Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:9]C(C)(C)[CH2:5][C:4]([CH3:10])=[CH:3]1.[C:11]([OH:14])(=[O:13])[CH3:12]>>[O:1]=[C:2]([CH3:9])[CH2:3][C:4]([CH3:10])([CH3:5])[CH2:12][C:11]([OH:14])=[O:13]
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: CC(=O)O
Product: CC(=O)CC(C)(C)CC(=O)O

Procedure:
In a manner similar to that described in Example I, 30 grams isophorone in 57 grams aqueous acetic acid (35% H2O) was ozonized at ambient temperature and pressure in a 300 ml glass cylinder for approximately 5 1/2 hours. The resulting reaction product was then slowly dropped into a small amount of refluxing acetic acid, stripped at 140° C. under vacuum to remove water and acetic acid, and then vacuum distilled. Ninety-five percent yield of high purity 5-keto-3,3-dimethylhexanoic acid was obtained boiling in the range 96° C.-106° C. (0.1 mm Hg).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.O1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:27]1[C:28]2[CH:29]=[CH:12][C:13]([C:2]3[N:7]4[N:8]=[CH:9][CH:10]=[C:6]4[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]4[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=4)[CH:3]=3)=[CH:14][C:15]=2[CH2:25][CH2:26]1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Reactant: C1COCCO1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(-c3ccc4c(c3)CCO4)n3nccc3n2)cc1
Temperature: 110 °C
Yield: 27 %

Procedure:
A suspension of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 151 mmol), 3-dihydrobenzofuran-5-ylboronic acid (50 mg, 305 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9 mg, 12 mmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (670 microliters of 1,4-dioxane and 330 microliters of saturated aqueous NaHCO3) was prepared in a 2 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 20 minutes. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC, 45-70% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (16.8 mg, 27%). Melting point (174.2.0-184.3° C.). 1HNMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6H) 3.32 (t, J=8.59 Hz, 2H) 4.67 (t, J=8.72 Hz, 2H) 6.56 (d, J=2.27 Hz, 1H) 7.01 (d, J=8.59 Hz, 1H) 7.62 (d, J=8.34 Hz, 2H) 7.95 (dd, J=8.46, 1.64 Hz, 1H) 8.00-8.08 (m, 4H) 8.19 (d, J=2.02 Hz, 1H) 11.20 (s, 1H). ESI-MS: m/z 415.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[F:11][C:12]1[CH:13]=[C:14]([CH2:19][CH2:20][NH2:21])[CH:15]=[CH:16][C:17]=1[F:18].C(=O)(O)[O-].[Na+].O>CCO>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:21][CH2:20][CH2:19][C:14]2[CH:15]=[CH:16][C:17]([F:18])=[C:12]([F:11])[CH:13]=2)[CH:7]=1
Reactant: NCCc1ccc(F)c(F)c1
Reactant: COc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1nc(Cl)cc(NCCc2ccc(F)c(F)c2)n1
Yield: 93.9 %

