Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([CH2:25][C@H:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36]3[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=3)[C:39](O)=[O:40])[CH:32]=2)[O:27]1)[CH2:9][C@H:10]([O:17][Si](C(C)(C)C)(C)C)[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=O)(C)(C)C.CN(C1C=CC=CN=1)C.[CH3:54][S:55]([NH2:58])(=[O:57])=[O:56].Cl>C(Cl)Cl.O1CCOCC1>[OH:17][C@H:10]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][NH:8][CH2:25][C@H:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36]3[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=3)[C:39]([NH:58][S:55]([CH3:54])(=[O:57])=[O:56])=[O:40])[CH:32]=2)[O:27]1
Reactant: CS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)N(C[C@H]1CCc2cc(-c3cccc(C(=O)O)c3)ccc2O1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)c1cccc(-c2ccc3c(c2)CC[C@H](CNC[C@H](O)c2cccnc2)O3)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
The product of Example 86 (100 mg, 0.16 mmol), 1-[(3-dimethylamino)propyl]-3-ethylcarbodiimide (36 mg, 0.19 mmol), dimethylaminopyridine (20 mg, 0.16 mmol), and methylsulfonamide (17 mg, 0.18 mmol) were dissolved in 2 mL methylene chloride and stirred overnight at room temperature. The mixture was treated with 0.5 mL 4 M HCl in 1,4-dioxane was added, the solution stirred for 0.5 hours, concentrated to dryness and the residue was purified by preparative HPLC to obtain the title compound (47 mg, 62%). 1H NMR (CD3CN-d3) δ: 8.91 (s, 1H), 8.76 (d, 1H), 8.51 (d, 1H), 8.07 (s, 1H), 7.97 (t, 1H), 7.88-7.83 (m, 2H), 7.62-7.56 (m, 1H), 7.50-7.47 (m, 2H), 6.98 (d, 1H), 5.46 (d, 1H), 4.54-4.47 (m, 1H), 3.52 (dd, 2H), 3.37 (s, 3H), 3.39-3.25 (m, 2H), 2.99-2.90 (m, 2H), 2.14-2.09 (m, 1H), 1.86-1.79 (m, 1H). MH+=482.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:12]=[C:11]([CH2:22][C@@H:23]([C:39]3[CH:40]=[C:41]([CH3:45])[CH:42]=[CH:43][CH:44]=3)[C:24](N3[C@H]4C5C=CC=CC=5C[C@H]4OC3=O)=[O:25])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:46]O.[Li+].[OH-].Cl>O.C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[N:12]=[C:11]([CH2:22][C@@H:23]([C:39]3[CH:40]=[C:41]([CH3:45])[CH:42]=[CH:43][CH:44]=3)[C:24]([OH:46])=[O:25])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OO
Reactant: COc1ccc(-n2nc(C[C@H](C(=O)N3C(=O)O[C@@H]4Cc5ccccc5[C@@H]43)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-n2nc(C[C@H](C(=O)O)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
To a stirred THF/toluene solution containing 3-{3-[5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionyl}-3,3a,8,8a-tetrahydro-indeno[1,2-d]oxazol-2-one (Example 520, 9.45 kg, 14.8 mol) at 0-10° C. was added H2O (5.25 L) and 30% hydrogen peroxide (4.35 L, 42.6 mol) followed by 19% aq. LiOH (9.40, 42.6 mol). The reaction mixture was stirred between 0-10° C. for 2 h. When HPLC analysis indicated the disappearance of the starting material, the reaction was quenched between 0-10° C. with 1.5 N sodium meta-bisulfite solution (8.0 L) maintaining the pH at 9-10. The quenched reaction mixture was then acidified to pH 1-2 using 6 N HCl (8.4 L). After removing the aqueous layer, ˜60.0 L of the organic phase was removed under reduced pressure, and EtOAc (8.5 L) was added. The resultant suspension was filtered and washed. The filtrate, containing the desired acid, was used directly in the next synthetic step without isolation. Chemical characterization data obtained herein for the title compound is not duplicated in this Example in light of the same data given in Example 1, Step H.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[C:9]3[C@H:16]([CH3:17])[CH2:15][CH2:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:25]>C(Cl)Cl>[ClH:25].[ClH:25].[CH3:17][C@H:16]1[C:9]2[C:8]([N:7]3[CH2:6][CH2:5][NH:4][CH2:3][C@@H:2]3[CH3:1])=[N:13][CH:12]=[N:11][C:10]=2[CH2:14][CH2:15]1
Reactant: C[C@@H]1CCc2ncnc(N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)c21
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1CCc2ncnc(N3CCNC[C@@H]3C)c21
Yield: 99 %

