Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C=O.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>CCO>[OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: CC(=O)Nc1cccc(O)c1
Agent: C=O
Solvent: CCO
Product: CC(=O)Nc1ccc(N2CCOCC2)c(O)c1
Yield: 13 %

Procedure:
N-(3-hydroxyphenyl)acetamide (0.50 g, 3.31 mmol), formaldehyde 37% (678 μL, 2.7 eq), and morpholine (290 μL, 1 eq) were dissolved in 10 mL of EtOH. The reaction mixture was refluxed overnight, evaporated and purified by flash chromatography (DCM/MeOH/NH4OH 9.6:0.4:0.1) to yield expected compound as a pale yellow oil (107 mg, 13% yield). LC-MS: m/z (ESI) 251.3 [M+H]+; 1H NMR (300 MHz, MeOH-d4) δ7.09; (d, J=1.3 Hz, 1H), 6.8-6.9; (m, 2H), 3.6-3.7; (m, 4H), 3.58; (s, 2H), 2.4-2.5; (m, 4H), 2.0; (s, 3H)
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([N:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:9](=[O:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1)=[O:2].N1C=CC=CC=1.[O-:35][Mn](=O)(=O)=O.[K+]>O>[CH2:13]([N:8]([C:9](=[O:12])[CH2:10][CH3:11])[C:6]1[S:7][C:3]([C:1]([OH:35])=[O:2])=[CH:4][CH:5]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCCCCCCCCCCCCCCCN(C(=O)CC)c1ccc(C=O)s1
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCCCCCN(C(=O)CC)c1ccc(C(=O)O)s1

Procedure:
57.8 g of N-(5-formyl-thien-2-yl)-N-hexadecyl-propionic acid amide are dissolved in 300 cc. of pyridine. A solution of 14.6 g of KMnO4 in 198 cc. of pyridine and 85 cc. of water is added with stirring and cooling such that the temperature of the reaction does not rise above -3° C. Stirring is continued until all of KMnO4 has been reacted. Thereafter, the solvent is distilled off, the residue is triturated with dillued acid and the mixture is extracted with chloroform. The chloroform layer is separated, washed with water and dried over Na2SO4. The solvent is evaporated and the resulting crude product is purified chromatographically on a column of silicic acid gel using chloroform as eluant.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:7][C:6](=O)[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]1=2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1.C(OCC)(=O)C>CC1C=CC=CC=1C>[CH3:1][C:2]1([CH3:21])[O:7][C:6](=[S:31])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]1=2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cccc(C#N)c3)cc21
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CC1(C)OC(=S)Nc2ccc(-c3cccc(C#N)c3)cc21
Temperature: 25 °C
Yield: 19.8 %

Procedure:
A mixture of 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo [d][1,3]oxazin-6-yl)-benzonitrile (1 g, 3.6 mmol) and Lawesson's reagent (1.8 g, 4.3 mmol) in o-xylene (30 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature, poured into ethyl acetate (50 mL) and washed with 1 N HCl (2×20 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified via flash chromatography (silica gel, 20% ethyl acetate/hexane) to give 3-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-benzonitrile (0.21 g, 20%) as a white solid: mp 236–237° C.; 1H-NMR (DMSO-d6) δ 12.3 (s, 1H), 8.24 (s, 1H), 8.05 (d, 1H, J=8.07 Hz), 7.82 (d, 1H, J=7.68 Hz), 7.74–7.64 (m, 3H), 7.14 (d, 1H, J=8.78 Hz), 1.71 (s, 6H); MS(APCI) m/z 295 ([M+H]+, 100%); Anal. Calc. For C17H14N2OS: C, 69.36, H, 4.79, N, 9.52. Found: C, 68.35, H, 4.91, N, 9.07
Reaction SMILES: [C:1]([S:4][C@@H:5]([CH2:11][O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6]CC(O)=O)(=[O:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.[S].[C:41](OC(=O)C)(=[O:43])[CH3:42]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[C:41]([O:3][CH:1]1[S:4][C@@H:5]([CH2:11][O:12][Si:13]([C:26]([CH3:27])([CH3:29])[CH3:28])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:6][CH2:2]1)(=[O:43])[CH3:42]
Reactant: CC(=O)S[C@H](CCC(=O)O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CC(=O)OC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [S]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OC1CC[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S1

