)(C)C>C(O)=O.Cl>[O:20]1[C:19]2[CH:23]=[C:15]([C:7]3[C:8]4[C:9](=[N:10][CH:11]=[N:12][C:13]=4[NH2:14])[NH:5][N:6]=3)[CH:16]=[CH:17][C:18]=2[O:22][CH2:21]1
Reactant: CC(C)(C)n1nc(-c2ccc3c(c2)OCO3)c2c(N)ncnc21
Agent: Cl
Solvent: O=CO
Product: Nc1ncnc2[nH]nc(-c3ccc4c(c3)OCO4)c12

Procedure:
1-tert-butyl-3-(benzo[d][1,3]dioxol-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (21 mg, 0.082 mmol) was dissolved in a solution of formic acid (1 mL) and conc. HCl (0.2 mL) and heated to reflux for 2 hours. Reaction was concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA). ESI-MS (M+H)+ m/z calcd 256.1, found 256.3.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1.[F:16][C:17]1[CH:23]=[C:22]([CH3:24])[C:21]([O:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][C:18]=1[NH2:19]>C(O)(C)C>[ClH:2].[F:16][C:17]1[CH:23]=[C:22]([CH3:24])[C:21]([O:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][C:18]=1[NH:19][C:3]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: COC(=O)Oc1cc(N)c(F)cc1C
Reactant: O=[N+]([O-])c1ccc2c(Cl)ncnc2c1
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)Oc1cc(Nc2ncnc3cc([N+](=O)[O-])ccc23)c(F)cc1C
Temperature: 50 °C
Yield: 44 %

Procedure:
A solution of 4-chloro-7-nitroquinazoline hydrochloride (2.46 g, 10 mmol) and 2-fluoro-5-methoxycarbonyloxy-4-methylaniline (2.2 g, 11 mmol), (prepared as described for the starting material in Example 12), in isopropanol (25 ml) was heated at 50° C. for 1 hour. The mixture was allowed to cool, the precipitated solid was collected by filtration recrystallised from methylene chloride/methanol/isopropanol to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-nitroquinazoline hydrochloride (1.8 g, 45%) as a yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6](=[NH:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[N:4]=1)[CH3:2].C[Sn]([N:28]=[N+:29]=[N-:30])(C)C.Cl>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[S:7][C:6](=[NH:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:30][N:29]=[N:28][N:23]=3)=[CH:12][CH:11]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2ccc(-c3ccccc3C#N)cc2)c(=N)s1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Agent: Cl
Solvent: Cc1ccccc1
Product: CCc1nn(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=N)s1
Yield: 16 %