Procedure:
(S)-tert-butyl 3-methyl-4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate was treated with HCl (4M in dioxane, 4 mL) in DCM (20 mL) for 6 hours to provide the (R)-5-methyl-4-((S)-2-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (0.18 g, 99%). MS (APCI+) [M+H]+233.
Reaction SMILES: [NH2:1][C@@H:2]1[C:9](=[O:10])[N:8]2[C@@H:3]1[S:4][CH2:5][C:6]([CH2:14][S:15][C:16]1[N:21]3[N:22]=[C:23]([CH2:25][OH:26])[N:24]=[C:20]3[N:19]=[C:18]([CH3:27])[CH:17]=1)=[C:7]2[C:11]([OH:13])=[O:12].[OH:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][C:37]=1[OH:38])[C:32](O)=[O:33].B(F)(F)F>C(#N)C>[NH2:1][C@@H:2]1[C:9](=[O:10])[N:8]2[C@@H:3]1[S:4][CH2:5][C:6]([CH2:14][S:15][C:16]1[N:21]3[N:22]=[C:23]([CH2:25][O:26][C:32](=[O:33])[C:31]4[CH:35]=[CH:36][C:37]([OH:38])=[C:29]([OH:28])[CH:30]=4)[N:24]=[C:20]3[N:19]=[C:18]([CH3:27])[CH:17]=1)=[C:7]2[C:11]([OH:13])=[O:12]
Reactant: O=C(O)c1ccc(O)c(O)c1
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)n2nc(CO)nc2n1
Agent: FB(F)F
Solvent: CC#N
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](N)[C@H]3SC2)n2nc(COC(=O)c3ccc(O)c(O)c3)nc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
(6R,7R)-7-Amino-3-[[[2-(hydroxymethyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (4.08 g) (known from EPOS 302,633) and 1.54 g of 3,4-dihydroxybenzoic acid are treated with 30 ml of a 20% solution of boron trifluoride in acetonitrile and stirred at room temperature for 2 hours. A further 25 ml of a 20% solution of boron trifluoride in acetonitrile are added; the reaction mixture is stirred at room temperature under argon for 2 days. After the addition of 100 ml of ice-water the reaction mixture is concentrated to about half. The product is precipitated by adjusting the pH value to 2.0 with concentrated aqueous ammonia. The precipitated material is suspended in water, brought into solution with 1N aqueous sodium hydroxide solution and purified by chromatography on RP12-Kieselgel with water/acetonitrile. The product fractions are concentrated to about 50 ml and the product is precipitated by acidification to pH 2.0. After drying in a high vacuum there are obtained 1.60 g of (6R,7R)-7-amino-3-[[[2-[[(3,4-dihydroxybenzoyl)oxy]methyl]-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a white powder.
Reaction SMILES: [CH2:1]([N:8](C)[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[N:20][CH:21]=3)[CH2:16]2)[CH2:11][CH2:10]1)C1C=CC=CC=1>CO>[CH2:16]1[C:17]2[C:22](=[CH:21][N:20]=[CH:19][CH:18]=2)[CH2:23][CH2:24][N:15]1[CH:12]1[CH2:13][CH2:14][CH:9]([NH:8][CH3:1])[CH2:10][CH2:11]1
Reactant: CN(Cc1ccccc1)C1CCC(N2CCc3cnccc3C2)CC1
Solvent: CO
Product: CNC1CCC(N2CCc3cnccc3C2)CC1
Reaction time: 8 h
Yield: 67 %