Procedure:
A solution of 4,6-dichloro-2-methoxypyrimidine (0.7 g), 2-(3,4-difluoro-phenyl)-ethylamine (0.66 g) and sodiumbicarbonate (0.88 g) in EtOH (25 mL) is heated at 80° C. for three hours, poured into water (400 mL) and the solid is filtered and air dried to afford (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(3,4-difluoro-phenyl)-ethyl]-amine (1.1 g). MS: 312 (M+H); 1H NMR (300 MHz, CDCl3) □6.9-7 (3H, m); 6.05 (1H, s); 3.95 (3H, s); 3.6-3.7 (2H, m); 2.95 (2H, t).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.C([Mg]Br)(C)C.[CH3:14][Si:15]([CH3:30])([CH3:29])[CH2:16][CH2:17][S:18]([N:21]1[CH2:26][CH2:25][CH2:24][CH:23]([CH:27]=[O:28])[CH2:22]1)(=[O:20])=[O:19]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:27]([CH:23]1[CH2:24][CH2:25][CH2:26][N:21]([S:18]([CH2:17][CH2:16][Si:15]([CH3:30])([CH3:29])[CH3:14])(=[O:19])=[O:20])[CH2:22]1)[OH:28]
Reactant: C[Si](C)(C)CCS(=O)(=O)N1CCCC(C=O)C1
Reactant: Brc1ccccc1I
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: C[Si](C)(C)CCS(=O)(=O)N1CCCC(C(O)c2ccccc2Br)C1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
A three neck 200-mL flask was charged with anhydrous THF (150 mL) and 1-bromo-2-iodobenzene (5.81 g, 20.5 mmol, 1.5 equiv), and cooled to −40° C. Isopropyl magnesium bromide (1.0 M in THF, 19.9 mL, 19.9 mmol, 1.45 equiv) was added to the solution via syringe at a rate such that the internal temperature did not rise above −35° C. An aliquot was removed, quenched with water and analyzed by LC-MS. The observed amount of bromobenzene showed >90% conversion to the desired Grignard reagent. A solution of 1-(2-trimethylsilyl-(ethanesulfonyl))piperidine-3-carbaldehyde (3.8 g, 13.7 mmol) in 20 mL of THF was added to solution containing the Grignard reagent at such a rate that the internal temperature did not rise above −35° C. The mixture was stirred for 1 h at −40° C.; after this period LC-MS analysis of an aliquot showed consumption of the aldehyde and formation of two peaks with the desired mass, consistent with formation of two diastereomers. The mixture was quenched with methanol and the THF removed in vacuo. The resulting solid was partitioned between EtOAc and water, and filtered through a pad of Celite to remove a sticky white solid. The layers were separated and the aqueous layer was extracted with additional EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and evaporated. The mixture of alcohols was purified by flash chromatography on 120 g silica, eluting with 0 to 50% EtOAc in hexanes. No attempt was made to separate the two diastereomers. This afforded (2-bromophenyl)(1-(2-(trimethylsilyl)ethanesulfonyl)piperidin-3-yl)methanol (3.64 g, 61%) as a white foam. 1H NMR (CDCl3) δ 0.01 (s, 9H), 0.95-2.06 (m, 8H), 2.6-3.0 (m, 6H), 3.6-3.9 (m, 3H), 4.96 (bs, 1H), 7.13 (m, 1H), 7.29 (m, 1H), 7.44 (m, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[NH2:28][CH2:29][CH2:30][CH2:31][OH:32]>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17](=[O:19])(=[O:18])[NH:28][CH2:29][CH2:30][CH2:31][OH:32])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Reactant: NCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)NCCCO)sc2Br)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (300 mg; 0.72 mmol; 1 eq), is dissolved in anhydrous DCM (20 ml). The reaction is put under nitrogen. Triethylamine (0.5 ml; 3.61 mmol; 5 eq) and 3-amino-1-propanol (0.27 ml; 3.61 mmol; 5 eq) are added successively and the reaction mixture is stirred for 1 hour at room temperature. It is washed with water, NaHCO3 sat., brine and dried over MgSO4, affording the title compound (230 mg; 70%).
Reaction SMILES: C(N1CCN(C2C=CC([NH:20][C:21]3[C:26]([F:27])=[CH:25][N:24]=[C:23](Cl)[N:22]=3)=CC=2)CC1)C1C=CC=CC=1.[CH2:29]1[CH2:39][O:38][C:37]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=2[O:30]1>>[CH2:29]1[CH2:39][O:38][C:37]2[CH:36]=[CH:35][C:33]([NH:34][C:23]3[N:22]=[C:21]([NH2:20])[C:26]([F:27])=[CH:25][N:24]=3)=[CH:32][C:31]=2[O:30]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Reactant: Nc1ccc2c(c1)OCCO2
Product: Nc1nc(Nc2ccc3c(c2)OCCO3)ncc1F
Yield: 127.1 %

