Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH:17]3C=N[C:20]4[CH:23]=[CH:24][CH:25]=C[C:19]=4[S:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].CI.O.[CH3:32][N:33]([CH3:36])[CH:34]=[O:35]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH:17]3[C:34](=[O:35])[N:33]([CH3:36])[C:32]4[CH:25]=[CH:24][CH:23]=[CH:20][C:19]=4[S:18]3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(N2CCN(CCCC3C=Nc4ccccc4S3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CN1C(=O)C(CCCN2CCN(c3ccc(F)cc3)CC2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 193 mg of 2-[3-[4-(4-fluorophenyl)-1-piperazinyl]propyl]-2H-1,4-benzothiazine in 2 ml of dimethylformamide was added 20 mg of 60% sodium hydride in oil. The mixture was stirred at room temperature for 30 minutes and cooled with ice. To the resultant was added 0.07 ml of methyl iodide, and the mixture was stirred for further one hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and concentrated to give 2-[3-[4-(4-fluorophenyl)-1-piperazinyl]propyl]-4-methyl-2H-1,4-benzothiazin-3(4H)-one as crystals. Recrystallization from ethyl acetate and hexane gave prisms, m.p. 103°-104° C. The yield was 84 mg (42%). IR and NMR spectra of this product was in agreement with those of the compound obtained in Example 34.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:35])=[C:13]([C:30]([O:32]CC)=O)[C:14](=[O:29])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:36]1([NH2:40])[CH2:39][CH2:38][CH2:37]1>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:35])=[C:13]([C:30]([NH:40][CH:36]3[CH2:39][CH2:38][CH2:37]3)=[O:32])[C:14](=[O:29])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][CH:20]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2ccc(S(C)(=O)=O)cc2)c1=O
Product: CS(=O)(=O)c1ccc(Cn2c(=O)c(C(=O)NC3CCC3)c(O)c3ncc(Cc4ccccc4)cc32)cc1

Procedure:
This compound was prepared from ethyl 7-benzyl-4-hydroxy-1-[4-(methylsulfonyl)benzyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclobutylamine employing methods similar to those described in Example 2. The product was obtained as a white solid: 1H NMR (CDCl3) δ 10.19 (1H, br d, J=7.4 Hz), 8.61 (1H, d, J=1.1 Hz), 7.82 (2H, d, J=8.4 Hz), 7.30 (3H, m), 7.18 (2H, d, J=8.4 Hz),7.06 (1H, s), 7.03 (2H, m), 5.41 (2H, br), 4.54 (1H, m), 4.05 (2H, s), 3.02 (3H, s), 2.44 (2H, m), 2.08 (2H, m), 1.83 (2H, m); HRMS calcd for C28H27N3O5S+H+: 518.1740. Found: 518.1741.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]([O:20][C@@H:21]([C@H:23]3[CH2:27][N:26]([C@@H](C4C=CC(OC)=CC=4)C)[C:25](=[O:38])[CH2:24]3)[CH3:22])[C:13]3[N:14]([N:16]=[C:17]([CH3:19])[CH:18]=3)[CH:15]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]>C(O)(C(F)(F)F)=O.C(OCC)(=O)C>[C:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]([O:20][C@@H:21]([C@H:23]3[CH2:27][NH:26][C:25](=[O:38])[CH2:24]3)[CH3:22])[C:13]3[N:14]([N:16]=[C:17]([CH3:19])[CH:18]=3)[CH:15]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(-c4cnn(C(C)(C)C)c4)cn4nc(C)cc34)CC2=O)cc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(O[C@H](C)[C@H]3CNC(=O)C3)cc(-c3cnn(C(C)(C)C)c3)cn2n1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
A solution of (R)-4-((R)-1-((6-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-methylpyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one (5 mg) in TFA (2 mL) was heated at 60° C. for overnight, cooled to rt. and then removed TFA under vaco., the residue was diluted with ethyl acetate, and washed with brine, dried, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to provide 3 mg of (R)-4-((R)-1-((6-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-methylpyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 6.60.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=O)[N:10](C)[C:11]([NH:20][C:21]([CH3:29])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:22])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:43])=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH3:22][C:21]([NH:20][C:11]1[N:10]=[C:9]([Cl:43])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:12]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:29]
Reactant: Cn1c(NC(C)(C)c2ccccc2)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(Nc1nc(Cl)c(-c2ccc(F)cc2)c(-c2ccncc2)n1)c1ccccc1
Temperature: 100 °C