Procedure:
N-Benzyl-4-(3,4-dihydro-2,6-naphthyridin-2(1H)-yl)-N-methylcyclohexanamine (250 mg, 0.746 mmol, 1.0 eq.) was dissolved in MeOH (5 ml) and degassed with N2. Pd(OH)2 (250 mg) was then added and hydrogenation was carried out for 8 hours. After monitoring by TLC, the reaction mixture was filtered over Celite and the filtrate was concentrated under reduced pressure. The crude product so obtained was used in the next stage without being purified further. Yield: 67% (124 mg, 0.506 mmol)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11](O)=[O:12].[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+].Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][OH:12]
Reactant: O=C(O)c1n[nH]c2ccc(F)cc12
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Product: OCc1n[nH]c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
A solution of 5-fluoro-1H-indazole-3-carboxylic acid [0.680 g, Reference Example 26(a)] in anhydrous tetrahydrofuran (15 ml), at 0° C., was treated portionwise with lithium aluminium hydride (0.716 g), then stirred for 2 hours at ambient temperature and then treated with saturated aqueous sodium sulfate. The reaction mixture was acidified by addition of hydrochloric acid (1N) and then extracted three times with ethyl acetate (30 ml). The combined organic extracts were dried over magnesium sulfate and then evaporated. The residual dark brown oil was subjected to flash column chromatography on silica eluting with a mixture of 40/60 petrol and ethyl acetate (1:1 to 1:3 v/v) to yield (5-fluoro-1H-indazol-3-yl)-methanol (0.144 g) as a brown solid. LC-MS (METHOD B): RT=2.40 minutes; 167 (M+H)+. (b) (6-Fluoro-1H-indazol-3-yl)-methanol
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[N:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([OH:26])=O)=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[O:33][NH2:34].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O.O.CCN(CC)CC>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[N:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24]([NH:34][O:33][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][O:27]3)=[O:26])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1ccc(NC2CCN(C(=O)c3ccccc3)CC2)nc1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(/C=C/c1ccc(NC2CCN(C(=O)c3ccccc3)CC2)nc1)NOC1CCCCO1
Temperature: 23 °C
Reaction time: 8 h
Yield: 22.9 %

Procedure:
To a suspension of (2E)-3-{6-[(1-benzoyl-4-piperidyl)amino]-3-pyridyl}acrylic acid (170 mg) in DMF (3 ml) was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (62.3 mg), EDCI HCl (102 mg), HOBt (71.9 mg), Et3N(0.201 ml), the mixture was stirred at 23° C. for 8 hours. The mixed solution was poured into a mixture of water (20 ml) and AcOEt (20 ml). The organic layer was separated, washed with water twice and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with 8% MeOH in dichloromethane to give (2E)-3-{6-[(1-benzoyl-4-piperidyl)amino]-3-pyridyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (50 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17]CN(C(C)(C)C(N(C)C)=O)C[CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:32][N:33]([CH3:40])[CH:34]1[CH2:39][CH2:38]CNC1>>[Cl:1][C:2]1[N:3]=[C:4]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:13][CH2:38][CH2:39][CH:34]([N:33]([CH3:40])[CH3:32])[CH2:17]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CN(C)C(=O)C(C)(C)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CN(C)C1CCCNC1
Product: CN(C)C1CCCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)C1