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-N2-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidineamine, the reaction of N4-[4-(N-benzylpiperazino)phenyl]-2-chloro-5-fluoro-4-pyrimidineamine (50 mg, 0.12 mmol) and 3,4-ethylenedioxyaniline (0.045 mL, 0.36 mmol) gave N4-[4-(N-benzylpiperazino)phenyl)]-N2-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine (40 mg, 63%). 1H NMR (CDCl3): δ 2.64 (t, J=4.8 Hz, 4H), 3.20 (t, J=4.8 Hz, 4H), 3.59 (s, 2H), 4.24 (m, 4H), 6.61 (d, 1H, NH), 6.68 (br, 1H, NH), 6.76 (d, J=8.7 Hz, 1H), 6.88 (dd, J=2.4 and 8.7 Hz, 1H), 6.93 (d, J=8.7 Hz, 2H), 7.19 (d, J=2.4 Hz, 1H), 7.28–7.36 (m, 5H), 7.47 (d, J=8.7 Hz, 2H), 7.87 (d, J=3.3 Hz, 1H); 19F NMR (282 MHz, CDCl3): δ −168.66; LCMS: ret. time: 18.05 min.; purity: 100%; MS (m/e): 513.10 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH3:11].[CH3:12][S:13]([C:15](SC)=[CH:16][N+:17]([O-:19])=[O:18])=O>>[CH3:12][S:13][C:15]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH3:11])=[CH:16][N+:17]([O-:19])=[O:18]
Reactant: Cc1[nH]cnc1CCCCN
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Product: CSC(=C[N+](=O)[O-])NCCCCc1nc[nH]c1C
Yield: 51 %

Procedure:
Reaction of 4-(4-aminobutyl)-5-methylimidazole (see Example 7 (ii), 0.765 g, 0.005 mol) with 1-methylsulphinyl-1-methylthio-2-nitroethylene(0.91 g, 0.005 mol), gave 1-methylthio-1-[4-(5-methylimidazol-4-yl)butylamino]-2-nitroethylene (0.69 g, 51%) which was treated directly with methylamine to yield 1-methylamino-b 1-[4-(5-methylimidazol-4-yl)butylamino]-2-nitroethylene (0.40 g, 61.9%). This compound was reacted with picric acid to give 1-methylamino-1-[4-(5-methylimidazol-4-yl)butylamino]-2-nitroethylene picrate hemihydrate (0.33 g, 26.3% last stage), m.p. 185°-187°.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Br.[O:26]=[C:27]1[C:36]2[CH2:35][CH2:34][NH:33][CH2:32][C:31]=2[NH:30][C:29]2[CH:37]=[CH:38][CH:39]=[C:40]([C:41]([O:43][CH3:44])=[O:42])[C:28]1=2.[CH3:45][C:46]1([C:49](O)=[O:50])[CH2:48][CH2:47]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:45][C:46]1([C:49]([N:33]2[CH2:32][C:31]3[NH:30][C:29]4[CH:37]=[CH:38][CH:39]=[C:40]([C:41]([O:43][CH3:44])=[O:42])[C:28]=4[C:27](=[O:26])[C:36]=3[CH2:35][CH2:34]2)=[O:50])[CH2:48][CH2:47]1
Reactant: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCNC3
Reactant: CC1(C(=O)O)CC1
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCN(C(=O)C1(C)CC1)C3
Yield: 24.8 %

Procedure:
A solution of HATU (340 mg, 0.9 mmol) in DMF (2 ml) was added to a mixture of methyl 5-oxo-1,2,3,4,5,10-hexahydrobenzo[b][1,7]naphthyridine-6-carboxylate (200 mg, 0.77 mmol) from Example 13 (Step 2), 1-methylcyclopropanecarboxylic acid (102 mg, 1.02 mmol), diisopropylethylamine (0.5 mL, 5.09 mmol) and DMF (8 ml). The resultant mixture was stirred at ambient temperature for 8 hours. The DMF was evaporated and the residue was purified by pre-TLC to give methyl 2-(1-methylcyclopropanecarbonyl)-5-oxo-1,2,3,4,5,10-hexahydrobenzo[b][1,7]naphthyridine-6-carboxylate (65 mg, 25%) as yellow solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][C:25]=1[N:26]1[CH2:30][C:29](=[O:31])[NH:28][S:27]1(=[O:33])=[O:32])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20](O)=[O:21])C1C=CC=CC=1.[CH3:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[OH:8][C:9]1[CH:10]=[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]([N:38]2[CH2:39][CH2:40][CH:35]([CH3:34])[CH2:36][CH2:37]2)=[O:21])[CH:23]=[CH:24][C:25]=1[N:26]1[S:27](=[O:33])(=[O:32])[NH:28][C:29](=[O:31])[CH2:30]1
Reactant: CC1CCNCC1
Reactant: O=C(O)Cc1ccccc1Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Product: CC1CCN(C(=O)Cc2ccccc2Cc2ccc(N3CC(=O)NS3(=O)=O)c(O)c2)CC1