Procedure:
5-(4-fluorophenyl)-3-methyl-2-((1-methyl-1-phenylethyl)amino)-6-(4-pyridyl)-(3H)-pyrimidin-4-one (1.24 g, 2.99 mmol), benzyltriethylammonium chloride (2.04 g, 8.97 mmol), and diisopropylethylamine (1.16 g, 1.6 mL 8.97 mmol) were combined in phosphorous oxychloride (ca. 20 mL) and the resulting solution was heated at 100° C. for 16 h. The reaction was cooled to RT, the phosphorous oxychloride was evaporated in vacuo and the residue was partitioned between sat. aq. NaHCO3 and CHCl3. The organic layer was dried over Na2SO4 and then concentrated. The residue was purified by flash chromatography (20% EtOAc:CHCl3) to provide the product as a white solid; MS m/z (M+H)+ 419; C24H20ClFN4 requir. 418.8.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([C:7]([OH:9])=[O:8])[O:5][C@@H:4]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:3]1[OH:28].[CH2:29]([O:36][C:37]([NH:39][C@H:40]([C:42](O)=[O:43])[CH3:41])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:20]([NH:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@@H:4]1[O:5][C@H:6]([C:7]([OH:9])=[O:8])[C@@H:2]([NH:1][C:42](=[O:43])[C@H:40]([CH3:41])[NH:39][C:37]([O:36][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:38])[C@H:3]1[OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Yield: 67.4 %

Procedure:
1-(6-Benzoylamino-9H-purin-9-yl)-3-(N-benzyloxycarbonyl-L-alanylamino)-1,3-dideoxy-β-D-ribofuranuronic acid (310 mg) was prepared by reacting 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronic acid (300 mg) prepared in Example 1 with N-hydroxysuccinimide ester of N-benzyloxycarbonyl-L-alanine (300 mg) according to a similar manner to that of Example 5, mp. 154°-156° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:16]=[C:17]([S:21]([CH2:23][CH3:24])=[O:22])[C:18]([Cl:20])=[CH:19][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])C.C1COCC1.[OH-].[Li+]>O>[Cl:20][C:18]1[C:17]([S:21]([CH2:23][CH3:24])=[O:22])=[CH:16][C:14]2[NH:15][C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]3)=[N:12][C:13]=2[CH:19]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(S(=O)CC)cc3[nH]2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCS(=O)c1cc2[nH]c(-n3cc(C(=O)O)cn3)nc2cc1Cl
Temperature: 23 °C
Reaction time: 56 h
Yield: 85.5 %

