Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.C([O:28][C:29](=O)[CH:30]([CH2:36][CH2:37][CH2:38]Cl)[C:31](OCC)=[O:32])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:20][CH2:21][N:22]([CH2:38][CH2:37][CH2:36][CH:30]([CH2:31][OH:32])[CH2:29][OH:28])[CH2:23][CH2:24]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)C(CCCCl)C(=O)OCC
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCNCC4)n3)ccc21
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCN(CCCC(CO)CO)CC4)n3)ccc21

Procedure:
The preparation was carried out analogously as described above starting from 200 mg (0.53 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperazine and 234 μl (0.1.06 mmol) of 2-(3-chloropropyl)malonic acid diethyl ester and subsequent reduction using lithium aluminium hydride prepared. The product is in the form of the hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([CH3:32])[C:21]=1[C:22]1[CH:30]=[CH:29][C:25]2[O:26][CH2:27][O:28][C:24]=2[C:23]=1[CH3:31])[C:16](O)=[O:17]>>[CH3:32][C:20]1[CH:19]=[C:15]([CH:14]=[C:13]([CH3:12])[C:21]=1[C:22]1[CH:30]=[CH:29][C:25]2[O:26][CH2:27][O:28][C:24]=2[C:23]=1[CH3:31])[C:16]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)=[O:17]
Reactant: Nc1ccc2cccnc2c1
Reactant: Cc1cc(C(=O)O)cc(C)c1-c1ccc2c(c1C)OCO2
Product: Cc1cc(C(=O)Nc2ccc3cccnc3c2)cc(C)c1-c1ccc2c(c1C)OCO2

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-aminoquinoline (D55) (17 mg, 0.12 mmol) and 3,5-dimethyl-4-(4-methyl-benzo[1,3]-dioxol-5-yl)-benzoic acid (D62) (41 mg, 0.15 mmol) as a yellow oil. MS(ES): MH+ 411, M-H+ 409.
Reaction SMILES: [CH2:1]([N:10]1[C:15](=[O:16])[C:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:13]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:12]=[N:11]1)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.Cl.[O:35]([NH2:37])[CH3:36].C([O-])(=O)C.[Na+]>CO>[CH3:36][O:35][N:37]=[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:1][N:10]1[C:15](=[O:16])[C:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:13]([C:24]2[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=2)[CH:12]=[N:11]1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(CC(=O)c3ccccc3)c(=O)c2-c2ccc(F)cc2)cc1
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CON=C(Cn1ncc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)c1=O)c1ccccc1

Procedure:
A mixture of the product from Example 46, 2-phenacyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (220 mg, 0.476 mmol), methoxylamine hydrochloride (318 mg, 3.8 mmol), and sodium acetate (518 mg, 3.8 mmol) in methanol (100 mL) was stirred at reflux for 48 hours. The reaction mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with brine then dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to provide a brown oil which was purified by column chromatography (silica gel, 70:30 hexanes/ethyl acetate). Fractions containing product were combined and concentrated in vacuo. The residue was crystallized from methanol/water to provide the title compound as a mixture of E and Z oximes (yield: 82 mg, 35%). mp 95–99° C. 1H NMR (300 MHz, CDCl3) δ 3.03 (s, 3H), 4.07 (s, 3H), 5.57 (s, 2H), 6.94 (t, J=9 Hz, 2H), 7.07 (dd, J=9 Hz, 3 Hz, 2H), 7.24 (d, J=9 Hz, 2H), 7.31–7.37 (m, 3H), 7.60–7.67 (m, 2H), 7.74 (s, 1H), 7.83 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 492 (M+H)+. Anal. calc. for C26H22FN3O4S: C, 63.53; H, 4.51; N, 8.54. Found: C, 63.40; H, 4.51; N, 8.31.
Reaction SMILES: CC(C)([O-])C.[K+].Cl.CON.[C:11]1([C:17]2[N:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][N:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+:27]>CS(C)=O.[Cl-].[Zn+2].[Cl-]>[C:11]1([C:17]2[N:22]=[C:21]([NH2:27])[C:20]([NH2:23])=[CH:19][N:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1cnc(-c2ccccc2)nc1
Agent: CC(C)(C)[O-]
Agent: CON
Agent: Cl
Solvent: CS(C)=O
Product: Nc1cnc(-c2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 80 %

