Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:14][CH2:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([Cl:1])[CH:11]=[C:10]2[CH3:12]
Reactant: Cc1ccc2nc(Cl)cc(C)c2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)nc2ccc(CBr)cc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
To a solution of 2-chloro-4,6-dimethylquinoline (1.31 g) in chloroform (20 mL) was added N-bromosuccinimide (1.24 g) at room temperature. The reaction solution was heated at 70° C., and benzoyl peroxide (0.25 g) was divided into 5 portions and added at intervals of a few tens of min. The mixture was stirred at the same temperature for 1 h. The reaction solution was cooled to room temperature and diluted with ethyl acetate, then the organic layer was washed with a mixed solution of saturated aqueous sodium thiosulfate and saturated brine and saturated brine. The organic layer was dried with anhydrous magnesium sulfate, then the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=10:1) to obtain 6-bromomethyl-2-chloro-4-methylquinoline (0.79 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(#N)C>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:14]
Reactant: Cn1ccnc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1ccnc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.4 %

Procedure:
To a solution of N-methylimidazole (10.0 g, 122 mmol) in acetonitrile (120 mL) was added benzoyl chloride (14.1 mL, 122 mmol) followed by triethylamine (17.0 mL, 122 mmol), while keeping the internal temperature at 5° C. The mixture was stirred 18 h at room temperature. After filtration, the filtrate was concentrated in vacuo, diluted with ethyl acetate (200 mL) and sequentially washed with sat. aq. sodium bicarbonate (150 mL), water (100 mL) and brine (100 mL). The organic layer was dried over MgSO4 and concentrated in vacuo.to afford (1-methyl-1H-imidazol-2-yl)(phenyl)methanone [21.0 g, yield 83%; HPLC/MS: m/z=187 (M+H); log P(HCOOH)=1.38].
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])=O)=[CH:4][CH:3]=1.[CH3:19][NH:20][NH2:21]>C1(C)C=CC=CC=1>[CH3:19][N:20]1[N:21]=[C:6]([C:5]2[CH:17]=[CH:18][C:2]([Br:1])=[CH:3][CH:4]=2)[C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10]1=[O:11]
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Br)cc1
Reactant: CNN
Solvent: Cc1ccccc1
Product: Cn1nc(-c2ccc(Br)cc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.4 %

Procedure:
To a suspension of 2-(4-bromobenzoyl)benzoic acid (15.0 g, 49.2 mmol) in toluene (75 mL) at room temperature was added methylhydrazine (2.88 mL, 54.1 mmol). The reaction mixture was heated to reflux while collecting water in a Dean Stark trap for 3 hours, additional methylhydrazine (2.0 mL) was added and refluxing was continued for 15 minutes. The reaction mixture was cooled to room temperature and the product was collected by filtration and dried in vacuo to afford 13.4 g (87%) of 2-methyl-4-(4-bromophenyl)-1-(2H)-phthalazinone, m.p. 168°-170 ° C.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[C:21]([CH:23]=[CH2:24])[C:20]3[CH:19]([N:25]([CH:27]4[CH2:29][CH2:28]4)[CH3:26])[CH2:18][CH2:17][C:16]([CH3:31])([CH3:30])[C:15]=3[CH:14]=2)=[CH:7][CH:6]=1.[OH-].[Li+]>CO.O1CCCC1>[CH:27]1([N:25]([CH3:26])[CH:19]2[CH2:18][CH2:17][C:16]([CH3:31])([CH3:30])[C:15]3[CH:14]=[C:13]([C:12]#[C:11][C:8]4[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:32])=[O:2])=[CH:10][CH:9]=4)[CH:22]=[C:21]([CH:23]=[CH2:24])[C:20]2=3)[CH2:28][CH2:29]1
Reactant: C=Cc1cc(C#Cc2ccc(CC(=O)OC)cc2)cc2c1C(N(C)C1CC1)CCC2(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=Cc1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1C(N(C)C1CC1)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A solution of {4-[5-(cyclopropyl-methyl-amino)-8,8-dimethyl-4-vinyl-5,6,7,8-tetrahydro-naphthalen-2-ylethynyl]-phenyl}-acetic acid methyl ester (Intermediate 71, 0.14 g, 0.327 mmol) in methanol (3 mL) and tetrahydrofuran (3 mL) was treated with a 2M solution of lithium hydroxide (1.5 mL, 3 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 h. The volatiles were evaporated in vacuo, the residue was neutralized with saturated aqueous ammonium chloride solution and extracted with diethyl ether and ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a white solid (0.135 g, 96%).
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[Cl:6][CH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:10]>C1COCC1>[Cl:6][CH2:7][CH2:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)([OH:10])[CH2:3][CH:2]=[CH2:1]
Reactant: O=C(CCCl)c1ccc(F)cc1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCC(O)(CCCl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.3 %

