Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10](=S)[NH:11][NH2:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14][CH:15]([C:21]([CH3:23])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>Cl.C(O)C>[ClH:14].[CH2:19]([O:18][C:16]([C:15]1[C:10]([NH:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:11][NH:12][C:21]=1[CH3:23])=[O:17])[CH3:20]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NNC(=S)NCCN1CCCCC1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(NCCN2CCCCC2)n[nH]c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.8 %

Procedure:
A stirred solution of 6 g (0.03 mole) of 4-(2-piperidinoethyl)-3-thiosemicarbazide in 30 mL of 2N ethanolic hydrogen chloride was diluted to 60 mL with absolute ethanol, treated with 4.9 g (0.03 mole) of ethyl 2-chloroacetoacetate, stirred at ambient temperature for 3 hr, and heated at reflux for 2 hr. The reaction mixture was filtered hot to remove amorphous sulfur and the filtrate concentrated to an orange oil. Trituration with refluxing 2-propyl ether and cooling gave a plastic mass with crystals. The 2-propyl ether was decanted and the residual material recrystallized from 2-propyl alcohol/2-propyl ether to give 8 g of crude product. A second recrystallization from 2-propyl alcohol/2-propyl ether gave 5.3 g of beige crystalline product, mp 198°-200° C. as the dihydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[C:3]=1[C:18]#[N:19].[OH:20]S(O)(=O)=O>>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[C:3]=1[C:18]([NH2:19])=[O:20]
Reactant: O=S(=O)(O)O
Reactant: Cc1cccc(Cl)c1-n1nc(C(C)C)c(C#N)c1N
Product: Cc1cccc(Cl)c1-n1nc(C(C)C)c(C(N)=O)c1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
Part C: A mixture of 1.5 g (5.5 mmol) of 5-amino-4-cyano-3-isopropyl-1-(2-chloro-6-methylphenyl)pyrazole in 5 mL conc. H2SO4 was stirred at room temperature for 24 hours. The reaction was slowly quenched with ice and then diluted with water. The solution was made basic with saturated Na2CO3, stirred 2 h and filtered. The solid was recrystallized from hexanes/EtOAc to afford 847 mg (53%) of 5-amino-3-isopropyl-1-(2-chloro-6-methylphenyl)pyrazole-4-carboxamide, mp 72-74° C. Mass Spec. (ES−): 291 (M−H)−.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)[CH3:2].C[N+](C)(C)C.[OH-].C(Br)[C:20]1[CH:25]=[CH:24]C=[CH:22][CH:21]=1>>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)[C:2]1[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: C[N+](C)(C)C
Agent: [OH-]
Product: C=Cc1ccc(OCc2ccccc2)cc1
Reaction time: 0.25 h
Yield: 81 %

Procedure:
Approximately 10 gs (6.17×10-2 moles) of 4-acetoxystyrene was added to a 25 wt % solution of TMAH (51 mL). After 15 minutes of stirring a clear yellowish solution was obtained. About 10.6 gs (6.17×10-2 moles) of benzyl bromide was added to this solution with stirring. Slow formation of product crystals was observed. Reaction was complete as seen by thin layer chromatography after about 5 hours. The crystals were filtered-off, washed with distilled water, and sucked dry. In this way, 10.5 gs (81% yield) of pure desired product was obtained. Analysis of the product indicated:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[CH2:18][C@H:17]([N:19]3[CH:23]=[C:22]([CH3:24])[CH:21]=[N:20]3)[C@@H:16]([OH:25])[C@H:15]2[OH:26])=[C:7]([NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:6]=1.[S:42](Cl)([CH3:45])(=[O:44])=[O:43]>>[OH:26][C@@H:15]1[C@H:16]([OH:25])[C@@H:17]([N:19]2[CH:23]=[C:22]([CH3:24])[CH:21]=[N:20]2)[CH2:18][C@H:14]1[N:11]1[CH:10]=[N:9][C:8]2[C:12]1=[N:13][C:5]([NH:4][CH2:3][CH2:2][NH:1][S:42]([CH3:45])(=[O:44])=[O:43])=[N:6][C:7]=2[NH:27][CH2:28][CH:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN)nc43)[C@H](O)[C@@H]2O)c1
Product: Cc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCNS(C)(=O)=O)nc43)[C@H](O)[C@@H]2O)c1

