Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([O-])(C)C.[K+].[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](OCC)=O)=[CH:11][CH:10]=1)[CH3:8].[Br:21][C:22]1[CH:27]=C(F)[C:25]([C:29]#[N:30])=[C:24]([F:31])[CH:23]=1.Cl>CN1C(=O)CCC1>[Br:21][C:22]1[CH:27]=[C:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([CH2:7][CH3:8])=[CH:14][CH:13]=2)[C:25]([C:29]#[N:30])=[C:24]([F:31])[CH:23]=1
Reactant: CCOC(=O)Cc1ccc(CC)cc1
Reactant: N#Cc1c(F)cc(Br)cc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCc1ccc(Cc2cc(Br)cc(F)c2C#N)cc1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
KOtBu (6.7 g) is added to a flask charged with a stir bar and dry NMP (30 mL) and chilled to −10° C. under argon atmosphere. A solution of ethyl (4-ethyl-phenyl)-acetate (5.6 g) and 1-bromo-4-cyano-3,5-difluoro-benzene (6.4 g) in NMP (20 mL) is added at such a rate that the solution temperature maintains below 10° C. After stirring for 1 hour at 10° C., the solution is neutralized with 1 M aqueous hydrochloric acid and extracted with ethyl acetate. The combined extracts are dried (Na2SO4) and the solvent is evaporated. The residue is dissolved in THF (20 mL) and treated with 1M aqueous NaOH solution (80 mL). After stirring overnight at room temperature, the solution is acidified with 4 M HCl solution and extracted with ethyl acetate. The organic extracts are combined and dried (Na2SO4) and the solvent is evaporated. The residue is dissolved in DMF (25 mL) and K2CO3 (5.5 g) is added. The resulting mixture is stirred at 100° C. for 1 h. After cooling to room temperature, the mixture is neutralized with 1 M aqueous hydrochloric acid and the resultant mixture is extracted with ethyl acetate. The combined organic extracts are dried (MgSO4) and the solvent is evaporated. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 1:0->1:1).
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]1(/[CH:28]=[CH:29]/[CH:30]=[O:31])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([CH2:28][CH:29]2[C:30](=[O:31])[O:13][C:12]3[NH:11][C:10]([C:14]4[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=4[F:21])=[N:9][C:8]=3[CH:1]2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Reactant: O=C/C=C/C1CCCCC1
Product: O=C1Oc2[nH]c(-c3cc(F)ccc3F)nc2C(c2ccccc2)C1CC1CCCCC1
Reaction time: 72 h
Yield: 56 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and (E)-3-cyclohexylacrylaldehyde. After 72 h, the reaction only reached 64% conversion by 1H NMR. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 19 as an off-white solid (71 mg, 56%). Analytical data for 19: 1H NMR (500 MHz, CDCl3) δ 9.45 (d, J=8.3 Hz, 1H), 7.90 (ddd, J=9.2, 6.1, 3.2 Hz, 1H), 7.36-7.27 (m, 3H), 7.13-7.04 (m, 3H), 7.01-6.93 (m, 1H), 4.24 (d, J=6.9 Hz, 1H), 3.29 (q, J=6.9 Hz, 1H), 1.74-1.61 (m, 6H), 1.49-1.40 (m, 1H), 1.29-1.18 (m, 2H), 1.18-1.04 (m, 2H), 0.91-0.81 (m, 2H); 13C NMR (CDCl3, 126 MHz) δ 169.5, 159.1 (d, JCF=243.4 Hz), 155.4 (dd, JCF=240.8, 2.1 Hz), 149.3, 137.3, 136.3, 129.2, 128.1, 127.7, 118.5 (dd, JCF=12.9, 9.1 Hz), 117.1 (dd, JCF=25.7, 8.7 Hz), 116.5 (dd, JCF=24.7, 9.5 Hz), 114.5 (dd, JCF=27.0, 3.8 Hz), 110.6 (d, JCF=3.9 Hz), 43.0, 39.6, 34.6, 34.4, 33.4, 32.8, 26.4, 26.2, 26.1; IR (film) cm−1 2923, 2851, 1770, 1637, 1619, 1529, 1481, 1463, 1450, 1387, 1172, 1115, 1094, 881, 812, 766, 737, 700; LRMS (ESI): Mass calcd for [M+H]+ C25H25F2N2O2: 423.2. found 423.4; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel OD-H; 15% IPA/hexanes 0.7 mL/min, 280 nm), Rt1 (major)=9.1, Rt2 (minor)=25.0 min; er=98:2.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C:9]1[CH:10]=[C:11]([NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[N:20]=2)[C:12]([C:15]([NH2:17])=[O:16])=[N:13][CH:14]=1.[CH2:27]([N:29]=[C:30]=[O:31])[CH3:28].C(N(CC)CC)C>C1COCC1>[CH3:25][C:23]1[CH:22]=[C:21]([CH3:26])[N:20]=[C:19]([NH:18][C:11]2[C:12]([C:15]([NH2:17])=[O:16])=[N:13][CH:14]=[C:9]([NH:8][C:30](=[O:31])[NH:29][CH2:27][CH3:28])[CH:10]=2)[CH:24]=1