Procedure:
A 250-mL flask was charged with anhydrous CeCl3 (5.58 g, 22.6 mmol) and THF (40 mL). The mixture was vigorously stirred for 3.5 h at rt. The suspension was then cooled to −78° C. and a solution of allylmagnesium bromide (1.0 M in THF, 21 mL, 21.0 mmol) was added. After stirring for 2 h at −78° C., a solution of 3-chloro-1-(4-fluorophenyl)propan-1-one (2.522 g, 13.5 mmol) in THF (30 mL) was added via cannula. The reaction mixture was allowed to slowly warm to 8° C. while stirring overnight (18 h). The reaction was then quenched with satd aq NaHCO3, extracted with EtOAc, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (3.0049 g, 97%) as an oil. LC-MS Method 1 tR=1.79 min, m/z 213, 211 (M-OH)+; 1H NMR (400 MHz, CDCl3) δ 7.37-7.32 (m, 2H), 7.07-7.02 (m, 2H), 5.57-5.47 (m, 1H), 5.20-5.19 (m, 1H), 5.16 (m, 1H), 3.59-3.52 (m, 1H), 3.24-3.18 (m, 1H), 2.70 (dd, J=13.8, 5.9 Hz, 1H), 2.50 (dd, J=13.8, 8.5 Hz, 1H), 2.29 (t, J=7.9 Hz, 2H), 2.22 (s, 1H); 19F NMR (376 MHz, CDCl3) δ −116.52 (m).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29](=[O:37])[C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:23]=2[CH3:38])=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([C:17]([O:19]CC)=[O:18])[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2].[OH-].[Na+].Cl>C(O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29](=[O:37])[C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[C:23]=2[CH3:38])=[C:8]2[C:16]=1[NH:15][C:14]1[CH:13]=[C:12]([C:17]([OH:19])=[O:18])[CH:11]=[CH:10][C:9]2=1)(=[O:3])[NH2:2]
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(-c3cccc(NC(=O)c4ccc(F)cc4)c3C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C(=O)O)ccc3c12
Temperature: 92.5 °C
Yield: 97.1 %

Procedure:
A suspension of ethyl 8-carbamoyl-5-(3-(4-fluorobenzamido)-2-methylphenyl)-9H-carbazole-2-carboxylate (Intermediate 3-100, 1.63 g, 3.20 mmol) in ethanol (12 mL) was treated with 1 M aqueous sodium hydroxide (1.5 mL, 1.500 mmol), forming a yellow suspension which was heated at 90-95° C. for 30 min. The mixture was cooled to rt and acidified with 1 M hydrochloric acid. The precipitate was collected by filtration, washed with water and dried to provide 8-carbamoyl-5-(3-(4-fluorobenzamido)-2-methylphenyl)-9H-carbazole-2-carboxylic acid as an off-white solid (1.496 g, 92%). 1H NMR (400 MHz, DMSO-d6) δ 12.76 (br. s., 1H) 11.84 (s, 1H) 10.15 (s, 1H) 8.38 (s, 1H) 8.24 (br. s., 1H) 8.03-8.13 (m, 3H) 7.56 (br. s., 1H) 7.46-7.54 (m, 2H) 7.42 (t, J=7.7 Hz, 1H) 7.35 (t, J=9.0 Hz, 2H) 7.23 (dd, J=7.5, 1.3 Hz, 1H) 7.04 (d, J=7.5 Hz, 1H) 7.01 (d, J=8.3 Hz, 1H) 1.88 (s, 3H). Mass spectrum m/z 482.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][NH:6][C:5](=[O:8])[CH:4]=1.CS(O)(=O)=O.[CH2:14](O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]C>>[CH2:1]([O:2][C:3]1[CH2:7][NH:6][C:5](=[O:8])[CH:4]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCO
Reactant: COC1=CC(=O)NC1
Agent: CS(=O)(=O)O
Product: CCCCCCCCOC1=CC(=O)NC1
Temperature: 100 °C

