Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C-:3]=[N:2]1.[Na+].[CH3:7][O:8][C:9]1[CH:62]=[CH:61][CH:60]=[CH:59][C:10]=1[CH2:11][O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH:24]2[O:36][CH2:37][CH2:38][O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[CH2:46][CH2:47]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:19][CH:18]=1>CN(C)C=O.COC(C)(C)C>[CH3:7][O:8][C:9]1[CH:62]=[CH:61][CH:60]=[CH:59][C:10]=1[CH2:11][O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[CH2:25][CH:24]2[O:36][CH2:37][CH2:38][O:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[CH2:46][CH2:47][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:21][CH:22]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: [c-]1nc[nH]n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCn2cncn2)cc1
Temperature: 90 °C
Reaction time: 0.67 h

Procedure:
0.051 g of sodium 1,2,4-triazolide is admixed with a solution of 0.10 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-(2-{2-[2-(toluene-4-sulphonyloxy)ethyl]phenoxy}-ethoxy)piperidine-1-carboxylate in 3 ml of N,N-dimethylformamide. The reaction mixture is stirred at 90° C. over 40 minutes. The mixture is cooled to room temperature, diluted with tert-butyl methyl ether and washed with water. The water phase is extracted with tert-butyl methyl ether. The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.13 (2:1 EtOAc-heptane); Rt=5.66.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([CH:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH2:20])=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[C:31](Cl)=[O:32]>CN(C)C=O>[Cl:8][C:9]1[C:10]([CH:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[NH:20][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:28]([O:27][CH3:26])[CH:29]=2)=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:14]=1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CCOC(=O)C(N)c1ncc(C(F)(F)F)cc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(NC(=O)c1ccc(OC)c(OC)c1)c1ncc(C(F)(F)F)cc1Cl
Reaction time: 0.75 h

Procedure:
Triethylamine (0.28 ml) was added to a solution of ethyl 2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycinate (1 g; prepared in a similar manner to the starting material for Example 3) in dimethylformamide (10 ml) with stiring followed by 3,4-dimethoxybenzoyl chloride (0.70 g). the mixture was stirred for 45 minutes and evaporated. The residue was extracted with ethyl acetate and the extracts worked up to give the title product, m.p. 40-3° C. (Compound 601)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([CH2:15][CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])[CH2:3][CH2:2]1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[O:16]=[C:7]1[C:4]2([CH2:3][CH2:2][N:1]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:6][CH2:5]2)[CH2:15][CH2:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: O=C1c2ccccc2CCC12CCNCC2
Reactant: CCOC(=O)CBr
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCC2(CCc3ccccc3C2=O)CC1
Temperature: 25 °C

Procedure:
A solution of 3,4-dihydro-1H-spiro[naphthalene-2,4′-piperidin]-1-one (72 mg, 0.286 mmol), ethyl bromoacetate (62.1 mg, 0.37 mmol) and triethylamine (0.20 mL, 1.43 mmol) in acetonitrile (5 ml) was heated at 80° C. for 3 h. The reaction was cooled to 25° C. and diluted with 20 mL of ethyl acetate and washed twice with 10 mL of water, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (gradient of 85:15 to 60:40 heptane/ethyl acetate over 20 min) to give the title compound as a white solid. MS calculated for C18H24NO3 302.4. found (ESI) m/z 302.5 (M+H)+, retention time 0.81 min.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH:27]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH3:2][N:3]([CH2:27][C:18]1[CH:19]=[CH:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:17]=1)[CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16]
Reactant: CNCCN1C(=O)c2ccccc2C1=O
Reactant: O=Cc1ccc2ccccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(CCN1C(=O)c2ccccc2C1=O)Cc1ccc2ccccc2n1
Reaction time: 16 h

