Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.Cl.[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16](O)=[O:17]>>[ClH:1].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:17]
Reactant: NCC(=O)CCC(=O)O
Reactant: OCc1ccc(Cl)cc1
Agent: Cl
Product: NCC(=O)CCC(=O)OCc1ccc(Cl)cc1
Reaction time: 24 h

Procedure:
From 4-chlorobenzyl alcohol (5.0 g; 35 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 24 h at 100° C. The yield was 0.56 g (32%). Mp 127–129° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:19]([OH:21])=O)[CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:34][C:35]1[NH:39][N:38]=[N:37][N:36]=1>>[NH:36]1[C:35]([NH:34][C:19]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:13][CH:14]=3)[N:6]=2)=[O:21])=[N:39][N:38]=[N:37]1
Reactant: Nc1nnn[nH]1
Reactant: COc1cc(C(=O)O)nc(-c2ccc(NC(C)=O)cc2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Product: COc1cc(C(=O)Nc2nnn[nH]2)nc(-c2ccc(NC(C)=O)cc2)c1
Yield: 84.5 %

Procedure:
In the same manner as described in Example 1-(1), 4-methoxy-6-(4-acetylaminophenyl)-2-pyridinecarboxylic acid (0.46 g), carbonyldiimidazole (0.29 g) and 5-aminotetrazole (0.15 g) are reacted to give N-(5-tetrazolyl)-4-methoxy-6-(4-acetylaminophenyl)-2-pyridinecarboxamide (0.48 g). M.P. 286°-288° C. (decomp.) (recrystallized from dimethylformamide-ethanol)
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:12]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1B(O)O)=[O:13]>>[CH:12]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:13]
Reactant: COC(=O)c1ccccc1I
Reactant: COc1ccc(B(O)O)c(C=O)c1
Product: COC(=O)c1ccccc1-c1ccc(OC)cc1C=O

Procedure:
Methyl 2-iodobenzoate was coupled to 2-formyl-4-methoxyphenylboronic acid using the procedure described in Example 4, Part A to provide methyl 2-(2′-formyl-4′-methoxyphenyl)benzoate. 1HNMR (300 MHz, CDCl3) δ 9.74 (s, 1H); 8.02 (d, 1H, J=7.7 Hz); 7.57 (t, 1H J=7.7 Hz); 7.50 (m, 2H); 7.28, 1, m); 7.17 (s, 2H); 3.91 (s, 3H); 3.64 (s, 3H).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[C:12]1([C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N+]=[N-])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)(=O)C>[C:1]([O:11][CH:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: O=C(O)[C@H](O)c1ccccc1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(OC(c1ccccc1)c1ccccc1)[C@H](O)c1ccccc1
Temperature: 25 °C
Yield: 91.4 %

