Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH:6]=O.[N:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N+:13]=[N-:14].Cl>CO>[Cl:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH:6]=[C:15]([N:12]=[N+:13]=[N-:14])[C:16]([O:18][CH3:19])=[O:17]
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: COC(=O)CN=[N+]=[N-]
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COC(=O)C(=Cc1ccc(F)c(Cl)c1)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.3 %

Procedure:
While cooling with an ice bath 1.35 g of sodium were dissolved in 30 ml of methanol and subsequently a solution of 4.65 g of 3-chloro-4-fluorobenzaldehyde and 6.75 g of methyl azidoacetate in 10 ml of methanol were added within 20 min. The reaction mixture was stirred at room temperature for 3 hours and then neutralized with 2N HCl. The mixture was extracted with ethyl acetate, washed with water and saturated sodium chloride solution and the organic phase was dried over sodium sulfate. The solvent was removed and the residue was chromatographed over 250 g of silica gel with n-hexane-toluene 2:1. There were obtained 2.5 g (33%) of methyl 3-chloro-4-fluoro-a-azidocinnamate as yellow crystals with m.p. 72°-74°.
Reaction SMILES: [CH3:1][S:2][C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2C(=O)C3=CC=CC=C3C2=O)=[C:11]([Cl:26])[CH:10]=1)([CH3:8])[C:4]([O:6][CH3:7])=[O:5].O.NN>CO>[CH3:1][S:2][C:3]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([Cl:26])[CH:10]=1)([CH3:8])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(C)(SC)c1ccc(N2C(=O)c3ccccc3C2=O)c(Cl)c1
Agent: NN
Solvent: O
Solvent: CO
Product: COC(=O)C(C)(SC)c1ccc(N)c(Cl)c1
Temperature: 25 °C
Yield: 92 %

Procedure:
Methyl α-methylthio-α-(3-chloro-4-phthalimidophenyl)propionate was suspended in 7 ml of methanol, and 97 mg of hydrazine hydrate was added. The mixture was stirred at room temperature, and then heated under reflux for 1 hour. The mixture was concentrated under reduced pressure, and an aqueous solution of ammonium chloride and methylene chloride were added. The organic layer was separated, and dried over anhydrous sodium sulfate. Concentration under reduced pressure yielded 231 mg of methyl α-methylthio-α-(3-chloro-4-aminophenyl)propionate as a pale yellow oil. Yield 92%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]=[O:10])=[C:4]([Cl:11])[N:3]=1.[CH2:12]([NH2:17])[CH2:13][CH2:14][CH2:15][CH3:16]>CO>[NH2:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]([CH:9]=[O:10])=[C:6]([NH:17][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:7]=1
Reactant: Nc1nc(Cl)c(C=O)c(Cl)n1
Reactant: CCCCCN
Solvent: CO
Product: CCCCCNc1nc(N)nc(Cl)c1C=O

Procedure:
A mixture of 2-amino-4,6-dichloropyrimidine-5-carbaldehyde (30 g), pentylamine (18.5 ml) and TEA (22 ml) in MeOH (600 ml) were heated under reflux for 3 h then partitioned between EtOAc/water. The organics were separated, washed with water, dried and evaporated under reduced pressure. The residue was triturated with ether/iso-hexane to afford the subtitle compound, 20 g.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH3:21].[CH:22]1([N:28]=[C:29]=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>N1C=CC=CC=1>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH3:21])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:29]([NH:28][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:30])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCOCCN
Reactant: O=C=NC1CCCCC1
Solvent: c1ccncc1
Product: Cc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)NC1CCCCC1
Reaction time: 18 h
Yield: 49.8 %