Procedure:
To the HCl salt of 2-(2-Methylamino-ethyl)-isoindole-1,3-dione (1 eq) in dichloromethane was added quinoline-2-carbaldehyde(1.2 eq), sodium triacetoxyborohydride (2 eq), and acetic acid (1.2 eq) at rt.; the solution was allowed to stir for 16 hours. After concentration, the solution was diluted with ethyl acetate, washed with NaHCO3(sat), NaCl(sat), dried over MgSO4, filtered, concentrated and pumped on. The yellow oil was then purified using flash chromatography (2% methanol/dichloromethane with 0.1% triethylamine) to yield 2-[2-(Methyl-quinolin-2-ylmethyl-amino)-ethyl]-isoindole-1,3-dione as a green solid. MH+(346).
Reaction SMILES: [CH:1]1([CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH3:20])[C:14]=3[O:17][CH3:18])[C:9](=[O:21])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([C:26]#[N:27])(C)C.[Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[NH2:27][CH2:26][C:9]1([OH:21])[C:10]2[C:15](=[C:14]([O:17][CH3:18])[C:13]([O:19][CH3:20])=[CH:12][CH:11]=2)[CH2:16][CH:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:8]1
Reactant: COc1ccc2c(c1OC)CC(C1CCCCC1)CC2=O
Reactant: C[Si](C)(C)C#N
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Product: COc1ccc2c(c1OC)CC(C1CCCCC1)CC2(O)CN

Procedure:
2-(2',3'-Dimethoxyphenyl)-1,3-dithiane, from Step 1 of Example 1, Method B, and ethyl 3-cyclohexylpropenoate, from Step 1 of this Example, were condensed as described in Step 2 of Example 1, Method B. The adduct was treated with Raney nickel and sodium hydroxide to give the corresponding acid. The acid was cyclized with polyphosphoric acid as described in Step 6 of Example 1, Method A, to give 3-cyclohexyl-5,6-dimethoxy-1,2,3,4-tetrahydronaphthalen-1-one. This ketone was treated with trimethylsilylcyanide in the presence of aluminum chloride and reduced with lithium aluminum hydride as described in Step 1 of Example 2 to give 1-aminomethyl-5,6-dimethoxy-1-hydroxy-3-cyclohexyl-1,2,3,4-tetrahydronaphthalene. The hydroxy group was eliminated by treatment with anhydrous hydrogen chloride in isopropyl alcohol as described in Step 2 of Example 2 to give 1-aminomethyl-3-cyclohexyl-5,6-dimethoxy-3,4-dihydronaphthalene hydrochloride, m.p. 178°-179° C.; 1H NMR (d6 -DMSO) δ: 1.0-1.4 (m, 7H), 1.5-1.9 (m, 6H), 2.0-2.2 (m, 1H), 2.5 (dd, 1H), 2.7 (dd, 1H), 3.6 (s, 3H), 3.81 (s, 3H), 5.8 (d, 1H), 6.6 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][N:13]=[C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]([C:25]3[CH:26]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=4[Cl:44])[C:27]([C:33]([O:35][CH3:36])=[O:34])=[C:28]([CH3:32])[NH:29][C:30]=3[CH3:31])=[O:24])[CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H].C>C(O)C.[Ni].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][N:13]=[C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]([C:25]3[CH:26]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[C:38]=4[Cl:44])[C:27]([C:33]([O:35][CH3:36])=[O:34])=[C:28]([CH3:32])[NH:29][C:30]=3[CH3:31])=[O:24])[CH:11]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCOc2cc(-c3ccc([N+](=O)[O-])cc3)[nH]n2)C1c1cccc(Cl)c1Cl
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCOc2cc(-c3ccc(N)cc3)[nH]n2)C1c1cccc(Cl)c1Cl
Yield: 54 %

