Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][O:30][CH:29]([CH2:33]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>CC(N(C)C)=O>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][O:30][CH:29]([CH2:33][O:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][CH2:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(C(=O)OC(C)(C)C)CCO2)cc1
Reactant: Oc1ccccc1CCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCOC(COc2ccccc2CCCCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
218 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) were added, whilst ice-cooling and stirring, to a solution of 1.13 g of 2-(4-phenylbutyl)phenol (prepared as described in Preparation 3) in 20 ml of dimethylacetamide, and the resulting mixture was stirred at room temperature for 30 minutes. At the end of this time, 2.04 g of 4-t-butoxycarbonyl-2-(p-toluenesulfonyloxymethyl)morpholine were added, and the reaction mixture was stirred at 60° C. for 6 hours. The mixture was then partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The oily residue thus obtained was purified by column chromatography through silica gel, using a 20:1 by volume mixture of benzene and acetonitrile as the eluent, to give 671 mg of the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@:10]([F:16])([C:13]([OH:15])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C@@H:19]([C@@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[C:42](=[O:61])[CH2:43][C@@H:44]([O:59][CH3:60])[C@@H:45]([N:50]([CH3:58])[C:51](=[O:57])[C@H:52]([CH:54]([CH3:56])[CH3:55])[NH2:53])[C@@H:46]([CH3:49])[CH2:47][CH3:48])[C@@H:20]([CH3:36])[C:21]([NH:23][C@H:24]([C:32]([O:34][CH3:35])=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:22].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([C:13]([NH:53][C@H:52]([C:51]([N:50]([CH3:58])[C@@H:45]([C@@H:46]([CH3:49])[CH2:47][CH3:48])[C@H:44]([O:59][CH3:60])[CH2:43][C:42]([N:38]2[CH2:39][CH2:40][CH2:41][C@H:37]2[C@H:19]([O:18][CH3:17])[C@@H:20]([CH3:36])[C:21]([NH:23][C@H:24]([C:32]([O:34][CH3:35])=[O:33])[CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:22])=[O:61])=[O:57])[CH:54]([CH3:55])[CH3:56])=[O:15])([F:16])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@](F)(C(=O)O)C1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(F)CCN(C(=O)OC(C)(C)C)C1)C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of #168 (36.9 mg, 0.158 mmol, 1 eq.) and #114 (100 mg, 0.158 mmol, 1 eq.) in dichloromethane (3.6 mL) and N,N-dimethylformamide (0.8 mL), was added diisopropylethylamine (0.083 mL, 0.474 mmol, 3 eq.) followed by HATU (60.7 mg, 0.158 mmol, 1 eq.). The reaction was allowed to stir at room temperature for 18 hours, diluted with ethyl acetate (25 mL), washed with water (1×), 10% citric acid (1×) and brine (1×). The organic layer was dried over sodium sulfate, filtered, and the filtrate concentrated in vacuo to give crude #216 (220 mg, 164% of theory) which was used in next step without further purification. HPLC (protocol Q): m/z 848.6 [M+H+], retention time=2.10 minutes.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Cl)=[CH:30][CH:29]=1)#[N:21].O>CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:32][C:31]2[CH:30]=[CH:29][C:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:20]#[N:21])=[CH:35][CH:34]=2)[C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(C(=O)OC)cccc2[nH]1
Reactant: N#Cc1ccccc1-c1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc2c(C(=O)OC)cccc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.33 h
Yield: 84.1 %

Procedure:
To a solution of methyl 2-butylbenzimidazole-7-carboxylate (1.5 g) in DMF (15 ml) was added sodium hydride (60% oil, 0.13 g) under ice-cooling. The mixture was stirred for 20 minutes and there was added 4-(2-cyanophenyl)benzyl chloride (1.5 g). The resultant mixture was stirred for further 5 hours at room temperature and there was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and dried. The solvent was evaporated to dryness, and the residue was purified by column chromatography on silica gel to give a pale yellow oil (2.3 g, 82%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:15](I)[CH:16]=[CH2:17].O>CN(C=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[N:9]2[CH2:17][CH:16]=[CH2:15])=[CH:4][CH:3]=1
Reactant: O=c1ccc2ccc(F)cc2[nH]1
Reactant: C=CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(=O)ccc2ccc(F)cc21
Yield: 47.7 %

