Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[CH:15][C:14]3[NH:17][C:18](=[O:19])[N:12]4[C:13]=3[C:8]=2[CH2:9][CH2:10][CH:11]4[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]([CH3:26])[O:4][N:3]=1.[C:27](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[CH:15][C:14]3[N:17]([CH3:27])[C:18](=[O:19])[N:12]4[C:13]=3[C:8]=2[CH2:9][CH2:10][CH:11]4[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1CCC3c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1noc(C)c1-c1ccc2c3c1CCC(c1ccccc1)n3c(=O)n2C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.6 %

Procedure:
A solution of 7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (10.7 g, 0.031 mmol) in N,N-dimethylformamide (0.50 mL) was treated with cesium carbonate (20.2 g, 0.062 mmol) followed by methyl iodide (2.9 μL, 46.5 μmol) and stirred at room temperature for 16 h. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) gave the desired product (8.2 mg, 74%) as a racemic mixture. 1H NMR (400 MHz, CDCl3) δ 7.35-7.20 (m, 3H), 7.03 (d, J=6.9 Hz, 2H), 6.99-6.93 (m, 1H), 6.93-6.84 (m, 1H), 5.53 (s, 1H), 3.49 (s, 3H), 2.48-2.11 (m, 7H), 2.09-1.84 (m, 3H); LCMS calculated for C22H22N3O2 (M+H)+: m/z=360.2. found: 360.1.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl>N1C=CC=CC=1>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([NH:16][C:13]2[S:14][CH:15]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=3)[N:12]=2)(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2nc(-c3cccc([N+](=O)[O-])c3)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.8 %

Procedure:
A mixture of 0.5 g of 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrochloride with 0.44 g of 4-methoxybenzenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 50 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and dissolved in a mixture of 40 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated upon neutralization with concentrated hydrochloric acid. Recrystallization from 40 ml of 50% ethanol yielded 0.31 g of 4-methoxy-N-[4-(3-nitro-phenyl)-thiazol-2-yl]-benzenesulfonamide as yellowish crystals.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[C:11]([N+:19]([O-])=O)[CH:12]=[CH:13][CH:14]=3)[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:23]S(O)(=O)=O.O=S(=O)=O.B(O)(O)O.[S]>>[OH:23][C:14]1[C:15]2[C:16](=[O:18])[C:17]3[C:8](=[CH:7][CH:6]=[CH:5][C:4]=3[N+:1]([O-:3])=[O:2])[C:9](=[O:22])[C:10]=2[C:11]([NH2:19])=[CH:12][CH:13]=1
Reactant: O=S(=O)(O)O
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2cccc([N+](=O)[O-])c21
Agent: O=S(=O)=O
Agent: OB(O)O
Agent: [S]
Product: Nc1ccc(O)c2c1C(=O)c1cccc([N+](=O)[O-])c1C2=O
Reaction time: 6 h

Procedure:
50 parts of 1,5-dinitroanthraquinone are heated in 500 parts of 30% strength oleum for 3 hours at 50° C. 25 parts of boric acid are then added with cooling in the course of 20 minutes, the resulting reaction mixture is then cooled down to 15° to 20° C. and 7 parts of sulphur are added to it. After 6 hours' further stirring at 15° to 20° C. the reaction mixture is worked up as indicated. 25.8 parts of 1-hydroxy-4-amino-8-nitroanthraquinone are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[O:12][C:11](=[O:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:23]([C:26]1[CH:37]=[CH:36][C:29]([O:30][CH2:31][CH:32]([OH:35])[CH2:33]Cl)=[C:28]([CH2:38][CH2:39][CH3:40])[C:27]=1[OH:41])(=[O:25])[CH3:24]>CN(C=O)C>[C:23]([C:26]1[CH:37]=[CH:36][C:29]([O:30][CH2:31][CH:32]([OH:35])[CH2:33][O:19][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11](=[O:20])[O:12]3)=[CH:17][CH:16]=2)=[C:28]([CH2:38][CH2:39][CH3:40])[C:27]=1[OH:41])(=[O:25])[CH3:24]
Reactant: O=c1cc(OCc2ccccc2)c2ccc(O)cc2o1
Reactant: CCCc1c(OCC(O)CCl)ccc(C(C)=O)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCC(O)COc2ccc3c(OCc4ccccc4)cc(=O)oc3c2)ccc(C(C)=O)c1O
Reaction time: 1 h

