Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([F:14])=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([C:21](OCC)=O)[CH2:17][CH2:16]3)[C:6]=2[CH2:26][O:27][CH3:28])[CH2:3][CH2:2]1>C(O)C.O>[CH:1]1([NH:4][C:5]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([F:14])=[C:7]([N:15]3[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]3)[C:6]=2[CH2:26][O:27][CH3:28])[CH2:2][CH2:3]1
Reactant: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(NC3CC3)c2COC)CC1
Solvent: O
Solvent: CCO
Product: COCc1c(NC2CC2)c([N+](=O)[O-])cc(F)c1N1CCN(C)CC1

Procedure:
N-Cyclopropyl-2-methoxymethyl-3-(4-ethoxycarbonyl-1-piperazinyl)-4-fluoro-6-nitroaniline, orange red needles, m.p. 89°-90° C. (ethanol-water)
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32]>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:23][CH2:24]1
Reactant: CC(C)CCBr
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCN(CCC(C)C)CC3)c2n1

Procedure:
Prepared similarly to Example 82 from 2-(butyloxy)-8-(methyloxy)-9-[4-(4-piperidinyl)butyl]-9H-purin-6-amine and 1-bromo-3-methylbutane.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([P:9]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=2)[C:10]2[N:15]=[C:14]([NH2:16])[CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>ClCCl>[CH3:8][C:6]1[CH:5]=[C:4]([P:9]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=2)[C:10]2[N:15]([C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[CH:14]([NH2:16])[CH:13]=[CH:12][CH:11]=2)[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc(C)cc(P(c2cc(C)cc(C)c2)c2cccc(N)n2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(P(C2=CC=CC(N)N2C(=O)C(C)(C)C)c2cc(C)cc(C)c2)c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 65.6 %

Procedure:
To a solution of 6-bis(3,5-dimethylphenyl)phosphino-2-aminopyridine (0.19 g, 0.58 mmol) in dichloromethane (45 mL) at 0° C., triethylamine (152 μL, 1.1 mmol) and pivaloyl chloride (107 μL, 0.87 mmol) are added consecutively. The solution is slowly warmed to ambient temperature, stirred for 40 hours, and concentrated under reduced pressure. The remaining suspension is stirred with activated charcoal (0.25 g) and filtered through a Celite pad. The filtrate is concentrated under reduced pressure and the white residue is purified by column chromatography to yield 6-bis(3,5-dimethylphenyl)phosphino-N-pivaloyl-2-aminopyridine (0.16 g, 65%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH3:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH3:22]
Reactant: CC(C)(C)OC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(C2CCCC2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C

Procedure:
A solution of tert.-butyl (1-oxo-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxy)acetate (4.13 g., 0.01 mole) and p-toluenesulfonic acid (0.3 g.) in benzene (50 ml.) is refluxed for ten minutes then cooled to 25°C. affording (1-oxo-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid which melts at 113°-114°C. after recrystallization from acetic acid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](OCC2C=CC=CC=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C@H:20]([CH2:24][OH:25])[CH:21]([CH3:23])[CH3:22]>ClC1C=CC=CC=1>[CH:21]([C@H:20]1[CH2:24][O:25][C:9]([CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:19]1)([CH3:23])[CH3:22]
Reactant: O=C(CCc1ccccc1)OCc1ccccc1
Reactant: CC(C)[C@H](N)CO
Solvent: Clc1ccccc1
Product: CC(C)[C@H]1COC(CCc2ccccc2)=N1
Yield: 74 %

Procedure:
Under an argon atmosphere, a mixture of benzyl 3-phenylpropionate (1.5 mmol), (L)-valinol (1.8 mmol), Zn4(OCOCF3)6O (0.15 mmol) and chlorobenzene (2.5 mL) was heated under reflux for 18 hours. From the resulting solution, the solvent was removed using an evaporator, and the residues were purified by silica gel column chromatography to give (S)-4-isopropyl-2-(2-phenylethyl)-1,3-oxazoline in 74% yield. The compound was identified by comparison with physical property data of the known compound.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([C:13]1[S:14][CH:15]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[C:17]=1[OH:18])(=[O:12])[CH3:11]>CN(C)C1C=CN=CC=1.ClCCl>[C:10]([C:13]1[S:14][CH:15]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[C:17]=1[O:18][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:12])[CH3:11]
Reactant: COC(=O)c1csc(C(C)=O)c1O
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1csc(C(C)=O)c1OC(=O)c1ccccc1
Reaction time: 2 h

