Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:26])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=3)[CH:13]=[CH:14][CH:15]=2)=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2].[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[NH4+]>CN(C)C=O.O>[C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:26])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[N:33]=[N:34][NH:35][N:25]=4)[CH:19]=3)[CH:13]=[CH:14][CH:15]=2)=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1c(OCc2cccc(NC(=O)c3cccc(C#N)c3)c2)ccc(C(C)=O)c1O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCc2cccc(NC(=O)c3cccc(-c4nn[nH]n4)c3)c2)ccc(C(C)=O)c1O
Yield: 32.7 %

Procedure:
Heat a mixture of N-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-3-cyano-benzamide (876 mg, 2.04 mmol), sodium azide (1.32 g, 20.4 mmol), and ammonium chloride (1.09 g, 20.4 mmol) in dimethylformamide (10 mL) at 110° C. overnight. Cool. Dilute with water (120 mL). Filter, and wash several times with water. Dry. Dissolve the residue in hot acetone (20 mL) and purify via chromatography, eluting with 1:1 hexanes:acetone with 1% acetic acid to afford the title compound as a light yellow powder (315 mg, 33%): 1H NMR (DMSO-d6) δ 0.89 (t, 3H), 1.51 (sextet, 2H), 2.50 (s, 3H), 2.63 (t, 2H), 5.29 (s, 2H), 6.74 (d, 1H), 7.21 (d, 1H), 7.42 (t, 1H), 7.71 (d, 1H), 7.74 (t, 1H), 7.78 (d, 1H), 7.98 (s, 1H), 8.15 (d, 1H), 8.24 (d, 1H), 8.62 (s, 1H), 10.55 (s, 1H), 12.85 (s, 1H); MS (APCI-neg mode) m/z (rel intensity) 470 (100).
Reaction SMILES: [Na].C(O)C.[Br:5][C:6]1[CH:7]=[C:8]([N:12]2[CH:16]=[N:15][C:14]([OH:17])=[N:13]2)[CH:9]=[CH:10][CH:11]=1.Br[CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CS(C)=O>[Br:5][C:6]1[CH:7]=[C:8]([N:12]2[CH:16]=[N:15][C:14]([O:17][CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:25])=[N:13]2)[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ncn(-c2cccc(Br)c2)n1
Agent: [Na]
Solvent: CS(C)=O
Solvent: CCO
Product: CCOC(=O)C(C)Oc1ncn(-c2cccc(Br)c2)n1
Yield: 77.4 %

Procedure:
The process was carried out as described in Example 3, starting with 2.8 g of sodium, 50 ml of ethanol, 75 ml of dimethylsulfoxide, 29 g of 1-(3-bromophenyl)-3-hydroxy-1,2,4-1H-triazole and 21.9 g of ethyl 2-bromopropionate. The yield was 31.8 g of the desired product, m.p. 83°-85°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:24](=[O:29])[C:25]([O:27]C)=[O:26])=[C:16]2[N:15]=1.O[Li].O>C1COCC1.CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([NH:23][C:24](=[O:29])[C:25]([OH:27])=[O:26])=[C:16]2[N:15]=1
Reactant: COC(=O)C(=O)Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(=O)Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.8 %

Procedure:
(R)-methyl 2-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-ylamino)-2-oxoacetate (Example 104; 100 mg, 0.249 mmol) was dissolved in a mixture solvent of THF:MeOH:water (2:2:1, 1 mL), followed by addition of LiOH—H2O (31.4 mg, 0.747 mmol). The reaction was stirred at ambient temperature for 10 minutes to reach completion. The reaction was concentrated, re-dissolved in water (20 mL) and acidified with 6 N HCl. The precipitate was vacuum-filtered, rinsed with water, heptane, and dried on high vacuum, giving the final product as a fine pale-yellowish powder (50 mg, 52% yield). MS (apci negative) m/z=386.1 (M−H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[Br:12]Br.S(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[Br:12][C:7]1[CH:6]=[C:5]([O:8][CH3:9])[C:4]([O:10][CH3:11])=[CH:3][C:2]=1[I:1]