Procedure:
A solution of 4-benzyloxy-7-hydroxycoumarin (5.36g; 6.02 mole) in dry DMF (30 ml) was treated with 100% sodium hydride (0.48g; 0.02 mole) and stirred at 100° for about 1 hr. To this was added a solution of 1-(4Acetyl-3-hydroxy-2-n-propylphenoxy)-3-chloro-2-propanol (7g) in DMF (2ml) and the mixture stirred at 100° for an additional 4hrs. After removal of the solvent in vacuo, water was added and the product extracted into chloroform. Chromatography of the extract on 300g of silica gel eluting with chloroform afforded the title compound as a white crystalline solid of Rf 0.38. mp (EtOH) 172°-173°. Yield 4.38g (42%). νmax (mull) 1715; 1630; 1620 cm-1. (DMSO) 9.19 (3H, t, J 7.0Hz); 8.58 (2H, sextuplet, J. 7.0Hz); 7.48 (3H, S + 2H m); 6.71 (1H sharp exchangeable); 5.80 (5H, S); 4.68 (2H, S), 4.50 (1H, broad exchangeable); 4.13 (1H, S); 3.32 (1H, d, J 9Hz); 3.12-2.15 (12H, m); 1 low field sharp exchangeable. (Found; C, 69.30; H, 5.80; C30H30O8 requires; C 69.49; H, 5.83%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([C:21]2[CH:25]=[CH:24][NH:23][CH:22]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=2.[OH-].[Na+]>CO.O>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8]([C:21]2[CH:25]=[CH:24][NH:23][CH:22]=2)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2
Reactant: COC(=O)c1ccc2nc(-c3cc[nH]c3)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1cc[nH]c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
To a solution of methyl 3-[(2S)-2-methylpyrrolidin-1-yl]-2-(1H-pyrrol-3-yl)quinoxaline-6-carboxylate (100 mg, 0.30 mmol) in methanol (30 ml) and water (2.0 ml) was added sodium hydroxide (48 mg, 1.20 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL1) and adjusted to pH 4 with HCl (3 N). The solids were collected by filtration to afford 3-[(2S)-2-methylpyrrolidin-1-yl]-2-(1H-pyrrol-3-yl)quinoxaline-6-carboxylic acid as a light yellow solid (70 mg, 73%).
Reaction SMILES: [NH2:1][C@@H:2]([C:47](=[O:82])[NH:48][CH2:49][CH2:50][CH2:51][CH2:52][C@@H:53]([C:75]([O:77]C(C)(C)C)=[O:76])[NH:54][C:55](=[O:74])[NH:56][C@H:57]([C:67]([O:69]C(C)(C)C)=[O:68])[CH2:58][CH2:59][C:60]([O:62]C(C)(C)C)=[O:61])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:46])[CH2:9][N:10]1[CH2:21][CH2:20][N:19]([CH2:22][C:23](=[O:29])[O:24]C(C)(C)C)[CH2:18][CH2:17][N:16]([CH2:30][C:31](=[O:37])[O:32]C(C)(C)C)[CH2:15][CH2:14][N:13]([CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])[CH2:12][CH2:11]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:1][C@H:2]([C:47](=[O:82])[NH:48][CH2:49][CH2:50][CH2:51][CH2:52][C@@H:53]([C:75]([OH:77])=[O:76])[NH:54][C:55](=[O:74])[NH:56][C@H:57]([C:67]([OH:69])=[O:68])[CH2:58][CH2:59][C:60]([OH:62])=[O:61])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:46])[CH2:9][N:10]1[CH2:11][CH2:12][N:13]([CH2:38][C:39]([OH:41])=[O:40])[CH2:14][CH2:15][N:16]([CH2:30][C:31]([OH:37])=[O:32])[CH2:17][CH2:18][N:19]([CH2:22][C:23]([OH:29])=[O:24])[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)[C@H](N)CCCCNC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CCCCNC(=O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1)C(=O)NCCCC[C@H](NC(=O)N[C@@H](CCC(=O)O)C(=O)O)C(=O)O
Yield: 5.9 %