Procedure:
3.48 mL of benzoyl chloride was added dropwise to a solution of 5.0 g of methyl 2-acetyl-3-hydroxythiophene-4-carboxylate (prepared as described in J. Chem. Soc. Perkin Trans I, 1986, 507) and 3.66 g of 4-dimethylaminopyridine in 100 mL of dichloromethane at 20-25° C. and stirred for 2 hours. The mixture was washed with 0.5N hydrochloric acid, water (2×20 mL), 2.5% aqueous sodium bicarbonate (2×40 mL) and water (2×20 mL). The organic layer was dried with sodium sulphate, evaporated to dryness in vacuo and purified by flash chromatography using chloroform/ethyl-acetate (100:1). The yield of Compound 1C was 7.089, as a yellow deliquescent solid, which was used in the next step without further purification.
Reaction SMILES: CS[C:3]1[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[NH:13]([C:3]1[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1
Reactant: CSc1ncnc2cnccc12
Product: c1ccc(Nc2ncnc3cnccc23)cc1
Temperature: 100 °C
Yield: 23 %

Procedure:
A mixture of 4-methylthiopyrido[3,4-d]pyrimidine (75 mg, 0.42 mmol), and aniline (1 mL) is heated to 100° C. under N2 for 2 h. The reaction mixture is then chromatographed on silica using MPLC and eluting with a gradient system (CHCl3 to 5% MeOH in CHCl3). The fractions are concentrated under reduced pressure, and the resulting solid is recrystallized from Et2O to yield 4-anilinopyrido[3,4-d]pyrimidine (21.2 mg, 23%) as a yellow solid. 1H NMR (DMSO) δ 10.09 (1H, s), 9.18 (1H, s), 8.74 (1H, d, J=5.3 Hz), 8.46 (1H, d, J=5.8 Hz), 7.89 (2H, d, J=8.5 Hz), 7.45 (2H, t, J=7.9 Hz), 7.21 (1H, t, J=7.4 Hz).
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.[CH2:14]([O:16]C=O)C>>[C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][C:4]([NH:7][CH:14]=[O:16])=[CH:5][CH:6]=1
Reactant: CCOC=O
Reactant: Nc1ccc(-c2ccccc2)cc1
Product: O=CNc1ccc(-c2ccccc2)cc1
Yield: 86.2 %