Procedure:
Prepared using the method used in the preparation of 2-[4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-N,N-dimethyl-isobutyramide using dimethyl-piperidin-3-yl-amine in place of N,N-dimethyl-2-piperazin-1-yl-isobutyramide. The title compound was obtained as an off-white solid (180 mg, 76%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([CH3:15])[C:11]=2[NH2:16])=[CH:6][CH:5]=1.[CH2:17]([N:24]=[C:25]=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([NH:24][C:25]([NH:16][C:11]1[C:12]([CH3:15])=[N:13][O:14][C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([Br:3])=[CH:9][CH:8]=1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C=NCc1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% in mineral oil, 0.040 g, 1.00 mmol) was added to a solution of 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine (0.170 g, 0.67 mmol) in DMF, and the mixture was stirred for 5 minutes at room temperature. Benzyl isocyanate (0.08 mL, 0.67 mmol) was added, and the reaction was stirred at 80° C. for 2 hours. After aqueous workup, the crude material was used directly in the coupling step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@@H:4]([CH:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)[N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([BH3-])#[N:33].[Na+].C([O-])(=O)C.[NH4+]>C(Cl)Cl.C(O)(C)C>[CH3:1][O:2][C:3](=[O:31])[C@@H:4]([CH:24]1[CH2:29][CH2:28][CH:27]([NH2:33])[CH2:26][CH2:25]1)[N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)[C@@H](C1CCC(=O)CC1)N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: COC(=O)[C@@H](C1CCC(N)CC1)N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of oxalyl chloride (1.25 g) in methylene chloride (30 ml) is cooled to -78° C. and dimethylsulfoxide (1.16 ml) is slowly added. The reaction mixture is stirred at -78° C. for about 30 minutes and a solution of (R)-N-(4-methoxybenzenesulfonyl)-4-hydroxycyclohexylglycine methyl ester (2.34 g) in methylene chloride (30 ml) is added dropwise. Stirring is continued for 30 minutes at -78° C. and then at 0° C. for 30 minutes. The reaction mixture is again cooled to -78° C., triethylamine (7.3 ml) is added dropwise, and the reaction mixture is stirred at -78° C. for 30 minutes, allowed to warm to room temperature over an hour, diluted with methylene chloride, washed first with 1N hydrochloric acid and then brine. The organic layer is dried over sodium sulfate, evaporated to dryness, and the resulting product is purified by flash chromatography using 50-60% ethyl acetate in hexane to yield (R)-N-(4-methoxybenzenesulfonyl)-4-oxocyclohexylglycine methyl ester as a white solid. Treatment with benzyl bromide in DMF in the presence of potassium carbonate at room temperature yields (R)-N-(4-methoxybenzenesulfonyl)-N-benzyl-4-oxocyclohexylglycine methyl ester as an oil. The ketone (2.2 g) is dissolved in methylene chloride (3 ml) and isopropanol (60 ml). Molecular sieves (3A°, 1.5 g), sodium cyanoborohydride (0.311 g), and ammonium acetate (3.81 g) are added. The reaction mixture is stirred at room temperature overnight, filtered and evaporated to dryness. The residue is partitioned between water and methylene chloride and the product extracted with methylene chloride. The resulting product is purified by flash chromatography using methanol/methylene chloride/0.5% ammonium hydroxide as eluent to yield (R)-N-(4-methoxybenzenesulfonyl)-N-benzyl-4-aminocyclohexylglycine methyl ester. N-Methylation with formic acid/formaldehyde/sodium formate at reflux temperature followed by hydrolysis with 3N hydrochloric acid at reflux temperature yields 2-(R)-[(4-methoxybenzenesulfonyl)(benzyl)amino]-2-(tran-4-dimethylaminocyclohexyl)-acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([Cl:11])[CH:5]=1.[N:13]([O-])=O.[Na+].[Sn](Cl)Cl.[OH-].[Na+]>Cl.O>[Cl:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][NH2:13])[C:3]([O:2][CH3:1])=[O:12]
Reactant: COC(=O)c1ccc(N)c(Cl)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(NN)c(Cl)c1
Temperature: -10 °C

Procedure:
3.0 g (16.0 mmol) methyl-4-amino-3-chlorobenzoate are suspended in 15 ml of conc. hydrochloric acid and cooled to −10° C. First a solution of 1.1 g (16.0 mmol) sodium nitrite in 15 ml of water is added dropwise, then a solution of 16.1 g (71.0 mmol) tin(II)-chloride in 13.5 ml hydrochloric acid. A precipitate settles out. The reaction mixture is made basic with 3 molar sodium hydroxide solution, then suction filtered. The precipitate is extracted with dichloromethane and water, the organic phase is dried, combined with activated charcoal and evaporated to dryness. The residue is purified by chromatography. Yield: 1.4 g (M.p.: 120° C.)
Reaction SMILES: [H-].[Na+].CN(C=O)C.[SH:8][CH2:9][CH2:10][CH2:11][OH:12].[NH2:13][C:14]1[N:22]=[C:21](Cl)[N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>[Cl-].[Na+].O>[NH2:13][C:14]1[N:22]=[C:21]([S:8][CH2:9][CH2:10][CH2:11][OH:12])[N:20]=[C:19]2[C:15]=1[N:16]=[CH:17][N:18]2[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: OCCCS
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(SCCCO)nc2c1ncn2Cc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 12.4 %

Procedure:
Sodium hydride (600 mg, 15 mmol 60% in mineral oil) were added DMF (10 ml), 3-mercapto-1-propanol (1 ml, 12 mmol) and 6-amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) in order. The mixture was stirred at 100° C. for 2 hours. After addition of saturated brine the reaction mixture was extracted with ethyl acetate. The organic layer was dried on magnesium sulfate and the solvent was removed in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (30 mg, yield 12%).
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[C:7]1([CH3:15])[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[CH:8]=1>>[CH3:15][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[C:8]=1[CH:2]([CH2:3][CH3:4])[C:1]([OH:6])=[O:5]
Reactant: O=C1CCCO1
Reactant: Cc1cc(C)cc(C)c1
Product: CCC(C(=O)O)c1c(C)cc(C)cc1C
Yield: 33.5 %

