Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][C:6]#[N:7])C.Cl.Cl.[CH:13]1([NH:16][NH2:17])[CH2:15][CH2:14]1>C(O)C>[CH:13]1([N:16]2[C:6]([NH2:7])=[CH:5][CH:4]=[N:17]2)[CH2:15][CH2:14]1
Reactant: CCOC(CC#N)OCC
Reactant: NNC1CC1
Agent: Cl
Solvent: CCO
Product: Nc1ccnn1C1CC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 39.9 %

Procedure:
A 100-mL round-bottom flask was charged with 3,3-diethoxypropanenitrile (0.600 g, 4.19 mmol), cyclopropylhydrazine di-hydrochloride (0.610 g, 4.21 mmol) and ethanol (20 mL), and the resulting solution stirred for 18 h at 80° C. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 10:1, dichloromethane/methanol) to afford 1-cyclopropyl-1H-pyrazol-5-amine (0.206 g, 36%) as light yellow oil. MS (ESI, pos. ion) m/z 124 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([O:18]C)=[O:17])=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([OH:18])=[O:17])=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C(C)NC(=O)CC1c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1=C(C(=O)O)C(c2ccc(Cl)cc2)CC(=O)N1
Temperature: 60 °C
Reaction time: 16 h
Yield: 70.7 %

Procedure:
The product from Step 1 (735 mg, 2.63 mmol, 1.00 equiv) was dissolved in 3/1 MeOH:THF (12 mL total). Following addition of 2.5N NaOH (3 mL), the reaction mixture was heated to 60° C. for 6 hours, then stirred at room temperature for an additional 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed again with 1N NaOH. The aqueous phases were combined and acidified to pH˜1 with 5N HCl, and extracted twice with ethyl acetate. The combined organic extracts were washed with satd. NaCl, dried over Na2SO4, and filtered. The filtrate was concentrated en vacuo and azeotroped several times with hexanes to afford 494 mg (71%) of the acid as an off-white solid. MS (ES+) m/e 266 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[C:4]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[N:3]=1.[Cl:21][C:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[CH:24][N:23]=1>>[Cl:21][C:22]1[CH:27]=[C:26]([C:2]2[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[C:4]([C:11]3[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=3)[N:3]=2)[CH:25]=[CH:24][N:23]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)nc2)nc(Cl)n1
Product: FC(F)c1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2ccnc(Cl)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example A.3) (2.0 g, 6.46 mmol) and commercially available 2-chloro-pyridine-4-boronic acid (1.12 g, 7.12 mmol) according to the general procedure IIb. Obtained as an off-white solid (0.6 g, 24%). MS (ISP) 387.1 [(M+H)+]; mp 185° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][OH:12])=[N:2]1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22])=[N:2]1
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1noc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1noc2ccccc12
Reaction time: 1 h
Yield: 103.1 %

Procedure:
To a solution of 2-benzo[d]isoxazol-3-yl-ethanol (0.537 g, 3.29 mmol, from step (i) above ) and triethylamine (0.55 mL, 3.95 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (0.31 mL, 3.95 mmol) at 0° C. The reaction mixture was stirred for 1 hour and was then extracted with water (2×20 mL) and brine (20 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo, which afforded 818 mg (98%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([C@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Br[C:16]1[CH:17]=[C:18]2[N:27]([CH3:28])[CH:26]=[CH:25][C:19]2=[N:20][C:21]=1[C@@H:22]([NH2:24])[CH3:23].CC([O-])(C)C.[K+].C([O-])(O)=O.[Na+]>CCOC(C)=O.O1CCOCC1>[NH2:24][C@H:22]([C:21]1[N:20]=[C:19]2[CH:25]=[CH:26][N:27]([CH3:28])[C:18]2=[CH:17][C:16]=1[N:12]1[CH2:13][CH2:14][C@H:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7])[CH2:11]1)[CH3:23]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCNC1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1Br
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@H](N)c1nc2ccn(C)c2cc1N1CC[C@H](N(C)C(=O)OC(C)(C)C)C1
Temperature: 90 °C
Yield: 49.3 %