Procedure:
A mixture of 4-methoxy-3-pyrrolin-2-one (3 g), 1-octanol (7.4 ml) and methanesulfonic acid (0.2 g) were heated at 100° C. for 2 hours under reduced pressure (40 mbars). The product was chromatographed on silica gel, eluting with 2% methanol in methylene chloride, to give 4-octyloxy-3-pyrrolin-2-one.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]([C:7](=[O:14])[CH2:8][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)=[CH:3][CH:2]=1.[SH:21][CH2:22][CH2:23]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(O)CCC>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:2]=[CH:3][C:4]([C:7]2([CH2:8][N:9]3[CH:13]=[N:12][CH:11]=[N:10]3)[S:21][CH2:22][CH2:23][O:14]2)=[CH:5][CH:6]=1
Reactant: O=C(Cn1cncn1)c1ccc(-c2ccccc2)cc1
Reactant: OCCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: c1ccc(-c2ccc(C3(Cn4cncn4)OCCS3)cc2)cc1
Yield: 41.6 %

Procedure:
To a slurry of 13.1 g of 1-[1,1'biphenyl]-4-yl-2-(1H-1,2,4-triazol-1-yl)ethanone in 175 ml dry toluene and 70 ml 1-butanol was added, with stirring, 7.8 g 2-mercaptoethanol and 12.3 g p-toluenesulfonic acid. The resultant thickened slurry was refluxed under a Dean-Stark [trademark] trap for 72 hours. At this point, no further water was collected. After the reaction was allowed to cool, the solid was filtered out, slurried in dichloromethane and shaken with 10% aqueous sodium hydroxide and once with water. The organic layer was dried and evaporated to leave an oil which solidified on high-vacuum pumping. This solid was triturated with petroleum ether to give 6.7 g of 1-[(2-[1,1'-biphenyl]-4-yl-1,3-oxathiolan-2-yl)methyl]-1H-1,2,4-triazole, the product of this reaction. The melting point of this compound was 85°-90° C.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[N:21]1([CH2:27][CH2:28][NH2:29])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:29][CH2:28][CH2:27][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Reactant: NCCN1CCOCC1
Product: COc1cc(CNCCN2CCOCC2)ccc1Oc1ccc(C(N)=O)cn1
Yield: 48.8 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and 2-morpholin-4-ylethylamine (0.0224 g, 0.184 mmol) gives the title compound (0.0347 g, 49.0%): TOF MS ES+ 387.2 (M+H)+, HRMS calcd for C20H27N4O4 387.2032 (M+H)+, found 387.2023, time 0.41 min; 1H NMR (DMSO-d6) δ 8.51 (d, J=2.0 Hz, 1H), 8.19 (dd, J=8.8, 2.4 Hz, 1H), 7.98 (s, 2H), 7.43 (s, 1H), 7.11 (d, J=1.95 Hz, 1H), 7.06 (d, J=8.3 Hz, 1H), 6.98 (d, J=8.3 Hz, 1H), 6.91 (dd, J=8.1, 1.7 Hz, 1H), 3.72 (s, 2H), 3.66 (s, 3H), 3.55 (t, J=4.6 Hz, 4H), 2.63 (t, J=6.6 Hz, 2H), 2.41 (t, J=6.3 Hz, 2H), 2.34 (s, 4H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([S:18][C:19]2[CH:20]=[C:21]([CH2:25][OH:26])[CH:22]=[CH:23][CH:24]=2)=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>C(Cl)Cl.C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([S:18][C:19]2[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=2)[CH:25]=[O:26])=[C:9]1[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Sc2cccc(CO)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: Cc1c(Sc2cccc(C=O)c2)c2ccc(Cl)cc2n1Cc1ccccc1