Procedure:
The title compound is prepared from (1R,2S,3R,5S)-3-[2-(2-Amino-ethylamino)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-methyl-pyrazol-1-yl)-cyclopentane-1,2-diol and mesyl chloride using a procedure analogous to that of Example 31. MS (ES+) m/e 632 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.F[C:15]1[C:20]([C:21]2[N:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH2:28])[N:22]=2)=[CH:19][C:18]([CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:17][N:16]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl>CN(C=O)C.O>[NH2:28][C:23]1[N:24]=[C:25]([CH3:27])[N:26]=[C:21]([C:20]2[C:15]([NH:1][C:2]3[CH:3]=[C:4]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=3)=[N:16][CH:17]=[C:18]([CH:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[CH:19]=2)[N:22]=1
Reactant: CS(=O)(=O)Nc1cc(N)cnc1Cl
Reactant: Cc1nc(N)nc(-c2cc(C3CCOCC3)cnc2F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(-c2cc(C3CCOCC3)cnc2Nc2cnc(Cl)c(NS(C)(=O)=O)c2)n1
Reaction time: 1.5 h

Procedure:
To a solution of N-(5-amino-2-chloropyridin-3-yl)methanesulfonamide (60 mg, 0.271 mmol) and 4-(2-fluoro-5-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (55 mg, 0.190 mmol) in anhydrous DMF (1 mL) cooled in an ice bath was added solid NaHMDS (210 mg, 1.088 mmol) under nitrogen. The resulting orange mixture was stirred with cooling. After 1.5 h, HCl (5N, 0.25 mL, 1.25 mmol) was added to the mixture. The resulting mixture was diluted with water (5 mL) and acidified with HCl, 5N) to about pH 5. The resulting slurry was filtered and washed with water (3×3 mL). The solid was washed with EtOAc to afford the product as a brown solid. The mother liquid was chromatographed on silica gel (0-5% MeOH in EtOAc) to give additional product. The combined product was about mg (32%). m/z (ESI, positive ion): 491.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.60-1.82 (m, 4H) 2.46 (s, 3H) 2.84 (t, J=11.35 Hz, 1H) 3.12 (s, 3H) 3.46 (t, J=10.76 Hz, 2H) 3.97 (d, J=12.13 Hz, 2H) 7.78 (br. s., 1H) 7.92 (br. s., 1H) 8.33 (s, 1H) 8.64 (d, J=3.33Hz, 2H) 8.72 (s, 1H) 9.64 (br. s., 1H) 12.17 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:11][C:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[C:25]([Cl:26])=[CH:24][N:23]=[C:22](Cl)[N:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1>C(O)C.C(N)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:11][C:12]([CH:14]2[CH2:15][CH2:16][N:17]([C:20]3[C:25]([Cl:26])=[CH:24][N:23]=[C:22]([NH:11][CH:8]([CH3:9])[CH3:4])[N:21]=3)[CH2:18][CH2:19]2)=[O:13])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(CO)c1cccc(Cl)c1)C1CCN(c2nc(Cl)ncc2Cl)CC1
Solvent: CC(C)N
Solvent: CCO
Product: CC(C)Nc1ncc(Cl)c(N2CCC(C(=O)NC(CO)c3cccc(Cl)c3)CC2)n1
Yield: 61.6 %