Procedure:
D-glutamic acid (1) was treated with sodium nitrite in hydrochloric acid to produce (R)-1,4-butyrolactone-4-carboxylic acid (2). Compound 2 was then reduced by borane-dimethyl sulfide complex in THF to give the corresponding (R)-4-(hydroxymethyl)-4-butyrolactone (4), which was subsequently treated with tert-butyldiphenylsilyl chloride in methylene chloride using imidazole as a catalyst to afford (R)-5-O-tert-butyldiphenylsilyl-4-hydroxymethyl-1,4-butyrolactone (53). The protected lactone 53 was opened with sodium hydroxide in ethanol and then converted to the methyl ester of 5-[(tert-butyldiphenylsilyl)oxy]-4-(R)-hydroxypentanoic acid (54) by reaction with dimethyl sulfate in dimethyl sulfoxide. Commpound 54 was transformed into the methyl ester of 5-[(tert-butyldiphenylsilyl)oxy]-4-(S)-iodopentanoic acid (55) by treatment with triphenylphosphine, imidazole and iodine. Displacement of the iodo group in compound 55 by thioacetate in toluene occurred readily to give the methyl ester of 4-(R)-(acetylthio)-5-[(tert-butyldiphenylsilyl)oxy]pentanoic acid (56). Compound 56 was then treated with 2 equivalents of diisobutylaluminum hydride (DIBAL) in toluene to reductively deprotect the sulfur and reduce the methyl ester to an aldehyde, thereby producing the thiolactol via spontaneous cyclization. The thiolactol was acetylated with acetic anhydride in pyridine to give 1-O-acetyl-5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-4-thio-L-ribofuranose (57): 1HNMR (CDCl3) delta 7.67 (m, 4H, ArH), 7.40 (m, 6H, ArH), 6.10 (m, 1H, 1-H), 3.70 (m, 1H, 4-H), 3.52 (m, 2H, 5-H), 2.20 (m, 2H, CH2), 2.00 (2 s, 3H, CH3CO--), 1.92 (m, 2H, CH2), 1.08 (s, 9H, tert-butyl).
Reaction SMILES: O1C=CC(=O)C=C1.[S].[O:9]=[C:10]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)CC#N.N1CCOCC1>C(O)C>[C:17]1([CH3:20])[CH:18]=[CH:19][C:14]([CH:10]=[O:9])=[CH:15][CH:16]=1
Reactant: Cc1ccc(C(=O)CC#N)cc1
Agent: O=c1ccocc1
Agent: [S]
Solvent: C1COCCN1
Solvent: CCO
Product: Cc1ccc(C=O)cc1
Temperature: 40 °C
Yield: 76.9 %

