Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][C:11]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.B.C1COCC1>C1COCC1>[F:1][C:2]1[C:3]([C:10]2[CH:18]=[CH:17][C:13]([CH2:14][OH:15])=[CH:12][C:11]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1cc(C(=O)O)ccc1-c1cc(OC)ncc1F
Agent: B
Solvent: C1CCOC1
Product: COC(=O)c1cc(CO)ccc1-c1cc(OC)ncc1F
Temperature: 23 °C
Reaction time: 46 h
Yield: 105.4 %

Procedure:
To a stirred solution of 4-(5-fluoro-2-methoxypyridin-4-yl)-3-(methoxycarbonyl)benzoic acid T6.2 (0.416 g, 1 mmol) in THF (14 mL) at 0° C. was added borane-THF (3 mL, 3 mmol, 1.0M). The reaction was warmed to 23° C. and stirred for 46 hours. The reaction was then concentrated in vacuo, diluted with 1N HCl and extracted three times with EtOAc. The organic layers were combined, dried over anhydrous MgSO4, and filtered. The organic solvent was removed under reduced pressure, and the product was purified on silica gel (0-40% EtOAc in hexanes) to yield T6.3 as a colorless solid (0.307 g, 77% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)[CH:7]=[CH:6][C:4]=1[NH2:5].[CH3:19][N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1[C:29](Cl)=[O:30]>CN(C)C1C=CN=CC=1.ClCCl.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)[CH:7]=[CH:6][C:4]=1[NH:5][C:29]([C:21]1[N:20]([CH3:19])[C:28]2[C:23]([CH:22]=1)=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:30]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: Cn1c(C(=O)Cl)cc2ccccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 96 h
Yield: 92.1 %

Procedure:
To a solution of 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (4.01 mmol, 1 g) and 4-dimethylaminopyridine (0.401 mmol, 0.049 g) in dichloromethane (5 ml) and pyridine (5 ml) was added 1-methyl-1H-indole-2-carbonyl chloride (5.22 mmol, 1.010 g) and this solution was stirred at room temperature for four days. The reaction mixture was concentrated and coevaporated with toluene. To the residue dichloromethane and water were added. The organic layer was separated, dried (sodium sulfate) and concentrated in vacuo. Purification using flash chromatography (silica gel, dichloromethane) yielded N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-indole-2-carboxamide (1.5 g).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][C:12]=2[O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].Br[C:23]1[CH:24]=[CH:25][C:26]([CH:29]=[O:30])=[N:27][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH:29]([C:26]1[N:27]=[CH:28][C:23]([C:16]2[CH:17]=[CH:18][C:12]3[O:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:14][C:13]=3[CH:15]=2)=[CH:24][CH:25]=1)=[O:30]
Reactant: O=Cc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(B(O)O)cc2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(C=O)nc3)cc2C1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
A mixture of (4-{[(1,1-dimethylethyl)oxycarbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)boronic acid (example 1, step 2) (500 mg, 1.7 mmol), 5-bromopicolinaldehyde (380 mg, 2.0 mmol), cesium carbonate (1.66 g, 5.0 mmol), and dichloro[1,1-bis(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (125 mg, 0.17 mmol) in dioxane (5.0 mL) and water (1.0 mL) was degassed with nitrogen, and then stirred at 90° C. with microwave irradiation for 30 min. The reaction mixture was cooled to room temperature, and partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×), the combined organic layers were washed with brine (1×), dried over sodium sulfate, filtered and concentrated. Column chromatography on silica (hexanes/ethyl acetate 4:1) provided 1,1-dimethylethyl 7-(6-formylpyridin-3-yl)-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxylate (580 mg, 96% yield) as a colorless solid. MS (EI) for C20H22N2O4: 355 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[CH3:25][O:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][N:28]=1>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:30]4[CH:29]=[N:28][C:27]([O:26][CH3:25])=[N:32][CH:31]=4)=[C:4]([CH:9]=3)[C:3]([OH:2])=[O:24])[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cn1
Yield: 1 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with and 2-methoxypyrimidine-5-boronic acid (available from Combi-Blocks Inc.; 62 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5-[4-(3,4-Dichloro-phenyl)-thiazol-2-yl]-2-(2-methoxy-pyrimidin-5-yl)-benzoic acid (0.9 mg, 1%). LCMS analysis indicated that the material was ˜100% pure, as measured by UV at 214 nm. LRMS m/z 457.8 and 459.8 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[CH:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].B(F)(F)F>C(#N)C>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[C:10]([C:17](=[O:19])[CH3:18])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Clc1cccc2cc(-c3ccncc3)nn12
Agent: FB(F)F
Solvent: CC#N
Product: CC(=O)c1c(-c2ccncc2)nn2c(Cl)cccc12
Temperature: 80 °C
Yield: 64.7 %

