Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10]=2[C:20](O)=[O:21])=[CH:5][CH:4]=1.Cl.[NH2:24][CH2:25][C:26]1[CH:40]=[CH:39][C:29]([C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[O:31])=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10]=2[C:20]([NH:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)=[O:31])=[CH:39][CH:40]=2)=[O:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(-c3ccccc3)[nH]c2C(=O)O)cc1
Reactant: NCc1ccc(C(=O)Nc2ccccn2)cc1
Agent: Cl
Product: COc1ccc(-c2cc(-c3ccccc3)[nH]c2C(=O)NCc2ccc(C(=O)Nc3ccccn3)cc2)cc1
Yield: 71 %

Procedure:
This material was prepared using a method substantially similar to that of Example 5 from 3-(4-methoxyphenyl)-5-phenyl-1H-pyrrole-2-carboxylic acid and 4-(aminomethyl)-N-pyridin-2-ylbenzamide hydrochloride, yielding the title compound. 3-(4-Methoxyphenyl)-5-phenyl-N-{4-[(pyridin-2-ylamino)carbonyl]benzyl}-1H-pyrrole-2-carboxamide: Yield 71%; m.p. 196° C. (dec.); IR 3402, 3239, 1623, 1536, 1432, 1304, 1246 cm−1; 1H-NMR (300 MHz, δ ppm, CDCl3) 9.75 (s, 1H), 8.77 (s, 1H), 8.39 (d, J=8.4 Hz, 1H), 8.29 (d, J=4.8 Hz, 1H), 7.88 (d, J=8.3 Hz, 2H), 7.77 (dt, J=7.0 Hz, J′=1.8 Hz, 1H), 7.57 (d, J=7.2 Hz, 2H), 7.45-7.27 (m, 7H), 7.07 (ddd, J=7.3 Hz, J′=5.0 Hz, J″=0.8 Hz, 1H), 6.90 (d, J=8.7 Hz, 2H), 6.49 (d, J=3.0 Hz, 1H), 6.13 (t, J=5.8 Hz, 1H), 4.52 (d, J=5.9 Hz, 2H), 3.82 (s, 3H); 13C-NMR (75 MHz, δ ppm, CDCl3) 165.7, 161.6, 159.7, 151.9, 148.1, 143.0, 138.8, 134.7, 133.6, 131.6, 430.9, 129.2, 128.3, 127.9, 127.8, 127.7, 125.0, 122.4, 120.1, 114.7, 109.9, 55.6, 43.1.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C[O-].[Na+].Cl[CH:13](Cl)[C:14]([O:16][CH3:17])=[O:15].Cl>CO.O>[CH3:17][O:16][C:14]([CH:13]1[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1)=[O:15]
Reactant: Oc1ccccc1O
Reactant: COC(=O)C(Cl)Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C1Oc2ccccc2O1
Temperature: 25 °C