Reactant: BrBr
Reactant: COc1ccc(I)cc1OC
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(Br)c(I)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
4-Iodoveratrole (26.0 g, 0.0985M) in acetic acid (25 ml) was treated with bromine (6.5 ml, 0.127M) in acetic acid (30 ml) and stirred at room temperature for one hour. The mixture was diluted with water (300 ml) and treated with sodium bisulfite to discharge the excess bromine. The white solid was filtered, washed with water and dried in vacuo over P2O5 to give 4-bromo-5-iodoveratrole (33.0 g, 95% yield) as a white solid, mp 98°-100° C. (literature: Baker et al., J. Chem. Soc. 3986 (1961), mp 102°-104° C.). NMR (CDCl3) δ 3.83 ppm (s, 6H, (2x) OCH3), 7.06 (s, 1H, ArH), 7.21 (s, 1H, ArH).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5].[C:14]([CH2:17][N:18]1[C:22](=[O:23])[C:21](=[CH:24][CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[S:20][C:19]1=[S:34])([OH:16])=[O:15].S1CC(=O)NC1=S.CO>O>[CH3:1][NH:2][CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5].[C:14]([CH2:17][N:18]1[C:22](=[O:23])/[C:21](=[CH:24]\[CH:25]=[CH:26]\[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])/[S:20][C:19]1=[S:34])([OH:16])=[O:15]
Reactant: Cc1ccccc1C=CC=C1SC(=S)N(CC(=O)O)C1=O
Agent: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C1CSC(=S)N1
Solvent: CO
Solvent: O
Product: Cc1ccccc1/C=C/C=C1/SC(=S)N(CC(=O)O)C1=O
Temperature: 25 °C
Yield: 72.5 %

Procedure:
To a solution of 2.001 g of N-methyl-D-glucamine in 20 ml of water was added 3.194 g of 3-carboxymethyl-5-(2-methylcinnamylidene)-rhodanine [prepared as described in Example 1 (35)], and the mixture was heated to dissolve the rhodanine derivative, and then 40 ml of methanol was added to the solution at the same temperature. The mixture was cooled to room temperature and the precipitated crystals were filtered. The resulting crystals were washed with 5 ml of mixture of water and methanol (1:2), and 5 ml of methanol, and dried under reduced pressure to obtain 3.73 g of the titled compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:39])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]4[CH:37]=[CH:36][C:27]5[C@H:28]([CH2:31][C:32]([O:34]C)=[O:33])[CH2:29][O:30][C:26]=5[CH:25]=4)[CH:17]=3)=[C:11]([CH3:38])[CH:10]=2)[CH2:4][CH2:3]1.CO.[OH-].[Na+].Cl>O.O1CCCC1>[O:39]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]4[CH:37]=[CH:36][C:27]5[C@H:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:29][O:30][C:26]=5[CH:25]=4)[CH:17]=3)=[C:11]([CH3:38])[CH:10]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCS(=O)(=O)CC5)cc4C)c3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OC2CCS(=O)(=O)CC2)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To a solution of methyl [(3S)-6-({4′-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy]-2′,6′-dimethylbiphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetate (0.427 g, 0.775 mmol) in a mixed solvent of methanol (2 mL) and tetrahydrofuran (4 mL) was added 2 M aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was diluted with water, acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals were recrystallized from hexane-ethyl acetate to give the title compound (0.352 g, yield 85%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[C:32]([F:33])=[CH:31][C:5]2[NH:6][C:7]([CH2:9][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:16]([C:18]3[N:19]=[C:20]([CH3:30])[S:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:17])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].I[CH3:37].O>CN(C=O)C.Cl>[F:1][C:2]1[C:32]([F:33])=[CH:31][C:5]2[N:6]([CH3:37])[C:7]([CH2:9][CH:10]3[CH2:15][CH2:14][CH2:13][CH2:12][N:11]3[C:16]([C:18]3[N:19]=[C:20]([CH3:30])[S:21][C:22]=3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[O:17])=[N:8][C:4]=2[CH:3]=1