Procedure:
[3-(1-Benzyl-6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-methanol (0.750 g, 1.9 mmol) was dissolved in DCM:ACN (9:1, 20 mL) then 4-methylmorpholine N-oxide (0.334 g, 2.85 mmol) and tetrapropylammonium perruthenate (0.067 g, 0.19 mmol) were added. After 30 minutes the reaction mixture was concentrated and loaded directly onto a silica gel column. Silica gel chromatography (0-30% EtOAc in hexanes) provided the title compound.
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:31]1(B2OC(C)(C)C(C)(C)O2)[CH2:35][CH2:34][CH2:33][CH:32]=1>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>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([C:31]4[CH2:35][CH2:34][CH2:33][CH:32]=4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
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: [Cs+]
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(C4=CCCC4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 125 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3-methyl-cyclohexylmethyl)-amide, cesium carbonate, 2-cyclopent-1-enyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and tetrakis(triphenylphosphine)Palladium (0). 1H NMR (400 MHz, DMSO-d6): δ 8.63 (t, J=5.91 Hz, 1H), 8.06 (d, J=8.92 Hz, 1H), 7.96 (dd, J=4.43, 8.92 Hz, 2H), 7.73 (d, J=9.01 Hz, 1H), 6.89 (s, 1H), 4.18 (s, 1H), 3.29 (s, 1H), 2.85-2.87 (m, 2H), 2.48-2.49 (m, 2H), 1.96-2.03 (m, 1H), 1.45-1.78 (m, 6H), 1.28-1.32 (m, 5H). m/z: 399.2 [M+H]+
Reaction SMILES: [C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[N:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:28].[OH-].[K+]>CO>[C:16]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH2:15])=[O:28])=[N:12][CH:13]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N#Cc1ccc(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1ccc(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
Dissolve 5g. of 5-(triphenylmethyl)-2-cyanopyridine in a mixture consisting of 50 ml. of water and 1.0 liter of methanol. Add 4 g. of potassium hydroxide and heat the mixture at reflux for 15 hours. Remove the methanol under reduced pressure, triturate the residue with water and dry the solids obtained thereby. Crystallize the product from acetonitrile to obtain the product of this example. m.p. 239°-240° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[CH3:9])=[C:4]([N+:16]([O-])=O)[CH:3]=1>CCO.O.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([N:8]([CH2:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])[CH3:9])=[CH:6][CH:7]=1
Reactant: CN(C)CCCN(C)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: CN(C)CCCN(C)c1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 4-chloro-N-(3-(dimethylamino)propyl)-N-methyl-2-nitrobenzenamine (4.0 g, 15 mmol) in EtOH (80 ml) and water (10 ml) was added Raney-Ni (10 g). The mixture was stirred for 5 hours at RT, filtered through a pad of Celite and concentrated to yield 4-chloro-N1-(3-(dimethylamino)propyl)-N1-methylbenzene-1,2-diamine as a deep red oil. MS m/z=242 [M+H+. Calc'd for C12H20ClN3: 241.77.
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:9](=[N:10][C:11](C#N)=[C:12]([C:15]#[N:16])[N:13]=2)[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.C([O-])(=O)C.[NH4+:23].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[NH2:23][C:11]1[N:10]=[C:9]2[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:2](=[O:1])[C:14]2=[N:13][C:12]=1[C:15]#[N:16]
Reactant: N#Cc1nc2c(nc1C#N)-c1ccccc1C2=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1nc2c(nc1N)-c1ccccc1C2=O
Temperature: 70 °C
Reaction time: 18 h
Yield: 89.5 %