Procedure:
4-Pyranone (2.31 mL, 24.97 mmol) and sulphur (801 mg, 24.97 mmol) were added to a solution of 3-oxo-3-p-tolyl-propionitrile (3.79 g, 23.8 mmol) in ethanol (40 mL) followed by morpholine (2.18 mL, 24.97 mmol) and the reaction heated at 40° C. for 16 hours, The reaction mixture was concentrated in vacuo and the residue purified by flash chromatography on silica eluting with 0-20% ethylacetate/heptanes to afford 12-Amino-4,7-dihydro-5H-thieno[2,3-c]pyran-3-yl)-p-tolyl-methanone as a yellow solid (2.2 g, 36% yield). LCMS (2 min acidic) 1.07 min ES+/AP+ 274 (MH+). 1HNMR (400 MHz, CDCl3) δ ppm 2.00-2.03 (m, 2H), 2.42 (s, 3H), 3.80-3.84 (m, 2H), 4.80 (s, 2H), 6.60 (br s, 2H), 7.20 (d, 2H), 7.41 (d, 2H).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:11](=[N:13][OH:14])[CH3:12].[H-].[Na+].[Cl:17][C:18]1[N:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31]Cl)[C:20](=[O:24])[N:21]([CH3:23])[N:22]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:17][C:18]1[N:19]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][O:14][N:13]=[C:11]([C:2]2[CH:3]=[CH:4][C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=3[CH:1]=2)[CH3:12])[C:20](=[O:24])[N:21]([CH3:23])[N:22]=1
Reactant: Cn1nc(Cl)n(-c2ccccc2CCl)c1=O
Reactant: CC(=NO)c1ccc2c(c1)CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=NOCc1ccccc1-n1c(Cl)nn(C)c1=O)c1ccc2c(c1)CCCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the title compound of Step C (700 mg, 3.7 mmol) in dimethylformamide (10 mL) was added sodium hydride as a 60% oil dispersion (160 mg) followed by the title compound of Step B. The mixture was stirred at room temperature for 4 h and then was diluted with ethyl acetate. The solution was washed with water and then saturated sodium chloride solution. The organic phase was dried (MgSO4) and concentrated under reduced pressure to afford an oil. Chromatography of this oil on silica gel with 20-30% ethyl acetate in hexanes afforded 1.0 g of the title compound of Step D, a compound of the invention, as an oil which solidified on standing. 1H NMR (CDCl3): δ 7.68 (m,7H), 5.2 (m,2H), 3.47 (s,3H), 2.75 (m,4H), 2.15 (s,3H), 1.78 (m,4H). This material was used in the preparation of Example 4 without further characterization.
Reaction SMILES: O[CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][C:4]([O:6]C(C)(C)C)=[O:5].[SH:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35].FC(F)(F)C(O)=O>C(Cl)Cl>[C:34]([CH2:33][CH2:32][S:31][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:3][C:4]([OH:6])=[O:5])([O:36][CH3:37])=[O:35]
Reactant: CC(C)(C)OC(=O)CC(O)c1ccccc1CCCCCCCCc1ccccc1
Reactant: COC(=O)CCS
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCSC(CC(=O)O)c1ccccc1CCCCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of t-butyl 3-hydroxy-3-[2-(8-phenyloctyl)phenyl]propanoate (4.0 gm, 9.7 mmole) in methylene chloride (40 ml) was stirred under an inert atmosphere at -10° C. To this cold solution was added methyl 3-mercaptopropionate (6.2 ml, 56 mmole) in one portion followed by dropwise addition of trifluoroacetic acid (80 ml). The reaction mixture was then stirred for 5 hours at 0° C. Solvent and excess trifluoroacetic acid were removed on a rotary evaporator. The residue was redissolved in methylene chloride and washed twice with water and once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. Chromatography on silica gel eluting with hexane-ethyl acetate formic acid (85/15/0.5) gave the title compound. Anal.: Calcd. for C27H36O4S: C, 71.17; H, 7.74. Found: C, 70.46; H, 7.72. 250 MHz NMR (CDCl3) δ 1.28-1.68 (12H,m) 2.48 (2H,t) 2.56-2.72 (6H,m) 2.93 (2H,d) 3.66 (3H,s) 4.60 (1H,t) 7.18-7.39 (9H,m).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][C:8]1[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=2)[C:10](=[O:24])[CH:9]=1.P(Br)(Br)[Br:26]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:26][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][N:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[CH:9][C:10]2=[O:24])=[CH:17][CH:18]=1
Reactant: BrP(Br)Br
Reactant: O=c1cc(OCc2ccco2)ccn1CCc1ccc(CO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1cc(OCc2ccco2)ccn1CCc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 80 mg (0.25 mmol) 4-(furan-2-ylmethoxy)-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (example 6.1a) in 3.0 mL of DCM is added at 0° C. 35 μL (0.37 mmol) phosphorus tribromide. After warming to RT, the mixture is stirred 2 h at RT and is diluted with half saturated aqueous NaHCO3-solution. The layers are separated, the aqueous phase is extracted three times with DCM/MeOH. The combined organic phase is dried over MgSO4, filtered and the solvent is evaporated to afford the product.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([C:11](=O)/[CH:12]=[CH:13]/[N:14](C)C)[CH:8]=[CH:7][C:6]=1[S:18]([CH3:21])(=[O:20])=[O:19])(=O)C.[NH:22]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][N:31]=1)[C:27]#[N:28])N>CCO.CC(O)=O>[CH3:1][O:4][C:5]1[CH:10]=[C:9]([C:11]2[N:22]([C:24]3[CH:25]=[C:26]([C:27]#[N:28])[CH:29]=[CH:30][N:31]=3)[N:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:6]=1[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: CC(=O)Oc1cc(C(=O)/C=C/N(C)C)ccc1S(C)(=O)=O
Reactant: N#Cc1ccnc(NN)c1
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(-c2ccnn2-c2cc(C#N)ccn2)ccc1S(C)(=O)=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 14.4 %