Procedure:
Catechol (10.26 g, 93.2 mmol), sodium methoxide (25% by weight in methanol, 40.3 g, 186 mmol), and methyl dichloroacetate (13.3 g, 93.2 mmol) were combined in dry methanol (100 mL). The solution was heated to reflux overnight. The reaction was cooled to room temperature, acidified by addition of concentrated hydrochloric acid and then reduced in volume under vacuum to about 50 mL. Water was added and the mixture was extracted with diethyl ether (3×100 mL). The combined organic solution was dried with MgSO4, concentrated to a brown solid, and chromatographed (2% ethyl acetate in hexane) to yield benzo[1,3]dioxole-2-carboxylic acid methyl ester as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[O:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:40]=[CH:39][C:38]([CH2:41][C:42]([O:44]CC)=[O:43])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].O1CCCC1.[OH-].[Na+].Cl>C(O)C>[CH2:1]([C:3]1[O:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[CH:37][C:38]([CH2:41][C:42]([OH:44])=[O:43])=[CH:39][CH:40]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4coc(CC)n4)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4ccc(CC(=O)O)cc4)oc3C)c(OC)c2)co1
Temperature: 50 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
To a mixture of ethyl {4-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (360 mg), tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.6 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid was added to the reaction mixture for neutralization, and the mixture was extracted with ethyl acetate. The residue was recrystallized from ethyl acetate-hexane and the precipitated crystals were collected by filtration to give {4-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid (196 mg, yield 37%) as colorless crystals. melting point: 117-119° C.
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][CH2:26][C:27](OCC)=O)[CH2:22][CH:23]=2)=[CH:14][CH:13]=1>>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][C:27]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:20][CH:19]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCCN1CC=C(c2ccc(OC)cc2)CC1
Reactant: ON=C1CCCCCC1
Product: COc1ccc(C2=CCN(CCCc3onc4c3CCCCC4)CC2)cc1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate, 3-(3-(4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([CH3:17])[CH3:16])=[C:10]([F:18])[C:9]=2[F:19])[CH2:4]1.[C:20]1([C:26]2[O:30][C:29]([C:31](OCC)=[O:32])=[N:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:16][N:15]([CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH:5]2[CH2:6][N:3]([C:31]([C:29]3[O:30][C:26]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:27][N:28]=3)=[O:32])[CH2:4]2)=[C:9]([F:19])[C:10]=1[F:18])[CH3:17]
Reactant: CN(C)Cc1ccc(OC2CNC2)c(F)c1F
Reactant: CCOC(=O)c1nnc(-c2ccccc2)o1
Agent: Cl
Product: CN(C)Cc1ccc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)c(F)c1F
Yield: 15.7 %

Procedure:
Using a similar protocol as described in Example 36 employing 39A (0.32 g, 1.00 mmol) and ethyl 5-phenyl-1,3,4-oxadiazole-2-carboxylate (0.24 g, 1.10 mmol) as starting materials afforded 65 mg (15%) of 39 as a solid. 1H NMR (500 MHz, CDCl3): δ 2.27 (s, 6H), 3.46 (s, 2H), 4.39 (dd, 1H), 4.65 (dd, 1H), 4.82 (m, 1H), 5.13 (m, 2H), 6.52 (t, 1H), 7.04 (t, 1H), 7.54 (t, 2H), 7.60 (t, 1H), 8.16 (d, 2H), MS (APCI+) m/z 415 [M+H]+, LC purity: 89%.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([O:17][CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[C:15]2[CH:14]([OH:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([O:17][CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1
Reactant: CCCOc1ccc(Cl)c2c(=O)c3ccccc3sc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCOc1ccc(Cl)c2c1Sc1ccccc1C2O

Procedure:
1-Chloro-4-propoxy-9H-thioxanthen-9-one (20 g, 65.6 mmol) was reduced with sodium borohydride (6.5 g, 0.17 mol) in methanol (320 ml) and worked up following the procedure described in Example 22(i) to give the title compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:50]=[C:49]([Cl:51])[CH:48]=[CH:47][C:46]=3[Cl:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: Clc1ccc(Cl)c(CBr)c1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cc(Cl)ccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-1,4-dichlorobenzene and isolated as white solid (6.6 mg, 37%). MS(m/e): 441.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22]S(C(F)(F)F)(=O)=O)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:7]2[CH3:21].C([Si]([O:37][C:38]([O:40][CH3:41])=[CH2:39])(C)C)(C)(C)C.C([O-])(=O)C.[Na+]>CN(C)C=O.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:41][O:40][C:38](=[O:37])[CH2:39][O:22][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:21])=[C:8]([O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:9]([CH3:12])=[N:10]2
Reactant: Cc1nc2c(Cl)ccc(OS(=O)(=O)C(F)(F)F)c2c(C)c1Oc1ccc(Cl)cc1
Reactant: C=C(OC)O[Si](C)(C)C(C)(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Oc3ccc(Cl)cc3)c(C)c12
Temperature: 120 °C