Procedure:
To a 50 mL pear flask were added (S)-tert-butyl methyl(pyrrolidin-3-yl)carbamate (235 mg, 1.173 mmol) and (S)-1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (166 mg, 0.652 mmol). After evacuating the flask and flushing it with nitrogen, the flask was charged with dioxane (1.7 mL) and potassium 2-methylpropan-2-olate (1.0 M in THF, 1.4 mL, 1.4 mmol). The mixture was then heated to 90° C. for 1 hour. After cooling, the mixture was worked up with saturated NaHCO3 and EtOAc. The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (acid mode, 25-50% ACN/water). The product-containing fractions were neutralized with a small amount of saturated NaHCO3, concentrated in vacuo to remove ACN, and then extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound (120 mg, 49.0%). ESI-MS m/z [M+H]+ calc'd for C20H31N5O2, 374. found 374.
Reaction SMILES: C([O:4][CH2:5][CH:6]([CH3:22])[CH:7]([C:9]1[CH:21]=[CH:20][C:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[Cl:8])(=O)C.C[O-].[Na+].C(O)(=O)C>CO.C(OCC)(=O)C>[Cl:8][CH:7]([C:9]1[CH:21]=[CH:20][C:12]([CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[CH:6]([CH3:22])[CH2:5][OH:4]
Reactant: CC(=O)OCC(C)C(Cl)c1ccc(Cc2cccnc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(CO)C(Cl)c1ccc(Cc2cccnc2)cc1
Yield: 62.3 %

Procedure:
In 10 ml of methanol was dissolved 740 mg of 3-[p-(3-acetoxy-1-chloro-2-methylpropyl)benzyl]pyridine, and to the resulting solution was added 40 mg of sodium methoxide with ice-cooling, after which the resulting mixture was subjected to reaction at room temperature for 30 minutes. To the reaction mixture was added 0.1 ml of acetic acid, and the solvent was removed by distillation under reduced pressure, after which the residue thus obtained was dissolved in 10 ml of ethyl acetate. The resulting solution was washed with 5 ml of water and then dried over anhydrous magnesium sulfate. The residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: benzene:ethyl acetate (1:1 by volume)] to obtain 400 mg (yield 62.3%) of colorless, oily 3-[p-(1-chloro-3-hydroxy-2-methylpropyl)benzyl]pyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)[CH2:12][CH:13]=2)=[CH:4][CH:3]=1.[ClH:26].C(O)C.[OH-].[Na+]>C(OCC)(=O)C.[Fe].O>[ClH:26].[ClH:26].[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH2:14][N:11]2[CH2:10][CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:13][CH2:12]2)=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(OCCN2CC=C(c3ccc(F)cc3)CC2)cc1
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(OCCN2CC=C(c3ccc(F)cc3)CC2)cc1

Procedure:
0.2 g. of powdered iron is added to a solution of 0.34 g. of 4-(p-fluorophenyl)-1,2,3,6-tetrahydro-1-[2-(p-nitrophenoxy) ethyl]pyridine in a mixture of 2 ml. of 1N hydrochloric acid, 10 ml. of ethanol and 10 ml. of water. The mixture is refluxed for 4 hrs., cooled and made alkaline by addition of 1N sodium hydroxide. After addition of 20 ml. of chloroform and celite, the mixture is filtered. The organic phase is separated, dried and evaporated. The oily residue obtained is dissolved in ethyl acetate and converted to the hydrochloride by addition of ethanolic hydrogen chloride. The 1-[2-(p-aminophenoxy)ethyl]-4-(p-fluorophenyl)-1,2,3,6-tetrahydropyridine dihydrochloride obtained in this way has m.p. 180°-181° after recrystallization from ethanol/ethylacetate/ether.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]([S:27]([C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=1)(=[O:29])=[O:28])[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19](=[O:22])[NH:20][CH3:21])[CH2:14][CH:13]2[C:23]([O:25]C)=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl.[Cl-].[Na+]>O1CCCC1.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([CH2:8][N:9]([S:27]([C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=1)(=[O:28])=[O:29])[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19](=[O:22])[NH:20][CH3:21])[CH2:14][CH:13]2[C:23]([OH:25])=[O:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CNC(=O)N1CC(C(=O)OC)c2cc(N(CC(=O)OC(C)(C)C)S(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc21
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)N1CC(C(=O)O)c2cc(N(CC(=O)OC(C)(C)C)S(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg methyl 5-[tert-butoxycarbonylmethyl-(3,5-dichloro-phenylsulphonyl)-amino]-1-methylcarbamoyl-2,3-dihydro-1H-indole-3-carboxylate are dissolved in 1.2 ml of tetrahydrofuran, combined with 349 μl of a 1 M solution of lithium hydroxide in water and stirred overnight at ambient temperature. Then the mixture is cooled to 0° C., combined with 350 μl 1 M hydrochloric acid and divided between ethyl acetate and saturated sodium chloride solution. The organic phase is dried on magnesium sulphate and the solvents are eliminated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol 20:1).
Reaction SMILES: [F:1][C:2](=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](O)=[O:4].S(Cl)([Cl:15])=O>ClCCl>[F:1][C:2](=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([Cl:15])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(F)=Cc1ccccc1
Solvent: ClCCl
Product: O=C(Cl)C(F)=Cc1ccccc1
Temperature: 50 °C