Procedure:
To a suspension of 7-fluoro-2(1H)-quinolinone (1.53 g, 9.39 mmol) in DMF at 0° C. was added sodium hydride (0.83 g of a 60% w:w dispersion in oil, 20.65 mmol) and the reaction was allowed warm to rt over 0.5 h before addition of allyl iodide (1.91 ml, 20.65 mmol). The reaction was stirred at rt for a further 0.25 h before addition of water (100 ml). The aqueous phase was then extracted with 10% MeOH in DCM (3×200 ml) and the combined organic phases were dried, evaporated and the residue was subjected to column chromatography on silica gel using a 10% MeOH in DCM gradient to provide the desired compound (0.91 g, 48%). This material contained approximately 10% of the isomeric 5-fluoro-1-(2-propen-1-yl)-2(1H)-quinolinone.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[OH:10][C:11]([C:14]1[N:15]=[C:16]([CH2:22][CH2:23][CH3:24])[NH:17][C:18]=1[C:19]([OH:21])=[O:20])([CH3:13])[CH3:12].[C:25]([O:31][CH2:32]Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27].C(OCC)(=O)C>CN(C)C(=O)C.O>[OH:10][C:11]([C:14]1[N:15]=[C:16]([CH2:22][CH2:23][CH3:24])[NH:17][C:18]=1[C:19]([O:21][CH2:32][O:31][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[O:20])([CH3:13])[CH3:12]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)O)[nH]1
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCOC(=O)C(C)(C)C)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.76 ml of N,N-diisopropylethylamine were added to a suspension of 1.14 g of 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylic acid [prepared as described in step (i) above] in 12 ml of N,N-dimethylacetamide, and the resulting mixture was stirred at room temperature for 10 minutes; 1.36 ml of pivaloyloxymethyl chloride was then added. The reaction mixture was stirred at 60° C. for 4 hours, after which it was mixed with ethyl acetate and water. The ethyl acetate layer was separated and concentrated by evaporation under reduced pressure. The crystals which precipitated were triturated with diisopropyl ether and collected by filtration to give 1.53 g of the title compound, melting at 177° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].S(Cl)([Cl:11])=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1([Cl:11])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8]
Reactant: CC1CCCCC1=O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(Cl)CCCCC1=O

Procedure:
112 g of 2-methylcyclohexanone and 500 ml carbon tetrachloride are mixed in a three neck flask and 90 ml of thionyl chloride in 150 ml of carbon tetrachloride are added dropwise in the course of 60 minutes, under vigorous stirring while keeping the temperature at about 15° with a water bath. Stirring is maintained for a further 2 hours. The reaction medium is then washed three times with dilute hydrochloric acid, twice with a saturated solution of sodium bicarbonate and finally with a saturated solution of sodium chloride. The organic phase is separated, dried over sodium sulphate and the solvent is evaporated off under reduced pressure. The dry residue of 2-methyl-2-chlorocyclohexanone weighing about 180 g is purified by fractional distillation. The main fraction boils at 85°-90° (20 mm Hg); nD25 =1.4672.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1.[CH3:25][C:26]1[N:27]=[C:28]([N:36]2[CH2:40][CH2:39][NH:38][C:37]2=[O:41])[S:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([CH2:15][CH2:14][N:38]2[CH2:39][CH2:40][N:36]([C:28]3[S:29][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:26]([CH3:25])[N:27]=3)[C:37]2=[O:41])=[CH:17]1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: BrCCc1c[nH]c2ccccc12
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCN(CCc3c[nH]c4ccccc34)C2=O)nc1C
Yield: 40 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with 3-(2-bromoethyl)-1H-indole to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 40% yield: 1H NMR (300 MHz, CDC3) δ 8.09 (s, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.39-7.36 (m, 1H), 7.24-7.09 (m, 3H), 4.29 (q, J=7.1 Hz, 2H), 4.04-3.99 (m, 2H), 3.69 (t, J=7.2 Hz, 2H), 3.52-3.46 (m, 2H), 3.08 (t, J=7.1 Hz, 2H), 2.62 (s, 3H), 1.34 (t, J=7.1 Hz, 3H); MS (ES+) m/z 399.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc2nc(Cl)[nH]c2c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
2-Chlorobenzimidazole (1.05 g) was dissolved in DMF (10 mL), and N-chlorosuccinimide (1.01 g) was added thereto. The mixture was stirred at 60° C. for 30 min and the reaction mixture was added to water. The precipitated solid was collected by filtration to give 2,5-dichlorobenzimidazole (0.480 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-])=O)=[N:6][CH:7]=1.[CH3:11][N:12]([CH3:18])[CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:11][N:12]([CH3:18])[CH:13]1[CH2:17][CH2:16][N:15]([C:2]2[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=2)[CH2:14]1
Reactant: CN(C)C1CCNC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CN(C)C1CCN(c2ccc(N)nc2)C1
Temperature: 100 °C