Procedure:
A mixture of 5-[(2E)-3-(dimethylamino)prop-2-enoyl]-2-(methylsulfonyl)phenyl acetate (1.5 g, 5.3 mmol) and 2-hydrazinylisonicotinonitrile (0.8 g, 6 mmol, PREPARATION 2) in EtOH (15 mL) and AcOH (3 mL) was stirred at 90° C. overnight. The reaction mixture was cooled, concentrated, and purified by prep-HPLC to afford the title compound (270 mg, 14%). 1H NMR (400 MHz, CDCl3): δ 3.26 (3H, s), 3.96 (3H, s), 6.58 (1H, d, J=1.6 Hz), 6.96 (1H, dd, J=8.4, 1.2 Hz), 7.05 (1H, d, J=1.2 Hz), 7.41 (1H, dd, J=4.8, 1.2 Hz), 7.81 (1H, d, J=2.0 Hz), 7.93 (1H, d, J=8.4 Hz), 8.18 (1H, s), 8.35 (1H, d, J=4.8 Hz). [M+H] Calc'd for C17H14N4O3S, 355. Found, 355.
Reaction SMILES: Cl.[CH:2]([NH:5][NH2:6])([CH3:4])[CH3:3].[C:7](NN)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].S([O-])([O-])(=O)=O.[Mg+2]>CC(C)=O>[CH3:3][C:2](=[N:5][NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:4]
Reactant: CC(C)NN
Reactant: CC(C)(C)OC(=O)NN
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CC(C)=NNC(=O)OC(C)(C)C

Procedure:
Scheme 1 shows the synthesis of intermediate isopropylhydrazine hydrochloride 4 from Boc-hydrazine 1. Condensation of 1 with acetone and magnesium sulfate gave Boc-hydrazone, tert-butyl 2-(propan-2-ylidene)hydrazinecarboxylate 2 (Example 1). Palladium-catalyzed hydrogenation of 2 in acetic acid and methanol gave Boc-isopropyl-hydrazine 3 (Example 2) which was treated in situ with hydrogen chloride gas to give 4 (Example 3).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#N.CC(C[AlH]CC(C)C)C.Cl.[OH-:28].[Na+]>C1COCC1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][N:6]2[CH2:7][CH2:8][CH:3]([CH:1]=[O:28])[CH2:4][CH2:5]2)=[CH:12][CH:13]=1
Reactant: N#CC1CCN(CCc2ccc(F)cc2)CC1
Reactant: [OH-]
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=CC1CCN(CCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-cyano-1-[2-(4-fluorophenyl)ethyl]piperidine (1.00 g, 4.3 mmol) in THF (20 mL) under argon at 0° C. was added DIBAL-H (4.6 mL of a 1.0 M solution in THF, 4.6 mmol) via syringe. After stirring overnight at room temperature, 10% aqueous HCl (25 mL) was added and the solution was stirred for 3 hours. The entire mixture was then poured into 10% aqueous NaOH (50 mL), then extracted 2× with ether. The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated to afford a pale yellow oil. The oil was chromatographed on silica gel, eluting with EtOAc. The appropriate fractions were combined and evaporated to afford an oil. This oil was distilled (b.p. 166° C., 0.05 mm Hg) to afford 1-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxaldehyde, obtained as a colorless oil. Anal. Calcd. for C14H18FNO: C, 71.46; H, 7.71; N, 5.95. Found: C, 71.08; H, 7.81; N, 5.86.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][CH:9]2[CH2:12][N:11]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[CH2:10]2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:23]1[CH2:28][CH2:27][CH:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+].CC(O)C>O>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[N:11]1[CH2:12][CH:9]([O:8][C:3]2[C:2]([N:23]3[CH2:28][CH2:27][CH:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]3)=[N:7][CH:6]=[CH:5][N:4]=2)[CH2:10]1
Reactant: CC(=O)C1CCNCC1
Reactant: Clc1nccnc1OC1CN(c2ccc3ccccc3n2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CC(=O)C1CCN(c2nccnc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Temperature: 160 °C
Yield: 18 %