Procedure:
In 10 ml of toluene, 1.6 g of 5-ethyl-2-imino-3-(2'-cyanobiphenyl-4-yl)methyl-1,3,4-thiadiazoline and 1.1 g of trimethyltin azide were suspended, followed by heating under reflux for 4 hours. After cooling, the reaction mixture was subjected to column chromatography on a silica gel and eluted using chloroform:methanol (20:1)→chloroform:methanol:acetic acid (20:10:1). The eluate fractions thus obtained were distilled off under reduced pressure. To the resulting residue, 40 ml of 2N sodium hydroxide and 40 ml of ethyl acetate were added. The aqueous layer so obtained was neutralized with 12N hydrochloric acid and powders so precipitated were collected by filtration. The powders were successively washed with water, ethanol and diethyl ether and then dried, whereby 290 mg of the title compound was obtained.
Reaction SMILES: [CH:1]1([CH:4]([OH:33])[C:5]2[CH:6]=[C:7]([C:11]([CH3:32])([CH3:31])[CH2:12][C:13]([OH:30])([C:26]([F:29])([F:28])[F:27])[CH2:14][N:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18](=[O:25])[CH:17]=[CH:16]3)[CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2]1>C(Cl)Cl.O=[Mn]=O>[CH:1]1([C:4]([C:5]2[CH:6]=[C:7]([C:11]([CH3:32])([CH3:31])[CH2:12][C:13]([OH:30])([C:26]([F:27])([F:28])[F:29])[CH2:14][N:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18](=[O:25])[CH:17]=[CH:16]3)[CH:8]=[CH:9][CH:10]=2)=[O:33])[CH2:2][CH2:3]1
Reactant: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cccc(C(O)C2CC2)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cccc(C(=O)C2CC2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1-{4-[3-(cyclopropylhydroxymethyl)phenyl]-2-hydroxy-4-methyl-2-trifluoromethylpentyl}-1H-quinolin-4-one (26 mg, 0.057 mmol) and MnO2 (5 mg, 0.57 mmol) in methylene chloride (2 mL) was stirred for 48 hours at room temperature under an atmosphere of argon and filtered over CELITE® filter aid. The filtrate was concentrated in vacuo and the residue purified by reversed phase HPLC to afford 1-[4-(3-cyclopropanecarbonylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one. Yield: 9 mg (35%).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][C@@H:6]([C:29]#[N:30])[NH:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[NH:16][C:17]([C:19]1[N:20]([CH3:28])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[O:9].O.[OH-].[Li+].Cl>C1COCC1.CO.O>[C:29]([C@@H:6]([NH:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[NH:16][C:17]([C:19]1[N:20]([CH3:28])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[O:9])[CH2:5][CH2:4][C:3]([OH:31])=[O:2])#[N:30]
Reactant: COC(=O)CC[C@@H](C#N)NC(=O)[C@@H]1CCCC[C@@H]1NC(=O)c1cc2ccccc2n1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(C(=O)N[C@H]2CCCC[C@H]2C(=O)N[C@H](C#N)CCC(=O)O)cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
To a solution of (S)-4-cyano-4-({(1R,2S)-2-[(1-methyl-1H-indole-2-carbonyl)-amino]-cyclohexanecarbonyl}-amino)-butyric acid methyl ester (prepared as described in Example 3 using glutamic acid amide methyl ester) (572 mg, 1.35 mmol) in 15 mL of THF and 2 mL of MeOH was added a solution of lithium hydroxide hydrate (370 mg, 8.82 mmol) in 15 mL of water. The reaction mixture was stirred at room temp for 30 minutes, then poured into a slurry of ice and 20 mL of a 1N HCl solution. The organic layer was extracted with 50 mL of ethyl acetate, separated, washed with 50 mL of water, dried with sodium sulfate, and concentrated to give 556 mg (100%) of (S)-4-cyano-4-({(1R,2S)-2-[(1-methyl-1H-indole-2-carbonyl)-amino]-cyclohexanecarbonyl}-amino)-butyric acid as a white amorphous solid. MS: 409 (M−H+).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:24]([CH3:26])([CH3:25])[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:27](O)=[O:28])[CH:21]=3)[NH:16]2)=[CH:11][C:10]=1[N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:24]([CH3:26])([CH3:25])[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:27]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:28])[CH:21]=3)[NH:16]2)=[CH:11][C:10]=1[N:30]1[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1
Reactant: CS(N)(=O)=O
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(F)c(N2CCOCC2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1ccc(F)c(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
To a suspension of methanesulfonamide (150 mg, 1.55 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (62 mg, 1.55 mmol). The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-(4-fluoro-3-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (120 mg, 0.31 mmol) and 1,1′-carbonyldiimidazole (100 mg, 0.62 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h. Then the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[2-(4-fluoro-3-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (36 mg, 25%) as a white solid: LC/MS m/e calcd for C23H28FN3O4S (M+H)+: 462.6, observed: 462.4.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:20](OC)=[O:21])=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:5]2=[N:6][CH:7]=1.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([CH2:20][OH:21])=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)c1c(Br)cnc2c1ncn2Cc1ccc(OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(Cn2cnc3c(CO)c(Br)cnc32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.8 %