Procedure:
A suspension of 5-bromo-2-nitropyridine (2 g), 3-(dimethylamino)pyrrolidine (1.14 g), (R)-(+)2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.5 g), palladium(II) acetate (0.09 g), cesium carbonate (4.5 g) in toluene (20 ml) was heated at 100° C. for 3 hours. Cooling to room temperature was followed by extraction with 1N hydrochloric acid (2×100 ml). The aqueous phase was adjusted to pH>10 with ammonia, extracted with ethyl acetate (2×100 ml), dried with sodium sulfate, filtered and concentrated. The substance was then treated as described for method B. This resulted in the product with the molecular weight of 206.29 (C11H18FN4); MS (ESI): 207 (M+H+).
Reaction SMILES: C([O:4][C@H:5]([C@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[C:10]1=[O:25])[C:6](Cl)=[O:7])(=O)C.[NH2:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31]([NH:37]C(=O)OC(C)(C)C)=[N:32][CH:33]=[N:34]2)=[CH:29][CH:28]=1.N1C=CC=CC=1.C(#N)C>ClCCl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:37][C:31]1[C:30]2[C:35](=[CH:36][C:27]([NH:26][C:6](=[O:7])[C@H:5]([OH:4])[C@H:9]3[O:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)[C:10]3=[O:25])=[CH:28][CH:29]=2)[N:34]=[CH:33][N:32]=1
Reactant: CC(=O)O[C@@H](C(=O)Cl)[C@H]1OCCN(c2ccc(C(F)(F)F)cc2)C1=O
Reactant: CC(C)(C)OC(=O)Nc1ncnc2cc(N)ccc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Nc1ncnc2cc(NC(=O)[C@H](O)[C@H]3OCCN(c4ccc(C(F)(F)F)cc4)C3=O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
To a solution of compound 98-6 (˜0.15 mmol) in 2 ml dichloromethane at 0° C. was added tert-butyl 7-aminoquinazolin-4-ylcarbamate (compound 98-4) (77 mg, 0.30 mmol, 2 eq.) followed by pyridine (24 μA, 0.30 mmol, 2 eq.) and DMAP (2 mg, 0.016 mmol, 0.1 eq.). To the mixture was added 1 ml of acetonitrile and stirred overnight while warming to rt. It was diluted with ethyl acetate, washed with aq. NaHCO3, water and brine, dried over MgSO4, filtered, concentrated to dryness. The residue was stirred overnight with 5 ml of 7N ammonia in methanol. The methanol was evaporated and the residue was stirred with 2 ml each of dichloromethane and trifluoroacetic acid for about 75 min. The mixture was evaporated to dryness and the residue was purified by RPHPLC to provide 14 mg of EXAMPLE 98.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12](O)(=O)CC(O)=O>>[O:5]=[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])[CH3:12]
Reactant: O=C(O)CC(=O)O
Reactant: O=C1OC(=O)c2ccccc21
Product: CC(=O)c1ccccc1C(=O)O

Procedure:
(i) Using the method of Preparation 3, phthalic anhydride and malonic acid gave 2-(1'-oxoethyl)benzoic acid (m.p. 110°) and thence 1-hydroxymethyl-2-(1'-hydroxyethyl)benzene (oil)
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:32][C:29]([F:31])([F:30])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][N:13]([C:37]3[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=3)[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1Cl
Reactant: OB(O)c1cccnc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(c1cccnc1)CN2c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.2 %

Procedure:
8-(3,5-Bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (253 mg) was dissolved in dichloromethane (5 mL), 3-pyridineboronic acid (246 mg), triethylamine (101 mg) and copper(II)-acetate (136 mg) were added. The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by chromatography on silica gel (hexane/ethylacetate=2:1) to yield the desired product (120 mg, 41%), MS: m/e=583.0 (M+H+).
Reaction SMILES: O[Li].O.C([O:6][C:7]([C:9]1[N:10]=[N:11][N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:8])C>C1COCC1.O>[C:14]1([N:12]2[CH:13]=[C:9]([C:7]([OH:8])=[O:6])[N:10]=[N:11]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1cn(-c2ccccc2)nn1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cn(-c2ccccc2)nn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 35.2 %