Procedure:
Zinc chloride (136 mg), potassium t-butoxide (505 mg) and O-methylhydroxylamine monohydrochloride (125 mg) were successively added to a solution of 2-phenyl-5-nitropyrimidine (201 mg, 1.00 mmol), which was prepared according to the method described in the Journal of American Chemical Society, 78, 1434-1437 (1956), in dimethyl sulfoxide (5 mL). The mixture was stirred at room temperature for 40 minutes, and saturated aqueous ammonium chloride was added thereto, then the mixture was extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium bicarbonate, dried over aqueous sodium sulfate, and concentrated in vacuo. The residue was dissolved in methanol (8 mL), and 10% palladium carbon (50 mg) was added thereto. The mixture was stirred at room temperature for one hour under a hydrogen atmosphere, and then filtered. The filtrate was concentrated in vacuo to give the title compound (148 mg, 80%) as a brown solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2.[C:20](OC(=O)C)(=[O:22])[CH3:21]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:20]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)(=[O:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(CO)c2C1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OCc1cccc2c1CN(C(=O)OC(C)(C)C)CC2
Reaction time: 1 h

Procedure:
In a 10 dram vial, added 1-7 (300 mg, 0.795 mmol) to pyridine (3975 μl) followed by acetic anhydride (225 μl, 2.385 mmol) and DMAP (9.71 mg, 0.080 mmol). After 1 h, LCMS showed complete consumption of R1 desired product. Partitioned between 10 mL H2O and 10 mL EtOAc, separated layers. Back-extracted aqueous with 1×5 mL EtOAc. Washed combined organics with 5×5 mL H2O. Dried combined organics over Na2SO4, filtered, concentrated to give a pale yellow oil. Purification by normal-phase HPLC (40 g ISCO column, 0-50% EtOAc:Hexanes) gave 7-1 as a clear, colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:10]([CH:12]([NH2:15])[CH2:13][CH3:14])[CH3:11].C(N(CC)C(C)C)(C)C>C(O)C>[Br:1][C:2]1[C:3]([NH:15][CH:12]([CH2:13][CH3:14])[CH2:10][CH3:11])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CCC(N)CC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCC(CC)Nc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (4.56 g, 20 mmol) in ethanol (9 mL) is added 1-ethylpropylamine (2.6 mL, 22 mmol) and N,N-diisopropylethylamine (7 mL, 40 mmol) at ambient temperature. The reaction mixture is stirred at ambient temperature for 16 h and concentrated in vacuo. The residue is purified by flash chromatography (SiO2, EtOAc/hexane 3:97 to 30:70) to give (5-bromo-2-chloro-pyrimidin-4-yl)-(1-ethyl-propyl)-amine. LCMS: 280 (M+H)+
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:29][C:30]1[N:34]([C:35]([CH3:38])([CH3:37])[CH3:36])[N:33]=[CH:32][C:31]=1[CH2:39]Br>C1COCC1>[Br:29][C:30]1[N:34]([C:35]([CH3:37])([CH3:36])[CH3:38])[N:33]=[CH:32][C:31]=1[CH2:39][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)n1ncc(CBr)c1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2cnn(C(C)(C)C)c2Br)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
A solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (0.37 mL, 1.47 mmol) in THF (15 mL) was cooled to −78° C. and then treated with lithium bis(trimethylsilyl)amide (1.48 mL, 1.48 mmol, 1 M toluene), dropwise. The reaction was stirred 15 minutes at −78° C., warmed to 0° C. for 30 minutes and then cooled back to −78° C. A solution of 5-bromo-4-(bromomethyl)-1-tert-butyl-1H-pyrazole (335 mg, 1.13 mmol) in THF (10 mL) was added, the mixture was stirred 1 hour at −78° C., and then allowed to stir 18 hours at room temperature. The reaction was quenched with saturated aqueous ammonium chloride (20 mL), stirred 30 minutes at room temperature, diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated. The resultant residue was purified by flash chromatography (5-40% ethyl acetate/heptane, 25 g silica gel) to yield 256 mg of 1-tert-butyl 4-ethyl 4-((5-bromo-1-tert-butyl-1H-pyrazol-4-yl)methyl)piperidine-1,4-dicarboxylate as a clear oil. +ESI (M+H) 474.2, (M+2+H) 476.2; 1H NMR (400 MHz, CDCl3, δ): 7.20 (s, 1H), 4.16 (q, J=7.2 Hz, 2H), 3.93 (br. s., 2H), 2.84 (m, 2H), 2.66 (s, 2H), 2.10 (d, J=12.5 Hz, 2H), 1.72 (s, 9H), 1.45 (m, 11H), 1.25 (t, J=7.1 Hz, 3H).
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.Cl.[NH2:24][C@@H:25]1[CH2:28][C@H:27]([OH:29])[CH2:26]1.CCN(C(C)C)C(C)C.CCOC(C)=O>CS(C)=O.O.CO.C(Cl)Cl>[OH:29][C@@H:27]1[CH2:28][C@H:25]([NH:24][C:2]2[C:3]([CH3:22])=[N:4][C:5]3[C:10]([N:11]=2)=[C:9]([C:12]2[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=2)[CH:8]=[CH:7][CH:6]=3)[CH2:26]1
Reactant: N[C@H]1C[C@@H](O)C1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@H]1C[C@@H](O)C1
Temperature: 23 °C