Procedure:
To a mixture of 2-(3-((3-chloropyrazin-2-yl)oxy)azetidin-1-yl)quinoline (see PREPARATION P2.6; 312 mg, 1.0 mmol) and 1-(piperidin-4-yl)ethanone (127 mg, 1.0 mmol) and K2CO3 (276 mg, 2.0 mmol) was added i-PrOH (3 mL) and water (1.0 ml). The solution was heated to 160° C. under microwave for 5 hours. Then the mixture was concentrated and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel (20% to 60% EtOAc in petroleum ether) to give the title product (72 mg, 0.18 mmol, 18% yield) as white solid. ESI-MS (M+1): 404 calc. for C23H25N5O2 403.
Reaction SMILES: [C:1]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][N:10]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[C:7]([OH:33])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CI.[C:36](=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][N:10]([CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[C:7]([O:33][CH3:36])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)c1ccc(CN(CCc2ccc(F)cc2)C(=O)c2cccc3cc[nH]c23)c(O)c1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1cc(C(C)(C)C)ccc1CN(CCc1ccc(F)cc1)C(=O)c1cccc2cc[nH]c12
Temperature: 60 °C
Yield: 39.3 %

Procedure:
133 mg (0.3 mmol) of 1H-indole-7-carboxylic acid (4-tert-butyl-2-hydroxy-benzyl)-[2-(4-fluoro-phenyl)-ethyl]-amide, 64 mg (0.45 mmol) of methyl iodide and 83 mg (0.6 mmol) of potassium carbonate were heated in 3 ml acetonitrile for 2 h to 60° C. Additional 32 mg (0.22 mmol) of methyl iodide were added and the reaction mixture was heated to 60° C. over night. The reaction mixture was filtered and the solvent was evaporated. The residue was purified by column chromatography (20 g silica gel; DCM/diethyl ether 10:1) to yield 54 mg (39%) product as a colorless gum. MS (ISP) 459.6 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[C:7]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=2)(=[O:21])=[O:20])[N:6]=[C:5]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35](N)=[O:36])[CH:30]=2)[N:4]=1.Cl.C1C[O:42]CC1>C1COCC1.O1CCOCC1>[CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[C:7]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=2)(=[O:21])=[O:20])[N:6]=[C:5]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]([OH:42])=[O:36])[CH:30]=2)[N:4]=1
Reactant: C1CCOC1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(C(N)=O)c2)nc1OC
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(C(=O)O)c2)nc1OC