Procedure:
To a solution of 7-chloro-2-(4-pyridinyl)pyrazolo[1,5-a]pyridine (2.0 g, 8.7 mmol) in acetonitrile (50 mL) at room temperature was added acetic anhydride (2.0 mL, 21 mmol). Boron trifluoride diethyletherate (5.3 mL, 42 mmol) was added dropwise and the resulting solution was heated at 80° C. for 12 hours. The reaction mixture was cooled to room temperature and quenched by the dropwise addition of saturated sodium bicarbonate. The reaction mixture was extracted with ethyl acetate, and the organic phase phase washed with brine, dried (magnesium sulfate), filtered and concentrated. The residue was purified by silica gel chromatography (5:95 methanol-dichloromethane) to give 1-[7-chloro-2-(4-pyridinyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (1.53 g, 65%) as a red foam. 1H NMR (CDCl3): δ 8.82 (m, 2H), 8.45 (d, 1H), 7.62 (m, 2H), 7.54 (t, 1H), 7.25 (d, 1H), 2.26 (s, 3H); MS m/272 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:13][CH3:14])=[N:5][C:6]([CH3:12])=[C:7]([CH:11]=1)[C:8]([NH2:10])=[O:9])[CH3:2].CO[C:17](OC)([N:19]([CH3:21])[CH3:20])[CH3:18]>>[CH3:20][N:19]([CH3:21])[C:17](=[N:10][C:8](=[O:9])[C:7]1[CH:11]=[C:3]([CH2:1][CH3:2])[C:4]([O:13][CH3:14])=[N:5][C:6]=1[CH3:12])[CH3:18]
Reactant: COC(C)(OC)N(C)C
Reactant: CCc1cc(C(N)=O)c(C)nc1OC
Product: CCc1cc(C(=O)N=C(C)N(C)C)c(C)nc1OC
Temperature: 100 °C
Reaction time: 1.08 h

Procedure:
In a round bottom flask under a nitrogen atmosphere 5-ethyl-6-methoxy-2-methyl-nicotinamide (195 mg, 1.00 mmol) of Step 1, Example 16 is treated with dimethylacetamide dimethylacetal (2 mL). The mixture is stirred at 100° C. for 65 min to give a dark solution. The reaction mixture is evaporated to give N-(1-dimethylaminoethylidene)-5-ethyl-6-methoxy-2-methylnicotinamide directly as a black oil that is used without purification. MS: m/e=264 (M+H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[N+]([O-])([O-])=[O:22].[Na+]>S(=O)(=O)(O)O.O>[OH:22][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=3)[N:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: O=[N+]([O-])[O-]
Reactant: Nc1cc2cccnc2c(-c2cccc([N+](=O)[O-])c2)n1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1cccc(-c2nc(O)cc3cccnc23)c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-amino-8-(3-nitrophenyl)-1,7-naphthyridine (500 mg, 1.87 mmol; prepared according to example 1) in concentrated sulfuric acid and water (3 ml, 2:1) is added sodium nitrate (155 mg, 2.25 mmol) at 4° C. After 30 minutes, the ice bath is removed, and the mixture is warmed to 70° C. for 30 minutes. the reaction mixture is poured onto ice, and the solution is neutralized by adding sodium bicarbonate. The precipitate is filtered and washed with water affording the title compound. mp 262-265° C.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:9])[CH2:5][C:6]([CH3:8])=[CH2:7].[Br:16][C:17]1[CH:18]=[C:19]([CH3:28])[C:20]([CH2:24][N:25]=[C:26]=[O:27])=[C:21]([CH3:23])[CH:22]=1>>[Br:16][C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([CH2:24][N:25]2[CH2:2][CH2:3][C:4]([CH2:5][C:6]([CH3:8])=[CH2:7])([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:9][C:26]2=[O:27])=[C:19]([CH3:28])[CH:18]=1
Reactant: C=C(C)CC(O)(CCCl)c1ccccc1
Reactant: Cc1cc(Br)cc(C)c1CN=C=O
Product: C=C(C)CC1(c2ccccc2)CCN(Cc2c(C)cc(Br)cc2C)C(=O)O1