Procedure:
The 1-(2,5-dichloro-pyrimidin-4-yl)-piperidine-4-carboxylic acid [1-(3-chloro-phenyl)-2-hydroxy-ethyl]-amide (60 mg, 0.14 mmol) compound was dissolved in absolute ethanol (1 mL) and isopropyl amine (0.2 mL). The mixture was heated in a sealed Teflon reaction vial at 70° C. overnight. The resulting mixture was filtered and purified by preparative HPLC (Gilson: Column=CombiHT SB-C189 5 μM 21.2 mm×100 mm, eluent=0.1% TFA MeCN/H2O gradient). Further purification by preparative TLC (1 mm silica; eluent ethyl acetate) afforded the title compound as a colorless oil (19.5 mg) Rt=4.82 minutes; LCMS 453.1 (M+1); 1H NMR δ 7.87 (s, 1H) 7.25 (m, 4H) 5.28 (NH) 4.95 (dd, J=5.9, 3.9 Hz, 1H) 4.81 (NH) 4.01 (m, 1H) 3.89 (dd, J=11.2, 3.9 Hz, 1H) 3.83 (dd, J=11.2, 5.9 Hz, 1H) 3.65 (m, 4H) 3.52 (m 4H) 2.1 (OH) 1.20 (d, J=6.5 Hz, 6H).
Reaction SMILES: ClC1C=CC=CC=1CN1C(CC(O)=O)=CN=C1SCCC.[CH2:22]([C:26]1[N:27]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[Cl:50])[C:28](/[C:31](/C)=C(\C2C=CN=CC=2)/C(O)=O)=[CH:29][N:30]=1)[CH2:23][CH2:24][CH3:25].[CH2:51]([CH:58]([C:64]1[S:65][CH:66]=[CH:67][CH:68]=1)[CH2:59][C:60]([O:62]C)=[O:61])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>>[CH2:22]([C:26]1[N:27]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[Cl:50])[C:28](/[CH:31]=[C:59](\[CH:58]([C:64]2[S:65][CH:66]=[CH:67][CH:68]=2)[CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)/[C:60]([OH:62])=[O:61])=[CH:29][N:30]=1)[CH2:23][CH2:24][CH3:25]
Reactant: COC(=O)CC(Cc1ccccc1)c1cccs1
Reactant: CCCCc1ncc(/C(C)=C(/C(=O)O)c2ccncc2)n1Cc1ccccc1Cl
Agent: CCCSc1ncc(CC(=O)O)n1Cc1ccccc1Cl
Product: CCCCc1ncc(/C=C(/C(=O)O)C(Cc2ccccc2)c2cccs2)n1Cc1ccccc1Cl

Procedure:
The title compound was prepared using the procedure of Example 1 (i, ii, iii, iv [Method B]) replacing methyl 3-(2-thienyl)propanoate with methyl 3-benzyl-3-(2-thienyl)propanoate [prepared following the procedure described in Tetra. 44 (7) 2055 (1988]; mp 200°-202° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[NH:20]1[CH2:23][CH:22]([NH:24][CH2:25][C@H:26]2[O:30][C:29](=[O:31])[N:28]([C:32]3[CH:33]=[CH:34][C:35]4[S:40][CH2:39][C:38](=[O:41])[NH:37][C:36]=4[CH:42]=3)[CH2:27]2)[CH2:21]1>CC#N.O>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:20]4[CH2:23][CH:22]([NH:24][CH2:25][C@H:26]5[O:30][C:29](=[O:31])[N:28]([C:32]6[CH:33]=[CH:34][C:35]7[S:40][CH2:39][C:38](=[O:41])[NH:37][C:36]=7[CH:42]=6)[CH2:27]5)[CH2:21]4)[N:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C1CSc2ccc(N3C[C@@H](CNC4CNC4)OC3=O)cc2N1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Solvent: CC#N
Solvent: O
Product: O=C1CSc2ccc(N3C[C@@H](CNC4CN(c5nc6c(cc5F)c(=O)c(C(=O)O)cn6C5CC5)C4)OC3=O)cc2N1
Temperature: 75 °C

Procedure:
A mixture of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid (commercial; 141 mg), 6-[(5R)-5-[(3-azetidinylamino)methyl]-2-oxo-3-oxazolidinyl]-2H-1,4-benzothiazin-3(4H)-one (prepared according to WO 2008/126034; 167 mg) and TEA (0.15 ml) in MeCN (4 ml) was heated at 75° C. for 2 h. The reaction mixture was allowed to reach rt, diluted with water, filtered and the solid was washed with MeOH and EA, affording a beige solid.
Reaction SMILES: [P].[Br:2]Br.[CH3:4][CH:5]([C:9]([OH:11])=[O:10])[C:6]([OH:8])=[O:7]>>[Br:2][C:5]([CH3:4])([C:9]([OH:11])=[O:10])[C:6]([OH:8])=[O:7]
Reactant: BrBr
Reactant: CC(C(=O)O)C(=O)O
Agent: [P]
Product: CC(Br)(C(=O)O)C(=O)O