Reactant: CI
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2nc3cc(F)c(F)cc3[nH]2)c(-c2ccc(F)cc2)s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc3cc(F)c(F)cc3n2C)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
(RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone, E35 (400 mg, 0.85 mmol) was slowly added to an ice-cooled slurry of NaH (68 mg, 60% dispersion on mineral oil, 1.7 mmol) in DMF (10 ml). After 0.5 h iodomethane (0.90 mmol) was added. The reaction mixture was stirred at room temperature, under argon for 16 h. 2N HCl (9 drops) then water (100 ml) were added. The aqueous phase was extracted with EtOAc(2×) and the combined organics washed with brine, dried (Na2SO4) and the solvent removed in vacuo. The residue was chromatographed (silica gel, 50-100% pentane-ethyl acetate). Residual DMF was removed by dissolving in ethyl acetate/diethyl ether and washing with water (2×). Drying (Na2SO4) and removal of the solvent in vacuo afforded the title compound as a pale yellow solid (142 mg, 34%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH:17]([N-]C(C)C)(C)C.[Li+].[Br:25][CH2:26][CH2:27][CH2:28][CH2:29]Br>O1CCCC1>[CH2:15]([O:14][C:12](=[O:13])[C:11]([C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][CH:9]=1)([CH3:17])[CH2:29][CH2:28][CH2:27][CH2:26][Br:25])[CH3:16]
Reactant: CCOC(=O)Cc1ccc(CC(C)C)cc1
Reactant: CC(C)[N-]C(C)C
Reactant: BrCCCCBr
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(CCCCBr)c1ccc(CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
Ethyl (4-isobutyl-phenyl)-acetate (10.5 g, 44.8 mmol) was dissolved in freshly distilled tetrahydrofuran (150 mL) and cooled to −78° C. Lithium diisopropylamide (2 N, 28 mL, 56 mmol) was added and the solution stirred for 1 hour at −78° C. under a nitrogen atmosphere. 1,4-Dibromobutane (25 mL, 37.5 g, 175 mmol) was then added drop-wise over 30 minutes. The solution was allowed to warm to room temperature over five hours. After stirring at room temperature for an additional 16 hours, the reaction was quenched with water (100 mL) and extracted with diethyl ether (2×100 mL). The ether was washed with 10% hydrochloric acid (2×100 mL), saturated sodium bicarbonate (100 mL) and water (100 mL). After drying with sodium sulfate (5 g), filtration and concentration, the product was purified by flash chromatography on silica gel (200 g), eluting with 5% ethyl acetate/hexanes. The product was then heated to 150° C. under vacuum (0.5 mm Hg) for 30 minutes to remove excess 1,4-dibromobutane. The reaction yielded 6-bromo-2-(4-isobutyl-phenyl)-2-methyl-hexanoic acid ethyl ester (14.49 g, 87.5% yield) as a clear, viscous oil. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 7.19 (d, 2H, J=8.0 Hz), 7.08 (d, 2H, J=8.0 Hz), 4.11 (q, 2H, J=7.0 Hz), 3.35 (t, 2H, J=6.8 Hz), 2.43 (d, 2H, J=7.3 Hz), 2.10-1.92 (m, 1H), 1.92-1.78 (m, 4H), 1.53 (s, 3H), 1.40-1.28 (m, 2H), 1.17 (t, 3H, J=7.0 Hz), 0.88 (6H, J=6.8). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm) 176.17, 141.12, 140.04, 129.14, 125.64, 60.77, 49.80, 44.99, 38.52, 33.51, 33.26, 30.22, 23.55, 22.69, 22.50, 14.19. HRMS (LSIMS, nba): Calcd. for C19H30O2Br (MH+): 369.1429, found: 369.1445.