Procedure:
A mixture of biphenyl-4-ylamine (100 mg, 0.59 mmol) and ethylformate (1 mL) was stirred at reflux temperature for 1 hr. After the completion of the reaction, the reaction mixture was quenched with cold water. The precipitate was filtered to afford 100 mg (86.2% Yield) of N-biphenyl-4-yl-formamide as the required product.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[CH2:16]([C@H:18]1[O:20][CH2:19]1)Cl>CN(C)C=O>[O:20]1[CH2:19][C@H:18]1[CH2:16][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: ClC[C@@H]1CO1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: c1ccc2c(c1)c1ccccc1n2C[C@@H]1CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
To a stirred solution of carbazole (5.0 g, 29.9 mmol) in anhydrous N,N-dimethylformamide (20 mL) was added 85% aqueous potassium hydroxide (2.171 g, 32.9 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was cooled in an ice bath and (S)-(+)-epichlorohydrin (4.68 mL, 59.8 mmol) was added. The mixture was stirred overnight at room temperature, and then partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated. The residue was purified by silica gel column chromatography (30% methylene chloride/hexanes) to afford the desired product as a white solid (3.9 g, 58%). [α]D-10.4 (c 1.92, CHCl3). 1H NMR (300 MHz, CDCl3) δ 8.10 (d, 2H, J=7.5 Hz), 7.60-7.40 (m, 4H), 7.35-7.20 (m, 2H), 4.64 (dd, 1H, J=15.9, 3.3 Hz), 4.41 (dd, 1H, J=15.9, 4.8 Hz), 3.37 (m, 1H), 2.82 (t, 1H, J=4.2 Hz), 2.59 (dd, 1H, J=4.5, 2.4 Hz).
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:17]2[C:12](=[C:13]([C:18]3[S:19][C:20]([C:23]4[CH:24]=[CH:25][C:26](F)=[C:27]([CH:30]=4)[C:28]#[N:29])=[CH:21][N:22]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:32][CH:33]([CH3:35])[O-:34].[Na+]>C(O)(C)C>[Si:1]([O:8][CH:9]1[C:17]2[C:12](=[C:13]([C:18]3[S:19][C:20]([C:23]4[CH:24]=[CH:25][C:26]([O:34][CH:33]([CH3:35])[CH3:32])=[C:27]([CH:30]=4)[C:28]#[N:29])=[CH:21][N:22]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCc2c(-c3ncc(-c4ccc(F)c(C#N)c4)s3)cccc21
Reactant: CC(C)[O-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)Oc1ccc(-c2cnc(-c3cccc4c3CCC4O[Si](C)(C)C(C)(C)C)s2)cc1C#N
Temperature: 60 °C

Procedure:
Prepared using General Procedure 2. To a solution of 5-(2-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-fluorobenzonitrile (0.043 g, 0.095 mmol) in isopropanol (2 mL) was added sodium isopropoxide (0.07 g, 0.090 mmol). The reaction mixture was heated at 60° C. for 12 h. Upon cooling, the solvent was removed under a stream of N2 and the crude reaction mixture was carried onto the next step without further purification. LCMS-ESI (m/z) calculated for C28H34N2O2SSi: 490.7, tR=5.06 min (Method 3).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[C:7]([C:14](=[O:17])[NH:15][CH3:16])[N:6]=1)=[O:4].[O:18]1CC[CH2:20][CH2:19]1.C1(N=C=NC2CCCCC2)CCCCC1>C(O)CO>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([O:13][CH2:20][CH2:19][OH:18])=[O:12])[CH:8]=[C:7]([C:14](=[O:17])[NH:15][CH3:16])[N:6]=1)=[O:4]
Reactant: CNC(=O)c1cc(C(=O)O)cc(C(=O)NC)n1
Reactant: C1CCOC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: OCCO
Product: CNC(=O)c1cc(C(=O)OCCO)cc(C(=O)NC)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,6-Bis(N-methylcarbamoyl)pyridine-4-carboxylic acid (2.3 g) prepared in Example 2 was mixed with 50 ml of tetrahydrofuran and 3.1 g of ethylene glycol. After addition of 2.5 g of dicyclohexyl carbodiimide, the mixture was stirred at room temperature overnight. The mixture was then evaporated and the residue was purified by a column chromatography on silica gel, and recrystallized from dimethylformamide/benzene to give 0.3 g of 2-hydroxyethyl 2,6-bis(N-methylcarbamoyl)pyridine-4-carboxylate. m.p. 214°-215° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[N:13]=[C:14]1[NH:18][CH2:17][CH2:16][NH:15]1.S(=O)(=O)(O)O.[OH-].[Na+]>>[Cl:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([N+:1]([O-:4])=[O:2])[C:7]=1[N:13]=[C:14]1[NH:15][CH2:16][CH2:17][NH:18]1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(N=C2NCCN2)c(Cl)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(Cl)c(N=C2NCCN2)c([N+](=O)[O-])c1
Yield: 0.9 %