Procedure:
Phosphorus and Bromine is added into dry 2-methylmalonic acid according to the procedure of Braun, in Berichte 42, p. 839 (1909) to form 2-Bromo-2-methyl malonic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[C:7]1(=O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[O:8]1>C(O)(=O)C>[NH:4]1[CH:5]=[CH:6][C:2]([N:1]2[C:7](=[O:8])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:16])=[N:3]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cc[nH]n1
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1cc[nH]n1
Temperature: 130 °C

Procedure:
1.2 3-Amino-pyrazole (278 mmol) is dissolved in acetic acid (240 ml) and isobenzofurane-1,3-dione (1 eq.) is added. The reaction solution is heated to 130° C. for 14 h. After cooling to RT, the precipitate is filtrated and washed with ethylacetate/heptane (1:1). 2-(1H-Pyrazol-3-yl)-isoindole-1,3-dione is obtained as a colourless powder; HPLC (Method B): 2.69 min; LC-MS (Method B): 1.360 min, 214.15 (M+H+).
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21]>O1CCCC1>[N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH:10][C:20](=[O:21])[O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Nc1ccc(-n2ccnc2)cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-n2ccnc2)cc1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of 4-(1H-imidazol-1-yl)aniline (1.00 g, 6.28 mmol) and pyridine (1.52 ml, 18.8 mmol) in tetrahydrofuran (20 ml) was added 2,2,2-trichloroethyl chloroformate (1.30 ml, 9.42 mmol) with ice-cooling, the mixture was stirred for 1 hour with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the desired product (1.83 g, 87.1%) as a solid.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:7]=[N:6]1)[CH2:2][C:3]#[CH:4].Br[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][F:25])[N:19]=1>>[F:25][CH2:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:4]#[C:3][CH2:2][CH2:1][N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=3)[N:7]=[N:6]2)[N:19]=1
Reactant: C#CCCn1cc(-c2ccc(F)cc2)nn1
Reactant: FCc1cccc(Br)n1
Product: FCc1cccc(C#CCCn2cc(-c3ccc(F)cc3)nn2)n1
Yield: 21.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 1-(but-3-ynyl)-4-(4-fluorophenyl)-1H-1,2,3-triazole (100 mg, 0.47 mmol) and 2-bromo-6-(fluoromethyl)pyridine (97 mg, 0.51 mmol, Example 190(E)). Reaction time: 2 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98.5:1.5) to yield 32 mg (0.10 mmol, 21%) of 2-(fluoromethyl)-6-(4-(4(4 fluorophenyl)-1H-1,2,3-triazol-1-yl)but-1-ynyl)pyridine as a yellow solid (M.P.=100-103° C.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N+:11]([O-:14])=[C:10]([CH3:15])[CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.CS(O[CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][C@H:33]([CH3:37])[CH2:32]1)(=O)=O.O>CN(C)C=O>[CH3:15][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][C@H:33]([CH3:37])[CH2:32]3)=[CH:7][CH:6]=2)[CH:13]=[CH:12][N+:11]=1[O-:14]
Reactant: C[C@H]1CCCN(CCCOS(C)(=O)=O)C1
Reactant: Cc1cc(-c2ccc(O)cc2)cc[n+]1[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2ccc(OCCCN3CCC[C@H](C)C3)cc2)cc[n+]1[O-]
Temperature: 25 °C