Procedure:
Fluorocinnamic acid (10 g, 0.06 mole) was dissolved in dichloromethane, and 8.59 g (0.07 mole) of thionylchloride was added dropwise to the solution. After the acid dissolved and the solution appeared clear, the reaction mixture was maintained at about 50° C. for 1 hour. The solvent and unreacted thionylchloride were removed at a reduced pressure and further the solvent was completely removed at a high vacuum pressure to give fluorocinnamoyl chloride. The fluorocinnamoyl chloride was dissolved in dried dichloromethane. A mixture of polyhydroxystyrene having a molecular weight of 22,000 and 6.07 g (0.06 mole) of triethylamine was dissolved in dichloromethane and a small amount of tetrahydrofuran. To this solution, the fluorocinnamoyl chloride solution was added dropwise while the temperature was maintained at 0° C. After keeping for 1 day, the resulting solution was washed with water to remove the solvent and amine salt. Polyhydroxystyrenylfluorocinnamate was obtained.
Reaction SMILES: O=[C:2]1[C:11]2[N:12]=[CH:13][N:14]=[CH:15][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:16]([O:18][CH3:19])=[O:17])=[CH:5][C:4]=2[NH:3]1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:31].O>C1(C)C=CC=CC=1>[Cl:31][C:2]1[C:11]2[N:12]=[CH:13][N:14]=[CH:15][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:16]([O:18][CH3:19])=[O:17])=[CH:5][C:4]=2[N:3]=1
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)c1ncncc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)nc(Cl)c1ncncc12
Temperature: 120 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
In a vial, methyl 5-oxo-5,6-dihydropyrimido[4,5-c]quinoline-8-carboxylate (1.0 eq, 151 mg, 0.59 mmol) was mixed in toluene (1 ml) with DIEA (1.5 eq, 155 ul, 0.89 mmol) and POCl3 (5 eq, 270 ul, 3.0 mmol). The mixture was stirred at 120° C. for 1 hour and cooled down to room temperature. After adding ice and water the compound was extracted with CH2Cl2 (4×). The solution was filtered over Na2SO4 and filtered through a pad of celite. After evaporation of the volatiles, the material was triturated in a mixture of ethyl acetate and hexanes, filtered and dried to afford methyl 5-chloropyrimido[4,5-c]quinoline-8-carboxylate as a light brown fluffy solid (115 mg, 71% yield). LCMS (ES): 95% pure, m/z 274 [M+1]+. 1H NMR (DMSO-d6, 400 MHz) δ 3.96 (s, 3H), 8.37 (dd, J=1.6, J=8.4, 1H), 8.60 (d, J=1.6, 1H), 9.15 (d, J=8.8, 1H), 9.74 (s, 1H), 10.61 (s, 1H) ppm
Reaction SMILES: [OH:1][C@@H:2]([C:4]1[N:15]([C@@H:16]2[CH2:21][O:20][C@@H:19]([CH2:22][C:23]#[N:24])[CH2:18][CH2:17]2)[C:7]2=[C:8]3[S:14][CH:13]=[CH:12][C:9]3=[N:10][CH:11]=[C:6]2[N:5]=1)[CH3:3].C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:2]([C:4]1[N:15]([C@@H:16]2[CH2:21][O:20][C@@H:19]([CH2:22][C:23]#[N:24])[CH2:18][CH2:17]2)[C:7]2=[C:8]3[S:14][CH:13]=[CH:12][C:9]3=[N:10][CH:11]=[C:6]2[N:5]=1)(=[O:1])[CH3:3]
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)OC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)OC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 163.2 %

Procedure:
To a solution of ((2R,5S)-5-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}tetrahydro-2H-pyran-2-yl)acetonitrile (154 mg, 0.450 mmol) in methylene chloride (2.0 mL) was added sodium bicarbonate (110 mg, 1.31 mmol) followed by Dess-Martin periodinane (219 mg, 0.517 mmol). The resulting mixture was stirred at room temperature for 3 h. The mixture was diluted with dichloromethane, filtered, and concentrated. The crude was purified on silica gel, eluted with 0-10% MeOH in dichloromethane to give 250 mg of crude product as a white gum. LCMS calculated for C17H17N4O2S (M+H)+: m/z=341.1. Found: 341.0 (M+H). 1H NMR (400 MHz, CDCl3) δ 9.23 (s, 1H), 7.77 (s, 2H), 4.52 (t, J=11.1 Hz, 1H), 4.07 (dd, J=10.1 and 4.4 Hz, 2H), 2.92-2.81 (m, 3H), 2.70-2.64 (m, 2H), 2.21-2.09 (m, 2H), 1.83 (qd, J=13.4 and 4.7 Hz, 1H), 1.62 (s, 2H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([O:21]C)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:23][CH:24]([CH3:26])[CH3:25])[CH:3]=1.[OH-].[Li+].Cl>C1COCC1.CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:23][CH:24]([CH3:26])[CH3:25])[CH:3]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)C)c2c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC(C)C)c12
Reaction time: 8 h