Procedure:
50 gm (0.183 mol) of 2-(2-chloro-4-methyl-phenylimino)-imidazolidine nitrate were slowly added over a period of two hours to 70 ml of concentrated sulfuric acid at 5°-10° C., while slightly cooling with ice and thoroughly stirring and the resulting black solution was stirred for one hour more at 5° C. Thereafter, ice was added, the aqueous mixture was made alkaline with 5 N sodium hydroxide, and the precipitate formed thereby was collected, recrystallized from methanol and separated from the mother liquor by suction filtration. The methanol was distilled out of the filtrate, and the residue was eluted on a silicagel column (mobile phase: 20 parts methanol, 10 parts acetone, 50 parts chloroform). The thin-layer chromatographically uniform fractions were combined and evaporated in vacuo, and the solid residue was dried, yielding 0.4 gm (0.86% of theory) of 2-(2-chloro-4-methyl-6-nitro-phenylimino)-imidazolidine, m.p. 198° C., Rf -value 0.7 in the mobile phase 50 parts benzene, 40 parts dioxane, 5 parts ethanol and 5 parts concentrated ammonium hydroxide; carrier: silicagel G, visualization: ultraviolet light and potassium iodoplatinate.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[C:4](=O)[CH2:3]1.Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+]>CO>[OH:19][N:18]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:6]=2)[C:2]([CH3:16])([CH3:1])[CH2:3]1
Reactant: NO
Reactant: COC(=O)c1ccc2c(c1)C(=O)CC2(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)C(=NO)CC2(C)C
Temperature: 80 °C

Procedure:
To a stirred solution of methyl 1,1-dimethyl-3-oxo-2,3-dihydro-1H-indene-5-carboxylate (430 mg, 1.97 mmol, 1.0 eq.) in methanol (7.5 ml) was added hydroxylamine hydrochloride (340 mg, 4.93 mmol, 2.5 eq.) followed by sodium acetate (807 mg, 9.85 mmol, 5.0 eq.) and the reaction mixture was heated at reflux for 2 h at 80° C. The reaction mixture was concentrated and then extracted with ethyl acetate (3×40 ml). The organic part was separated, washed with water (20 ml) and brine (20 ml) and dried over sodium sulfate. After concentrating the filtrate the crude product thus obtained was directly taken through to the next step without purification.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]([C:5]1[C:10](=[O:11])[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:8]([CH3:22])=[CH:7][N:6]=1)=[O:4].[Br:24]N1C(=O)CCC1=O>CN(C=O)C>[Br:24][C:7]1[N:6]=[C:5]([C:3]([N:2]([CH3:23])[CH3:1])=[O:4])[C:10](=[O:11])[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[C:8]=1[CH3:22]
Reactant: Cc1cnc(C(=O)N(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cc1c(Br)nc(C(=O)N(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
N,N,5-Trimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide (0.14 g, 0.43 mmol) was dissolved under argon in DMF (2 ml) in a vial. N-Bromosuccinimide (0.089 g, 0.5 mmol) was added. The vial was sealed and stirred for 30 minutes. The crude mixture was purified on preparative HPLC to give 0.100 g (57%) of the title compound as a solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]=[CH:14][CH:13]=2)[CH:10]=1)[C:6]#[N:7].Cl.Cl[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[K+].[K+].CCN(C(C)C)C(C)C>C(#N)C>[NH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([N:11]=[C:12]2[C:21]3[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:14]=[CH:13]2)[CH:10]=1)[C:6]#[N:7]
Reactant: N#Cc1cc(N)cc(Nc2ccnc3cc(Cl)ccc23)c1
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#Cc1cc(N)cc(N=c2ccn(CCN3CCCCC3)c3cc(Cl)ccc23)c1
Yield: 2.9 %