Reactant: CCN=C=O
Reactant: Cc1cc(C)nc(Nc2cc(N)cnc2C(N)=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cnc(C(N)=O)c(Nc2cc(C)cc(C)n2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-amino-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide TFA salt (50 mg, 0.13 mmol) in THF (1 mL) was added ethyl isocyanate (12 mg, 0.18 mmol) and triethylamine (0.075 mL, 0.54 mmol), and the reaction mixture was stirred for 2 hours at room temperature. Additional ethyl isocyanate (12 mg, 0.18 mmol) and triethylamine (0.075 mL, 0.54 mmol) were added, and the reaction mixture was heated to 55° C. for 18 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to afford 3-[(4,6-dimethylpyridin-2-yl)amino]-5-[(ethylcarbamoyl)amino]pyridine-2-carboxamide. MS ESI calc'd. for C16H21N6O2 [M+H]+ 329. found 329. 1H NMR (500 MHz, DMSO-d6) δ 11.61 (s, 1H), 9.24 (s, 1H), 8.86 (s, 1H), 8.23 (d, J=2.2 Hz, 1H), 8.13 (s, 1H), 7.57 (s, 1H), 6.63 (s, 1H), 6.53 (s, 1H), 6.33 (t, J=5.3 Hz, 1H), 3.20-3.07 (m, 2H), 2.40 (s, 3H), 2.23 (s, 3H), 1.06 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl.[C:2]([N:6]1[CH2:9][C:8](CO)([N+:10]([O-:12])=[O:11])[CH2:7]1)([CH3:5])([CH3:4])[CH3:3].[OH-].[Na+].[N:17]([O-:19])=[O:18].[Na+].S(OOS([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>O.[Fe-4](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+].[K+]>[C:2]([N:6]1[CH2:7][C:8]([N+:10]([O-:12])=[O:11])([N+:17]([O-:19])=[O:18])[CH2:9]1)([CH3:3])([CH3:4])[CH3:5]
Reactant: CC(C)(C)N1CC(CO)([N+](=O)[O-])C1
Reactant: O=N[O-]
Agent: N#C[Fe-4](C#N)(C#N)(C#N)(C#N)C#N
Agent: Cl
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: O
Product: CC(C)(C)N1CC([N+](=O)[O-])([N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.3 %

Procedure:
To a solution (60 ml) of N-tert-butyl-3-hydroxymethyl-3-nitroazetidine hydrochloride (13.50 g, 0.060 mol) prepared in the Example 3 in distilled water, 30 ml of aqueous solution of NaOH (7.173 g, 0.179 mol) was added. The resulting yellow solution was stirred for 3 hours at room temperature. The resultant was cooled to 8° C. and a chilled solution (45 ml) of sodium nitrite (NaNO2) (16.5 g, 0.239 mol) and potassium ferrocyanide (K3Fe(CN)6) (1.974 g, 0.060 mol) in distilled water was added slowly. Then, solid sodium persulphate (Na2S2O8) (17.80 g, 0.075 mol) was added in a single portion. The resulting yellow solution was warmed to room temperature as the solution gradually turned into light orange color. The solution was stirred for another 1 hour and then extracted with dichloromethane (CH2Cl2) (150 ml). The organic layer was dried with magnesium sulfate (MgSO4) and the solvent was removed via vacuum evaporation to give N-tert-butyl-3,3-dinitroazetidine (12.583 g, 0.062 mol, yield: 86.66%) as a yellow oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:13]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:14]2[N:18]=[C:17]([C:19](OC)=[O:20])[CH:16]=[N:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[OH-].[Na+]>O1CCCC1>[OH:20][CH2:19][C:17]1[CH:16]=[N:15][N:14]([C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:18]=1
Reactant: COC(=O)c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