Procedure:
The title compound was prepared from 1-chloro-5-methyl-3-phenyl-hex-5-en-3-ol and 5-bromo-2-isocyanatomethyl-1,3-dimethyl-benzene following a procedure analogous to that described in Step 1 of Example 96. LC-MS (Method 5): tR=4.95 min; Mass spectrum (ESI+): m/z=428/430 (Br) [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[CH2:6]2.[N:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]2[C:31]3[C:26](=[CH:27][C:28]([CH:32]=O)=[CH:29][CH:30]=3)[NH:25][N:24]=2)=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])/[C:6]/2=[CH:32]/[C:28]1[CH:27]=[C:26]2[C:31]([C:23](/[CH:22]=[CH:21]/[C:18]3[CH:17]=[CH:16][N:15]=[CH:20][CH:19]=3)=[N:24][NH:25]2)=[CH:30][CH:29]=1
Reactant: COc1cc2c(cc1OC)NC(=O)C2
Reactant: O=Cc1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Product: COc1cc2c(cc1OC)/C(=C\c1ccc3c(/C=C/c4ccncc4)n[nH]c3c1)C(=O)N2
Yield: 42.4 %

Procedure:
The title compound (36 mg, 42%) was synthesized as an orange red solid according to the method described for Example A67 (oil temp 75° C., reflux 90 min) using 5,6-dimethoxyindolin-2-one (38.6 mg, 0.2 mmol) and (E)-3-(2-(pyridin-4-yl)vinyl)-1H-indazole-6-carbaldehyde (49.8 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.54 (s, 1H), 10.39 (s, 1H), 8.60-8.53 (m, 2H), 8.35 (d, J=7.2 Hz, 1H), 7.94 (s, 1H), 7.87 (d, J=16.4 Hz, 1H), 7.75-7.67 (m, 2H), 7.63-7.50 (m, 3H), 7.25 (s, 1H), 6.53 (s, 1H), 3.80 (s, 3H), 3.55 (s, 3H); MS ESI 425.2 [M+H]+, calcd for [C25H20N4O3+H]+ 425.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][CH:11]([C:13]([O:15]C(C)(C)C)=[O:14])[N:10]([CH3:20])[C:9]2=[O:21])=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[N:10]([CH3:20])[C:9]2=[O:21])=[N:6][CH:7]=1
Reactant: CN1C(=O)N(c2ncc(F)cn2)CC1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)N(c2ncc(F)cn2)CC1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.2 %