Procedure:
3-Amino-5-[(7-chloroquinolin-4-yl)amino]benzonitrile hydrochloride prepared from step B of example 19 (200 mg, 0.68 mmol), 1-(2-chloroethyl)piperidine hydrochloride (125 mg, 1 eq), K2CO3 (468 mg, 5 eq) and DIEA (0.11 mL, 1 eq) were refluxed in 30 mL of acetonitrile for 72 h. The reaction mixture was then filtered. The filtrate was evaporated and the residue was purified by flash chromatography on silica gel (AcOEt/MeOH//100/0 to 95/5) to yield expected compound as a yellow powder (8 mg, 3% yield). m/z (ESI) 406.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH3:30])[CH3:29])=[CH:23][CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:32](OCC)=[O:33])=[CH:16][C:15]([F:37])=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:3].O.[NH2:39][NH2:40]>CO>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:39][NH:40][C:32](=[O:33])[C:17]=4[CH:16]=[C:15]([F:37])[CH:14]=3)[CH:20]2[C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH3:30])[CH3:29])=[CH:23][CH:22]=2)=[CH:7][CH:6]=1)[CH3:3]
Reactant: CCOC(=O)c1cc(F)cc2c1C(=O)C(c1ccc(CN(C)C)cc1)C(c1ccc(CN(C)C)cc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: CN(C)Cc1ccc(C2Nc3cc(F)cc4c(=O)[nH]nc(c34)C2c2ccc(CN(C)C)cc2)cc1
Temperature: 23 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
A mixture of ethyl 2,3-bis(4-((dimethylamino)methyl)phenyl)-7-fluoro-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (520 mg) in 85% hydrazine monohydrate (10 mL) and methanol (50 mL) was stirred at 23° C. for overnight. Methanol was removed under reduced pressure. The mixture was filtered and washed with water to give the title compound (11 mg, yield 20%). LC-MS (ESI) m/z: 472 (M+1)+. 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.09 (s, 12H), 3.31 (s, 4H), 4.22 (d, J=8.0 Hz, 1H), 4.67 (d, J=8.0 Hz, 1H), 6.80 (dd, 1H), 6.97-6.99 (m, 2H), 7.06-7.11 (m, 5H), 7.14-7.16 (m, 2H); 19F-NMR (400 MHz, CD3OD) 6 (ppm): −105.58 (s).
Reaction SMILES: [C:1]([C:3]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])C(C#N)=[N:18]2)=[CH:13][CH:12]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:4])#[N:2].Cl.[C:28]([OH:31])(=[O:30])[CH3:29]>>[C:1]([C:3]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:22](=[O:23])[NH:21][C:20](=[O:24])[C:29]([C:28]([OH:31])=[O:30])=[N:18]2)=[CH:13][CH:12]=1)([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH3:4])#[N:2]
Reactant: CC(=O)O
Reactant: CC(C#N)(c1ccccc1)c1ccc(-n2nc(C#N)c(=O)[nH]c2=O)cc1
Agent: Cl
Product: CC(C#N)(c1ccccc1)c1ccc(-n2nc(C(=O)O)c(=O)[nH]c2=O)cc1

Procedure:
A mixture of 6.86 parts of 2-[4-(1-cyano-1-phenylethyl)phenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carbonitrile, 30 parts of concentrate hydrochloric acid and 150 parts of acetic acid was stirred and refluxed for 24 hours. The reaction mixture was evaporated and the residue was dissolved in trichloromethane. The latter was dried, filtered and evaporated, yielding 7.2 parts of 2-[4-(1-cyano-1-phenylethyl)phenyl]-2,3,4,5-tetrahydro-3,5-dioxo-1,2,4-triazine-6-carboxylic acid (intermediate 86).
Reaction SMILES: [Na].[CH3:2][O:3][C:4]([C:6]1[O:7][C:8]2[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5].Cl.Cl[CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>CO>[CH3:2][O:3][C:4]([C:6]1[O:7][C:8]2[C:14]([O:15][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5]
Reactant: ClCc1cccnc1
Reactant: COC(=O)c1cc2cccc(O)c2o1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COC(=O)c1cc2cccc(OCc3cccnc3)c2o1
Reaction time: 0.25 h
Yield: 44.1 %