Procedure:
A mixture of 1 (201 mg, 0.86 mmol), ammonium acetate (331 mg, 4.3 mmol) and Na2SO4 (200 mg) in THF (2.9 ml) was stirred at 70° C. in sealed tube for 18 hours. The solvent was evaporated, water (5 ml) was added and the precipitate filtered, washed with water and dried under vacuum, affording 7 (171 mg, 90%) as green solid.
Reaction SMILES: [C:1](=[N:9][OH:10])([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](Cl)=O.O>CC(C)=O>[C:2]1([C:1]2[N:8]=[C:18]([C:14]3[S:13][CH:17]=[CH:16][CH:15]=3)[O:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccs1
Reactant: NC(=NO)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: c1ccc(-c2noc(-c3cccs3)n2)cc1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 82.8 %

Procedure:
Benzamide oxime (5.00 g, 36.7 mmol) was dissolved in acetone (50 mL) at 0° C. The solution was stirred and 50% aqueous sodium hydroxide (4.5 mL) added. An exotherm was noted and a precipitate formed in the reaction mixture. The exotherm lasted for about 15 minutes and the slurry became thick. The solution was warmed to 20° C. and external cooling was added. The 2-thiophenecarbonyl chloride (5.36, 36.7 mmol) was added over 15 minutes maintaining the reaction mixture below 30° C. The reaction was maintained at 30° C. for 15 minutes and the slurry became thinner. The reaction mixture was cooled to room temperature and stirred for 20 additional minutes. Water (50 mL) was added and the resulting solids were stirred for 1 hour. The solids were collected by vacuum filtration, washed with water (2×50 mL) and dried on a Buchner funnel with air flow from vacuum overnight. 3-Phenyl-5-(2-thienyl)-1,2,4-oxadiazole (6.94 g, 30.4 mmol) was obtained as a white solid (83% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=1.[C:18](O)(=[O:21])[CH:19]=[O:20].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C(Cl)CCl>[C:13]([C:8]1[C:9]2[O:12][C:19](=[O:20])[CH:18]([OH:21])[C:10]=2[CH:11]=[C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:17])[CH:7]=1)([CH3:14])([CH3:16])[CH3:15]
Reactant: COC(=O)CCc1ccc(O)c(C(C)(C)C)c1
Reactant: O=CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCCl
Product: COC(=O)CCc1cc2c(c(C(C)(C)C)c1)OC(=O)C2O

Procedure:
3-(4-hydroxy-3-tert.butylphenyl) propionic acid methyl ester (10.0 g), glyoxylic acid (7.4 g of the 50% solution in water) and p-toluene sulphonic acid (40 mg) are heated in 40 ml ethylene chloride under nitrogen at reflux for 3 hours distilling off all water present and formed during the reaction. The reaction mixtures is washed with water, dried over magnesium sulphate and evaporated under reduced pressure to give 13.0 g of 7-tert.butyl-5-(2-methoxycarbonylethyl)-3-hydroxy-3H-benzofuran-2-one.
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[N:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1)[CH3:2].Cl.[CH2:15]([OH:18])[CH2:16][CH3:17]>>[CH2:12]([N:3]([CH2:1][CH3:2])[C:4]1[N:9]=[CH:8][C:7]([C:10](=[NH:11])[O:18][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1)[CH3:13]
Reactant: CCN(CC)c1ccc(C#N)cn1
Reactant: CCCO
Agent: Cl
Product: CCCOC(=N)c1ccc(N(CC)CC)nc1
Temperature: 0 °C