Procedure:
A A mixture of 4-(4-hydroxyphenyl)-2-methylpyridine 1-oxide (55 mg), potassium carbonate (187 mg) and (3S)-1-(3-methanesulfonyloxypropyl)-3-methylpiperidine hydrochloride in N,N-dimethylformamide (3 mL) is heated at a temperature close to 65° C. overnight and cooled back to room temperature. Water (5 mL) is added; the solution is washed with methylcyclohexane (twice 10 mL) and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (eluent dichloromethane/methanol from 95/5 to 80/20). Fraction containing the expected product are pooled and concentrated under reduced pressure. The crude base is diluted in ethanol, oxalic acid (7 mg) is added and solvent is removed under reduced pressure to give 32 mg of (3S)-2-methyl-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide, oxalate as a brown crystalline material.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:14][N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1.[OH2:24].[OH2:25].O.O.O.O.C1(=O)OOOOC(=O)C2=CC=CC=C12.[Mg]>CN(C)C=O.CCOC(C)=O>[CH3:1][S:2]([CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[CH2:14][N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1)(=[O:25])=[O:24]
Reactant: CSCCn1c(Cn2nnc3ccccc32)nc2ccccc21
Reactant: O
Agent: O=c1ooooc(=O)c2ccccc12
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)CCn1c(Cn2nnc3ccccc32)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
1-[1-(2-Methylthio-ethyl)-1H-benzimidazol-2-ylmethyl]-1H-benzotriazole (100 mg, 0.309 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL). Magnesium monoperoxy phthalate hexahydrate (611 mg, 1.24 mmol) was added and the reaction mixture was stirred at room temperature overnight under N2. The solvent was stripped under reduced pressure. The yellow oily residue was taken up in EtOAc (100 mL) and washed with water (2×50 mL) dried over magnesium sulfate, filtered and evaporated. Column chromatography on silica gel (EtOAc) gave 45 mg (41%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[NH:4][C:5]([C:22](F)([F:24])[F:23])=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]([CH:14]2[CH2:16][CH2:15]2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C1CCN2C(=NCCC2)CC1>C1COCC1>[F:24][CH:22]([F:23])[C:5]1[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([CH:14]2[CH2:15][CH2:16]2)[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:3]([C:2]([F:27])([F:1])[F:26])[N:4]=1
Reactant: CCOC(=O)C1=C(C(F)(F)F)NC(C(F)(F)F)=C(C(=O)OCC)C1C1CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1C1CC1
Yield: 85 %