Procedure:
In the same 100 ml autoclave as in Example 1, 1.5 g of tungstosilicic acid, 40 ml of mesitylene and 2.55 ml of γ-butyrolactone were charged and reacted at 180° C. for 6 hours, and then analysis was conducted. As a result, the conversion ratio of γ-butyrolactone was 85.1% and 2,4,6-trimethylphenylbutyric acid (yield based on γ-butyrolactone: 33.5%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(C)(N)CO
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(C(=O)NC(C)(C)CO)cn1
Yield: 94 %

Procedure:
As described for example 61b, 6-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (83 mg, 0.25 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of 4-aminotetrahydropyran, to the title compound (95 mg, 94%) which was obtained as a white foam. MS: m/e=400.2 [M+H]+.
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([C:20](=[O:30])[CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OC)=O.O>C1COCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][CH:17]([C:20](=[O:30])[CH:21]([CH:2]=[O:4])[CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(CCCc1ccccc1)C1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: COC=O
Solvent: O
Solvent: C1CCOC1
Product: O=CC(CCc1ccccc1)C(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 103.6 %

Procedure:
To a solution of potassium t-butoxide (0.673 g) in THF (20 mL) under nitrogen and cooled in an ice bath was added a solution of 1-(1-benzylpiperidin-4-yl)-4-phenylbutan-1-one from Step D (0.71 g) and methyl formate (3.76 mL) in THF (12 mL) over 5 minute. The reaction was stirred for 15 min before being allowed to warm to rt for 2 h. The reaction was poured into water and extracted with ether (4×100 mL), methylene chloride (100 mL), and THF (100 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrate under reduced pressure. The crude product was purified by FC on silica gel eluting with 5 and 20% methanol in ethyl acetate with 4% TEA to afford the title compound (0.8 g).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[C:12]([O:19][CH3:20])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>C(O)C.C(OCC)(=O)C.[Pd].[C]>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([O:19][CH3:20])[CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: COc1cc(N2CCN(C(C)=O)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C(C)=O)CC2)ccc1N
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a solution of 1-acetyl-4-[3-(methyloxy)-4-nitrophenyl]piperazine (0.4 g, 1.43 mmol) in ethanol: ethyl acetate (5:1) was added 10% Pd/carbon (˜0.100 g, Lancaster) and the mixture was rapidly stirred under 50 psi H2 overnight. The catalyst was removed by vacuum filtration through a celite pad, rinsed with methanol, and concentrated by rotary evaporation to give 4-(4-acetyl-1-piperazinyl)-2-(methyloxy)aniline (0.3 g, 84%). ESIMS (M+H)+=250.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19](O)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19]([N:32]5[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]5)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to 1-methylpiperazine via General Procedure B. The product was purified via reverse phase HPLC to give 17.6 mg of 261. MS (Q1) 561.8 (M)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([C:7]([O:9]C2C=CC=CC=2)=O)[CH:6]=1.[ClH:16].Cl.[NH2:18][C@@H:19]1[CH:24]2[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1.CCN(C(C)C)C(C)C>CN(C=O)C>[ClH:16].[N:21]12[CH2:26][CH2:25][CH:24]([CH2:23][CH2:22]1)[C@@H:19]([NH:18][C:7]([N:5]1[CH:6]=[C:2]([I:1])[CH:3]=[N:4]1)=[O:9])[CH2:20]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(Oc1ccccc1)n1cc(I)cn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CN2CCC1CC2)n1cc(I)cn1
Reaction time: 36 h
Yield: 83.4 %

Procedure:
Phenyl 4-iodo-1H-pyrazole-1-carboxylate (1.6 g, 5.2 mmol) and (R)-(+)-3-aminoquinuclidine dihydrochloride (1.0 g, 5.2 mmol) are suspended in 10 mL DMF. DIEA (2.7 mL, 15.5 mmol) is added dropwise. After 36 h, the solvent is removed and the residue is taken up in 1N NaOH and CHCl3. The aqueous layer is extracted with CHCl3, dried (MgSO4), filtered and concentrated. The residue is purified by chromatography (Biotage 40S, 90:9:1 CHCl3/MeOH/NH4OH) to provide 1.66 g (93%) of the product as a white solid. A portion of the material is converted into the hydrochloride salt and recrystallized from MeOH/EtOAc. HRMS (FAB) calcd for C11H15IN4O+H 347.0370, found 347.0357.