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (300 mg, 1.498 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2-chloro-5-fluoropyrimidine (0.194 ml, 1.573 mmol) in 1,4-dioxane (10 ml) was treated with cesium carbonate (732 mg, 2.247 mmol), Xantphos™ (65.0 mg, 0.112 mmol), and tris(dibenzylideneacetone)dipalladium(0) (34.3 mg, 0.037 mmol) and then heated at reflux for ˜3 hrs. The mixture was cooled to room temperature, diluted with water (˜25 ml) and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with water and then with brine and evaporated to give a yellow/brown residue. This was purified by automated silica-gel column chromatography (Biotage SP-4), eluting with a 0-100% gradient of ethyl acetate in isohexane (8 column volumes), to give 1,1-dimethylethyl 1-(5-fluoro-2-pyrimidinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (232 mg, 52.3% yield) as a white solid. (ii) 1,1-Dimethylethyl 1-(5-fluoro-2-pyrimidinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (232 mg, 0.783 mmol) was dissolved in a mixture of trifluoroacetic acid (2 ml, 26.0 mmol) and dichloromethane (4 ml) at 0° C. and then left to warm to room temperature and stirred overnight. The mixture was evaporated (azeotroping with toluene and then with dichloromethane to remove all TFA traces) to give 1-(5-fluoro-2-pyrimidinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylic acid (211 mg) as a white solid which was used without further purification in subsequent chemistry. LC/MS MH+=240.85.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[OH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=O)[CH2:13][N+:14]([O-:16])=[O:15]>CO>[CH3:2][O:3][N:4]=[C:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[OH:5])[CH2:13][N+:14]([O-:16])=[O:15]
Reactant: CON
Reactant: O=C(C[N+](=O)[O-])c1ccccc1O
Agent: Cl
Solvent: CO
Product: CON=C(C[N+](=O)[O-])c1ccccc1O
Temperature: 47.5 °C
Reaction time: 10 h
Yield: 77.9 %

Procedure:
At 20° C., 73.5 g (0.88 mol) of methoxyamine hydrochloride are added to a solution of 80.0 g (0.44 mol) of o-hydroxy-ω-nitroacetophenone in 500 ml of methanol, and the mixture is stirred at 45 to 50° C. for 8 to 12 hours. The solution is cooled to 20° C., poured into 1 l of ice-water and stirred for one hour. The crystalline product is filtered off and washed with 500 ml of water a little at a time and dried at 40° C. in a vacuum drying cabinet. 72 g (74.6% of theory) of 1-(2-hydroxyphenyl)-2-nitro-ethanone O-methyl-oxime are obtained as a mixture of stereoisomers.
Reaction SMILES: [C:1]1([O:7][C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([OH:17])C>>[C:1]1([O:7][C:8]([N:10]2[CH2:14][CH2:13][C@H:12]([OH:17])[CH2:11]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Oc1ccccc1)N1CCCC1
Reactant: CCO
Product: O=C(Oc1ccccc1)N1CC[C@H](O)C1
Reaction time: 24 h
Yield: 28 %