Procedure:
The title compound is prepared from {2-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-benzyl]-phenyl}-acetic acid and 4-methylpiperidine analogous to Example 314, steps B and C. (M−1)−=456. HPLC retention time=1.07 min (Method A).
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][C:8]3([NH2:11])[CH2:10][CH:4]([CH2:5]2)[CH2:3][CH:2]1[CH2:9]3.C(OC([NH:19][C:20](=[N:23]C(OC(C)(C)C)=O)SC)=O)(C)(C)C.O>CN(C=O)C.Cl[Hg]Cl>[C:8]12([NH:11][C:20]([NH2:23])=[NH:19])[CH2:10][CH:4]3[CH2:5][CH:6]([CH2:1][CH:2]([CH2:3]3)[CH2:9]1)[CH2:7]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl[Hg]Cl
Solvent: O
Solvent: CN(C)C=O
Product: N=C(N)NC12CC3CC(CC(C3)C1)C2

Procedure:
Amantadine (0.30 g, 2 mmol), HgCl2 (0.54 g, 2 mmol), and 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (0.58 g, 2 mmol) were stirred in DMF (10 mL) under a N2 atmosphere for 24 h. H2O was added to the reaction mixture, and the white precipitate was removed by filtration. The precipitate was washed with CH2Cl2 twice, and the combined filtrate was extracted with CH2Cl2, washed with brine and dried over MgSO4, concentrated in vacuo, and purified by flash chromatography. The Boc protecting group was removed by 50% TFA/CH2Cl2 for 2 h at RT. Excess TFA was removed by passing N2 through the solution to give a yellow solid which was subsequently purified by flash chromatography (0.41 g, 74% over two steps). 1H-NMR (360 MHz, CD3OD) δ 2.13 (br s, 3H), 1.97 (br s, 6H), 1.76 (br s, 6H); 13C-NMR (90 MHz, CD3OD) δ 160.35, 53.83, 42.45, 36.86, 31.03; ESI-MS: Calculated for C11H19N3 (M+H)+ 194.2. Found: 194.7.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9][CH2:10][CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[O:21]=[C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:22])[N:12]1[CH2:11][CH2:10][CH2:9][N:8]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]1[C:2]([NH:1][C:29](=[O:36])[CH:30]2[CH:31]=[CH:32][CH2:33][CH2:34][CH2:35]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Nc1cccnc1N(CCCN1C(=O)c2ccccc2C1=O)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(Nc1cccnc1N(CCCN1C(=O)c2ccccc2C1=O)c1ccccc1)C1C=CCCC1

Procedure:
2-[3-[(3-Amino-2-pyridinyl)phenylamino]propyl]-1H-isoindole-1,3-(2H)-dione is reacted with benzoyl chloride to prepare the title compound.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[O:35]1[C:39]2([CH2:44][CH2:43][CH:42](O)[CH2:41][CH2:40]2)[O:38][CH2:37][CH2:36]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.O1CCCC1>[O:35]1[C:39]2([CH2:44][CH2:43][CH:42]([O:34][C:31]3[CH:32]=[CH:33][C:28]([N:4]4[C:5](=[O:27])[C:6]([CH2:12][C:13]5[CH:18]=[CH:17][C:16]([C:19]6[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=6)=[CH:15][CH:14]=5)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=[C:3]4[CH2:1][CH3:2])=[CH:29][CH:30]=3)[CH2:41][CH2:40]2)[O:38][CH2:37][CH2:36]1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: CCCc1nc(CC)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc(OC3CCC4(CC3)OCCO4)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A mixture of 4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (4.0 g), 1,4-dioxaspiro[4.5]decan-8-ol (2.82 g), diisopropyl azodicarboxylate (1.9 M in toluene, 3.2 mL), triphenylphosphine (4.67 g) and tetrahydrofuran (20 ml) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, successively washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the title compound as a pale yellow amorphous solid (5.13 g, 98%).
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[C:13]1(C)C=CC=CC=1>CO>[NH2:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([O:6][CH3:13])=[O:5]
Reactant: Cc1ccccc1
Reactant: CC(C)(N)CC(=O)O
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)CC(C)(C)N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-amino-3-methyl-butyric acid 10-1 (1 eq.) in methanol at 0° C. was added 2 eq. of thionyl chloride. The reaction mixture was warmed to room temperature and stirred overnight. The solvent was evaporated to give azeotropic mixture of 10-2 and toluene (x=3) which was used for Step B. MS: MH+=132.1
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:20].Br[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[CH:28]([O:30][CH3:31])[CH3:29].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[CH3:31][O:30][CH:28]([C:27]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[C:8]1[CH:9]=[CH:10][C:5]2[O:4][C:3](=[O:20])[N:2]([CH3:1])[C:6]=2[CH:7]=1)[CH3:29]
Reactant: COC(C)c1ccncc1Br
Reactant: Cn1c(=O)oc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)c1ccncc1-c1ccc2oc(=O)n(C)c2c1
Yield: 68.8 %