Procedure:
Sodium (0.37 g.) was dissolved in methanol (70 ml.) and 7-hydroxybenzofuran-2-carboxylic acid methyl ester (1.54 g.) was added. The solution was stirred for 15 minutes ad then 3-chloromethylpyridine hydrochloride (1.32 g.) was added. The mixture was heated under reflux for 8 hours and then evaporated. Water was added to the residue and the mixture was extracted sevral times with ethyl acetate. The combined extracts were washed with water and dried (Na2SO4). Evaporation of the solvent gave a solid which was chromatographed on silica gel. Elution with chloroform gave a solid which was crystallized from methanol/water to give 7-(3-pyridylmethoxy)benzofuran-2-carboxylic acid methyl ester (1.0 g.), m.p. 117°-118° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:42]1[CH:47]=[CH:46][C:45]([C:48](=[NH:50])[NH2:49])=[CH:44][C:43]=1[O:51][CH3:52])(=O)=O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][C:42]2[CH:47]=[CH:46][C:45]([C:48](=[NH:49])[NH2:50])=[CH:44][C:43]=2[O:51][CH3:52])=[O:18])=[CH:20][CH:21]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=N)N)ccc1OS(C)(=O)=O
Reactant: O=C(NCc1ccc(C(=O)O)cc1)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: COc1cc(C(=N)N)ccc1OC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
To a solution of 3.7 g of 4-benzyloxycarbonylaminomethylbenzoic acid in 40 ml of dried pyridine, was added 3.1 g of DCC with cooling in ice. The mixture was stirred for 30 minutes. After addition of 3.1 g of 4-amidino-2-methoxyphenol methanesulfonate, the mixture was further stirred overnight at room temperature. The reaction mixture was removed of the insolubles and mixed with ethyl ether to precipitate a colorless solid substance which on recrystallization from a methanol-ethyl ether mixture gave 3.2 g of colorless crystals of 4-amidino-2-methoxyphenyl 4-benzyloxycarbonylaminomethylbenzoate methanesulfonate.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])=[O:4].[N-:14]=[N+:15]=[N-:16].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[N:14]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])=[O:4])=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: [N-]=[N+]=NCC(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
2-Bromo-2′-nitroacetophenone (2.69 g, 11.0 mmol) in acetonitrile (20 mL) was cooled to 0° C. under nitrogen and treated with tetrabutylammonium azide (3.29 g, 11.6 mmol, TCI America, Portland, Oreg.) in acetonitrile (20 mL) dropwise. After stirring at room temperature for 30 minutes, the solution was poured into ice water (100 mL) and extracted with diethyl ether (3×30 mL). The extracts were combined, dried over magnesium sulfate, and the volatiles were removed by evaporation under reduced pressure to yield 2.19 g of 2-azido-2′-nitroacetophenone.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[OH:11].C([Li])CCC.[Cl:17][Si:18](Cl)([CH3:20])[CH3:19]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[O:11][Si:18]([Cl:17])([CH3:20])[CH3:19]
Reactant: Oc1c(F)c(F)cc(F)c1F
Reactant: C[Si](C)(Cl)Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: C[Si](C)(Cl)Oc1c(F)c(F)cc(F)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.32 g (20 mmol) of 2,3,5,6-tetrafluorophenol are dissolved in 50 ml of toluene, and 8 ml of n-butyllithium (2.5 M in hexane) are added at 0° C. After warming to room temperature, the solution is stirred for 2 hours. Then 2.6 g of dichlorodimethylsilane (20 mmol) are added dropwise. The resulting suspension is filtered and the solvent is stripped off in vacuo. The colorless liquid which remains is subjected to fractional distillation.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(COC)OC.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([N:22](CC)CC)C>>[NH:22]1[C:7]2[CH:6]=[CH:5][CH:4]=[N:3][C:2]=2[N:1]=[CH:20]1
Reactant: Nc1ccccn1
Reactant: CCN(CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: c1cnc2nc[nH]c2c1

Procedure:
Imidazopyridine salt E-3 is prepared from aminopyridine E-1 (also D-1) (refer to Chart D) (commercial source) or the amino pyridine A-2 (refer to Chart A) and dihaloacetone E-2 (Aldrich) either by a two-step procedure whereby E-1 and E-2 are stirred in a solvent such as dimethoxyethane with or without the addition of a base such as triethylamine or potassium carbonate to give imidazopyridine salt E-3. If dimethoxyethane alone is used as solvent, it is then replaced with alcoholic solvent and E-3 is heated until no additional E-4 is formed.