Procedure:
1 g of 4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxylic acid amide, product of example 20, dissolved in a mixture of THF/dioxane (40 ml/30 ml) were treated at RT with 3N HCl (40 ml) and the solution was refluxed for 24 h, further THF (12 ml) and 3M HCl (12 ml) was then added and the solution was heated to reflux for further 24 h until the transformation was complete according to TLC analysis. The reaction mixture was concentrated in vacuo and the product was extracted into CH2Cl2. The organic layer was dried over Na2SO4, the solvent removed in vacuo. The remaining crystalline solid was washed with ether and dried in a vacuum to give 4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxylic acid as an off-white solid. ISN mass spectrum, m/e 522 (M−1 calculated for C24H21N5O7S: 522).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([S:19]([C:16]3[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=3)(=[O:21])=[O:20])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2cc[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3ncc(Br)cc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a solution of 6-bromo-1H-pyrrolo[3,2-b]pyridine (4.0 g, 20.3 mmol) in DMF (40 mL) at 0° C. was added sodium hydride (893 mg, 22.33 mmol). The reaction mixture was stirred at 0° C. for 30 minutes. Next, p-toluensulfonyl chloride (4.64 g, 24.26 mmol) was added, and the reaction mixture was stirred for 1 hour while warming to RT. The reaction mixture was subsequently diluted with DCM (300 mL) and washed with brine. The combined organic layers were dried over MgSO4, concentrated in vacuo, and purified by silica gel chromatography (1% to 2% MeOH/DCM) to give the title compound as a white solid (6.87 g, 96%). 1H NMR (500 MHz, CDCl3) δ ppm 8.58 (d, 1H, J=2.0 Hz), 8.43 (d, 1H, J=2.0 Hz), 7.74-7.78 (m, 3H), 7.29 (d, 2H, J=8.0 Hz), 6.83 (d, 1H, J=4.0 Hz), 2.38 (s, 3H); ESI-MS m/z [M+H]+ calc'd for C14H11BrN2O2S, 351, 353; found 351, 353.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C([O-])(=O)C.[NH4+].C(O)(=O)C>O>[N+:17](/[CH:20]=[CH:13]/[C:12]1[CH:15]=[CH:16][C:9]([CH2:8][O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:10][CH:11]=1)([O-:19])=[O:18]
Reactant: O=Cc1ccc(COc2ccccn2)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])/C=C/c1ccc(COc2ccccn2)cc1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 74.5 %

Procedure:
A mixture of 4-(pyridin-2-yloxymethyl)-benzaldehyde (23.4 g, 110 mmol) described in Manufacturing Example 2-1-2, nitromethane (33.6 g, 550 mmol), ammonium acetate (17.0 g, 220 mmol) and acetic acid (200 mL) was stirred for 1 hour and 45 minutes at 100° C. The reaction solution was stirred on an ice bath while adding a small amount of water, and the precipitated solids were filtered to obtain the title compound (21.0 g, 74.5%).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[CH2:6]([N:8]([CH2:29][CH3:30])[CH2:9][CH:10]([N:12]1[C:25]2[CH:24]=[C:23]([C:26](=[S:28])N)[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])[CH3:7]>C(O)C>[CH2:1]([NH:5][C:26]([C:23]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH:10]([CH3:11])[CH2:9][N:8]([CH2:29][CH3:30])[CH2:6][CH3:7])[C:25]=2[CH:24]=1)=[S:28])[CH2:2][CH2:3][CH3:4]
Reactant: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: CCCCN
Solvent: CCO
Product: CCCCNC(=S)c1ccc2c(c1)N(C(C)CN(CC)CC)c1ccccc1S2
Reaction time: 16 h

Procedure:
n-Butylamine (2.4 cc) is added to a solution of 10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbothioamide (1.86 g) in absolute ethanol (25 cc). The mixture is brought to 150° C. for 16 hours and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue obtained is purified by chromatography on a column (height: 17 cm; diameter: 2.6 cm) of silica gel (0.04-0.06 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with mixtures of cyclohexane and ethyl acetate in proportions (by volume) of 90:10 (250 cc), 80:20 (500 cc) and 50:50 (750 cc) and then with pure ethyl acetate (750 cc), collecting 50-cc fractions. Fractions 10 to 18 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give N-butyl-10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbothioamide (0.96 g).