Procedure:
A solution of ((8R,15S,19S)-tri-tert-butyl 8-amino-2,9,17-trioxo-1-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-3,10,16,18-tetraazahenicosane-15,19,21-tricarboxylate (64 mg) in TFA (1.0 mL) and DCM (1.0 mL) was stirred at rt for overnight. The solvent was removed under a stream of nitrogen to give crude (8S,15S,19S)-8-amino-2,9,17-trioxo-1-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-3,10,16,18-tetraazahenicosane-15,19,21-tricarboxylic acid (57.9 mg). A small amount (9 mg) crude product was purified by HPLC to give pure (8S,15S,19S)-8-amino-2,9,17-trioxo-1-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)-3,10,16,18-tetraazahenicosane-15,19,21-tricarboxylic acid (MIP-1457, (2.7 mg)) as a white solid. MS (ESI), 832.2 (M−H)−.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH:11]([O:17][CH2:18][P:19]([O:25][CH:26]([CH3:28])[CH3:27])([O:21][CH:22]([CH3:24])[CH3:23])=[O:20])[CH2:12][O:13][CH2:14][O:15][CH3:16])C1C=CC=CC=1>C(O)C.C1CCCCC=1.[OH-].[OH-].[Pd+2]>[CH:22]([O:21][P:19]([CH2:18][O:17][C@@H:11]([CH2:10][CH2:9][OH:8])[CH2:12][O:13][CH2:14][O:15][CH3:16])([O:25][CH:26]([CH3:28])[CH3:27])=[O:20])([CH3:24])[CH3:23]
Reactant: COCOCC(CCOCc1ccccc1)OCP(=O)(OC(C)C)OC(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: COCOC[C@H](CCO)OCP(=O)(OC(C)C)OC(C)C
Temperature: 25 °C
Yield: 97.7 %

Procedure:
Palladium hydroxide on carbon (20%, 10 g) was added to a solution of 4-O-benzyl-2-O-(diisopropylphosphonomethyl)-1-O-methoxymethyl-1,2,4-butanetriol (21.9 g, 52.33 mmol) in a mixture of ethanol and cyclohexene (200 mL of each). The resulting mixture was heated at reflux for 6 hours. The mixture was cooled to room temperature and filtered. The filtrate was evaporated and the residue was purified by flash chromatography on silica gel (methylene chloride:methanol=20:1 to 10:1) to give 16.79 g (98% yield) of the title compound as an oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[OH:15][CH2:16][CH:17]([NH:24][C:25](=[O:29])[C:26](O)=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:26](=[O:27])[C:25]([NH:24][CH:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:16][OH:15])=[O:29]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)C(=O)NC(CO)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C(=O)NC(CO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.6 %

Procedure:
The mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.256 g; 1.09 mmol), 2-(2-hydroxy-1-phenylethylamino)-2-oxoacetic acid (0.250 g; 1.19 mmol), HATU (0.413 g: 1.09 mmol) and N,N-diisopropylethylamine (0.474 mL; 2.71 mmol) in DMF (5 mL) was stirred at room temperature overnight and was concentrated under reduced pressure. The residue was dissolved in dichloromethane and the organic layer was washed with water and was concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 1 to 10% methanol in dichloromethane) to yield 0.440 g of N1-(2-(5-chloro-1H-indol-3-yl)ethyl)-N2-(2-hydroxy-1-phenylethyl)oxalamide as a white solid.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:16]([CH3:27])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].I[CH2:29][CH3:30]>>[CH2:29]([N:15]1[C:16]([CH3:27])=[C:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:13]([O:12][C@@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]2[OH:3])=[N:14]1)[CH3:30]
Reactant: CCI
Reactant: COc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C)cc1
Product: CCn1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c(Cc2ccc(OC)cc2)c1C

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 63 using 3-(β-D-glucopyranosyloxy)-4-[(4-methoxyphenyl)methyl]-5-methyl-1H-pyrazole instead of 3-(β-D-glucopyranosyloxy)-4-[(4-isopropoxyphenyl)methyl]-5-methyl-1H-pyrazole and using iodoethane instead of 1-iodpropane.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].C([N:8]([CH2:15][CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.N1C2C(=CC=CC=2)CC1=O.O>C1(C)C=CC=CC=1>[Cl:3][C:15]1[NH:8][C:9]2[C:10]([CH:16]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCN(CC)c1ccccc1
Agent: O=C1Cc2ccccc2N1
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1cc2ccccc2[nH]1
Yield: 92.7 %