Procedure:
Methyl 4-(4-fluoro-2-isopropoxyphenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylate (451 mg) and lithium hydroxide (865 mg) was dissolved in a mixture of THF: methanol:water (1:1:1; 100 ml) and was stirred at room temperatruer overnight. Then the mixture was acidified with conc. HCl, the resultant precipitate was filtered, dried and triturated with diisopropyl ether to afford the title compound.
Reaction SMILES: P(OC1C=CC=CC=1)(OC1C=CC=CC=1)(O[C:4]1[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15](OC(F)(F)F)=[CH:14][CH:13]=2)[C:6](=[O:10])[CH2:7][CH2:8][CH:9]=1)=O.[F:37][C:38]([F:50])([F:49])[O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O>>[F:37][C:38]([F:50])([F:49])[O:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:4][N:5]2[CH:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[O:39][C:38]([F:50])([F:49])[F:37])[CH2:9][CH2:8][CH2:7][C:6]2=[O:10])=[CH:42][CH:41]=1
Reactant: O=C1CCC=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)N1Cc1ccc(OC(F)(F)F)cc1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Product: O=C1CCCC(c2ccccc2OC(F)(F)F)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 9 (GP9) with 6-oxo-1-(4-(trifluoromethoxy)benzyl)-1,4,5,6-tetrahydropyridin-2-yl diphenyl phosphate and commercially available (2-(trifluoromethoxy)phenyl)boronic acid. Subsequent hydrogenation and purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.83 min.; [M+H]+: 433.70 g/mol.
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:35][CH:34]3[N:36](C(OC(C)(C)C)=O)[CH:31]([CH2:32][CH2:33]3)[CH2:30]2)[C:9]=1[C:44]([O:46]CC)=[CH2:45].[ClH:59]>O1CCOCC1.O>[NH2:7][C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:29]2[CH2:35][CH:34]3[NH:36][CH:31]([CH2:32][CH2:33]3)[CH2:30]2)[C:9]=1[C:44](=[O:46])[CH3:45].[ClH:59]
Reactant: C=C(OCC)c1c(C2CC3CCC(C2)N3C(=O)OC(C)(C)C)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)c1c(C2CC3CCC(C2)N3)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a mixture of tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.1 g, 1.3 mmol) in dioxane (7 mL) was added 4 M HCl in water (2.6 ml) at 0° C. After stirring for 10 min at 0° C., 4 M HCl in dioxane (2.6 mL) was added. The reaction mixture was stirred at 0° C. for 30 min and the cooling bath was removed to warm it up to room temperature for 15 h, at which time LC/MS analysis confirmed full consumption of starting material. The solvent was removed in vacuo to get the desired product as an HCl salt.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16](F)=[O:17])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[CH2:30][OH:31])[C:23](=[N:25]O)[NH2:24].CCN(C(C)C)C(C)C>C(#N)C.ClCCl>[F:19][C:20]1[CH:21]=[C:22]([C:23]2[N:25]=[C:16]([C:10]3[O:9][N:8]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:11]=3[C:12]([F:15])([F:14])[F:13])[O:17][N:24]=2)[CH:27]=[CH:28][C:29]=1[CH2:30][OH:31]
Reactant: NC(=NO)c1ccc(CO)c(F)c1
Reactant: O=C(F)c1onc(-c2ccccc2)c1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: ClCCl
Product: OCc1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1F
Temperature: 25 °C
Yield: 50.1 %