Procedure:
A mixture of trifluoromethanesulfonic acid 8-chloro-3-(4-chlorophenoxy)-2,4-dimethylquinolin-5-yl ester (0.20 g), tert-butyl-(1-methoxyvinyloxy)dimethyl silane (0.40 g), sodium acetate (0.044 g), tris(dibenzylideneacetone) dipalladium (0.020 g) and 1,1′-bis(diphenylphospino) ferrocene (0)(0.012 g) in N,N-dimethylformamide (5.0 mL) was heated by microwave irradiation at 120° C. for 15 minutes. The mixture was purified by column chromatography on silica gel, eluting with a mixture of pentane and dichloromethane (9:1 to 0:1 by volume) to afford title compound as a yellow oil, 0.034 g.
Reaction SMILES: [C:1]([CH:3]([OH:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=1)#[N:2].[CH3:18][C:19]1([CH3:30])[C@@H:21]([CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])[C@@H:20]1[C:27](Cl)=[O:28].N1C=CC=CC=1.O>C1C=CC=CC=1>[CH3:18][C:19]1([CH3:30])[C@@H:21]([CH2:22][C:23]([Cl:24])([Cl:25])[Cl:26])[C@@H:20]1[C:27]([O:17][CH:3]([C:1]#[N:2])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=1)=[O:28]
Reactant: CC1(C)[C@@H](CC(Cl)(Cl)Cl)[C@@H]1C(=O)Cl
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Solvent: c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)[C@@H](CC(Cl)(Cl)Cl)[C@@H]1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
α-Cyano-3-phenoxybenzyl alcohol (8.5 g) was added to a solution of 10.0 g of trans-2,2-dimethyl-3-(2,2,2-trichloroethyl)cyclopropanecarbonyl chloride in 80 ml of dry benzene, then 4.5 g of pyridine was added gradually and the mixture was stirred at room temperature overnight. Thereafter, about 70 ml of water was added to the reaction mixture, the benzene layer was separated, washed with water and dried over anhydrous magnesium sulfate, and low-boiling fractions were distilled off under reduced pressure. There was obtained an oily product, which was purified by preparative liquid chromatography under the conditions mentioned in SYNTHESIS EXAMPLE 25 to give 13.3 g (77% yield) of α-cyano-3-phenoxybenzyl trans-2,2-dimethyl-3-(2,2,2-trichloroethyl)cyclopropanecarboxylate with a ratio of racemic modifications D1 '/D2 ' of about 50/50.
Reaction SMILES: Br.[CH2:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH3:3].Cl.[CH2:16](O)[CH3:17]>>[CH2:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH2:16][CH3:17])=[O:13])=[CH:7][CH:6]=1)[CH3:3]
Reactant: CCNc1ccc(CC(=O)O)cc1
Reactant: CCO
Agent: Br
Agent: Cl
Product: CCNc1ccc(CC(=O)OCC)cc1