Procedure:
A solution of the compound of Example 45, 1-[2-(2-aminoethoxy)ethyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.50 mmol) in 30 mL of pyridine was chilled in an ice water bath. With vigorous stirring, the solution was treated with cyclohexyl isocyanate (0.45 mL, 3.50 mmol). After 18 h, the reaction was concentrated to yield an off white solid. Purification by column chromatography (SiO2, 95:5:0.5 CHCl3:MeOH:NH4OH) gave 716 mg of N-{2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}-N′-cyclohexylurea as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH:10]2[NH:15][C:14](=O)[CH2:13][NH:12][C:11]2=O)[CH:6]=[CH:5][N:4]=1.[OH-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH:10]2[CH2:11][NH:12][CH2:13][CH2:14][NH:15]2)[CH:6]=[CH:5][N:4]=1
Reactant: COc1cc(CC2NC(=O)CNC2=O)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(CC2CNCCN2)ccn1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a 100-mL round-bottomed flask was added 3-((2-methoxy-4-pyridinyl)methyl)-2,5-piperazinedione (398 mg, 1.69 mmol) and borane methyl sulfide complex (0.64 mL, 6.77 mmol, Aldrich, St. Louis, Mo.) in THF (10 mL). The reaction mixture was stirred at 70° C. for 2 h and allowed to cool to room temperature. The reaction mixture was diluted with MeOH (1 mL), followed by 1N NaOH (12 mL), and extracted with DCM (2×50 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the 2-((2-methoxy-4-pyridinyl)methyl)piperazine as a colorless viscous oil, which was used without further purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:4][CH2:3]1.[CH3:19][O:20][C:21]1[C:29](O)=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][NH:25]2.C(C=P(CCCC)(CCCC)CCCC)#N.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:19][O:20][C:21]1[C:29]([O:1][CH:2]2[CH2:3][CH2:4][CH:5]([N:8]3[C:9](=[O:18])[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:16]3=[O:17])[CH2:6][CH2:7]2)=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][NH:25]2
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1
Reactant: COc1c(O)ccc2[nH]ncc12
Agent: CCCCP(=CC#N)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1c(OC2CCC(N3C(=O)c4ccccc4C3=O)CC2)ccc2[nH]ncc12
Temperature: 25 °C
Yield: 65.8 %

Procedure:
Under nitrogen, the 2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (1.23 g, 5.01 mmol) obtained in Example 385, (b), the 4-methoxy-1H-indazol-5-ol (0.906 g, 5.52 mmol) obtained in Example 469 and 90%-cyanomethylenetri-n-butylphosphorane (161 g, 6.02 mmol) were dissolved in toluene (20 ml), and the resulting solution was heated under reflux for 5 hours. The reaction solution was cooled to room temperature and water and a 1N-aqueous sodium hydroxide solution were added thereto. The resulting solution was separated by the addition of toluene and the desired compound was extracted from the aqueous layer with toluene. The combined toluene layer was washed with a saturated aqueous sodium chloride solution, dried by the addition of anhydrous magnesium sulfate, and then filtered. The solvent was distilled off under reduced pressure and the concentration residue thus obtained was purified by a silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1, 1/1) to obtain 2-[4-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]-1H-isoindole-1,3(2H)-dione (1.29 g, yield 66%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[NH2:1][C:2]1[CH:10]=[C:6]([C:7]([O:9][CH2:17][CH3:18])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: Nc1ccc(O)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(N)ccc1O
Reaction time: 8.5 h

Procedure:
A mixture of 5-aminosalicylic acid (15 g), absolute ethanol (250 ml) and concentrated sulphuric acid (7.5 ml) was boiled under reflux with stirring for 8.5 hours. The reaction mixture was evaporated to dryness. Water (20 ml) was added to the residue and the mixture filtered. The filtrate was basified with saturated bicarbonate solution and the solid collected by filtration. The solid was extracted into dichloromethane and the extract evaporated to dryness. The residue was triturated with petroleum ether b.p. 40°-60° C. and filtered to give ethyl 5-aminosalicylate, m.p. 44° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].F[C:16](F)(F)[C:17](O)=[O:18].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.C(Cl)(=O)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:17]([N:50]1[CH2:49][CH2:48][CH:47]([CH2:46][CH2:45][O:44][C:36]2[CH:37]=[CH:38][C:39]3[NH:40][C:41]4[N:42]=[C:26]([NH:27][C:28]5[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=5)[CH2:33][CH2:34][C:35]=2[CH:43]=3)[N:25]=[CH:24][C:23]=4[Cl:22])[CH2:52][CH2:51]1)(=[O:18])[CH3:16]
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Product: CC(=O)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 66 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and acetyl chloride as the starting materials in 66% yield. LCMS for C26H30ClN6O2 (M+H)+: m/z=493.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][C:34]([CH2:44][CH3:45])([CH2:42][CH3:43])[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[O:36])=[C:6]([CH:8]2[CH2:13][C:12](=O)[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:47]>C1(C)C=CC=CC=1>[Cl:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C:9]3([CH:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:33][C:34]([CH2:42][CH3:43])([CH2:44][CH3:45])[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])=[O:36])[CH2:13][C:12](=[S:47])[NH:11][CH:10]3[C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:30]2=[CH:29][CH:28]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Solvent: Cc1ccccc1
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=S)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Temperature: 60 °C
Yield: 58.2 %