Procedure:
Oxalyl chloride (4.7 g, 30.1 mL, 37.0 mmol) was added to a cold (0-4° C.) solution of DMF (2.25 g, 2.4 mL, 30.8 mmol) in CHCl3 (20 mL) and stirring was continued for 10 minutes. The reaction mixture was heated at 40° C. for 10 minutes and cooled to −10° C. Diazoacetic acid ethyl ester (3.5 g, 3.5 mL, 30.6 mmol) was then added and stirred at room temperature for 1 hr. The reaction mixture was concentrated ether was then added, the precipite was collected and dissolved in 10% aq Hac (10 mL) and stirring was continued for 1 hr. The reaction mixture was extracted with ether, washed with saturated sodium bicarbonate solution and brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 590 mg (21% Yield) of 2-diazo-3-oxo-propionic acid ethyl ester. 1H NMR (300 MHz, CDCl3): δ 9.7 (s, 1H), 4.4 (q, 2H), 1.4 (t, 3H). Aniline (143 mg, 1.5 mmol) was added to a solution of 2-diazo-3-oxo-propionic acid ethyl ester (200 mg, 1.4 mmol) and HOAc (0.2 mL) in EtOH (0.5 mL) and stirring was at room temperature overnight. The reaction mixture was concentrated and cold water was then added, the solid was collected to afford 264 mg (87.41% Yield) of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester. 1H NMR (300 MHz, CDCl3): δ 8.5 (s, 1H), 7.8 (d, 2H), 7.6-7.48 (m, 3H), 4.5 (q, 2H), 1.4 (t, 3H). LiOH.H2O (80 mg, 1.9 mmol) was added to a stirred solution of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (130 mg, 0.6 mmol) in THF:H2O (1:1, 4 mL), and the resulting mixture was stirred at room temperature for 45 min. The reaction mixture was concentrated under reduced pressure. Cold water was then added and it was acidified with 10% aqueous HCl, the solid was collected to afford 40 mg (35.4% yield) of 1-phenyl-1H-[1,2,3]triazole-4-carboxylic acid. 1H NMR (300 MHz, DMSO-d6): δ 13.4 (bs, 1H), 9.4 (s, 1H), 8.0 (d, 2H), 7.7 (t, 2H), 7.6 (t, 1H).
Reaction SMILES: COC1C=C(C)C(S(N(CCOCC(O)=O)C)(=O)=O)=C(C)C=1.N1C=CC=C(C2(O)CCNCC2)C=1.C(=O)(O)[O-].[Na+].[OH:41][C:42]1([C:69]2[CH:70]=[N:71][CH:72]=[CH:73][CH:74]=2)[CH2:47][CH2:46][N:45]([C:48](=[O:68])[CH2:49][O:50][CH2:51][CH2:52][N:53]([CH3:67])[S:54]([C:57]2[C:62]([CH3:63])=[CH:61][C:60]([O:64][CH3:65])=[CH:59][C:58]=2[CH3:66])(=[O:56])=[O:55])[CH2:44][CH2:43]1.[Cl:75][Si](C)(C)C>C(Cl)Cl.C(OCC)C.C(C(C)=O)C>[ClH:75].[OH:41][C:42]1([C:69]2[CH:70]=[N:71][CH:72]=[CH:73][CH:74]=2)[CH2:43][CH2:44][N:45]([C:48](=[O:68])[CH2:49][O:50][CH2:51][CH2:52][N:53]([CH3:67])[S:54]([C:57]2[C:58]([CH3:66])=[CH:59][C:60]([O:64][CH3:65])=[CH:61][C:62]=2[CH3:63])(=[O:55])=[O:56])[CH2:46][CH2:47]1
Reactant: C[Si](C)(C)Cl
Agent: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)N2CCC(O)(c3cccnc3)CC2)c(C)c1
Agent: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)O)c(C)c1
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCC(C)=O
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N′-Carbonyldiimidazole (77 mg, 0.475 mmol) was added to a solution of 2-(2-(4-methoxy-N,2,6-trimethylphenylsulfonamido)ethoxy)acetic acid (acid unit S2) (150 mg, 0.453 mmol) in methylene chloride (5 ml) and the mixture was stirred for 1 h at room temperature. A solution of 4-(pyridin-3-yl)piperidin-4-ol (A2) (80 mg, 0.453 mmol) in methylene chloride (2 ml) was subsequently added and the reaction mixture was stirred for 15 h at room temperature. Thereafter, saturated sodium bicarbonate solution (10 ml) was added to the reaction mixture and the aqueous phase was subsequently extracted with methylene chloride (20 ml). The combined organic phases were extracted with saturated sodium chloride solution (10 ml), dried with sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography with diethyl ether/methylene chloride/methanol/ammonia solution (25% aq.) (50:50:5:1). N-(2-(2-(4-Hydroxy-4-(pyridin-3-yl)piperidin-1-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylphenylsulfonamide (170 mg. 0.346 mmol) was dissolved in diethyl ether/methyl ethyl ketone (15:1, 32 ml), and chlorotrimethylsilane (81 μl, 0.692 mmol) was slowly added. The mixture was subsequently stirred for 30 min at 0° C. The precipitate formed was filtered off, washed with diethyl ether/hexane and dried.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]#[N:9].[NH2:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([CH:18]=O)=[CH:13][N:12]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([NH2:9])=[N:17][C:15]2[N:16]=[C:11]([NH2:10])[N:12]=[CH:13][C:14]=2[CH:18]=1
Reactant: Nc1ncc(C=O)c(N)n1
Reactant: N#CCc1ccccn1
Product: Nc1ncc2cc(-c3ccccn3)c(N)nc2n1