Procedure:
Three Fernbach flasks each containing 0.5 L of medium 2 as described in Example 2 were inoculated with spores of C. echinulata ATCC 8688b and incubated at 29° C. on a rotary shaker (220 rpm). After about 24 hours, the contents of the three flasks were combined and used to inoculate two fermentors, each containing 8 L of medium 2. Fermentors (Fermentors A and B) were operated at 29° C. with 600 rpm agitation and 8 liter per minute aeration. The pH was controlled between 6 and 7. After 24 hours, the bioconversion was started by adding 4.8 g of substrate (I), dissolved in 20 mL ethanol, to each fermentor. The bioconversion was followed by removing samples, extracting with ETOAc, and analyzing by reverse phase and chiral HPLC as described in Example 1. The results of these HPLC analyses are summarized in Table 4. About 9 days after substrate addition, the contents of the fermentors were pooled and filtered through a triple-layer of cheesecloth. The filtrate was passed through a column containing about 500 g of XAD-16 resin. The resin was then washed with 1 L of water and eluted with 6 L of ETOAc. The ETOAc eluates were washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was applied to a silica flash cartridge (Biotage Herts SGI3 7NW ENGLAND) and eluted with mixtures of ETOAc and hexanes, (2:3, 1·1) beginning with 10% ETOAc, and increasing in 10% increments to 80% ETOAc. Fractions eluted with 60-80% ETOAc were combined and concentrated under reduced pressure to give 2.9 g (28% yield, 88% ee) of (S)-3-hydroxypyrrolidine-1-carboxylic acid phenylester (II).
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([C:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH:18]=2)[CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[H][H]>CCO.[Pd]>[C:1]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:26])=[C:11]([CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:17][CH2:18]2)[CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A mixture of tert-butyl 4-[5-(isobutyrylamino)-2-methylphenyl]-3,6-dihydro-1(2H)-pyridinecarboxylate (335 mg, 0.93 mmol) and 10% Pd/C (35.0 mg) in EtOH (20.0 mL) was hydrogenated at room temperature overnight using the hydrogen balloon method. The reaction mixture was filtered through Celite and washed with ethanol (3×10 mL). The combined extracts were concentrated in vacuo to afford tert-butyl 4-[5-(isobutyrylamino)-2-methylphenyl]-1-piperidinecarboxylate (335 mg, 100%): ESMS m/e: 361.4 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.ClC(Cl)C.[CH:29]1([NH:35][C:36]2[N:44]=[C:43]([F:45])[CH:42]=[CH:41][C:37]=2[C:38]([OH:40])=O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.[NH2:46][C:47]1[CH:56]=[C:55]2[C:50]([CH2:51][CH2:52][C:53](=[O:58])[N:54]2[CH3:57])=[CH:49][CH:48]=1>C(N(CC)CC)C>[CH:29]1([NH:35][C:36]2[N:44]=[C:43]([F:45])[CH:42]=[CH:41][C:37]=2[C:38]([NH:46][C:47]2[CH:56]=[C:55]3[C:50]([CH2:51][CH2:52][C:53](=[O:58])[N:54]3[CH3:57])=[CH:49][CH:48]=2)=[O:40])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: O=C(O)c1ccc(F)nc1NC1CCCCC1
Reactant: CN1C(=O)CCc2ccc(N)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(F)nc3NC3CCCCC3)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
HATU was added to a dichloroethane solution of 2-(cyclohexylamino)-6-fluoronicotinic acid and triethylamine. After 30 minutes of stirring at room temperature, 7-amino-1-methyl-3,4-dihydroquinolin-2(1H)-one was added thereto. The reaction liquid was stirred overnight at room temperature and then hearted under reflux for 3 hours. By post-treating the reaction liquid, 2-(cyclohexylamino)-6-fluoro-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)nicotinamide was obtained.
Reaction SMILES: [Cl:1][C:2]1(Cl)[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:12][C:5]=2[NH:4][C:3]1=[O:19].C([O-])(=O)C.[Na+]>[C].[Pd].C(O)(=O)C>[Cl:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:12][C:5]=2[NH:4][C:3]1=[O:19]
Reactant: O=C1Nc2cc(-c3ccccc3)ccc2CCC1(Cl)Cl
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1Nc2cc(-c3ccccc3)ccc2CCC1Cl
Reaction time: 2 h
Yield: 20.7 %

Procedure:
A mixture comprising 2.88 g (9.4 mmol) of 3,3-dichloro-8-phenyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one obtained in the Synthesis Example A-4, 0.89 g (11.89 mmol) of sodium acetate, 0.2 g of 10% palladium-carbon and 40 ml of acetic acid was catalytically hydrogenated at room temperature under 3 atm for 2 hours. After filtering off the insoluble matters, the filtrate was concentrated. Then, dichloromethane was added to the residue, followed by neutralization with a saturated aqueous solution of sodium hydrogencarbonate. The dichloromethane phase was separated, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, a small amount of dichloromethane was added to the residue, followed by collection of crystals by filtration. Thus, 0.53 g of the title compound was obtained. The mother liquor was subjected to silica gel column chromatography. After successively eluting with hexane:ethyl acetate in a ratio ranging from 6:1 (v/v) to 3:1 (v/v) and then with dichloromethane:methanol in a ratio of 200:1 (v/v), 0.4 g of the title compound was further obtained. By combining with the one obtained above, 0.93 g of the title compound was obtained in total. Yield 36%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17]C)=[C:13]([F:19])[CH:12]=2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.B(Br)(Br)[Br:22]>ClCCl>[NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:19])[CH:12]=2)=[O:9])=[C:6]([Br:22])[N:5]=[CH:4][N:3]=1
Reactant: COc1ccc(NC(=O)c2c(N)ncnc2Cl)cc1F
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ncnc(Br)c1C(=O)Nc1ccc(O)c(F)c1
Yield: 37.5 %