Procedure:
To a solution of 25.0 g (164 mmol) of D-mandelic acid in 200 ml of ethyl acetate was added 38.9 g (164 mmol) of diphenyldiazomethane under stirring at room temperature. The completeness of reaction was monitored by TLC and the reaction mixture was concentrated. The residue was recrystallized from ether-petroleum ether to give 47.7 g of the aimed product D-5 in 91% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10](Cl)[C:11]([C:14]#[N:15])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].CCCCCC.[C:26](OCC)(=[O:28])C>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([O:28][CH3:26])[C:11]([C:14]#[N:15])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1ncc(-c2cccc(Cl)c2)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: COc1cc(-c2cccc(Cl)c2)cnc1C#N
Temperature: 5 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A 20 L reactor equipped with a mechanical stirred, condenser, thermometer and nitrogen inlet was charged with 5-(3-chlorophenyl)-3-chloro-2-cyanopyridine, 1, (558 g, 2.24 mol) and sodium methoxide (25% solution in methanol, 726.0 g, 3.36 mol). With agitation, the reaction solution was heated to reflux for 24 hours, resulting in a beige-colored suspension. The reaction was determined to be complete due to the disappearance of 5-(3-chlorophenyl)-3-chloro-2-cyanopyridine as measured by TLC analysis using hexane/ethyl acetate (6:3) as the mobile phase and UV 435 nm to visualize the reaction components. The reaction mixture was cooled to 5° C. and then charged with water (5580 mL). The resulting slurry was agitated for 3 hours at 5° C. The solid product was isolated by filtration and washed with water (5580 mL) until the filtrate had a pH of 7. The filter cake was air dried under vacuum for 16 hours. The filter cake was then charged back to the reactor and triturated in MeOH (2210 g, 2794 mL) for 1 hour at ambient temperature. The solid was collected by filtration and washed with MeOH (882 g, 1116 mL, 5° C.) followed by heptane (205 mL, 300 mL), and dried under high vacuum at 45° C. for 72 hours to afford 448 g (82% yield) of the desired product as an off-white solid. Purity by HPLC was 97.9%. 1H NMR (DMSO-d6) δ 8.68 (d, 1H), 8.05 (d, 1H), 8.01 (s, 1H) 7.86 (m, 1H), 7.59 (s, 1H), 7.57 (s, 1H) and 4.09 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([N:14]1[CH2:19][CH2:18][C:17]([O:23][CH3:24])([C:20]([OH:22])=O)[CH2:16][CH2:15]1)[CH2:10]2)=[O:5])[CH3:2].Cl.[CH3:26][C:27]1([NH2:31])[CH2:30][CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:24][O:23][C:17]1([C:20](=[O:22])[NH:31][C:27]2([CH3:26])[CH2:30][CH2:29][CH2:28]2)[CH2:16][CH2:15][N:14]([CH:9]2[CH2:8][CH:7]3[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[CH2:19][CH2:18]1
Reactant: CCOC(=O)N1C2CCC1CC(N1CCC(OC)(C(=O)O)CC1)C2
Reactant: CC1(N)CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)N1C2CCC1CC(N1CCC(OC)(C(=O)NC3(C)CCC3)CC1)C2
Temperature: 25 °C
Reaction time: 60 h
Yield: 25.4 %

Procedure:
1-[8-(Ethoxycarbonyl)-8-azabicyclo[3.2.1]oct-3-yl]-4-methoxypiperidine-4-carboxylic acid (0.093 g, assumed 0.27 mmol) was dissolved in DMF (5 mL) and (1-methylcyclobutyl)amine hydrochloride (0.05 g, 0.411 mmol), HATU (0.156 g, 0.41 mmol) and DIPEA (0.177 g, 0.24 mL, 1.37 mmol) were added. The reaction mixture was stirred at rt for 60 h and the solvents were removed in vacuo. The residue was partitioned between DCM and sat. NaHCO3 sol., the organic layer was washed with sat. NaCl sol. and dried (MgSO4). The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63 μm, 60 A, 25 mL per min, gradient 0% to 10% MeOH in DCM]) to give ethyl 3-{4-methoxy-4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-8-azabicyclo[3.2.1]octane-8-carboxylate isomer 1 (0.028 g, 25%) as a pale yellow gum.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][O:9][C:10]1[C:11]([N:16]=[C:17](SC)[S:18][CH3:19])=[N:12][CH:13]=[CH:14][N:15]=1.O>C(#N)C>[CH3:8][O:9][C:10]1[C:11]2[N:12]([C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:17]([S:18][CH3:19])[N:16]=2)[CH:13]=[CH:14][N:15]=1
Reactant: COc1nccnc1N=C(SC)SC
Reactant: CCOC(=O)CBr
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1c(SC)nc2c(OC)nccn12
Temperature: 100 °C
Reaction time: 14 h