Procedure:
To a solution of 40 g (0.0916 mole) of diethyl 2,6-bis(trifluoromethyl)-2,6-dihydroxy-4-cyclopropyl-tetrahydropyran-3,5-dicarboxylate in 200 ml of THF is introduced 55.5 g (3.26 moles) of ammonia. The reaction mixture is concentrated to give 38.5 g (96.7%) of a solid. A portion (28 g) of this material is stirred with 27.08 g (0.129 mole) of trifluoroacetic anhydride for one day. The reaction mixture is concentrated and diluted with ether. The ether solution is washed with saturated sodium bicarbonate, dried (MgSO4), and concentrated to give 21 g (81.3%) of an oil, nD25 1.4460. This oil is identified as diethyl 2,6-bis(trifluoromethyl)- 4-cyclopropyl-1,4-dihydro-pyridine-3,5-dicarboxylate. A portion (18 g) of this oil and 150 ml of THF is treated with 6.82 g (0.0449 mole) of DBU. The reaction mixture is held at reflux for 24 hours and concentrated. The residue is stirred with water and extracted with ether. The ether extract is washed with diluted HCl, dried (MgSO4), and concentrated. The residue is crystallized to give 13 g (76.0%) of crude product. A portion (2.0 g) of this product is recrystallized from petroleum ether at low temperature to give 1.17 g (85%) of desired product, m.p. 30°-32° C.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:19])([CH3:16])([CH3:15])[CH3:14].CO>C(Cl)Cl>[CH3:1][O:30][C:29](=[O:31])[CH2:28][CH2:27][CH2:26][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][N:20]1[C:18]([O:17][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCCC(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCCC1CCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
1,1′-Carbonyldiimidazole (23.3 g, 143.7 mmol) was added to a solution of 4-(1-tert-butoxycarbonyl)piperidin-2-yl)butanoic acid (2) (26 g, 95.8 mmol) in methylene chloride. The reaction mixture was stirred at room temperature for 1 h. Methanol (19.4 ml, 479 mmol) was then added and the reaction mixture was stirred overnight. The complete reaction was checked by means of TLC. When the reaction was complete, the reaction mixture was washed 3× with sat. NH4Cl solution (aqueous) and 2× with sat. NaCl solution. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to obtain tert-butyl 2-(4-methoxy-4-oxobutyl)piperidine-1-carboxylate (3) (25.67 g, 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:16](=[O:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19]>C(Cl)Cl>[CH3:21][O:20][C:18](=[O:19])[CH2:17][C:16]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22]
Reactant: Nc1ccccc1
Reactant: COC(=O)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To the ice-cooled solution of aniline (3,72 g, 40 mmol) in methylene chloride (300 mL) containing triethylamine (11.2 mL, 80 mmol) was added dropwise methyl 3-chloro-3-oxopropionate (5.37 mL, 50 mmol). The reaction mixture was then stirred at room temperature for 2 hours and washed with saturated aqueous NaHCO3 (2×150 mL). The organic layer was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography over silica gel (ethyl acetate-hexane, 1:2) to give the title compound (7.2 g, 93.3%). 1H NMR (400 MHz, CDCl3) δ: 9.17 (brs, 1H), 7.53 (d, 2H), 7.32 (t, 2H), 7.10 (t, 1H), 3.80 (s, 2H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:21][CH3:22])=[C:10]([N:13]3[CH2:18][C@H:17]([CH3:19])[NH:16][C@H:15]([CH3:20])[CH2:14]3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C=O.[BH3-][C:26]#N.[Na+]>CO>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:21][CH3:22])=[C:10]([N:13]3[CH2:18][C@H:17]([CH3:19])[N:16]([CH3:26])[C@H:15]([CH3:20])[CH2:14]3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: COc1cc2c(cc1N1C[C@@H](C)N[C@@H](C)C1)N(C(C)=O)CC2
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(cc1N1C[C@@H](C)N(C)[C@@H](C)C1)N(C(C)=O)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
A stirred solution of D2 (1.48 g, 4.9 mmole) in MeOH (50 ml) at room temperature under Ar was treated with aqueous formaldehyde (2.4 ml of 37% w/v, 29 mmole), followed by portionwise addition of NaBH3CN (920 mg, 15 mmole). The mixture was stirred at room temperature for 3 h, then concentrated under vacuum and the residue treated with 10% Na2CO3 solution and extracted with DCM. The extract was dried (Na2SO4) and concentrated under vacuum to afford the title compound as a yellow solid (1.4 g, 90%). MH+ 318.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[N:14]=[C:13](Cl)[CH:12]=[C:11]([CH3:16])[N:10]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1>[CH2:17]([NH:24][C:13]1[CH:12]=[C:11]([CH3:16])[N:10]=[C:9]([NH2:8])[N:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc(Cl)nc(N)n1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cc(NCc2ccccc2)nc(N)n1
Temperature: 80 °C
Reaction time: 12 h
Yield: 88.4 %

Procedure:
Triethylamine (3.4 mL, 24.6 mmol) was added to a suspension of 2-amino-4-chloro-6-methylpyrimidine (Aldrich, 1.77 g, 12.3 mmol) and benzylamine (1.98 g, 18.5 mmol) in anhydrous dioxane (20 mL). The reaction was heated to 80° C. and allowed to run for 12 h. Upon cooling to room temperature, a white precipitate formed which was collected by vacuum filtration. The solid was recrystallized from acetone: hexanes to afford N4-benzyl-6-methylpyrimidine-2,4-diamine (2.33 g, 89% yield) as a white solid.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:18][CH2:19][CH:20]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[CH:27][C:28]=1[CH3:29].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:31][CH2:32][N:33]([CH2:20][CH2:19][CH2:18][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:34][CH2:35]2)[CH:26]=[CH:27][C:28]=1[CH3:29]
Reactant: O=CCCc1cc(-c2ccccc2)n(-c2ccccc2)n1
Reactant: Cc1ccc(N2CCNCC2)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCc3cc(-c4ccccc4)n(-c4ccccc4)n3)CC2)cc1C

Procedure:
Example 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (55 mg, 0.199 mmol), 1-(3,4-dimethylphenyl)piperazine (32 mg, 0.166 mmol), DIPEA (0.035 mL, 0.199 mmol) and NaBH(OAc)3 (148 mg, 0.697 mmol).