Procedure:
A mixture of chiral (2′R, 3R, 4′S)-4′-[5-chloro-2-(2-methanesulfonylamino-1,1-diethyl-2-oxo-ethoxy)-phenyl]-6-chloro-2′-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (200 mg, 0.3 mmol) and P2S5 (130 mg, 0.6 mmol) was heated at 60° C. for 1 h, and then diluted with toluene (20 mL). The mixture was concentrated in vacuo and the residue was washed with DCM for 2 times. The DCM solution was collected and purified by flash column to give the title compound as white solid (121 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[N:18]1([CH2:23][CH2:24][C:25]2[CH:26]=[C:27]([NH2:31])[CH:28]=[N:29][CH:30]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:31][C:27]1[CH:28]=[N:29][CH:30]=[C:25]([CH2:24][CH2:23][N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:26]=1
Reactant: Nc1cncc(CCN2CCCC2)c1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: O=C(c1cnc2ccc(Br)cc2c1Nc1cncc(CCN2CCCC2)c1)C1CC1
Yield: 45.3 %

Procedure:
Following general procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (262 mg, 0.845 mmol) was reacted with 5-[2-(pyrrolidin-1-yl)ethyl]pyridin-3-amine (161 mg, 0.845 mmol) to afford the desired product (178 mg, 45%) as a white solid: ESI MS m/z 465 [C24H25BrN4O+H]+.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].Cl[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1>>[OH:4][CH2:3][CH2:2][N:1]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH2:5][CH2:6][OH:7]
Reactant: OCCNCCO
Reactant: COc1ccc(CCCl)cc1
Product: COc1ccc(CCN(CCO)CCO)cc1

Procedure:
2-{(2-Hydroxy-ethyl)-[2-(4-methoxy-phenyl)-ethyl]-amino}-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (10.0 g, excess). and 1-(2-chloroethyl)-4-methoxybenzene (8.5 g, 50 mmol). Yield 11 g, (92%); yellow oil; MS: 240 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:23])[C:7](=[O:22])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)=[C:4](Cl)[N:3]=1.O.[NH2:26][NH2:27]>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:23])[C:7](=[O:22])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)=[C:4]([NH:26][NH2:27])[N:3]=1
Reactant: COc1ccc(Cn2c(=O)n(C)c3c(Cl)nc(N)nc32)cc1OC
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(Cn2c(=O)n(C)c3c(NN)nc(N)nc32)cc1OC
Temperature: 92.5 °C
Yield: 73.1 %

Procedure:
A mixture of 2-amino-6-chloro-9-[(3,4-dimethoxyphenyl)methyl]-7-methyl-purin-8-one obtained in step 3 (9.0 g, 25.73 mmol), Hydrazine hydrate (16 ml, 257.3 mmol) and ethanol (675 ml) were heated at 90-95° C. for 40 hours. The reaction mixture was concentrated and solid obtained was filtered off and dried to obtain 2-amino-9-[(3,4-dimethoxyphenyl)methyl]-6-hydrazino-7-methyl-purin-8-one (6.5 g, 74%) as an off white solid.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:7][N:6]=[CH:5][N:4]=1)#[N:2].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][Br:16])=[CH:11][CH:10]=2)=[CH:7][N:6]=[CH:5][N:4]=1)#[N:2]
Reactant: Cc1ccc(-c2cncnc2C#N)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ncncc1-c1ccc(CBr)cc1