A solution of lithium aluminium hydride (1.04 ml, 1M in tetrahydrofuran, 1.04 mmol) was added dropwise to a stirred solution of methyl 2-(triphenylmethyl)-1, 2,3-triazole-4-carboxylate (from step (a), 500 mg, 1.38 mmol) in anhydrous tetrahydrofuran (30 ml) at 0° C. under nitrogen. The mixture was stirred for 1 hour at 0° C. and then water (2 ml), 15% aqueous sodium hydroxide (4 ml) and then more water (4 ml) were added. The resulting suspension was filtered through Arbocel filter aid and the filtrate was dried (MgSO4) and concentrated under reduced pressure. The residue was partitioned between dichloromethane (150 ml) and water (150 ml). The dichloromethane layer was washed with water (600 ml) and then dried (MgSO4) and concentrated under reduced pressure to leave the title compound as a white solid (401 mg, 85%).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([NH:14][CH2:15][CH:16]([OH:26])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24][OH:25])[CH:18]=2)([CH3:13])[CH3:12])[CH:5]=1.[OH-].[Li+]>O1CCCC1.O>[OH:26][C@H:16]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24][OH:25])[CH:18]=1)[CH2:15][NH:14][C:11]([CH3:13])([CH3:12])[CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:27])=[O:2]
Reactant: COC(=O)c1cccc(CC(C)(C)NCC(O)c2ccc(O)c(CO)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(Cc1cccc(C(=O)O)c1)NC[C@H](O)c1ccc(O)c(CO)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 3-{2-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-2-methylpropyl}-benzoic acid methyl ester (preparation 139) (2.35 g, 6.32 mmol) and lithium hydroxide (303 mg, 12.64 mmol) in tetrahydrofuran (20 mL) and water (20 mL) was stirred at room temperature for 3 days. The reaction mixture was then concentrated in vacuo and the residue was diluted with water and acidified with 1M hydrochloric acid (12 mL). The mixture was stirred for 2 hours at room temperature and was then concentrated in vacuo. The crude residue was used in subsequent reactions without further purification. 1H NMR (400 MHz, CD3OD) δ: 7.87 (1H, m), 7.84 (1H, bs), 7.39-7.31 (3H, m), 7.19 (1H, dd), 6.79 (1H, d), 4.86 (1H, m), 4.66 (2H, s), 3.22-3.11 (2H, m), 3.02 (2H, m), 1.32 (6H, s) ppm; LRMS ESI m/z 360 [M+H]+
Reaction SMILES: N1N[N:3]=[N:4][C:5]=1[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:8][CH:7]=1.[C:18](Cl)(=[O:28])[C:19]1[CH:27]=[CH:26][CH:25]=[C:21]([C:22](Cl)=[O:23])[CH:20]=1.O>N1C=CC=CC=1>[N:11]1[C:6]([C:5]2[O:28][C:18]([C:19]3[CH:27]=[CH:26][CH:25]=[C:21]([C:22]4[O:23][C:5]([C:6]5[N:11]=[C:10]([C:12]6[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=6)[CH:9]=[CH:8][CH:7]=5)=[N:4][N:3]=4)[CH:20]=3)=[N:3][N:4]=2)=[CH:7][CH:8]=[CH:9][C:10]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: c1ccc(-c2cccc(-c3nn[nH]n3)n2)nc1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Solvent: O
Solvent: c1ccncc1
Product: c1ccc(-c2cccc(-c3nnc(-c4cccc(-c5nnc(-c6cccc(-c7ccccn7)n6)o5)c4)o3)n2)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
0.63 g of 6-(2H-tetrazol-5-yl)-2,2′-bipyridine was dissolved in 10 ml of dehydrated pyridine, and 0.29 g of isophthaloyl dichloride was gradually added. Temperature was elevated to 115° C., and stirring was conducted for 6 hours under reflux. After cooling to room temperature, the reaction solution was poured into water, and a precipitated white solid was taken out by suction filtration, and washed with water. The solid obtained was vacuum dried at 80° C. for 20 hours, and purified with column chromatography (carrier: silica gel, eluting solution: chloroform/methanol=20/1) to obtain 0.62 g (yield 81%) of BpyOXDm. The product was identified with NMR analysis. The result of NMR analysis (CDCl3) was as follows. 9.071 ppm (1H), 8.639-8.714 ppm (6H), 8.325-8.477 ppm (4H), 8.037 ppm (2H), 7.756-7.854 ppm (3H), 7.330 ppm (2H).