Procedure:
Ethyl bromoacetate (18.5 mL) and iso-dipropylethylamine (29 mL) were added to a solution of methyl N-(3-methoxy-2-pyrazinyl)-(methylsulfanyl)methaneimidothioate (19.1 g) in acetonitrile (42 mL), and the mixture was heated under stirring at 100° C. for 14 hours. After the reaction mixture was cooled to room temperature, water was added thereto, which was extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and evaporated. The resulting residue was washed with n-hexane to give the title compound (10.7 g) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5](N)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C(O)(C)C.N([O-])=O.[Na+]>O>[Cl:1][C:2]1[CH:10]=[C:6]([CH:5]=[CH:4][CH:3]=1)[C:7]([OH:9])=[O:8]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: O=C(O)c1cccc(Cl)c1
Yield: 89 %

Procedure:
172 parts of 5-chloroanthranilic acid are introduced into 550 parts of 45 percent strength by weight sulfuric acid and 600 parts of isopropanol. A solution of 100 parts of sodium nitrite in 140 parts of water is run in at 80° C. over 6 hours; nitrogen is evolved. The mixture is cooled, 1,500 parts of water are added and the product is filtered off. 140 parts (89% of theory) of 3-chlorobenzoic acid of melting point 151°-153° C. are obtained.
Reaction SMILES: [CH:1]1([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7](I)=[N:6]2)[CH2:4][CH2:3][CH2:2]1.[C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:26]3[CH:25]=[C:24]4[C:29]([CH:30]=[CH:31][C:22]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[N:23]4)=[CH:28][CH:27]=3)=[N:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ncnc2c1c(I)nn2C1CCC1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)nn2C1CCC1
Temperature: 80 °C

Procedure:
Nitrogen was bubbled into a mixture of 1-cyclobutyl-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (60.0 mg, 0.190 mmol), 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (64.4 mg, 0.194 mmol), Na2CO3 (50.5 mg, 0.476 mmol), and Pd(PPh3)4 (13.7 mg, 0.0119 mmol) in DMF (4 mL)/water (1 mL) for 5 min, then the mixture was heated under nitrogen to 80° C. (bath temp.) for 17 h. The solvents were evaporated, water was added, the mixture was extracted with CH2Cl2 (3×20 mL), and the combined extracts were washed with brine and dried over MgSO4. MgSO4 was filtered off, and the filtrate was concentrated and chromatographed on an SCX column (1 g/6 mL barrel). The amine-containing fraction was adsorbed onto Hydromatrix and chromatographed on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with CH2Cl2 (1-11)→1% MeOH in CH2Cl2 (12-28)→2% MeOH in CH2Cl2 (29-46)], yielding the title compound as off-white solid. 1H NMR (CDCl3, 400 MHz): δ=1.87-2.04 (m, 2H), 2.48-2.58 (mc, 2H), 2.86-2.98 (mc, 2H), 5.50 (quint, J=8.0 Hz, 1H), 5.57 (brs, 2H), 7.47-7.52 (m, 1H), 7.53-7.58 (m, 2H), 7.96 (dd, J=1.6, 8.3 Hz, 1H), 7.97 (d, J=8.6 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 8.19-8.23 (m, 2H), 8.31 (d, J=8.6 Hz, 1H), 8.42 (s, 1H), 8.49-8.52 (m, 1H). 13C NMR (CDCl3, 100.6 MHz, DEPT135): δ=14.99 (−), 29.91 (2C, −), 50.61 (+), 98.68 (Cquart), 119.59 (+), 126.53 (+), 126.97 (Cquart), 127.56 (2C, +), 128.66 (+), 128.79 (2C, +), 129.00 (+), 129.53 (+), 134.83 (Cquart), 136.53 (+), 139.14 (Cquart), 143.40 (Cquart), 148.22 (Cquart), 154.00 (Cquart), 155.53 (+), 157.92 (Cquart), 158.18 (Cquart). MS (ES+): m/z 393.1 (53) [MH+]. HPLC: tR=3.1 min (OpenLynx, nonpolar—5 min), 3.6 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH2:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH:2]1[O:4][CH2:3]1.[Cl:10][C:11]1[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:12]=1[NH:18][C:19](=[O:30])[C@:20]([O:26][C:27](=[O:29])[CH3:28])([CH3:25])[C:21]([F:24])([F:23])[F:22]>C(OCC)C.FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O>[Cl:10][C:11]1[CH:16]=[C:15]([NH:17][CH2:3][CH:2]([OH:4])[CH2:1][O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH:14]=[CH:13][C:12]=1[NH:18][C:19](=[O:30])[C@:20]([O:26][C:27](=[O:29])[CH3:28])([CH3:25])[C:21]([F:24])([F:23])[F:22]
Reactant: CC(=O)O[C@](C)(C(=O)Nc1ccc(N)cc1Cl)C(F)(F)F
Reactant: CC(C)(C)OCC1CO1
Agent: [Cu+2]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCOCC
Product: CC(=O)O[C@](C)(C(=O)Nc1ccc(NCC(O)COC(C)(C)C)cc1Cl)C(F)(F)F
Reaction time: 40 h