Procedure:
Methyl 6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridine-7-carboxylate x210 (1.2 g, 3.19 mmol) is dissolved in absolute ethanol. NaBH4 (0.36 g, 3 eq, 9.57 mmol) is added at 5° C. under stirring. The cooling bath is removed after 4 h, and the reaction mixture is allowed to heat up to room temperature. The stirring is continued at this temperature for 20 h. The reaction mixture is evaporated in the vacuum of a rotary evaporator at 35° C., and the residue is partitioned in ethyl acetate/saturated aqueous NaHCO3 mixture. The organic layer is dried with anhydrous sodium sulfate and evaporated. The crude product is purified by chromatography on silicagel (dichloromethane/methanol) to afford 0.72 g of [6-bromo-3-(4-methoxybenzyl)-3H-imidazo[4,5-b]pyridin-7-yl]methanol x211.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=1>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:9][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=1
Reactant: Nc1nccc(Cl)n1
Reactant: Nc1cc(O)ccc1F
Product: Nc1nccc(Oc2ccc(F)c(N)c2)n1
Yield: 59.9 %

Procedure:
Using a procedure analogous to Example A3, 3-amino-4-fluorophenol (491 mg, 3.86 mmol) and 4-chloropyrimidin-2-amine (500 mg, 3.86 mmol) were combined to give 4-(3-amino-4-fluorophenoxy)pyrimidin-2-amine (509 mg, 59% yield). MS (ESI) m/z: 221.0 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].C([O-])([O-])=O.[K+].[K+].[CH3:29][O:30][CH2:31][CH2:32][OH:33]>>[Br:1][C:2]1[C:3]([O:33][CH2:32][CH2:31][O:30][CH3:29])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: COCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COCCOc1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 44.2, 250 mg, 0.632 mmol) and K2CO3 (131 mg, 0.948 mmol) in 2-methoxyethanol (997 μl, 12.64 mmol) was stirred at 110° C. for 4 h. The solvent was evaporated off under reduced pressure to afford the title compound which was used directly. UPLC-MS (Condition 2) tR=1.18 min, m/z=435.2/437.2 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 3.32 (s, 3H) 3.64-3.76 (m, 2H) 4.48-4.59 (m, 2H) 7.38 (d, J=8.66 Hz, 2H) 7.85 (d, J=9.03 Hz, 2H) 8.55 (d, J=2.07 Hz, 1H) 8.72 (d, J=2.07 Hz, 1H) 10.47 (s, 1H).
Reaction SMILES: CC1(C)C2C(OC3N=CC(NC(=O)[C@@H](C)N)=CC=3)=CC=CC=2[O:4][CH2:3]1.[NH2:25][C@H:26]([CH2:48][CH3:49])[C:27]([NH:29][C:30]1[CH:31]=[N:32][C:33]([O:36][C:37]2[C:42]3[C:43]([CH3:47])([CH3:46])[CH2:44][O:45][C:41]=3[CH:40]=[CH:39][CH:38]=2)=[CH:34][CH:35]=1)=[O:28]>>[CH3:47][C:43]1([CH3:46])[C:42]2[C:37]([O:36][C:33]3[N:32]=[CH:31][C:30]([N:29]4[C:27](=[O:28])[C@@H:26]([CH2:48][CH3:49])[NH:25][C:3]4=[O:4])=[CH:35][CH:34]=3)=[CH:38][CH:39]=[CH:40][C:41]=2[O:45][CH2:44]1
Reactant: CC[C@@H](N)C(=O)Nc1ccc(Oc2cccc3c2C(C)(C)CO3)nc1
Reactant: C[C@@H](N)C(=O)Nc1ccc(Oc2cccc3c2C(C)(C)CO3)nc1
Product: CC[C@H]1NC(=O)N(c2ccc(Oc3cccc4c3C(C)(C)CO4)nc2)C1=O

Procedure:
The title compound was made in a similar fashion to the preparation of Example 8 replacing N1-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}-D-alaninamide (Intermediate 61) with (2R)-2-amino-N-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}butanamide (Intermediate 63, 57 mg). This afforded the title compound as a white solid (40 mg).