Procedure:
12.86 g (20 mmole) of 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5-p-nitrophenyl-3-pyrazolyloxy)hexyl ester (Example 60) was dissolved in 100 ml of ethanol, to which was added 5 ml of Raney nickel, and catalytic hydrogenation was effected at room temperature and atmospheric pressure, thereby 1350 ml (60 mmole) of hydrogen was absorbed. The Raney nickel was filtered off from the reaction mixture, and the filtrate was concentrated under reduced pressure to obtain a pale yellow oily residue. This residue was purified by chromatography on a silica gel column using a mixed solution of chloroform-methanol (the ratio by volume of 3:1) as an eluent, and the fractions containing the intended compound were concentrated under reduced pressure to obtain a pale yellow oily residue. This residue was dissolved in ethyl acetate, and after adding 5 g of activated charcoal, stirred well, and filtered. The filtrate was concentrated to dryness under reduced pressure to obtain 6.63 g (yield 54.0%) of the 1,4-dihydro-2,6-dimethyl-4 -(2,3-dichlorophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5-p-aminophenyl-3-pyrazolyloxy)hexyl ester as a pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].C[Si]([N:14]=[C:15]=[O:16])(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:15]([NH2:14])=[O:16])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: Nc1cc(F)cc(F)c1
Solvent: ClCCl
Product: NC(=O)Nc1cc(F)cc(F)c1
Reaction time: 8 h
Yield: 37.6 %

Procedure:
To a stirred solution of 3,5-difluoroaniline (4.0 g, 31 mmol, 1.00 equiv) in CH2Cl2 (50 mL) under argon at room temperature was added dropwise trimethylsilyl isocyanate (3.56 g, 30.90 mmol, 1.00 equiv). The reaction mixture was stirred overnight and quenched by the dropwise addition of CH3OH (50 mL). The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by flash chromatography (silica gel, eluting with CHCl3/CH3OH (10:1 to 7:1)) to yield 2.0 g (38%) of the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6): δ ppm 8.96 (s, 1H), 7.16-7.10 (m, 2H), 6.72-6.66 (m, 1H), 6.07 (br s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[C:5]([Cl:12])=[C:4]([Cl:13])[C:3]=1[Cl:14].O.[NH2:16]N>CS(C)=O>[Cl:1][C:2]1[C:7]([NH:8][NH2:16])=[C:6]([Cl:11])[C:5]([Cl:12])=[C:4]([Cl:13])[C:3]=1[Cl:14]
Reactant: O=[N+]([O-])c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: NN
Solvent: O
Solvent: CS(C)=O
Product: NNc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Pentachloronitrobenzene containing 5-10% hexaxchlorobenzene, (3.0 g, 10.1 mmole) was dissolved in dimethylsulphoxide (35 ml). Hydrazine hydrate (1.25 g, 25 mmole) was added dropwise with stirring at 25° C. A slight 4°-5° C. increase in temperature was recorded and the solution became red-brown. After approximately 20 minutes a white solid began to be precipitated. Stirring was continued for one hour after which time TLC (1:1 ethyl acetate: 60°-80° C. petrol) indicated that the reaction was complete. The mixture was poured into stirred water (200 ml) and the solid filtered off and dried at 50° C. overnight. The TLC and IR was identical to an authentic sample of pentachlorophenylhydrazine. Yield=2.27 g, 80%.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][NH:6][C:7]1([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH:22]4[CH2:27][CH2:26][CH:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:24][CH2:23]4)[CH:17]=3)[CH:12]=2)[CH2:10][O:9][CH2:8]1.[OH-].[Li+].O1CCCC1.O>>[C:28]([C@H:25]1[CH2:24][CH2:23][C@H:22]([O:21][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[CH:12]=[C:11]([C:7]2([NH:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])[CH2:8][O:9][CH2:10]2)[CH:20]=[CH:19]3)[CH2:27][CH2:26]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)CCNC1(c2ccc3cc(OC4CCC(C(C)(C)C)CC4)ccc3c2)COC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C4(NCCC(=O)O)COC4)ccc3c2)CC1