Reaction SMILES: [CH2:1]([C:6]1[C:12]([OH:13])=[CH:11][C:10]([OH:14])=[CH:9][C:7]=1[OH:8])[CH:2]=[C:3]([CH3:5])[CH3:4].[C:15](Cl)(=[O:19])[CH2:16][CH2:17][CH3:18]>>[OH:8][C:7]1[C:9]([C:15](=[O:19])[CH2:16][CH2:17][CH3:18])=[C:10]([OH:14])[C:11]([C:7](=[O:8])[CH2:6][CH2:1][CH3:2])=[C:12]2[C:6]=1[CH2:1][CH2:2][C:3]([CH3:5])([CH3:4])[O:13]2
Reactant: CC(C)=CCc1c(O)cc(O)cc1O
Reactant: CCCC(=O)Cl
Product: CCCC(=O)c1c(O)c2c(c(C(=O)CCC)c1O)OC(C)(C)CC2

Procedure:
Phloroglucinol was treated with prenylchloride using the same procedure as described in Example 2 to yield prenylphloroglucinol. Prenylphloroglucinol was treated with butyrylchloride, according to the same procedure as described for the preparation of 2,4-dibutyrylphoroglucinol in Example 34 (Method 2) to yield 5,7-dihydroxy-6,8-dibutyryl-2,2-dimethylchroman (36 after chromatography with silica gel (petroleum ether, ethyl acetate, 4:1).
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[C:11]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)(=[O:23])=[O:22])[N:10]([CH3:30])[N:9]=1)(=O)C.[OH-].[Na+]>O1CCOCC1>[OH:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[C:11]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)(=[O:22])=[O:23])[N:10]([CH3:30])[N:9]=1
Reactant: CC(=O)OCCOc1nn(C)c(NS(=O)(=O)c2ccccn2)c1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccccn2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
To N-[3-(2-acetoxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazole-5-yl]-2-pyridine sulfonamide (Preparation 35) (1.05 g) in dioxan (10 ml) was added 1N NaOH (aq.) (5.34 ml). The mixture was stirred at 50° C. for 1 hour. The reaction was concentrated under reduced pressure to low volume and then partitioned between ethyl acetate (20 ml) and water (15 ml). The aqueous layer was separated and acidified to pH 6 with 2N hydrochloric acid (aq.). the product was extracted with ethyl acetate (2×20 ml), washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with solvent gradient, pentane:ethyl acetate (4:6 to 0:1, by volume) to yield the title compound as a colourless foam (560 mg).
Reaction SMILES: OC(COC1C=CC=CC=1C=CC)CN.[OH:16][CH:17]([CH2:38][O:39][C:40]1[C:49]2[C:44](=C[CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1)[CH2:18][NH:19][C:20]1[C:21]2[N:22]=[CH:23][N:24]([C:34]=2[N:35]=[CH:36][N:37]=1)[C@@H:25]1[O:33][C@H:30]([CH2:31][OH:32])[C@@H:28]([OH:29])[C@H:26]1[OH:27]>>[OH:16][CH:17]([CH2:38][O:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:49]=1[CH2:48][CH:47]=[CH2:46])[CH2:18][NH:19][C:20]1[C:21]2[N:22]=[CH:23][N:24]([C:34]=2[N:35]=[CH:36][N:37]=1)[C@@H:25]1[O:33][C@H:30]([CH2:31][OH:32])[C@@H:28]([OH:29])[C@H:26]1[OH:27]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(NCC(O)COc4cccc5ccccc45)ncnc32)[C@H](O)[C@@H]1O
Agent: CC=Cc1ccccc1OCC(O)CN
Product: C=CCc1ccccc1OCC(O)CNc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
By substituting 2-hydroxy-3-(propenylphenoxy)propylamine (3.61 g, 0.0174 moles) for the starting material of Example 1, N6 -{2-hydroxy-3-[(2-propenyl)phenoxy]propyl}adenosine was obtained.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]2)=[N:10][N:9]=1.[CH3:33][N:34]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=[N:35]1.C1(C)C=CC=CC=1>ClCCl.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.O.C(O)C>[CH3:32][N:24]([CH:21]1[CH2:22][CH2:23][N:18]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([C:38]3[N:34]([CH3:33])[N:35]=[CH:36][CH:37]=3)=[N:9][N:10]=2)[CH2:19][CH2:20]1)[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2nnc(Cl)c3ccccc23)CC1
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: ClCCl
Solvent: Cc1ccccc1
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2nnc(-c3ccnn3C)c3ccccc23)CC1