Procedure:
To a solution of 1-(5-chloro-6-ethanesulfinyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (100 mg, 0.273 mmol), THF (1.0 mL), and water (0.33 mL) was added lithium hydroxide (31.3 mg, 0.818 mmol). The mixture was sonicated briefly, and stirred at 23° C. for 56 h. The solvent was evaporated, water was added, and the resulting solution was acidified to pH 1 with 1M aq. HCl. The precipitate was collected to yield the titled compound (79.1 mg, 85% yield). MS (ESI/CI): mass calcd. for C13H11ClN4O3S, 338.0; m/z found, 339.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 13.88 (br s, 1H), 13.01 (br s, 1H), 8.94 (s, 1H), 8.40 (s, 1H), 8.03-7.55 (m, 2H), 3.23-3.11 (m, 1H), 2.89-2.78 (m, 1H), 1.08 (t, J=7.4 Hz, 3H).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([NH:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=1)=[O:9].CCN(C(C)C)C(C)C.[C:28]([O:32][C:33]([NH:35][C@@H:36]([CH3:40])[C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C.O>[Br:7][C:4]1[CH:5]=[CH:6][N:2]([NH:1][C:37](=[O:38])[C@@H:36]([NH:35][C:33](=[O:34])[O:32][C:28]([CH3:30])([CH3:29])[CH3:31])[CH3:40])[C:3]=1[C:8](=[O:9])[NH:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nn1ccc(Br)c1C(=O)Nc1cc(Cl)cc(Cl)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1ccc(Br)c1C(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
To a solution of 1.58 g (4.53 mmol) of 1-amino-3-bromo-N-(3,5-dichlorophenyl)-1H-pyrrole-2-carboxamide in 30 mL DMF were added 2.60 mL (14.93 mmol) of DIEA and 0.94 g (4.97 mmol) of (S)-2-(tert-butoxycarbonylamino)propanoic acid. The solution was cooled to 0° C. and 4 mL of T3P® (50% solution in DMF, 6.78 mmol) were added dropwise. The mixture was stirred at room temperature overnight and an additional 2.60 mL (14.93 mmol) of DIEA, 0.94 g (4.97 mmol) of (S)-2-(tert-butoxycarbonylamino)propanoic acid and 4 mL of T3P® (50% solution in DMF, 6.78 mmol) were added. The stirring was kept for 24 hours more and water was added to the reaction mixture. The product was extracted three times with ethyl acetate and the combined organic extracts were washed with water and brine, dried over magnesium sulphate, filtered and the solvents evaporated in vacuum. The product was purified by flash chromatography (0% to 50% hexane/AcOEt) to give 1.11 g (47% yield) of the title compound as a beige solid.
Reaction SMILES: [O:1]=[C:2]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)[CH2:3][CH2:4][CH2:5][Cl:6].[I].[Na].[CH3:20][N:21]([CH3:24])[CH:22]=O.Cl>CC(C)=O.CO>[ClH:6].[O:1]=[C:2]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2)[CH2:3][CH2:4][CH2:5][N:13]1[CH2:14][CH2:22][N:21]([C:24]2[CH:16]=[CH:7][CH:2]=[CH:3][CH:4]=2)[CH2:20][CH2:12]1
Reactant: O=C1CCc2cc(C(=O)CCCCl)ccc2N1
Reactant: CN(C)C=O
Agent: Cl
Agent: [I]
Agent: [Na]
Solvent: CO
Solvent: CC(C)=O
Product: O=C1CCc2cc(C(=O)CCCN3CCN(c4ccccc4)CC3)ccc2N1
Reaction time: 5 h

Procedure:
5.0 Grams of 6-(1-oxo-4-chlorobutyl)-3,4-dihydrocarbostyril and 3.5 g of sodium iodine were mixed in 100 ml of acetone and the mixture was stirred at 40°-50° C. for 5 hours. Then 80 ml of dimethylformamide was added to the mixture and acetone was removed from the mixture by distillation under reduced pressure. To this reaction mixture, 5.0 g of 4-phenylpiperazine and 5 g of triethylamine were added and stirred at 70°-80° C. for 6 hours. The reaction mixture was concentrated under a reduced pressure and 50 ml of 5%-sodium hydrogencarbonate solution was stirred to effect crystallization. Crude crystals thus formed were collected by filtration and washed with water and dried. Then the dried crude crystals were dispersed in 80 ml of chloroform and stirred at a room temperature for 1 hour. Insoluble matters in the chloroform solution were removed from the solution and chloroform was removed by distillation to obtain the residue. To the residue thus obtained was added 50 ml of methanol and 10 ml of concentrated hydrochloric acid and mixture was concentrated under a reduced pressure to dryness. To the residue thus obtained was added 50 ml of acetone and stirred to obtain crude crystals. The crude crystals were collected by filtration and washed with acetone and recrystallized from ethanol-water to obtain 5.7 g of 6-[1-oxo-4-(4-phenyl-1-piperazinyl)butyl]-3,4-dihydrocarbostyril monohydrochloride in yellowish powdery crystals.
Reaction SMILES: [CH:1]1([N:4]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:5][C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=2)=[CH:24][CH:23]=1)=[O:20].C(NC(C)C)(C)C>CN(C)C=O>[F:37][C:35]([F:36])([F:38])[C:32]1[CH:33]=[CH:34][C:29]([O:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][C:19]([N:15]3[CH2:16][CH2:17][CH:12]([N:4]([CH:1]4[CH2:2][CH2:3]4)[CH2:5][C:6]4[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=4)[CH2:13][CH2:14]3)=[O:20])=[CH:23][CH:24]=2)=[N:30][CH:31]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: c1cc(CN(C2CCNCC2)C2CC2)ccn1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(N(Cc2ccncc2)C2CC2)CC1