Procedure:
A solution of 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 85.0 mg, 0.287 mmol), cis-3-aminocyclobutanol hydrochloride (46.2 mg, 0.374 mmol), and DIPEA (0.150 mL, 0.861 mmol) in DMSO (2.0 mL) was stirred under argon at 100° C. for 30 min. The reaction mixture was subsequently cooled to 23° C. and diluted with water (10 mL). The resulting mixture was extracted with 5% MeOH/DCM (2×30 mL), and the combined extracts were sequentially washed with water (2×10 mL) and then concentrated onto silica gel. Chromatographic purification (silica gel, 50-100% EtOAc/Hexanes, then 100% EtOAc, then 0-10% MeOH/DCM) provided 2-(3-((cis-3-hydroxycyclobutyl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (9.3 mg, 0.026 mmol, 11% yield) as a yellow solid. The combined aqueous layers from the aqueous workup were filtered through a fine glass frit, and the collected solid was sequentially washed with water (40 mL) and ether (30 mL), then dried in vacuo to provide additional 2-(3-((cis-3-hydroxycyclobutyl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (92.2 mg, 0.254 mmol, 88% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.35 (1H, br. s.), 7.90 (1H, d, J=8.0 Hz), 7.56 (1H, d, J=7.6 Hz), 7.27-7.40 (2H, m), 7.09 (1H, br. s.), 6.95 (1H, br. s.), 5.18 (1H, d, J=6.3 Hz), 3.92-4.08 (1H, m), 3.41-3.50 (3H, m), 2.86-2.96 (2H, m), 2.74-2.86 (2H, m), 2.55 (3H, br. s.), 1.93-2.07 (2H, m). m/z (ESI, +ve) 364.0 (M+H)+.
Reaction SMILES: [O:1]([C@H:13]1[C@@H:30]([OH:31])[C@@H:29]([CH2:32][OH:33])[O:28][C@@H:15]([O:16][C@@H:17]2[C@@H:23]([CH2:24][OH:25])[O:22][CH:20]([OH:21])[C@H:19]([NH2:26])[C@H:18]2[OH:27])[C@@H:14]1[OH:34])[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O.C1C(=O)NC(=O)N([C@@H]2O[C@H](COP(OP(O[C@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=1>>[O:16]([C@@H:17]1[C@@H:23]([CH2:24][OH:25])[O:22][CH:20]([OH:21])[C@H:19]([NH2:26])[C@H:18]1[OH:27])[C@@H:15]1[O:28][C@H:29]([CH2:32][OH:33])[C@H:30]([OH:31])[C@H:13]([OH:1])[C@H:14]1[OH:34]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O[C@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@H]2O)[C@@H]1O
Agent: O=c1ccn([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)O[C@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@@H](O)[C@H]2O)c(=O)[nH]1
Product: N[C@H]1C(O)O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@@H]1O

Procedure:
Synthesis of Galα1-3Galβ1-4GlcNH2 βSEt. Galβ1-4GlcNH2 βSEt is prepared as described above and used directly or after isolation as acceptor for a α1-3-D-galactosyltransferase (e.g. EC 2.4.1 151) reaction with a suitable glycosyl donor such as UDP-Gal.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][CH:17]=[CH:18][C:19]([O:21]CC)=O)=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].CC[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:19](=[O:21])[CH:18]=[CH:17][NH:16][C:14]2=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C=CNC(=O)Nc1ccc(Cl)c(C(=O)OCC)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(-n2c(=O)cc[nH]c2=O)ccc1Cl