Procedure:
A solution of 3-{3-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-oxetan-3-ylamino}-propionic acid methyl ester (18.0 mg, 0.0409 mmol) and Lithium hydroxide (6.41 mg, 0.268 mmol) in Tetrahydrofuran (0.6 mL, 8 mmol) and Water (0.2 mL, 9 mmol) was stirred at r.t. overnight. LCMS showed a single desired product peak M+Na at m/z 448.20, RT 1.56 min. The solvent was concentrated and neutralized with citric acid and concentrated and purified on HPLC to give product (5.8 mg, 33%). 1H NMR (400 MHz, MeOD) δ=7.91 (d, J=8.4 Hz, 1H), 7.87 (s, 1H), 7.83 (d, J=8.9 Hz, 1H), 7.38 (d, J=8.2 Hz, 1H), 7.31 (s, 1H), 7.20 (d, J=6.8 Hz, 1H), 5.26 (d, J=7.9 Hz, 2H), 5.13 (d, J=7.7 Hz, 2H), 4.43-4.32 (m, 1H), 3.05 (t, J=5.1 Hz, 2H), 2.70-2.62 (m, 2H), 2.27 (d, J=11.2 Hz, 2H), 1.96-1.85 (m, 2H), 1.50-1.35 (m, 2H), 1.34-1.18 (m, 2H), 1.17-1.04 (m, 1H), 0.91 (s, 9H).
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[N:4][C:3]=1[CH3:7].C(N(CC)CC)C.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]#[CH:23]>COCCOC.C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]#[C:23][C:2]1[S:6][CH:5]=[N:4][C:3]=1[CH3:7]
Reactant: C#Cc1ccccc1F
Reactant: Cc1ncsc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: Cc1ncsc1C#Cc1ccccc1F
Yield: 113.4 %

Procedure:
5-Bromo-4-methyl-1,3-thiazole (500 mg, 2.8 mmol) and CuI (120 mg, 0.63 mmol) were combined in DME (5 mL) and argon gas was bubbled through the suspension for several minutes to deoxygenate the mixture. Triethylamine (2.0 mL, 14 mmol) and PdCl2(PPh3)2 (220 mg, 0.32 mmol) were added, followed by the dropwise addition of (2-fluorophenyl)acetylene (1.0 g, 8.3 mmol). The reaction mixture was heated and after 3 h at reflux, allowed to cool, diluted with ethyl acetate (20 mL), and filtered through Celite™. The filter pad was washed thoroughly with ethyl acetate and the combined filtrates were washed with water (20 mL), brine (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography on silica gel eluting with 95:5 hexane:ethyl acetate to afford 5-[(2-fluorophenyl)ethynyl]-4-methyl-1,3-thiazole (690 mg, 56% yield) as a red oil. 1H NMR (CDCl3, 300 MHz) δ 8.65 (s, 1H), 7.53–7.47 (m, 1H), 7.36–7.26 (m, 1H), 7.17–7.09 (m, 2H), 2.62 (s, 3H). MS (ESI) 217.3 (M+).
Reaction SMILES: [ClH:1].[CH2:2]([C:5]1[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=1)[C:3]#[CH:4].[N:11]([CH2:14][C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)=[N+:12]=[N-:13]>>[ClH:1].[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[CH2:14][N:11]1[CH:4]=[C:3]([CH2:2][C:5]2[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=2)[N:13]=[N:12]1
Reactant: [N-]=[N+]=NCc1ccco1
Reactant: C#CCc1c[nH]c(N)n1
Agent: Cl
Product: Nc1nc(Cc2cn(Cc3ccco3)nn2)c[nH]1
Yield: 455.5 %

Procedure:
4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.096 g, 0.061 mmol) was reacted with 2-azidomethyl-furan (0.089 g, 0.729 mmol) following the general procedure for click reactions outlined above to produce 4-(1-Furan-2-ylmethyl-1H-[1,2,3]triazol-4-ylmethyl)-1H-imidazol-2-ylamine hydrochloride (0.078 g, 46%) as a pale yellow solid, 1H NMR (300 MHz, CD3OD) δ 7.93 (s, 1H), δ 7.41 (s, 1H), 6.49 (s, 2H), δ 6.32 (s, 1H), δ 5.56 (s, 2H), δ 3.89 (s, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 146.2, 146.1, 142.4, 141.5, 122.3, 122.2, 108.9, 109.2, 108.8, 51.6, 18.9 ppm; HRMS (ESI) calcd for C11H12N6O (M+) 245.1145. Found 245.1147.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].ClCCl.[OH:9][CH2:10][CH:11]([CH3:26])[CH2:12][CH2:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][C:21](=[O:25])[NH:22]2)=[CH:17][CH:16]=1.C(N(CC)CC)C>O>[CH3:26][CH:11]([CH2:12][CH2:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][C:21](=[O:25])[NH:22]2)=[CH:17][CH:16]=1)[CH2:10][O:9][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CC(CO)CCOc1ccc2c(c1)NC(=O)CC2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(CCOc1ccc2c(c1)NC(=O)CC2)COS(C)(=O)=O