Procedure:
4-Amino-6-chloro-N-(3-fluoro-4-methoxyphenyl)pyrimidine-5-carboxamide (675 mg, 2.28 mmol) was treated with boron tribromide (1M in dichloromethane, 6.80 ml, 6.80 mmol) and using dichloromethane (10 ml) as a solvent according to the method described in Example 23. The solid residue (280 mg, 38% yield) was used in the next synthetic step without further purification. Purity 99%.
Reaction SMILES: O1CCCCC1[O:7][CH:8]1[CH:12]2[O:13][CH2:14][CH:15]([NH2:16])[CH:11]2[O:10][CH2:9]1.[ClH:17]>C(Cl)Cl.CCOC(C)=O>[ClH:17].[NH2:16][CH:15]1[CH:11]2[O:10][CH2:9][CH:8]([OH:7])[CH:12]2[O:13][CH2:14]1
Reactant: NC1COC2C(OC3CCCCO3)COC12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC1COC2C(O)COC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-((tetrahydro-2H-pyran-2-yl)oxy)hexahydrofuro[3,2-b]furan-3-amine (2.8 g, 12.2 mmol) in DCM (50 mL) was added a solution of HCl in EtOAc (15 mL, 3.8M), and the mixture was stirred at rt overnight and concentrated in vacuo. The residue was washed with DCM (50 mL), and then dried in vacuo at 60° C. overnight to give the crude product as a brown solid (3.3 g, not pure).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][O:17][C:18]2=[O:23].S([O-])([O-])(=O)=O.[Mg+2]>C(#N)C>[N:1]1[C:10]2[C:5](=[CH:6][C:7](/[CH:11]=[N:13]/[C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][O:17][C:18]4=[O:23])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc2ncccc2c1
Reactant: Nc1cccc2c1COC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: O=C1OCc2c(/N=C/c3ccc4ncccc4c3)cccc21
Yield: 93.5 %

Procedure:
A solution of quinoline-6-carbaldehyde (786 mg, 5.0 mmol), 4-aminoisobenzofuran-1(3H)-one (745 mg, 5.0 mmol) and anhydrous magnesium sulfate (6.0 g, 50.0 mmol) in acetonitrile (100 ml) was heated at reflux for two days. The solution was filtered and removed in vacuum. The crude product was re-crystallized from isopropanol to give the title compound (1.348 g, yield 93%) LC-MS (ESI) m/z: 289 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 5.57 (s, 2H), 7.63-7.77 (m, 4H), 8.14-8.16 (d, J=8.8 Hz, 1H), 8.39-8.42 (m, 1H), 8.53-8.56 (m, 2H), 8.99-9.01 (m, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[C:16]([OH:23])[C:15]=1[CH2:24][CH2:25][CH3:26].[C-:27]#[N:28].[Na+].[I-].[Na+]>CN(C)C=O>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][C:27]#[N:28])=[C:15]([CH2:24][CH2:25][CH3:26])[C:16]=1[OH:23])(=[O:22])[CH3:21]
Reactant: CCCc1c(OCCOCCOCCOCCBr)ccc(C(C)=O)c1O
Reactant: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCOCCOCCOCCC#N)ccc(C(C)=O)c1O
Yield: 98.8 %

Procedure:
A solution of 2.23 g of 1-[4-[2-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]ethoxy]-2-hydroxy-3-propylphenyl]ethanone, 0.34 g of sodium cyanide and 0.77 g of sodium iodide in 40 ml of dimethyl formamide was stirred and heated at 80° for 70 minutes. The solvent was removed in vacuo, water was added to the residue and the product was extracted with ether. The dried (over magnesium sulfate) extract was concentrated in vacuo to give 1.93 g of crude 3-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]propanenitrile. The low resolution mass spectrum showed the molecular ion at m/e 379.