Procedure:
The title product was prepared from cyclopropyl-piperidine-4-yl-pyridin-4-ylmethyl-amine and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, 3 equivalent of diisopropylamine was added, solvent: dimethylformamide. The crude reaction mixture was evaporated without addition of acetic acid, preparative HPLC (method C) (19%, yellow oil). HPLC-MS m/z=(M+1), Rt: 2.82 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([NH:19][CH3:20])=[O:18])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.O.[C:22](O)(=O)[CH3:23]>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([NH:19][CH3:20])=[O:18])=[CH:14][CH:15]=3)[C:10]([C:3]3[CH2:4][CH2:5][NH:8][CH2:22][CH:23]=3)=[CH:9]2)=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: CNC(=O)c1ccc2c(ccn2-c2ccc(F)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CNC(=O)c1ccc2c(c1)c(C1=CCNCC1)cn2-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of 1-(4-Fluorophenyl)-N-methyl-1H-indole-5-carboxamide (3) (12.3 g) in a mixture of acetic acid (60 mL) and trifluoroacetic acid (15 rnL) was added during 0.5 h to a refluxing solution of 4-piperidon, HCl, H2O (36.6 g) in a mixture of acetic acid (50 mL) and trifluoroacetic acid (100 mL). The reaction mixture was refluxed for 1h, cooled to room temperature and the solvents were removed in vacuo. Water was added and pH was adjusted to 10 by addition of aqueous NaOH. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine and dried over MgSO4. Evaporation of the solvents in vacuo afforded the title compound as a foam.Yield 16 g. 1H-NMR (DMSO) 2.48 (s, broad, 2H), 2.80 (d. 3H), 2.98 (t, 2H), 3.50 (d, 2H), 6.40(s, 1H) 7.45 (t, 2H), 7.50 (d, 1H), 7.65 (dd, 2H), 7.70-7.80 (m, 2H), 8.40 (s, 1H), 8.45 (q, broad, 1H)
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1O)=[CH:13][CH:12]=[CH:11][C:10]=2[Br:17])([O:3][CH2:4][CH3:5])=[O:2].P(Cl)(Cl)(Cl)=O.C(O)(=O)C.C(OCC)(=O)C>O1CCOCC1.[Zn]>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[Br:17])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1cnc2c(Br)cccc2c1O
Agent: [Zn]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2c(Br)cccc2c1
Temperature: 65 °C
Reaction time: 12 h
Yield: 7.6 %

Procedure:
A mixture of 2.5 g (8.4 mmol) of 3-carbethoxy-4-hydroxy-8-bromoquinoline and 10 ml of phosphorus oxychloride was heated under reflux for 1 hour. After the completion of the reaction, phosphorus oxychloride was removed and the residue was purified by NH silica gel, to give 2.6 g of a chlorinated derivative. Next, 500 mg (1.6 mmol) of the chlorinated derivative was dissolved in 20 ml of dioxane, and 1 g of powdered zinc and 3 ml of acetic acid were added thereto, followed by heating at 65° C. for 30 minutes. To the reaction mixture was added ethyl acetate, followed by filtering through Celite. The filtrate was washed with brine, dried over magnesium sulfate and concentrated. To the residue was added 1 ml of acetic acid, and the mixture was left stand for 12 hours. Then, acetic acid was removed, and the residue was subjected to silica gel column chromatography and eluted with an eluent (ethyl acetate-n-hexane=1-7), to give 180 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH2:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[N+:14]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[S:24](Cl)(=[O:26])=[O:25])([O-:16])=[O:15]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH:13][S:24]([C:18]3[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=3[N+:14]([O-:16])=[O:15])(=[O:25])=[O:26])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COc1cc(N)c2ncccc2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Product: COc1cc(NS(=O)(=O)c2ccc(C)cc2[N+](=O)[O-])c2ncccc2c1
Yield: 58.2 %