Temperature: 25 °C
Yield: 1261.5 %

Procedure:
Place sodium carbonate (3.82 g, 36.09 mmol), tert-butyl 1-(4-chlorophthalazin-1-yl)piperidin-4-yl(methyl)carbamate (6.8 g, 18.04 mmol) and 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (5.63 g, 27 1 mmol) in a flask with a mixture of toluene (50 mL), ethanol (17 mL), and water (17 mL). Degas the mixture for 10 min with nitrogen gas. Add tetrakis(triphenylphosphine)palladium (0.4 g, 0.35 mmol) and heat the mixture at 74° C. overnight. Cool the mixture to ambient temperature and dilute with dichloromethane. Wash the organic portion with brine, dry over Na2SO4, and concentrate under reduced pressure. Purify the resulting residue by flash silica gel chromatography (hexane:ethyl acetate:2 M NH3 in MeOH=20:5:1) to provide the title compound as a yellow foam (5.33 g, 70%). ES/MS m/z 423.2 (M+1).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][CH2:12][NH:11][C:10]1=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1>C1COCC1>[Si:1]([O:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[C:10]1=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1ccc(CBr)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(CN2CC[C@H](O[Si](C)(C)C(C)(C)C)C2=O)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 88 %

Procedure:
(S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-one (5 g, 23.22 mmol, intermediate G) was dissolved in anhydrous THF (46.4 ml) and the reaction mixture was cooled to 0° C. under a nitrogen atmosphere. Sodium hydride (1.393 g, 34.8 mmol) was then added in one portion and the reaction mixture was allowed to stir for 5 min before the dropwise addition of 1-(bromomethyl)-4-methylbenzene (5.37 g, 29.0 mmol) in anhydrous THF (46.4 ml). The reaction was allowed to stir at 0° C. for 5 min, then the cooling bath was removed and mixture was allowed to warm to rt overnight. The reaction was cautiously quenched with water (100 mL) and then extracted with ethyl acetate (3×100 mL). The combined organic layers were then washed with brine (200 mL) and dried (MgSO4). Evaporation of the solvent in vacuo gave the crude product (9.6 g, oil) which was then purified by silica gel chromatography (330 g of silica) eluting with a gradient of 0% to 20% ethyl acetate in hexanes to provide 6.53 g (88%) of the desired product. LC/MS (Conditions B), RT=4.320 min, (M+H)+=320.3. 1H NMR (400 MHz, chloroform-d) δ 7.15 (s, 4H), 4.42 (s, 2H), 4.37 (t, J=7.6 Hz, 1H), 3.32-3.18 (m, 1H), 3.10 (dt, J=9.7, 7.5 Hz, 1H), 2.36 (s, 3H), 2.29 (dtd, J=12.6, 7.6, 3.1 Hz, 1H), 1.97-1.84 (m, 1H), 0.95 (s, 9H), 0.20 (d, J=10.3 Hz, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][NH:9][C:10](=O)OC)[CH:2]=1.[OH-].[Na+].N[C:17]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[CH:21][C:18]=1C=O>OS(O)(=O)=O>[CH3:26][O:25][C:23]1[CH:24]=[C:17]2[C:10](=[CH:21][C:22]=1[O:27][CH3:28])[N:9]=[CH:8][C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[CH:18]2
Reactant: COc1cc(N)c(C=O)cc1OC
Reactant: COC(=O)NC=Cc1cccnc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2cc(-c3cccnc3)cnc2cc1OC
Temperature: 22 °C

Procedure:
A solution of 600 mg (3.37 mmol) of methyl N-2-(pyrid-3-yl)vinylcarbamate in 10 mL of 6N H2SO4 is refluxed for 10 minutes, cooled to 0° C. and basified to pH 11 with 50% NaOH. A solution of 400 mg (2.03 mmol) of 2-amino-4,5-dimethoxybenzaldehyde is immediately added and the mixture refluxed for 2.5 hours, cooled to 22° C. and partitioned between ether (150 mL) and water (100 mL). The aqueous layer is back extracted with chloroform and the combined organics are dried (MgSO4) and evaporated to obtain an oil which is recrystallized from hexane/ethyl acetate twice to give 3-(6,7-dimethoxyquinolin-3-yl)pyridine (m.p. 131°-132° C.).