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[C:15]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:14]=1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>C1COCC1.O>[CH2:21]([O:20][C:15]1[CH:14]=[C:13]([NH:12][C:10]([NH2:9])=[S:11])[CH:18]=[C:17]([Br:19])[CH:16]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(NC(=S)Nc1cc(Br)cc(OCc2ccccc2)c1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NC(=S)Nc1cc(Br)cc(OCc2ccccc2)c1
Temperature: 65 °C
Reaction time: 15 h
Yield: 93.3 %

Procedure:
To an ice-cold solution of 1-benzoyl-3-(3-benzyloxy-5-bromo-phenyl)-thiourea (33.0 g, 74.70 mmol) in THF (500.0 mL) was added a solution of NaOH (15.0 g, 375.0 mmol) in H2O (180.0 mL). The resulting reaction mixture was stirred at 65° C. for 15 h. The reaction mass was then cooled to room temperature, added water and extracted with EtOAc (3×1.0 L). The combined organics was washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure to get the desired compound (23.50 g, 94%) that was carried forward to the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:11](=[O:13])[O:10][C:9]([C:14]3[C:15](F)=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:8][C:7]=2[CH:6]=[C:5]([O:21][CH3:22])[CH:4]=1)[CH3:2].[NH:23]1[CH2:27][CH2:26][C@@H:25]([N:28]2[CH2:33][CH2:32][S:31](=[O:35])(=[O:34])[CH2:30][CH2:29]2)[CH2:24]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH2:1]([C:3]1[C:12]2[C:11](=[O:13])[O:10][C:9]([C:14]3[C:15]([N:23]4[CH2:27][CH2:26][CH:25]([N:28]5[CH2:29][CH2:30][S:31](=[O:35])(=[O:34])[CH2:32][CH2:33]5)[CH2:24]4)=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:8][C:7]=2[CH:6]=[C:5]([O:21][CH3:22])[CH:4]=1)[CH3:2]
Reactant: O=S1(=O)CCN([C@@H]2CCNC2)CC1
Reactant: CCc1cc(OC)cc2nc(-c3cccnc3F)oc(=O)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCc1cc(OC)cc2nc(-c3cccnc3N3CCC(N4CCS(=O)(=O)CC4)C3)oc(=O)c12

Procedure:
To 5-ethyl-2-(2-fluoropyridin-3-yl)-7-methoxy-4H-benz[d][1,3]oxazin-4-one (50.0 mg, 0.17 mmol) in anhydrous 1,4-dioxane (850 μL) was added compound Z (52.9 mg, 0.22 mmol) and diisopropylethyl amine (120 μL, 0.85 mmol) at room temperature under N2 overnight. The solution was concentrated, and the resulting residue was purified on a Biotage 40M amine column using a gradient of 20-75% ethyl acetate/hexanes to obtain the title compound. The fractions containing the title compound were combined and concentrated by speedvac to afford the title compound as a yellow oil (19.2 mg, 23% yield). 1H NMR (CDCl3, 400 MHz) δ: 8.33 (dd, 1H, J=1.0 Hz), 8.1 (d, 1H, J=7.0 Hz), 6.92 (dd, 2H, J=2.5 Hz), 6.83 (m, 1H), 3.93 (s, 3H), 3.83 (m, 1H), 3.62 (m, 2H), 3.39 (m, 1H), 3.26 (m, 1H), 3.22 (m, 4H), 3.17 (m, 6H), 2.16 (m, 1H), 1.94 (m, 1H), 1.29 (t, 3H, J=7.5 Hz); ESMS m/z 485.2 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C:5]([OH:6])=[C:3]1[OH:4].[H][H]>O.[Pd]>[C:2]1(=[O:1])[O:8][C@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[C@H:5]([OH:6])[C@@H:3]1[OH:4]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)[C@H](O)[C@@H]1O
Yield: 100 %

Procedure:
A solution of L-ascorbic acid (23.1 g, 0.13 mol) in 170 ml of water was hydrogenated using 10% Pd/C (2.2 g) in a Parr hydrogenator at 50° C. and 50 psi hydrogen pressure for 24 hours. The catalyst was removed by filtration and the water removed in vacuo to afford 23.2 g (0.13 mol, 99%) of a white crystalline solid. Upon recrystallization from methanol-ethyl acetate, 22.0 g of the desired product was obtained. 1H NMR (DMSO): δ 5.80 (d, 1H). 5.30 (d, 1H), 4.95 (d, 1H), 4.65 (t, 1H), 4.45 (m, 1H), 4.23-4.15 (m, 2H), 3.75 (m, 1H), 3.48 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](N(C)C=O)[CH:3]=1.[CH2:18]([OH:20])C.[CH3:21][NH2:22]>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:18]([NH:22][CH3:21])=[O:20])[CH:3]=1
Reactant: CCO
Reactant: COc1ccc2nc(N(C)C=O)cc(Cl)c2c1
Reactant: CN
Product: CNC(=O)c1cc(Cl)c2cc(OC)ccc2n1

Procedure:
Embodiment 6: Preparation of 4-chloro-6-methoxyl-N-methyl-2-quinolinyl formamide 10 g of 4-chloro-6-methoxyquinolinyl-2-carbonyl chloride (obtained from embodiment 1) was reacted with 200 ml of 2M methylamine ethanol solution under 0° C. for 36 hours until the reaction finished. The solvent was evaporated under vacuum and the residues were added with water followed by stirring evenly. Ethyl acetate was added for extracting and the ethyl acetate layer was dried with anhydrous sodium sulfate. The ethyl acetate layer was removed under vacuum to obtain 9 g of 4-chloro-6-methoxy-N-methyl-2-quinoline carboxamide.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C.CCOC(C)=O>CN1C(=O)CCC1>[CH3:11][C:10]1[C:3]2[C:4]([NH:5][CH:6]=[N:7][C:2]=2[N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)=[N:8][CH:9]=1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: O=C(NC1CCNCC1)c1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc2[nH]cnc(N3CCC(NC(=O)c4ccccc4)CC3)c1-2
Temperature: 150 °C

Procedure:
A mixture of 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine D4 (136 mg), N-4-piperidinylbenzamide (249 mg, 1.217 mmol) and DIPEA (0.354 mL, 2.029 mmol) in NMP (1 mL) was heated in the microwave at 150° C. for 20 minutes. EtOAc (10 mL) was added to the mixture and a precipitate formed which was filtered off—this was shown to be remaining piperidinylbenzamide starting material. The filtrate was diluted with further EtOAc (10 mL) and washed with water (3×15 mL). On the third washing a precipitate formed—this was filtered off and found to be mainly desired product. The filtrate was dried (phase separator) and concentrated to give further solid. Both solids were purified by MDAP and the clean fractions combined and concentrated in vacuo before drying in a drying pistol to give E17 (117 mg); 1H NMR (d6-DMSO) δ 11.54 (1H, brs), 8.48 (1H, d), 8.21 (1H, s), 7.86 (2H, d), 7.52 (1H, t), 7.45 (2H, t), 7.08 (1H, s), 4.13-3.98 (3H, m), 3.04 (2H, t), 2.33 (3H, s), 1.93 (2H, dd), 1.72 (2H, ddd), MS(ES+) 336 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[CH:6])[CH3:2].C([Li])CCC.CCCCCC.CON(C)[C:24](=[O:26])[CH3:25]>C1COCC1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[C:6][C:24](=[O:26])[CH3:25])[CH3:2]
Reactant: C#CC(OCC)OCC
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(C#CC(C)=O)OCC
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
Propargylaldehyde diethylacetal (40 g, 312 mmol) was dissolved in THF (200 mL) under argon and cooled to −70° C. Then a 1.6 M solution of n-butyllithium in hexane (234 mL, 374 mmol) was added and stirring continued for 30 min at −30° C. Then N-methoxy-N-methylacetamide (38.6 g, 374 mmol) in THF (10 mL) was added. After 30 min at −30° C., the reaction was quenched by addition of saturated NH4Cl solution (20 mL). The product was extracted with AcOEt (2×200 mL), saturated solution of NH4Cl (2×200 mL), dried and concentrated. Chromatography on silica gel with a heptane/ethyl acetate gradient 100:0 to 95:5 gave 38.5 g (72%) of a colorless oil. GC/MS: m/z=232(M).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].CO.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(-n2cnnn2)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-n2cnnn2)cc1C(=O)O