Procedure:
In a similar fashion using route 14 general procedure 26, 6-methoxyquinolin-8-amine (Intermediate 23) (120 mg, 0.69 mmol) and 4-methyl-2-nitrobenzenesulfonyl chloride (Intermediate 20) (186 mg, 1.03 mmol) gave the title compound (150 mg, 58%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]=[C:9]([CH2:11][CH2:12][CH3:13])[NH:10][C:3]=12.[H-].[Na+].[C:16]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30]Br)=[CH:26][CH:25]=1)#[N:17].CC(O)=O>CN(C=O)C.C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:27]3[CH:26]=[CH:25][C:24]([C:23]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[C:16]#[N:17])=[CH:29][CH:28]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:3]=12
Reactant: CCCc1nc2nccc(C)c2[nH]1
Reactant: N#Cc1cnccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(-c2ccncc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 7-methyl-2-propylimidazo[4,5-b]pyridine (170 mg, 1.0 mmol) from Step B in DMF at rt was added NaH (1.0 mmol). After 20 min, 3-cyano-4-(4-bromomethylphenyl)pyridine (1 mL of a 2M solution in CH2Cl2, 2 mmol) was added and the mixture was stirred at rt for 3 h. HOAc (100 μL) was added, the excess DMF was removed in vacuo then the crude product was isolated by extraction with EtOAc from brine. Purification by flash chromatography (100% EtOAc) gave the above titled compound as a glassy solid.
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]([OH:18])=O)=[C:4]([F:19])[CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][N:25]=[C:24]2[CH3:30].C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[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]([NH:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][N:25]=[C:24]3[CH3:30])=[O:18])=[C:4]([F:19])[CH:3]=1
Reactant: CC1=C(C(=O)O)C(c2ccc(Cl)cc2F)CC(=O)N1
Reactant: Cc1n[nH]c2ccc(N)cc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(C)c3c2)C(c2ccc(Cl)cc2F)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.5 %

Procedure:
The product of Example 3, Step 2 (50 mg, 0.176 mmol, 1.00 equiv), 5-amino-3-methylindazole (26 mg, 0.176 mmol, 1.0 equiv), and EDC (41 mg, 0.212 mmol, 1.20 equiv) were suspended in 0.5 mL DMF. Et3N (0.030 mL, 0.212 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (20-100% EtOAc in Hexanes) to provide 20 mg (27%) of the title compound as an off white solid. MS (ES+) m/e 413 [M+H]+
Reaction SMILES: [CH:1](=[CH:8][C:9](=[O:13])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14](N(CC)CC)[CH3:15].ClC(OCC)=O>O>[CH:1](=[CH:8][C:9](=[O:13])[C:10]([O:12][CH2:14][CH3:15])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(=O)C=Cc1ccccc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: O
Product: CCOC(=O)C(=O)C=Cc1ccccc1
Reaction time: 1 h
Yield: 95 %