Procedure:
At room temperature, POCl3 (1 ml, 10.82 mmol, 2 eq) is added to a well stirred suspension of N,N-diethylaniline (1 ml, 5.41 mmol, 1 eq) and 1,3-dihydro-2H-indol-2-one x159 (0.72 g, 5.41 mmol, 1 eq) in dry toluene (15 ml). The mixture is heated at reflux during 3 hours. After cooling, water (15 ml) is carefully added and the organic layer is washed with water (3×25 ml). The organic layer is dried on anhydrous MgSO4, filtered off and concentrated under reduced pressure to obtain 0.76 g of 2-chloro-1H-indole x160 as an orange solid (0.76 g, 93%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[N:13]1[C:17](=[O:18])[N:16]([CH2:19]O)[C:15](=[O:21])[O:14]1)([O-:3])=[O:2].S(Cl)([Cl:24])=O>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[N:13]1[C:17](=[O:18])[N:16]([CH2:19][Cl:24])[C:15](=[O:21])[O:14]1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=c1on(-c2c([N+](=O)[O-])cccc2[N+](=O)[O-])c(=O)n1CO
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: O=c1on(-c2c([N+](=O)[O-])cccc2[N+](=O)[O-])c(=O)n1CCl

Procedure:
2-(2,6-Dinitrophenyl)-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dione (0.03 mole) dissolved in chloroform (40 ml) and thionyl chloride (0.06 mole) dissolved in chloroform (10 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 2 hours. Aftr this time the reaction mixture is stripped of solvent under reduced pressure, leaving a residue. This residue is dissolved in toluene, and the toluene solution is stripped of solvent and unreacted starting materials to yield the desired product 2-(2,6-dinitrophenyl)-4-chloromethyl-1,2,4-oxadiazolidin-3,5-dione as the residue.
Reaction SMILES: [BH4-].[Na+].O1CCCC1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([N:27]3[CH:31]=[CH:30][N:29]=[C:28]3[CH3:32])[O:18][C:19]=2[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:11][CH:10]=1>CC(O)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[C:17]([N:27]3[CH:31]=[CH:30][N:29]=[C:28]3[CH3:32])[O:18][C:19]=2[CH:20]([OH:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C(=O)c1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCOC(=O)C(O)c1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
Sodium borohydride(95 mg) was added to a tetrahydrofuran(60 ml)-2-propanol(30 ml) solution of ethyl 2-(4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]-2-oxoacetate(2.93 g) at 0° C. After stirring for 30 minutes, the reaction mixture was poured into ice water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried(MgSO4). The solvent was evaporated to give ethyl 2-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]-2-hydroxyacetate(2.20 g, 75%). This was recrystallized from acetone-ethyl acetate to give colorless prisms. mp 197-198° C. (degradation)
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:8][CH:7]=1)=[CH2:5].Br[CH:20]([C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=1)[C:21]([F:24])([F:23])[F:22].N1C=CC=CC=1C1C=CC=CN=1>ClC1C=CC=CC=1Cl.Cl[Cu]>[N:12]1([C:9]2[CH:10]=[CH:11][C:6]([C:4](=[O:5])[CH2:3][CH:20]([C:25]3[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=3)[C:21]([F:24])([F:23])[F:22])=[CH:7][CH:8]=2)[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: FC(F)(F)C(Br)c1cc(Cl)cc(Cl)c1
Reactant: C=C(O[Si](C)(C)C)c1ccc(-n2cncn2)cc1
Agent: Cl[Cu]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: Clc1ccccc1Cl
Product: O=C(CC(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(-n2cncn2)cc1
Temperature: 180 °C
Yield: 31.5 %