Reaction SMILES: [CH:1]1([CH2:4][C@@H:5]2[O:13][CH2:12][C@:8]3([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=4[F:21])[NH:9][O:10][CH2:11][C@@H:7]3[CH2:6]2)[CH2:3][CH2:2]1.N[C@@]1(C2C=CC(F)=CC=2F)CO[C@@H](COCC2C=CC=CC=2)C[C@H]1CO>>[NH2:9][C@@:8]1([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH2:12][O:13][C@@H:5]([CH2:4][CH:1]2[CH2:2][CH2:3]2)[CH2:6][C@H:7]1[CH2:11][OH:10]
Reactant: Fc1ccc([C@]23CO[C@@H](CC4CC4)C[C@H]2CON3)c(F)c1
Agent: N[C@@]1(c2ccc(F)cc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO
Product: N[C@@]1(c2ccc(F)cc2F)CO[C@@H](CC2CC2)C[C@H]1CO
Yield: 90.5 %

Procedure:
rel-(3aR,5S,7aS)-5-(Cyclopropylmethyl)-7a-(2,4-difluorophenyl) hexahydro-1H-pyrano[3,4-c][1,2]oxazole (C70) (1.1 g, 4.09 mmol) was converted to the product according to the method described for the synthesis of [(2R,4R,5S)-5-amino-2-[(benzyloxy)methyl]-5-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl]methanol (C6) in Preparation P1. The product was obtained as a dark oil (1.1 g), which was taken directly to the following step without additional purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:10]([C:15](=[O:25])[N:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[N:17]=3)=[CH:11][NH:12][C:13]=2[CH3:14])=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([N:16]2[C:15](=[O:25])[C:10]3=[CH:11][NH:12][C:13]([CH3:14])=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[CH:3][CH:4]=4)[C:9]3=[N:17]2)=[CH:19][CH:20]=1
Reactant: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1ccc(Br)cc1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1-c1ccc(N2CCOCC2)cc1
Temperature: 80 °C
Reaction time: 47 h
Yield: 25.5 %

Procedure:
A mixture of 7-(4-bromophenyl)-2-(4-chlorophenyl)-2,5-dihydro-6-methylpyrazolo[4,3-c]pyridin-3-one (69.1 mg, 0.167 mmol), morpholine (34.9 ml, 0.400 mmol) and sodium tert-butoxide (61.1 mg, 0.636 mmol) in Ianhydrous DMF (3 ml) was degassed by evaporating the flask under vacuum and refilling with nitrogen several times. Solid (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl [(S)-BINAP] (10.5 mg, 0.0169 mmol) and tris(dibenzylideneacetone)dipalladium(0) (7.6 mg, 0.0083 mmol) were added and the mixture was stirred at 80° C. under nitrogen for 47 h, adding more (S)-BINAP (10.7 mg, 0.172 mmol) and tris(dibenzylideneacetone)dipalladium(0) (7.9 mg, 0.0086 mmol) after 23 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, 3-5% MoOH/CH2Cl2) and preparative HPLC (YMCSIL D column, 7% MeOH/1-chlorobutane) to give 17.9 mg (26%) of the title compound; mp 306-315° C. (CH2Cl2-MeOH-EtOAc); 1H NMR (360 MHz, DMSO-d6) δ2.27 (3H, s), 3.20 (4H, m), 3.77 (4H, m), 7.05 (2H, d, J8.8 Hz), 7.40 (2H, d), 7.42 (2H, d, J8.9 Hz), 8.15 (2H, d, J9.0 Hz), 8.51 (1H, s), 12.35 (1H, br s); MS (ES+) m/z 421/423[MH]+. Anal. found: C, 65.57; H, 4.84; N, 13.22. C23H21CIN4O2 requires: C, 65.63; H, 5.03; N, 13.31%.