Procedure:
using ethyl 2-chloro-5-{3-[2-(ethoxycarbonyl)vinyl]ureido}-benzoate with sodium ethylate in ethanol there is obtained ethyl 2-chloro-5-[3,6-dihydro-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 170°-172° C.,
Reaction SMILES: [C:1]([C@@:9]([C:24]([OH:26])=[O:25])([OH:23])[C@@:10]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:14])[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:27][C:28]1[CH:39]=[CH:38][C:31]([CH2:32][CH:33]2[CH2:37][CH2:36][CH2:35][NH:34]2)=[CH:30][CH:29]=1>CC(C)=O>[C:15]([C:10]([C:11]([OH:13])=[O:12])([OH:14])[C:9]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([OH:23])[C:24]([OH:26])=[O:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl:27][C:28]1[CH:39]=[CH:38][C:31]([CH2:32][CH:33]2[CH2:37][CH2:36][CH2:35][NH:34]2)=[CH:30][CH:29]=1
Reactant: O=C(O)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)O)C(=O)c1ccccc1
Agent: Clc1ccc(CC2CCCN2)cc1
Solvent: CC(C)=O
Product: O=C(O)C(O)(C(=O)c1ccccc1)C(O)(C(=O)O)C(=O)c1ccccc1
Reaction time: 12 h
Yield: 27.9 %

Procedure:
Add a solution of 37.6 g of dibenzoyl-L-tartaric acid in 250 ml of acetone to 19.57 g of 2-(4-chlorobenzyl)pyrrolidine dissolved in 200 ml of acetone. Allow the resulting reaction mixture to stand for 12 hours and then filter off the precipitated crystals (25.8 g); [α]58920 =-84.7° (25 mg/ml in methanol). Recrystallize from 75 ml methanol/100 ml acetone to obtain 15.43 g of (-)-2-(4-chlorobenzyl)pyrrolidine dibenzoyl tartrate (m.p. 178° to 179°); [α]58920 =-88° (25 mg/ml in methanol). Stir 14.85 g of this salt with sodium hydroxide solution/diethyl ether until two clear phases form. Collect the ether phase and dry it over sodium sulfate. Thereafter, concentrate the dried ether phase to obtain the title compound as a colorless oil (5.0 g). Treat the colorless oil with methanol/ethereal hydrochloric acid to convert it into 4.83 g of the corresponding hydrochloride (m.p. 216° to 218°); [α]58920 =-31.4° (25 mg/ml in methanol).
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.B(Cl)(Cl)Cl.O>ClCCl>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C:8]2[C:3](=[O:2])[NH:4][CH:5]=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(Cc2cccnc2OC)cc1
Agent: ClB(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Cc2ccc[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.9 %

Procedure:
To a solution of mesityl bromide (0.77 g) in tetrahydrofuran(2.6 mL) was added tert-butyllithium (1.48 mol/L solution in pentane, 5.3 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 1 hour. To the reaction mixture was added a solution of 2-methoxypyridine (0.33 g) in tetrahydofuran (3 mL). The temperature was raised to 0° C., and the mixture was stirred for 1 hour. The temperature was raised to room temperature, and the reaction mixture was stirred for additionally 1 hour. To the reaction mixture was added a solution of 4-methoxybenzaldehyde (0.57 g) in tetrahydrofuran (4.2 mL), and the mixture was stirred for 1 hour. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1-2/1) to give 4-methoxyphenyl 2-methoxypyridin-3-yl methanol (0.43 g). To a solution of the obtained 4-methoxyphenyl 2-methoxypyridin-3-yl methanol (0.41 g) in acetic acid (2.1 mL) was added 10% palladium carbon powder (0.21 g), and the mixture was stirred for 10 hours at room temperature under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1-4/1) to give 2-methoxy-3-(4-methoxybenzyl)-pyridine (0.29 g). To a solution of the obtained 2-methoxy-3-(4-methoxybenzyl)pyridine (0.023 g) in dichloromethane (0.5 mL) was added boron trichloride (1 mol/L solution in dichloromethane, 0.06 mL) at 0° C. The temperature was raised to room temperature, and the mixture was stirred for 1 hour. After boron trichloride (1 mol/L solution in dichloromethane, 0.06 mL) was added to the reaction mixture, the mixture was stirred for additionally 15 hours. To the reaction mixture was added water, and the mixture was extracted with a mixture of dichloromethane and ethanol (10/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: dichloromethane/methanol=8/1) to give 3-(4-methoxy-benzyl)-1H-pyridin-2-one (0.0017 g).
Reaction SMILES: C[O:2][C:3]1[N:4]=[N:5][C:6]([S:9]([C:12]2[NH:13][C:14]3[C:19]([C:20]=2[Cl:21])=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:11])=[O:10])=[CH:7][CH:8]=1.Cl>O1CCOCC1>[Cl:21][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]=1[S:9]([C:6]1[CH:7]=[CH:8][C:3](=[O:2])[NH:4][N:5]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(S(=O)(=O)c2[nH]c3ccccc3c2Cl)nn1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1ccc(S(=O)(=O)c2[nH]c3ccccc3c2Cl)n[nH]1
Temperature: 100 °C
Yield: 102.6 %