Reaction time: 0.5 h

Procedure:
Alternately, combine methyl 2-methoxy-5-(1H-tetrazol-1-yl)benzoate (13.3 g, 56.8 mmol) and methanol (150 mL). Add 1M aqueous solution of sodium hydroxide (62.5 mL, 62.5 mmol). Heat to reflux. After 30 minutes, add methanol (50 mL) and water (50 mL) and continue the heat at reflux. After 1 hour, concentrate invacuo to remove most of the solvent. Adjust the pH to about 1 to 2 using a 1M aqueous hydrochloric acid solution to give a solid. Collect the solid by filtration, rinse with water, and dry to give 2-methoxy-5-(1H-tetrazol-1-yl)benzoic acid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:5][C@@H:4]1[O:17][CH3:18].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:16])[CH2:5][C@@H:4]1[O:17][CH3:18])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CO[C@H]1C[C@@H](NC(=O)OC(C)(C)C)CC[C@@H]1CO
Solvent: ClCCl
Product: CO[C@H]1C[C@@H](NC(=O)OC(C)(C)C)CC[C@@H]1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of tert-butyl [(1S,3S,4R)-4-(hydroxymethyl)-3-methoxycyclohexyl]carbamate (racemic) (720 mg, 2.8 mmol) in dichloromethane (9 mL) was added methanesulfonyl chloride (0.430 mL, 5.56 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h. The mixture was then concentrated and partitioned between ethyl acetate and water. The organic phase was concentrated and purified by flash chromatography (eluting with a gradient of 50% ethyl acetate in hexanes) to give the desired product (0.859 g, 92%). LCMS calculated for C9H20NO4S (M+H-Boc)+: m/z=238.1. Found: 238.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[N:24]2[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]2)=[CH:4][CH:3]=1.[CH3:31][CH:32]([NH2:34])[CH3:33].Cl.[C-:36]#[N:37].[Na+]>CO.O.CC(N)C.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:15][C:14]3[C:9]2=[N:10][CH:11]=[N:12][C:13]=3[N:24]2[CH2:29][CH2:28][C:27]([NH:34][CH:32]([CH3:33])[CH3:31])([C:36]#[N:37])[CH2:26][CH2:25]2)=[CH:4][CH:3]=1
Reactant: O=C1CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Reactant: [C-]#N
Reactant: CC(C)N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)NC1(C#N)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A suspension of 1-[9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-piperidin-4-one 7A-96 (48 mg, 0.11 mmol) in methanol (0.4 ml) was cooled to 0° C. and then treated with 2-propylamine (15 μl, 0.15 mmol) and then concentrated aqueous HCl. After stirring 5 minutes, a solution of sodium cyanide (8.1 mg, 0.16 mmol) in water (0.4 ml) was added; the heterogeneous reaction was warmed to room temperature and then allowed to stir overnight. Tetrahydrofuran (0.4 ml) was then added to solubilize all reactants. Additional sodium cyanide (8 mg, 0.16 mmol) and 2-propylamine (3 drops) were added and stirred overnight. The reaction was filtered and then concentrated under reduced pressure to give title compound 22A-1 (27 mg, 48%) as a colorless solid: +ESI MS (M+1) 506.1; 1H NMR (400 MHz, CD2Cl2) δ 8.32 (s, 1H), 7.52 (d, J=7.9 Hz, 1H), 7.45–7.33 (m, 5H), 7.21 (d, J=8.7 Hz, 2H), 5.50 (v br s, 2H), 3.88 (v br s, 2H), 3.18 (septuplet, J=6.0 Hz, 1H), 2.16 (m, 2H), 1.82 (ddd, J=13.3, 10.4, 3.7 Hz, 2H), 1.16 (d, J=6.2 Hz, 6H).