Procedure:
t-Butyl glycidyl ether (0.19 ml) and copper(II) trifluoromethanesulphonate (0.018 g) were added to a solution of (R)-N-(2-chloro-4-aminophenyl)-2-acetoxy-2-methyl-3,3,3-trifluoropropanamide (0.325 g) (Method 32) in diethyl ether (5 ml). The mixture was stirred for 40 hours then volatile material was removed by evaporation and the residue was purified by chromatography to give the title compound (0.141 g) as a foam; MS (ESP−): 453.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[C:8]([CH:11]([CH3:13])[CH3:12])[CH:7]=[CH:6][C:5]=2[CH3:14].C([Li])CCC.[Cl-].[CH3:21][SiH:22]([CH3:36])[CH:23]1[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2.[Cl-].[NH4+]>CCOCC.CCCCCC>[CH3:21][Si:22]([CH3:36])([CH:3]1[C:4]2[C:9](=[C:8]([CH:11]([CH3:12])[CH3:13])[CH:7]=[CH:6][C:5]=2[CH3:14])[CH:10]=[C:2]1[CH3:1])[CH:23]1[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2
Reactant: C[SiH](C)C1c2ccccc2-c2ccccc21
Reactant: CC1=Cc2c(C(C)C)ccc(C)c2C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1=Cc2c(C(C)C)ccc(C)c2C1[Si](C)(C)C1c2ccccc2-c2ccccc21
Temperature: -78 °C
Yield: 46 %

Procedure:
A 100 ml four-necked flask equipped with a reflux tube, a thermometer and a dropping funnel was thoroughly purged with nitrogen and dried. To the flask, 2-methyl-4-i-propyl-7-methylindene (1.50 g, 8.06 mmol) and dehydrated ether (25 ml) were introduced. Under stirring at −78° C., a hexane solution of n-butyllithium (8.46 mmol) was dropwise added. After the dropwise addition, the temperature of the system was allowed to spontaneously and slowly rise to room temperature. The reaction mixture was stirred at room temperature over night, whereby a colourless solution came, through a white slurry and a light yellow slurry, to a yellow slurry. To the slurry, the dimethyl(9-fluorenyl)silane chloride (2.06 g, 8.06 mmol) synthesized above was added under stirring at 0° C., followed by stirring at room temperature for 1.5 hours. After ether (100 ml) and a saturated ammonium chloride aqueous solution (100 ml) were added, the resulting mixture was introduced into a separatory funnel to separate out an organic phase. The organic phase was washed with a saturated ammonium chloride aqueous solution, water and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After the solvent was removed, the obtained product (a yellow oil) was purified by column chromatography (developer: hexane) to obtain 1.50 g so a yellow oil (yield: 46%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([CH:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:12]([O:14]CC)=O)=[O:10].S(=O)(=O)(O)[OH:30].[OH-].[Na+]>C(O)C>[CH2:17]([C:11]1[C:12](=[O:14])[C:4]2[C:3]([C:8](=[O:30])[C:9]=1[OH:10])=[C:2]([CH3:1])[CH:7]=[CH:6][CH:5]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCC(C(=O)Cc1ccccc1C)C(=O)OCC
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCC1=C(O)C(=O)c2c(C)cccc2C1=O
Temperature: 25 °C
Reaction time: 66 h