Procedure:
The procedure of Example 1 was followed to react 0.84 mL of 2-pyridylacetonitrile and 1.0 g of 2,4-diamino-5-pyrimidinecarboxaldehyde to afford the title compound, mp 312-321° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:15]O>C([O-])(O)=O.[Na+]>[NH2:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([O:10][CH3:15])=[O:9])=[N:6][CH:7]=1
Reactant: CO
Reactant: Nc1cnc(C(=O)O)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ncc(N)cn1
Yield: 68 %

Procedure:
A suspension of 5-aminopyrimidine-2-carboxylic acid (Goldenbridge Pharma, Inc.; 5.70 g, 41.0 mmol) in MeOH (120 mL) was cooled in an ice-water bath and treated dropwise with thionyl chloride (8.97 mL, 123 mmol). The resulting suspension was heated at reflux for 20 h and then concentrated to give a yellow solid. The solid was dissolved in saturated aqueous NaHCO3 (60 mL) and extracted into EtOAc using a Gregar Extractor. The extract was concentrated to give methyl 5-aminopyrimidine-2-carboxylate (4.26 g, 68% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.32 (s, 2H), 4.35 (br s, 2H), 4.02 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[C:7]([NH2:15])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[S:4]1[CH:5]=[CH:6][C:2]([NH:15][C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3]1
Reactant: Brc1ccsc1
Reactant: NC(=O)c1ccccc1
Product: O=C(Nc1ccsc1)c1ccccc1
Yield: 98 %

Procedure:
Using general procedure C, 3-bromothiophene was coupled with benzamide with the reaction time of 21 h. Chromatography gave 198.9 mg (98%) of the title compound as a solid. 1H NMR (CDCl3, 300 MHz): δ 8.34 (br s, 1H), 7.85 (dd, 2H, J=1.2, 8.1 Hz), 7.72 (dd, 1H, J=1.2, 3.0 Hz), 7.55-7.41 (m, 3H), 7.26 (dd, 1H, J=3.3, 4.8 Hz), 7.14 (dd, 1H, J=1.5, 5.4 Hz).
Reaction SMILES: C([O:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])(=O)C.Cl.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].C(N(CC)CC)C>C1C=CC=CC=1>[OH:4][C:5]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:8]
Reactant: COC(=O)CCCCCN
Reactant: COc1cccc(C(=O)Cl)c1OC(C)=O
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCNC(=O)c1cccc(OC)c1O
Yield: 54.9 %

Procedure:
2.3 g (10 mmol) of 2-acetoxy-3-methoxybenzoyl chloride dissolved in 18 ml of anhydrous benzene were dropwise added to the suspension of 1.80 g (10 mmol) methyl 6-aminohexanoate hydrochloride in 2.2 g (22 mmol) of anhydrous triethylamine and 18 ml of anhydrous benzene under nitrogen at room temperature while stirring. After boiling under reflux for 2 hours while stirring, the reaction mixture was cooled down, the precipitate was filtered by suction and the filtrate was evaporated 20 ml of water were portionwise added to the residue, the solution was extracted with ethyl acetate, the organic phase was washed with 1M hydrochloric acid and water, then dried. The solvent was evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column by using a 3:4 mixture of petroleum ether and ethyl acetate to obtain 1.62 g (55%) of the title compound, m.p.: 69°-70° C.