Procedure:
Methanesulfonyl chloride (1.0 ml) was added to a dichloromethane (80 ml) solution of 2.8 g of 7-(4-hydroxy-3-methyl butoxy)-3,4-dihydro-1H-quinolin-2-one and 2.4 ml of triethylamine while being stirred under ice-cooling and stirred at room temperature overnight. Water was added to the reaction solution, which was then extracted with dichloromethane and, after washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=30:1), and methanesulfonic acid 2-methyl-4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)butyl ester (2.8 g) was obtained in the form of a green powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8](S(C1C=CC(C)=CC=1)(=O)=O)[CH:7]([CH2:22][N:23]1[CH2:28][CH2:27][C:26]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)([OH:29])[CH2:25][CH2:24]1)[CH2:6]2.[H-].COCCO[Al+]OCCOC.[Na+].[H-].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH2:22][N:23]1[CH2:28][CH2:27][C:26]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=3)([OH:29])[CH2:25][CH2:24]1)[CH2:6]2
Reactant: COc1ccc2c(c1)CC(CN1CCC(O)(Cc3ccc(C)cc3)CC1)N2S(=O)(=O)c1ccc(C)cc1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CC(CN1CCC(O)(Cc3ccc(C)cc3)CC1)N2
Yield: 75.2 %

Procedure:
To a solution of (RS)-1-[5-methoxy-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-2-ylmethyl]-4-(4-methyl-benzyl)-piperidin-4-ol (300 mg, 0.576 mmol) in toluene (15 ml) was added sodium bis(2-methoxy-ethoxy) aluminium hydride (3.5 M in THF) (0.66 ml, 2.31 mmol), and the mixture refluxed 18 hr. After cooling, 2N NaOH was added to pH 14, the mixture was extracted with EtOAc (3x 25ml) and the combined extracts washed with satd. NaCl (25 ml), dried with (Na2SO4) then filtered and evaporated. The residue was chromatographed over SiO2 (Merck 230-400 mesh) eluting with EtOAc-cyclohexane-Et3N (9:10:1) to afford (RS)-1-(5-methoxy-2,3-dihydro-1H-indol-2-ylmethyl)-4-(4-methyl-benzyl)-piperidin-4-ol as a viscous yellow oil (158.4 mg, 0.433 mmol, 75%), MS: m/e=367.3 (M+H+).
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:11][N:12]1[CH2:18][CH:17]2[N:19]([C:20]3[CH:21]=[CH:22][C:23]([NH2:26])=[N:24][CH:25]=3)[CH:14]([CH2:15][CH2:16]2)[CH2:13]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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:8][C:6]1[CH:7]=[C:2]([NH:26][C:23]2[CH:22]=[CH:21][C:20]([N:19]3[C@H:14]4[CH2:15][CH2:16][C@@H:17]3[CH2:18][N:12]([CH3:11])[CH2:13]4)=[CH:25][N:24]=2)[C:3](=[O:10])[N:4]([CH3:9])[N:5]=1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Reactant: CN1CC2CCC(C1)N2c1ccc(N)nc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1C[C@H]2CC[C@@H](C1)N2c1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
A solution of 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (492 mg, 2.20 mmol), 5-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyridin-2-amine (437 mg, 2.0 mmol), Xantphos (86.8 mg, 150 μmol) and cesium carbonate (1.95 g, 6.00 mmol) in dry dioxane (10 ml) was vacuum de-gassed and place under argon atmosphere. To this mixture was added tris(dibenzylideneacetone)dipalladium (0) (31.1 mg, 30 μmol) and the vacuum de-gas cycle was repeated. The reaction was heated at 90° C. (oil bath) with vigorous stirring overnight. The flask was cooled to ambient and the contents were filtered through a plug of celite, rinsing well with dioxane. The combined filtrate and washes were concentrated. The resultant crude residue was triturated with ether to provide the desired product as a light yellow solid (345 mg, 47.8%). (M+H)+=361.0, 363 m/e.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:13])[CH3:12])=[N:7][C:6]=1[CH3:14])=O.[F:15][C:16]([F:24])([F:23])[C:17]1([C:20](=[S:22])[NH2:21])[CH2:19][CH2:18]1>CO.[OH-].[O-2].[P-3].[Mo]>[CH3:14][C:6]1[N:7]=[C:8]([NH:10][C:11](=[O:13])[CH3:12])[S:9][C:5]=1[C:3]1[N:21]=[C:20]([C:17]2([C:16]([F:24])([F:23])[F:15])[CH2:19][CH2:18]2)[S:22][CH:2]=1
Reactant: CC(=O)Nc1nc(C)c(C(=O)CBr)s1
Reactant: NC(=S)C1(C(F)(F)F)CC1
Agent: [Mo]
Agent: [O-2]
Agent: [OH-]
Solvent: CO
Product: CC(=O)Nc1nc(C)c(-c2csc(C3(C(F)(F)F)CC3)n2)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-[5-(2-bromo-acetyl)-4-methyl-thiazol-2-yl]-acetamide (0.29 g, prepared as described in WO 2005/068444) in MeOH (15 mL) at rt was added 1-trifluoromethyl-cyclopropanecarbothioic acid amide [871913-36-9] (0.20 g) and ammoniumphosphomolybdate (0.15 g). After stirring 18 h at rt, the reaction mixture was partitioned between EtOAc and water, the organic layers dried over Na2SO4 and evaporated to give the crude product. Purification by flash chromatography with an eluent of 1% MeOH in CH2Cl2 gave the title compound. MS (ESI): positive 348.1 (M+H), negative 346.1 (M−H).
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][N:17]=[C:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[C:19]#[N:20])(=[O:15])=[O:14])=[CH:9][CH:8]=1)(=O)C.Cl.C(OCC)C>O.O1CCCC1>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][N:17]=[C:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[C:19]#[N:20])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: CC(=O)Oc1ccc(S(=O)(=O)ON=C(C#N)c2cccs2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#CC(=NOS(=O)(=O)c1ccc(O)cc1)c1cccs1
Reaction time: 1 h
Yield: 68.9 %