Procedure:
Four parts of crude ethyl 2-[(2-methylphenyl)acetyl]tetradecanoate obtained in Example 3 was combined with 12 parts of cold concentrated sulfuric acid and stirred at room temperature for 66 hours. The mixture was poured into ice water and made slightly basic by the addition of 50% aqueous sodium hydroxide. Enough ethanol was added to dissolve the organic matter and air was then bubbled through the solution for 3 hours. The resulting solution was extracted with 100 parts petroleum ether (twice), acidified with hydrochloric acid and re-extracted with diethylether. The ether extract was washed with saturated sodium chloride, dried over magnesium sulfate and evaporated. The residue was taken up in acetonitrile and filtered. The filtrate was evaporated to dryness and the residue triturated with petroleum ether to give 0.2 g of 2-dodecyl-3-hydroxy-5-methyl-1,4-naphthoquinone, m.p. 92°-93° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:25][NH:26][O:27][CH3:28].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:4]([O:3][C:1]([NH:8][C@@H:9]([CH3:10])[C:11]([N:26]([O:27][CH3:28])[CH3:25])=[O:13])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CNOC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 81.5 %

Procedure:
To a solution of Boc-alanine (20 grams, 105.7 mmol) in dichloromethane (170 ml) was added HOBT (14.28 g, 105.7 mmol) and N,O-dimethylhydroxylamine hydrochloride (10.31 g, 105.7 mmol). The mixture was chilled with an ice water bath then triethylamine (30 ml, 211.4 mmol) and 1,3-dicyclohexylcarbodiimide (21.81 g, 105.7 mmol) were added. The reaction was stirred in the ice water bath for 1 hour and then allowed to warm to room temperature overnight. The crude reaction was then chilled in an ice water bath and the precipitate filtered. The resulting organic solution was then washed twice with 1N aqueous sodium hydroxide (50 mL), twice with 10% aqueous citric acid (50 mL), and once with brine. The solution was then dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. The resulting residue was purified by chromatography on a normal phase silica gel column with 30-100% ethyl acetate in hexanes. Fractions containing clean product were combined and the solvent evaporated to give the title compound (20 g, 81%): ES-MS (m/z) 233.2 [M+1]+.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)=[CH:16][CH:15]=1.C(N(CC)CC)C>C(#N)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]2[CH2:25][CH2:24][CH2:23][N:22]([CH2:2][CH:3]3[O:8][C:7]4[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=4[O:5][CH2:4]3)[CH2:21]2)=[CH:18][CH:19]=1
Reactant: Clc1ccc(C2CCCNC2)cc1
Reactant: BrCC1COc2ccccc2O1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Clc1ccc(C2CCCN(CC3COc4ccccc4O3)C2)cc1
Temperature: 130 °C
Yield: 69.8 %