Procedure:
A solution of 4-cyano-5-(p-tolyl)pyrimidine (1.2 g, 6 mmol), N-bromosuccinimide (1.15 g, 6 mmol) and benzoyl peroxide (catalytic amount) in carbon tetrachloride (50 ml) was refluxed under light radiation for 1 hour. After cooling, insoluble materials were removed and the filtrate was concentrated to dryness. Recrystallization from ether-isopropyl ether afforded colorless powders (1 g, 59%), m.p. 114°-116° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[C:21]([CH3:26])=[N:22][CH:23]=[CH:24][CH:25]=1>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[C:21]([CH3:26])=[N:22][CH:23]=[CH:24][CH:25]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: Cc1ncccc1Br
Product: Cc1ncccc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 19, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and 3-bromo-2-methylpyridine (Synchem-OHG), the title compound was obtained as a yellow sticky solid after purification by preparative HPLC.
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][O:2]1.[CH2:7]([NH2:11])[CH2:8][CH2:9][CH3:10]>>[CH2:7]([NH:11][C:1](=[O:6])[O:2][CH2:3][CH2:4][OH:5])[CH2:8][CH2:9][CH3:10]
Reactant: O=C1OCCO1
Reactant: CCCCN
Product: CCCCNC(=O)OCCO
Reaction time: 8 h
Yield: 89.5 %

Procedure:
274.8 grams of ethylene carbonate (3.12 moles) were placed in a round bottom flask equipped with stirrer, thermometer, addition funnel and reflux condenser. 228.2 grams (3.12 mole) of butylamine were charged to the addition funnel and added to the flask at a rate sufficient to maintain the flask contents at 50°-80° C. The resultant reaction product was allowed to stand overnight. Thereafter, stripping of the reaction product in a rotary evaporator gave 449.9 g of crude product. A portion of the crude product was distilled at a pressure of 2 mm Hg, and a temperature of from 124° C. to 126° C. to purify same. The HLB value of 2-hydroxyethyl 1 butyl carbamate calculated as previously described is 12.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@H:17]([CH3:21])[C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:34]([NH:37][CH2:38][CH2:39][CH3:40])[CH2:35][CH3:36]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([C@H:17]([CH3:21])[C:18]([N:37]([CH2:38][CH2:39][CH3:40])[CH2:34][CH2:35][CH3:36])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CCCNCCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)[C@@H](C)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Yield: 30.7 %

Procedure:
A solution of (R)-2-(4-chlorophenyl)-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0166 mole), 1,1'-carbonyldiimidazole (2.69 g, 0.0166 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 2.25 hours with nitrogen bubbling through it. A solution of dipropylamine (5.04 g, 0.050 mole) in tetrahydrofuran (7 ml) was added and the reaction mixture was refluxed under nitrogen for two days. The solvents were removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The ethyl acetate layer was washed twice with water, twice with a 5% potassium hydroxide solution, and twice again with water. It was then dried over magnesium sulfate, charcoaled, filtered, and evaporated to an oil which crystallized upon trituration with isopropyl ether. The solid was collected by filtration and dried under high vacuum at 50° C. overnight to give 1.96 g (31%) of title compound, mp 95°-97° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[C:16]([C:34]([NH2:36])=[O:35])=[N:17][C:18]([C:31]([CH3:33])=[CH2:32])=[C:19]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-])=O)[CH:23]=4)[N:20]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(O)C>[Pd].O1CCCC1>[NH2:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[O:21][C:19]1[N:20]=[C:15]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[CH:13][CH:12]=2)[C:16]([C:34]([NH2:36])=[O:35])=[N:17][C:18]=1[CH:31]([CH3:32])[CH3:33]
Reactant: C=C(C)c1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)c1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cccc(N)c1
Reaction time: 6 h
Yield: 65.9 %