Procedure:
A mixture of 3-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-benzooxazol-2-one (255 mg, 0.93 mmol), 3-Bromo-4-(1-methoxy-ethyl)-pyridine (200 mg, 0.93 mmol), Na2CO3 (2 M in water, 1.6 mL, 0.8 mmol) and PdCl2(PPh3)2 (52 mg, 0.07 mmol) in DMF (3 was heated at 100″C for overnight. After concentration, the residue was diluted in DCM and saturated NH4Cl solution. After filtration and extraction, the combined extracts were dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by flash column (MeOH—CH2Cl2, v/v, 0-1.5%) to give the title compound (182 mg, 69%). The racemate was resolved by chiral HPLC (ChiralPak, IA-H column, 40% EtOH/Heptane) to the first peak (enantiomer 1, retention time=10.90 min) and the second peak (enantiomer 2, retention time 14.25 min). ESI-MS m/z: 285 [M+1]+, Retention time 1.13 min; 1HNMR (MeOD, 400 MHz) δ 1.38 (d, J=6.8 Hz, 3H), 3.30 (s, 3H), 3.48 (s, 3H), 4.69 (q, J=6.8 Hz, 1H), 7.27 (dd, J=8.0, 1.6 Hz, 1H), 7.32 (d, J=1.6 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 8.25 (d, J=6.0 Hz, 1H), 8.78 (s, 1H), 8.89 (id, J=6.0 z, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([OH:23])=O)[C:9]=2[S:24][CH3:25])=[CH:4][CH:3]=1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[NH2:48][N:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:48][N:49]3[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]3)=[O:23])[C:9]=2[S:24][CH3:25])=[CH:6][CH:7]=1
Reactant: NN1CCCCC1
Reactant: CSc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CSc1c(C(=O)NN2CCCCC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 16 h