Procedure:
To a stirred solution of 1-(4-(1-(trimethylsilyloxy)vinyl)phenyl)-1H-1,2,4-triazole (6 g, 23 mmol) and 1-(1-bromo-2,2,2-trifluoro-ethyl)-3,5-dichlorobenzene (7.1 g, 34.7 mmol) in 1,2-dichlorobenzene (30 mL) was degassed with argon. To this CuCl (0.23 g, 2.31 mmol) and 2,2-bipyridyl (0.73 g, 4.63 mmol) was added to the above reaction mixture and the resultant reaction mixture was heated to 180° C. for 18 h. After completion of the reaction (by TLC), the reaction mixture was absorbed onto silica gel and purified by column chromatography (SiO2; 10% EtOAc in petroleum ether) to afford title compound as a solid (3 g, 31%): 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.15 (s, 1H), 8.10 (d, J=8.3 Hz, 2H), 7.82 (d, J=8.3 Hz, 2H), 7.33 (m, 1H), 7.30 (m, 2H), 4.20 (m, 1H), 3.63 (m, 2H); ESIMS m/z 412. 14 ([M−H]−).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.CS(C)=O.[O:13]1[CH2:18][CH2:17][CH:16]([CH2:19][NH2:20])[CH2:15][CH2:14]1>C(OCC)(=O)C>[Cl:8][C:4]1[N:3]=[C:2]([NH:20][CH2:19][CH:16]2[CH2:17][CH2:18][O:13][CH2:14][CH2:15]2)[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: NCC1CCOCC1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Clc1cncc(NCC2CCOCC2)n1
Temperature: 75 °C
Reaction time: 6 h
Yield: 81.6 %

Procedure:
A mixture of 2,6-dichloropyrazine (950 mg, 6.38 mmol), DMSO (14 ml), TEA (1.067 ml, 7.65 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (771 mg, 6.70 mmol) was stirred at 75° C. for 6 hours, and the reaction progress was followed by LCMS. The crude reaction mixture was cooled to ambient temperature, diluted with 300 ml of ethyl acetate, washed with 1M NaOH soln.(1×), water (1×), saturated salt soln. (1×), dried with sodium sulfate, filtered, and concentrated to constant mass, giving 1185 mg of titled compound as free base, used without further purification. LCMS (m/z): 228.0 (MH+), retention time=0.73 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH:30]([C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:31].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7](=[O:8])[C:6]1[CH:20]=[C:2]([C:35]2[CH:36]=[N:37][C:32]([CH:30]=[O:31])=[CH:33][CH:34]=2)[CH:3]=[C:4]([N:22]([CH3:29])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Reactant: O=Cc1ccc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 66.6 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (0.4 g, 0.86 mmol) and (6-formylpyridin-3-yl)boronic acid (0.3 g, 1.29 mmol) in dioxane/water mixture (10 mL+2 mL), Na2CO3 (0.32 g, 3.09 mmol) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.092 g, 0.086 mmol) was added and argon was purged again for 10 min. The reaction mixture was heated at 100° C. for 6 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(6-formylpyridin-3-yl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (0.28 g, 66%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:11](O)(=[O:18])[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[ClH:31]>C1C=CC=CC=1>[ClH:31].[C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)(=[O:18])[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1ccncc1
Reactant: OCCCN1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: c1ccccc1
Product: O=C(OCCCN1CCNCC1)c1ccncc1
Yield: 66 %

Procedure:
In 150 ml of absolute benzene there were dissolved 2.88 g of 1-piperazinepropanol, 3.2 g of isonicotinic acid and 30.4 g of p-toluene sulfonic acid. The resulting solution was heated for 15 hours to reflux while removing the formed water. The reaction liquid was cooled, washed with 15% potassium carbonate and then extracted with 10% hydrochloric acid. After the aqueous layer was washed with ether, the system was rendered alkaline with potassium carbonate and then extracted with ether. After the ethereal layer was dehydrated with a Glauber's salt, the ether was distilled off. The resultant residue was subjected to chromatography using silica gel to obtain a colorless transparent liquid. This liquid was converted to the hydrochloride thereof in accordance with a conventional manner. It was recrystallized from ethanol to give 1-piperazinepropanol isonicotinate hydrochloride. The melting point of the product was 201°-202°C. The Yield was 66%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccccc1CCCCCCCBr
Reactant: COc1ccc(S)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(SCCCCCCCc2ccccc2C(=O)O)cc1

Procedure:
The compound of Example 14(a), 2-(7-bromoheptyl)benzoic acid (1 g., 3.34 mm) was reacted with 4-methoxybenzenethiol (0.618 ml, 5.03 mm), and triethylamine (1.87 ml, 13.42 mm) in DMF (40 ml) as in Example 14(b) to afford the desired product.