Procedure:
To a mixture of 3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5-(3-nitrophenoxy)-6-(prop-1-en-2-yl)pyrazine-2-carboxamide (1.13 g), ethanol (60 mL), and tetrahydrofuran (30 mL) was added 10% palladium-supported carbon (53% wet product) (1.23 g), followed by stirring for 6 hours under a hydrogen gas atmosphere (4 atm). The reaction mixture was filtered through celite and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=100:1:0.1-30:1:0.1) to obtain 5-(3-aminophenoxy)-6-isopropyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (702 mg) as a yellow solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:33])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:30]([CH3:32])[CH3:31])[CH:25]=2)[CH:18]=[CH:19][C:20]=1[CH3:21].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:32][N:30]([CH3:31])[C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:23]([NH:22][C:17]1[CH:18]=[CH:19][C:20]([CH3:21])=[C:15]([NH:14][C:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)=[O:13])[CH:16]=1)=[O:33]
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1N
Reactant: O=C(O)c1ccc2ncccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccc2ncccc2c1
Yield: 24.4 %

Procedure:
6-Quinolinecarboxylic acid (0.173 g) was added to a stirred suspension of N-(3-amino4-methylphenyl)3-dimethylaminobenzamide (0.135 g), diisopropylethylamine (0.325 ml), 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(V) (0.39 g) in DMF (10 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The solvent was evaporated and the residue was dissolved in methylene chloride and washed with a saturated aqueous sodium bicarbonate solution, dried over magnesium sulphate and evaporated. The residue was triturated under a mixture of ethyl acetate and isohexane. There was thus obtained the title compound as a solid (0.052 g); NMR Spectrum: (DMSOd6) 2.24 (s, 3H), 2.95 (s, 6H), 6.89 (d, 1H), 7.25 (m, 4H), 7.6 (m, 2H), 7.85 (s, 1H), 8.12 (d, 1H), 8.4 (d, 1H), 8.52 (d, 1H), 8.65 (m, 1H), 8.99 (d, 1H), 10.11 (s, 1H), 10.16 (s, 1H); Mass Spectrum: M+H+ 425.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6].[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C=O)C>[N:15]([CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6])=[N+:16]=[N-:17]
Reactant: COc1ccc(C(=O)CCCCl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)CCCN=[N+]=[N-])cc1
Temperature: 70 °C
Yield: 94.7 %

Procedure:
To a solution of 4-chloro-4′-methoxybutyrophenone (Acros Organics) (22.45 g, 106 mmol) in DMF (300 mL) was added sodium azide (13.7 g, 211 mmol). The solution was heated under N2 (g) at 70° C. for 4 h. The milky reaction mixture was partitioned between ethyl acetate (700 mL) and water (500 mL). The organic layer was washed with another portion of water (500 mL), followed by saturated aqueous sodium bicarbonate (500 mL) and brine (500 mL). The organic layer was dried (sodium sulfate) and concentrated to give an oil (22 g, 95% yield) which solidified slowly upon standing. MS m/e 220; HPLC retention time 3.09 min.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][C:13]([OH:15])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([OH:38])=[O:37])=[CH:32][CH:31]=1.Cl[Si](C)(C)C.Cl>C(Cl)Cl.C(N(CC)CC)C>[C:36]([C:33]1[CH:34]=[CH:35][C:30]([CH2:29][NH:28][C:13](=[O:15])[CH2:12][O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:31][CH:32]=1)([OH:38])=[O:37]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: O=C(O)COc1ccc2ccccc2c1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COc1ccc2ccccc2c1)NCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2-Naphthoxy)acetic acid (8.5 g) is suspended in 160 mL methylene chloride and treated with 1,1'-carbonyldiimidazole (6.8 g) which is added in small portions. After stirring for 3 hrs at room temperature under a nitrogen atmosphere, the mixture is added dropwise to a previously prepared solution of alphaamino-p-toluic acid (1.4 g), chlorotrimethylsilane (10 mL), and triethylamine (11 mL) in 250 mL methylene chloride at 0° C. The final mixture is stirred at room temperature under a nitrogen atmosphere overnight. The mixture is combined with 200 mL 1N HCl and shaken, after which the resultant precipitate is collected by suction filtration. The precipitate is recrystallized from methanol/2N HCl, m.p. 188°-189° C. as N-(4-carboxybenzyl)-(2-naphthoxy)acetamide.