Procedure:
Into a solution of 6-diethylamino-3-cyanopyridine (460 mg, 2.63 mmol) in 1-propanol (15 ml) was passed hydrogen chloride gas at a temperature of 0°-5° C. for 30 minutes. The reactor was tight sealed, and the mixture was stirred at 0° C. over night. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was added to a concentrated sodium carbonate solution. After it was confirmed that the solution showed an alkaline pH (9 or more), it was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product of propyl 6-diethylamino-3-pyridinecarboximidate as an oil. The oil was dissolved in acetonitrile (2 ml), and an aqueous solution (5 ml) of NaH2PO4 ·2H2O (1.62 g, 10.4 mmol), Na2HPO4 (370 mg, 2.61 mmol) and cyanamide (220 mg, 5.24 mmol) was added to the solution. The mixture was stirred at room temperature over night. After the reaction was completed, the reaction mixture was extracted with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography with a mixed solvent of methanol and chloroform to give propyl N-cyano-6-diethylamino-3-pyridinecarboximidate (630 mg, yield 92%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[CH3:13][C:14]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)=[O:15].[OH-].[Na+]>CO>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[CH:13]/[C:14]([C:16]2[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=2)=[O:15])=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: CCCOc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCOc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 26.6 %

Procedure:
To a stirred solution of 4-propoxybenzaldehyde (1.5 ml, 9.5 mmol) and 3,4,5-trimethoxyacetophenone (2.0 g, 9.5 mmol) in methanol (30 ml) was added 50% w/v of aqueous sodium hydroxide (7.6 ml, 0.095 mol). The reaction was stirred for 24 h at room temperature. A precipitate was isolated by filtration, washed with pet:ether and subsequently recrystallised from ethanol to give 0.9 g (27%) of a pale yellow powder. 1H-NMR (CDCl3) δ 7.8 (d, 1H), 7.6 (d, 2H), 7.3 (d, 1H), 7.2 (m, 1H), 6.8 (d, 2H), 3.95 (m, 2H), 3.9 (s×2, 9H), 1.8 (t, 2H), 1.0 (t, 3H).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5](=[O:10])([O:8][CH3:9])OC>>[CH3:9][O:8][C:5]([NH:3][CH2:2][CH2:1][NH:4][C:5]([O:8][CH3:9])=[O:10])=[O:10]
Reactant: NCCN
Reactant: COC(=O)OC
Product: COC(=O)NCCNC(=O)OC
Reaction time: 24 h

Procedure:
Ethylene diamine (6 g) and dimethyl carbonate (18 g) were mixed together in a round bottom flask at 20° C. TBD (0.1 g) was added and the mixture allowed to stand for 24h. After this time a white solid product was collected and recrystallised from methanol to give bis (methoxycarbonyl) ethylene diamine. NMR and IR spectra were consistent with the desired compound.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[C:11]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:12][CH:13]=[C:14](Br)[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Li]C.C([Li])CCC.[CH:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>>[CH2:2]([O:9][C:10]1[CH:15]=[C:14]([CH:31]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[OH:38])[CH:13]=[N:12][C:11]=1[NH:17][C:18]1[S:19][CH:20]=[C:21]([CH3:23])[N:22]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Agent: Cl
Agent: [Li]C
Agent: [Li]CCCC
Product: Cc1csc(Nc2ncc(C(O)c3ccccc3)cc2OCc2ccccc2)n1
Yield: 48.5 %

Procedure:
3-(Benzyloxy)-5-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine (Example 1; 0.350 g, 0.930 mmol), MeLi (0.727 ml, 1.16 mmol), butyllithium (0.465 ml, 1.16 mmol), and benzaldehyde (0.0987 g, 0.930 mmol) were reacted according to Example 7 to provide (5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-yl)(phenyl)methanol (0.182 g, 48.5% yield) after HCl salt formation. 1H NMR (DMSO-d6) δ 7.94 (s, 1H), 7.58 (s, 1H), 7.55 (d, 2H), 7.40-7.28 (m, 7H), 7.22 (m, 1H), 6.81 (s, 1H), 5.75 (s, 1H), 5.29 (s, 2H), 2.30 (s, 3H). Mass spectrum (apci) m/z=404.1 (M+H-HCl).