Procedure:
With vigorous stirring, a solution of 12 g of NaOH in 20 ml of water is added to a solution of 27 g (0.08 mole) of α-(4-acetoxybenzenesulfonyloxyimino)thienylacetonitrile (3c) in 125 ml of tetrahydrofuran. After 1 hour, the reaction mixture is acidified with 20% hydrochloric acid and, after the addition of water and diethyl ether, the phases are separated. The aqueous phase is extracted with ether, the combined organic phases are dried over MgSO4, and the solvent is distilled off. The residual crude product is recrystallised from toluene, affording 17 g of beige-coloured crystals which melt at 151°-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH2:16][CH2:17][CH3:18])=[C:11]([C:13]([OH:15])=O)[N:12]=1.[CH2:19]([N:21]([CH3:29])[C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][N:23]=1)[CH3:20]>>[CH2:19]([N:21]([CH3:29])[C:22]1[N:23]=[CH:24][C:25]([NH:28][C:13]([C:11]2[N:12]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[O:9][C:10]=2[CH2:16][CH2:17][CH3:18])=[O:15])=[CH:26][CH:27]=1)[CH3:20]
Reactant: CCN(C)c1ccc(N)cn1
Reactant: CCCc1oc(-c2ccccc2Cl)nc1C(=O)O
Product: CCCc1oc(-c2ccccc2Cl)nc1C(=O)Nc1ccc(N(C)CC)nc1

Procedure:
With a procedure similar to example 16 above, 2-(2-chloro-phenyl)-5-propyl-oxazole-4-carboxylic acid [6-(ethyl-methyl-amino)-pyridin-3-yl]-amide was prepared from 2-(2-chloro-phenyl)-5-propyl-oxazole-4-carboxylic acid and N2-ethyl-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C21H23ClN4O2 (m/e) 398, obsd 399 (M+H).