Procedure:
To a magnetically stirred solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-3-carboxylic acid (4.69 g, 11.3 mmol) in dichloromethane (100 ml) was successively added 7-aza-1-hydroxybenzotriazole (HOAt) (2.2 g, 16.0 mmol), (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (3.1 g, 16.1 mmol) and 1-aminopiperidine (1.6 gram, 16.0 mmol). After stirring for 16 h, the resulting mixture was successively washed with water (3×), dried over Na2SO4, filtered and concentrated to give a crude solid. This crude solid was further purified by flash chromatography (silica gel, EtOAc/heptane=22178 (v/v)) and trituration with n-heptane/methanol to give 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide: compound 1 (0.55 gram, 10% yield). Melting point: 172.4-174.5° C. 1H-NMR (CDCl3, 400 MHz) δ 1.41-1.49 (m, 2H), 1.72-1.81 (m, 4H), 2.40 (s, 3H), 2.83-2.95 (m, 4H), 7.15 (br d, J=8 Hz, 2H), 7.28-7.35 (m, 4H), 7.42 (br d, J=2 Hz, 1H), 7.94 (br s, 1H). 13C-NMR (CDCl3, 100 MHz) δ 20.03, 23.32, 25.29, 57.02, 113.66, 126.20, 127.99, 128.74, 130.36, 130.48, 131.24, 132.85, 135.59, 135.64, 136.41, 147.08, 147.30, 158.62.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)O)=[C:4]([CH2:15][CH3:16])[CH:3]=1.CC(C)=[O:19]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12](=[O:11])[CH:13]=[CH:14][CH:10]2[OH:19])=[C:4]([CH2:15][CH3:16])[CH:3]=1
Reactant: CC(C)=O
Reactant: CCc1cc(Br)ccc1C(O)c1ccco1
Solvent: O
Product: CCc1cc(Br)ccc1C1C(=O)C=CC1O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (4-bromo-2-ethylphenyl)furan-2-yl-methanol (13.6 g, 0.039 mol) in acetone (300 ml) and water (30 ml) at 55° C. is added polyphosphoric acid (5.0 g, 0.05 mol). After stirring at this temperature for 20 hours the reaction mixture is cooled to room temperature then concentrated in vacuo. The crude product is then partitioned between ethyl acetate (200 ml) and water (200 ml), and the organic phase is separated. After drying over anhydrous magnesium sulfate, all solvents are removed and the crude product is purified by flash column chromatography (1:1 ethyl acetate/hexane) to afford 5-(4-bromo-2-ethylphenyl)-4-hydroxycyclopent-2-enone as a brown gum.
Reaction SMILES: CO[CH:3]=[C:4]([CH2:7][NH:8][CH:9]=[O:10])[C:5]#[N:6].[C:11]([NH2:14])(=[NH:13])[CH3:12]>>[CH3:12][C:11]1[N:14]=[C:5]([NH2:6])[C:4]([CH2:7][NH:8][CH:9]=[O:10])=[CH:3][N:13]=1
Reactant: CC(=N)N
Reactant: COC=C(C#N)CNC=O
Product: Cc1ncc(CNC=O)c(N)n1

Procedure:
The α-methoxymethylene-β-formylaminopropionitrile solution and the acetamidine solution are combined. The mixture is reacted at 25°C for 10 minutes. The reaction mixture is subjected to concentration at not higher than 40°C to give crystals. The produced crystals are washed with 50 parts by volume of ethanol, whereby 24.8 parts of 2-methyl-4-amino-5-formylaminomethylpyrimidine is obtained as crystals (Purity: 93 %). The ethanol washing is concentrated to give 16 parts of 2-methyl-4-amino-5-formylaminomethylpyrimidine as crystals (Purity: 47.5 %).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH3:15])=[CH:10][CH:9]=1)=[O:7].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH:14]([Br:16])[CH3:15])=[CH:12][CH:13]=1)=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc(C(=O)c2cccs2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(Br)c1ccc(C(=O)c2cccs2)cc1

Procedure:
A mixture of 23.5 parts of p-ethylphenyl 2-thienyl ketone, 19.5 parts of N-bromosuccinimide, 220 parts of carbon tetrachloride, 1.1 parts of benzoyl peroxide and one drop of toluene is stirred and refluxed for 2 hours. The precipitated succinimide is filtered off and the carbon tetrachloride filtrate is dried and evaporated. The oily residue solidifies on cooling. The solid product is dissolved in 2-propanol and the product is allowed to crystallize. It is filtered off and dried in vacuo, yielding α-bromo-α-methyl-p-tolyl 2-thienyl ketone; m.p. 71.1° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[CH:4]=O.[CH3:11][NH:12][NH2:13]>CS(C)=O.O>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:3]=1[CH:4]=[N:13][N:12]2[CH3:11]
Reactant: O=Cc1c(F)cccc1Br
Reactant: CNN
Solvent: O
Solvent: CS(C)=O
Product: Cn1ncc2c(Br)cccc21
Temperature: 85 °C

Procedure:
The product of Example 2B (2.0 g) was dissolved in DMSO (2 g) and the solution was added to methylhydrazine (98%, 3.2 g, 7 eq.). The mixture was heated for 24 hours at 85° C., cooled to ambient temperature and diluted with water (50 mL). The solution was extracted with CH2Cl2 (2×50 mL) and the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to provide the title compound.