Procedure:
Ethyl iodide (35.1 g) was gradually added dropwise to a mixed liquid of ethyl 4-(N-benzenesulfonyl)aminophenylacetate (60 g), potassium carbonate (39 g), and acetone (500 ml) while stirring and refluxing it. Then, the mixture was refluxed for 2 hours with stirring. The mixture was cooled, and the precipitated crystals were removed by filtration. The filtrate was distilled for removal of the solvent. The residue was dissolved in benzene, and the solution was washed in water, followed by drying over magnesium sulfate. The dried product was distilled to remove the solvent, and the residue was recrystallized from n-hexane to obtain 64.3 g (m.p. 99.8°-100.8° C.) of ethyl 4-(N-ethyl-N-benzeneslfonyl) aminophenylacetate as prismatic crystals. Subsequently, 48% hydrobromic acid (380 ml) and phenol (64.3 g) were added to the ethyl ester, and the mixture was refluxed for 4 hours. While being cooled, the refluxed mixture was washed with benzene, and distilled to remove the aqueous layer. To the residue was added benzene, and the mixture was distilled to remove moisture and crude 4-(N-ethyl)aminophenylacetic acid hydrobromide was obtained. Then, ethanol (300 ml) was added to the hydrobromide. While being cooled, the mixture was saturated with hydrogen chloride gas. With the introduction of hydrogen chloride gas, the mixture was refluxed for 4 hours. After the reaction, the solvent was distilled off. The residue was dissolved in water, and the solution was washed with ether. The aqueous layer was neutralized with potassium carbonate while cooling the layer with ice, and extracted with ether. The extract was dried over magnesium sulfate. After the solvent was distilled off, the residue was vacuum-distilled to obtain 26.8 g of the desired N-ethyl-4-ethoxycarbonylmethylaniline as a fraction boiling at 112.5° C. at 0.02 mmHg.
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([OH:11])[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].[CH3:20]I>O>[CH3:20][O:11][C:2]([CH3:1])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: CC(O)(C(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(C)(C(=O)c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
Portions of 2.85 g α-methyl-benzoin are dissolved in a nitrogen atmosphere in 25 ml of solvent and mixed with 5.5 ml of a 10% by weight sodium hydroxide solution and then with 0.8 ml methyl iodide, while maintaining a temperature of 25°C. After stirring for 2 hours, the reaction products are poured into water, isolated and analysed by NMR-spectroscopy.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12](O)=[O:13])=[C:10]([C:15]([F:18])([F:17])[F:16])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C(OC(Cl)=O)C.[BH4-].[Na+]>C1COCC1.O.Cl>[C:1]1([C:7]2[C:11]([CH2:12][OH:13])=[C:10]([C:15]([F:17])([F:18])[F:16])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1c(-c2ccccc2)noc1C(F)(F)F
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OCc1c(-c2ccccc2)noc1C(F)(F)F
Temperature: -10 °C
Yield: 66 %

Procedure:
To a solution of 3-phenyl-5-trifluoromethyl-isoxazole-4-carboxylic acid (5.0 g, 19 mmol in THF (60 mL) at −10° C. was added triethylamine (2.0 g, 2.71 mL, 19 mmol) and then a solution of ethylchloroformate (2.1 g, 1.9 mL, 19 mmol) in THF (10 mL) added keeping the temperature below −5° C. After 30 min the mixture was filtered and the filtrate cooled to −10° C. and a suspension of sodiumborohydride (1.8 g, 49 mmol) in water (20 mL) added over 15 minutes keeping the temperature below −5° C. The mixture was then allowed to warm up to room temperature overnight and diluted with HCl (1 N) and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (3.1 g, 66%) as a white solid. MS: m/e=243.1 [M]′.
Reaction SMILES: [CH3:1][N:2]([CH2:14][CH:15](O)[CH3:16])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1.S(Cl)([Cl:20])=O>>[CH3:1][N:2]([CH2:14][CH:15]([Cl:20])[CH3:16])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: CC(O)CN(C)CCc1ccc([N+](=O)[O-])cc1
Product: CC(Cl)CN(C)CCc1ccc([N+](=O)[O-])cc1

Procedure:
Thionyl chloride (50 ml) was added dropwise with stirring and cooling in an ice/water bath to 1-(N-methyl-N-(4-nitrophenethyl)amino)-2-hydroxypropane (1.5 g). After stirring at room temperature for 1 hour, the solution was refluxed on a steam bath for a further 2 hours. The solution was evaporated to dryness and the residual oil partitioned between 2N aqueous sodium carbonate solution and ethyl acetate. After two further extractions with ethyl acetate, the organic portions were combined, washed with a saturated brine solution, dried over anhydrous magnesium sulphate, filtered and evaporated to dryness. The resultant brown oil was chromatographed on silica ("Kieselgel 60"- Trade Mark) eluting with ethyl acetate followed by collection and evaporation of suitable fractions to give the title compound as a yellow oil, (0.75 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH:12]([CH3:20])[C:13]([O:15]C(C)(C)C)=[O:14])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.FC(F)(F)C(O)=O>>[Br:1][C:2]1[C:3]([O:11][CH:12]([CH3:20])[C:13]([OH:15])=[O:14])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1
Reactant: COC(=O)c1scc(Br)c1OC(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1scc(Br)c1OC(C)C(=O)O
Yield: 94.9 %