Procedure:
A heterogeneous mixture of 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride (1-E, 0.973 g, 3.75 mmol), 3-fluoro-N′-hydroxy-4-(hydroxymethyl)benzimidamide (0.691 g, 3.75 mmol), and Hunig's Base (0.852 mL, 4.88 mmol) in acetonitrile (7 mL) was stirred at room temperature over the weekend. The reaction mixture was diluted with dichloromethane, washed with a saturated aqueous solution of sodium bicarbonate, and dried over anhydrous sodium sulfate. The dichloromethane was removed under reduced pressure to give an orange oily residue which was purified by flash silica gel chromatography using a 20% mixture of ethyl acetate in hexane to give (2-fluoro-4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)methanol (0.762 g, 1.88 mmol, 50% yield) as a pale yellow solid. The compound had an HPLC ret. time=3.33 min.−Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. MS M+1=406.1.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:23])[CH2:4][C@@:5]23[CH2:18][CH2:17][N:16]([CH3:19])[C@@H:13]([C@@H:14]2[CH:15]=1)[CH2:12][C:11]1[CH:10]=[CH:9][C:8]([O:20][CH3:21])=[C:7]([OH:22])[C:6]3=1.[NH4+].[Cl-].[NH4+].[OH-].[CH2:28](Cl)Cl>CCOCC>[OH:22][C:7]1[C:6]2[C@:5]34[CH2:18][CH2:17][N:16]([CH3:19])[C@@H:13]([C@@H:14]3[C@@H:15]([CH3:28])[C@H:2]([CH3:1])[C:3](=[O:23])[CH2:4]4)[CH2:12][C:11]=2[CH:10]=[CH:9][C:8]=1[O:20][CH3:21]
Reactant: ClCCl
Reactant: COc1ccc2c(c1O)[C@]13CCN(C)[C@H](C2)[C@@H]1C=C(C)C(=O)C3
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Product: COc1ccc2c(c1O)[C@]13CCN(C)[C@H](C2)[C@@H]1[C@@H](C)[C@H](C)C(=O)C3
Reaction time: 1 h

Procedure:
Compound 14 (20.0 g, 64 mmole) in methylene chloride (400 ml) was added to a solution of lithium dimethyl cuprate (165 mmole) prepared in ether (800 ml) with cooling in an ice-salt bath under an argon atmosphere. The mixture was stirred at this temperature for 1 hour after which it was poured into saturated NH4Cl solution (1 liter). After the addition of concentrated NH4OH to pH~12 and stirring for 30 minutes, the organic phase was separated and washed twice with dilute NH4OH. The aqueous phase was extracted with additional methylene chloride and the combined organic phases dried and evaporated to give a quantitative yield of 16b as a thick syrup, NMR: δ 6.63, s, 2H (aromatic); 4.25, d, 1H (H-5α, J=13H); 3.80 (CH3O--); 2.43 (CH3N--); 1.08; unsymmetrical t, 3H (8β-CH3, J=6H); 0.90, symmetrical d, 3H (7α-CH3, J=6H). A portion of this material was converted to the hydrochloride salt by dissolving the syrupy free base in ethanol and adding excess concentrated HCl. The solution was evaporated to dryness and the residue azeotroped with ethanol, 1:1 V/V ethanol:benzene, then benzene. The residue was crystallized from ethyl acetate to give 16b HCl, mp 259°-262°.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Cl)=[CH:7][N:6]=1.O>C(#N)C>[Cl:4][C:5]1[N:6]=[CH:7][C:8]([CH2:11][NH:3][CH:1]=[CH2:2])=[CH:9][CH:10]=1
Reactant: CCN
Reactant: ClCc1ccc(Cl)nc1
Solvent: CC#N
Solvent: O
Product: C=CNCc1ccc(Cl)nc1

Procedure:
To a solution of aqueous ethylamine, an appropriate amount of acetonitrile is, added. Then 2-chloro-5-(chloromethyl)pyridine in acetonitrile is added dropwise in ice bath. The reaction is monitored by TLC. After completion, the mixture is added large amount of water, extracted by DCM, dried, filtered and evaporated to obtain N-((6-chloropyridin-3-yl)methyl)ethenamine as oil.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:3]=1[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.O=P(Cl)(Cl)[Cl:35]>>[Cl:35][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:3]=1[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1ccc2nc(-c3ccc(OC)cc3)c(-c3ccc(OC)cc3)c(O)c2c1
Product: CCOC(=O)c1ccc2nc(-c3ccc(OC)cc3)c(-c3ccc(OC)cc3)c(Cl)c2c1
Yield: 77 %

Procedure:
A solution of ethyl 4-hydroxy-2,3-bis(4-methoxyphenyl)quinoline-6-carboxylate (1 g, 2.33 mmol, 1.00 equiv) in POCl3 (10 mL) was heated to reflux for 4 h in an oil bath. The resulting mixture was concentrated under vacuum, then diluted with 30 mL of ethyl acetate, and washed with 1×50 mL of sodium bicarbonate (aq.). The organic layer was concentrated under vacuum and purified by column chromatography (ethyl acetate/petroleum ether (1:10)) yielding 0.8 g (77%) of ethyl 4-chloro-2,3-bis(4-methoxyphenyl)quinoline-6-carboxylate as a yellow solid.