Procedure:
To the benzalpyruvic acid of step A in water-saturated ethyl acetate there was added triethylamine (56.2 g, 0.55 mol) at a rate less than 0.5 ml/min with good agitation. Water was then azeotropically removed by vacuum distillation and the benzalpyruvic acid concentration readjusted to 120 g/l with dry ethyl acetate. Ethyl chloroformate (59.7 g, 0.55 mol) was then added over a one hour period at 20°-25° C. followed by a one hour age. The mixture was cooled to 0°-5° C. and quenched with 350 ml of cold water. The aqueous layer was discarded and the organic layer was washed with cold (0°-5° C.) 5% sodium bicarbonate solution (350 ml) followed by cold (0°-5° C.) 5% sodium chloride (350 ml). The ethyl acetate was removed by vacuum concentration affording crude ethyl benzalpyruvate in a yield of 95-97%. The ester was subsequently purified by distillation using a short-path wiped film evaporator (WFE) apparatus (150° C., 0.1 mm Hg).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:12]([Br:13])=[CH:11][C:8]([C:9]#[N:10])=[C:7]([Cl:14])[CH:6]=1)[CH:2]=C.[CH2:15](O)CO>>[Br:13][C:12]1[C:5]2[O:4][CH:1]([CH3:2])[CH2:15][C:6]=2[C:7]([Cl:14])=[C:8]([C:9]#[N:10])[CH:11]=1
Reactant: OCCO
Reactant: C=CCOc1cc(Cl)c(C#N)cc1Br
Product: CC1Cc2c(Cl)c(C#N)cc(Br)c2O1
Temperature: 25 °C
Yield: 52 %

Procedure:
The compound 38 (2.03 g, 7.45 mmol) in ethylene glycol (5 mL) was subjected to microwave conditions (Biotage®) at 250° C. for 90 min. The reaction mixture was cooled to r.t. and extracted with EtOAc/H2O (50 mL/100 mL). The organic layer was dried over MgSO4, filtered off, and evaporated in vacuo. The residue was purified using normal phase column chromatography to obtain the title product (1.05 g, 52%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][O:20][CH:21]([CH3:23])[CH3:22])[CH2:15][C@H:14]1[C@@H:13]([CH3:24])[S:12][C:11]([NH:25]C(=O)C1C=CC=CC=1)=[N:10]2.FC1C=C(F)C=CC=1[C@]12CO[C@@H](COC)C[C@H]1[C@@H](C)SC(NC(=O)C1C=CC=CC=1)=N2.FC1C=C(F)C=CC=1[C@]12CO[C@@H](COC)C[C@H]1[C@@H](C)SC(N)=N2>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][O:20][CH:21]([CH3:22])[CH3:23])[CH2:15][C@H:14]1[C@@H:13]([CH3:24])[S:12][C:11]([NH2:25])=[N:10]2
Reactant: CC(C)OC[C@H]1C[C@H]2[C@@H](C)SC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Agent: COC[C@H]1C[C@H]2[C@@H](C)SC(N)=N[C@@]2(c2ccc(F)cc2F)CO1
Agent: COC[C@H]1C[C@H]2[C@@H](C)SC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Product: CC(C)OC[C@H]1C[C@H]2[C@@H](C)SC(N)=N[C@@]2(c2ccc(F)cc2F)CO1

Procedure:
N-{(4R,4aR,6R,8aS)-8a-(2,4-Difluorophenyl)-4-methyl-6-[(propan-2-yloxy)methyl]-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl}benzamide (C27) was deprotected using the method described for conversion of N-[(4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(methoxymethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C20) to (4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(methoxymethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-amine (2) in Example 2. The product was isolated as a white solid. Yield: 26.6 mg, 71.8 μmol, 88%. LCMS m/z 371.2 [M+H+]. 1H NMR (400 MHz, CD3OD) δ 7.32 (ddd, J=9.6, 8.6, 6.5 Hz, 1H), 6.92-7.01 (m, 2H), 4.10 (dd, J=11.1, 2.0 Hz, 1H), 3.73 (d, J=11.3 Hz, 1H), 3.7-3.77 (m, 1H), 3.67 (septet, J=6.1 Hz, 1H), 3.51 (dd, half of ABX pattern, J=10.2, 6.3 Hz, 1H), 3.45 (dd, half of ABX pattern, J=10.2, 4.2 Hz, 1H), 3.06-3.14 (m, 1H), 2.75 (ddd, J=12.2, 3.9, 3.6 Hz, 1H), 1.58-1.65 (m, 1H), 1.36-1.47 (m, 1H), 1.13-1.20 (m, 9H).