Procedure:
A mixture of 3-methoxy-6-(3-chloro-indole-2-sulfonyl)-pyridazine (0.34 mmol, 110 mg), conc. HCl (1 mL), and dioxane (3 mL) was heated at 100° C. for 2 hours. The reaction mixture was cooled and evaporated to dryness. The dried residue was triturated with water (10 mL), and filtered to obtain 6-(3-chloro-indole-2-sulfonyl)-2H-pyridazin-3-one (99%, 108 mg); mp 250° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[C:15]([CH3:20])[N:14]=1.CC(C)([O-])C.[Na+]>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:12][C:13]1[N:18]=[C:17]([NH:9][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:8]=[CH:7][N:6]=2)[CH:16]=[C:15]([CH3:20])[N:14]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: Nc1cc(C(F)(F)F)ccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(Cl)n1
Temperature: 25 °C

Procedure:
Nitrogen was bubbled through a solution of 4-(trifluoromethyl)pyridin-2-amine (10.96 g, 67.6 mmol), 2,4-dichloro-6-methylpyrimidine (11.02 g, 67.6 mmol) in dioxane (198 mL) for 10 minutes. Sodium tert-butoxide (6.50 g, 67.6 mmol) and 1,1′ bis(di-t-butylphosphino ferrocene) (3.21 g, 6.76 mmol) were added, followed by Pd2(dba)3 (3.10 g, 3.38 mmol) and the solution was evacuated and then purged with nitrogen. After heating to reflux for 3 h, the reaction mixture was cooled to room temperature and EtOAc (1 L) was added. The organic layer was washed with saturated sodium bicarbonate, water and brine, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/hexanes; to afford 2-chloro-6-methyl-N-[4-(trifluoromethyl)pyridin-2-yl]pyrimidin-4-amine as a yellow solid. MS ESI calcd. for C11H18ClF3N4[M+H]+ 289. found 289.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][C:19]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:20]=1[NH2:21].Cl.[OH-].[Na+]>O.C(O)C>[CH3:18][C:19]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1
Yield: 25.8 %

Procedure:
A mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (1 g, 3.90 mmol), 2-methyl-5-nitroaniline (890 mg, 5.90 mmol), and 2N HCl (3 ml) in water:ethanol (1:1, 200 ml) was refluxed for 48 h. The mixture was cooled to room temperature and basified with aqueous 2N NaOH to pH 10–12. The mixture was extracted with ethyl acetate (200 ml), washed with water (2×100 ml), with aqueous saturated NaCl (1×100 ml) and dried over anhydrous sodium sulfate. The ethyl acetate solution was rotary evaporated to dryness to give a tan solid (377 mg, 30%). 1H NMR (CDCl3): 8.90 (s, 1H), 8.80 (dd, J=1.8, 4.8 Hz, 2H), 8.30 (dd, J=1.5, 4.5 Hz, 2H), 8.09 (dd, J 2.4, 8.1 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 6.99 (s, 1H), 6.87 (s, 1H), 2.47 (s, 3H).
Reaction SMILES: [C:1]([CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=O)([O:3][CH3:4])=[O:2].C(O)(=O)C(C)C.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>C1(C)C=CC=CC=1>[C:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]=1[NH:29][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O:3][CH3:4])=[O:2]
Reactant: NCc1ccccc1
Reactant: COC(=O)C1C(=O)CCc2ccccc21
Solvent: Cc1ccccc1
Solvent: CC(C)C(=O)O
Solvent: O
Product: COC(=O)C1=C(NCc2ccccc2)CCc2ccccc21
Yield: 102.4 %

Procedure:
To a solution of 1-carbomethoxy-2-oxo-1,2,3,4-tetrahydronaphthalene (10.2 g) and isobutyric acid (4.84 g) in toluene (150 mL) stirring at room temperature under argon, was added benzylamine (5.35 g). The resulting mixture was heated to reflux for 2 h with water removal using a Dean-Stark trap. The solvent was then evaporated under vacuum to provide the title compound (15 g) as a yellow gum.