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (34 mg, 0.15 mmol), 3-(4-chloro-phenyl)piperidine (38 mg, 0.165 mmol) and triethylamine (38 mg, 0.38 mmol) in acetonitrile (2 ml) was heated in a microwave reactor at 110-150° C. for 290 min. After evaporation to dryness, the crude product was purified by flash chromatography using a gradient of heptane and EtOAc as eluent to give 36 mg of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[N:16]=[C:15]([N:17]4[CH2:22][CH2:21][CH2:20][C@H:19]([NH:23][C:24](=[O:26])[OH:25])[CH2:18]4)[C:14]([C:27]#[N:28])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.C[Sn](C)(C)[C:31]1[CH:36]=[N:35][CH:34]=[C:33]([CH3:37])[N:32]=1>>[C:27]([C:14]1[C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@H:19]([NH:23][C:24](=[O:26])[O:25][C:5]([CH3:8])([CH3:6])[CH3:4])[CH2:18]2)=[N:16][C:11]([N:10]2[C:4]3[CH:3]=[C:2]([C:31]4[CH:36]=[N:35][CH:34]=[C:33]([CH3:37])[N:32]=4)[N:7]=[CH:6][C:5]=3[CH:8]=[N:9]2)=[CH:12][CH:13]=1)#[N:28]
Reactant: N#Cc1ccc(-n2ncc3cnc(Cl)cc32)nc1N1CCC[C@H](NC(=O)O)C1
Reactant: Cc1cncc([Sn](C)(C)C)n1
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C#N)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)n1
Temperature: 150 °C
Yield: 188.1 %

Procedure:
A mixture of [(3S)-1-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)-3-cyano-2-pyridyl]-3-piperidyl]carbamic acid (0.5166 mmol; 205.5 mg), trimethyl-(6-methylpyrazin-2-yl)stannane (0.7749 mmol; 199.1 mg), and palladium(0)tetrakis (triphenylphosphine); (0.05166 mmol; 59.8 mg) in N,N-Dimethylacetamide (12 mL) was purged with Argon. The reaction mixture was sealed in a pressure vial and heated at 150° C. for 2 hours. The mixture was cooled to room temperature, and then partitioned between EtOAc and water. The organic layer was concentrated and the residue was purified on silica eluted with 0 to 5% MeOH in DCM to afford tert-butyl N-[(3S)-1-[3-cyano-6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate as a yellow solid (248.6 mg, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH2:18]P(=O)(OCC)OCC)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:35])[N:13]2[C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:34].[H-].[Na+].[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH:18]=[C:48]2[CH2:49][CH2:50][N:45]([C:43]([O:42][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:44])[CH2:46][CH2:47]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:35])[N:13]2[C:27]1[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:34]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(Cc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of diethyl [5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]methylphosphonate (422 mg, 0.762 mmol) in a mixture of THF (9 mL) and DMF (2 mL) at 0° C. was added sodium hydride (60%, 61 mg, 1.52 mmol). The resulting mixture was stirred at rt for 20 min and then cooled to 0° C. again. To this was added a solution of t-butyl-4-oxo-1-piperidinecarboxylate (310 mg, 1.524 mmol) in THF (2 mL). Then the reaction was stirred at rt for 22 h. The mixture was quenched with brine, and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. Removal of the solvent and subsequent purification by flash chromatography using 20% acetone/hexane as eluent provided tert-butyl 4-{[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]methylene}piperidine-1-carboxylate as a white solid. 1H NMR (CDCl3, 500 MHz): δ 1.48 (s, 9H), 2.24 (brs, 2H), 2.31 (t, 2H, J=5.7 Hz), 3.31 (t, 2H, J=5.5 Hz), 3.45 (t, 2H, J=5.5 Hz), 4.35 (abq, 2H, J=14.4 Hz), 5.10 (s, 1H), 5.96 (s, 1H), 6.21 (s, 1H), 6.74 (s, 1H), 7.30-7.58 (m, 7H). MS (API-ES+): 600 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:17]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
4'-Hydroxyacetophenone (40g) and potassium carbonate (60.9 g) were mixed in dimethyl formamide (250 ml). Benzyl bromide (36.7 ml) was added dropwise to the mixture, and the mixture was stirred at room temperature for 1 hour and further at 50° to 60° C. for 1 hour. The reaction mixture was poured into ice-water, and the precipitating crystals were collected by filtration and recrystallized from methanol to give 4'-benzyloxyacetophenone (55.4g, 83.3%). m.p. 93°-94° C.