Procedure:
A solution of methyl 4-bromo-3-(2-tert-butoxy-1-methyl-2-oxoethoxy)thiophene-2-carboxylate (890 mg) and trifluoroacetic acid (5 ml) was stirred at room temperature for 20 min. The reaction mixture was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate, washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of Et2O and hexane to give the title compound (715 mg, 95%) as colorless crystals.
Reaction SMILES: [H-].[Na+].C(S)C.[NH2:6][C:7]1[C:29]([Cl:30])=[CH:28][C:10]([C:11]([NH:13][CH2:14][CH:15]2[O:20][CH2:19][CH2:18][N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:16]2)=[O:12])=[C:9]([O:31]C)[CH:8]=1>CN(C)C=O>[NH2:6][C:7]1[C:29]([Cl:30])=[CH:28][C:10]([C:11]([NH:13][CH2:14][CH:15]2[O:20][CH2:19][CH2:18][N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:16]2)=[O:12])=[C:9]([OH:31])[CH:8]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CN(Cc2ccccc2)CCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: Nc1cc(O)c(C(=O)NCC2CN(Cc3ccccc3)CCO2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a stirred suspension of 60% sodium hydride (0.52 g) in dimethylformamide (20 ml) is added under ice-coolinga solution of ethanethiol (0.81 g) in dimethylformamide (5 ml). After the mixture is stirred at 25° C. for 0.5 hour, 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chloro-2-methoxybenzamide (3.4 g) is added, and the mixture is stirred at 100° C. for 1 hour. After cooling, the reaction mixture is evaporated under reduced pressure. The residue is diluted with water, washed with chloroform, and neutralized with 10% hydrochloric acid. The precipiate is collected, washed with water, and recrystallized from isopropyl alcohol to give the monohydrate of the title compound (2.3 g), mp 153°-155° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH:12]1([NH:18][C@@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH3:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CCOCC>[Cl:1][C:2]1[N:7]=[C:6]([N:18]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C@@H:19]([C:21]([O:23][CH3:24])=[O:22])[CH3:20])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: COC(=O)[C@@H](C)NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: COC(=O)[C@@H](C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
To a solution of 2,4-dichloro-5-nitropyrimidine (28.5 g, 146.9 mmol) in ether (200 mL) was added methyl N-cyclohexyl-D-alaninate (17.0 g, 91.8 mmol) at −10° C. To the resulting solution was then added aqueous potassium carbonate (19.0 g in 100 mL water) drop wise while maintaining the temperature below 0° C. Reaction mixture was then warmed to rt and stirred at rt for 16 h. The organic layer was separated and the aqueous layer was extracted with ether (3×75 mL). Combined ether solution was washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel flash chromatography using ethyl acetate-hexane mixture (v:v=5:95) as eluent to give titled compound (yield, 41%). 1HNMR (300 MHz, CDCl3): δ 1.06-1.29 (m, 3H), 1.43-1.53 (m, 2H), 1.58 (s, 1H), 1.64 (d, J=6.9 Hz, 3H), 1.90-1.82 (m, 2H), 2.02-1.98 (m, 1H), 2.17-2.14 (m, 1H), 3.09-3.01 (m, 1H), 3.73 (s, 3H), 4.13 (q, J=6.9 Hz, 1H), 8.59 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([C:24]3[CH:28]=[C:27]([CH:29]=O)[O:26][CH:25]=3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][C:13]=1[C:31]#[N:32].[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([C:24]3[CH:28]=[C:27]([CH2:29][N:37]4[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]4)[O:26][CH:25]=3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][C:13]=1[C:31]#[N:32]
Reactant: CN1CCNCC1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(-c4coc(C=O)c4)c(OC)cc23)c(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4coc(CN5CCN(C)CC5)c4)c(OC)cc23)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 50.5 %

Procedure:
A mixture of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-(5-formyl-3-furyl)-6-methoxy-3-quinolinecarbonitrile (200 mg, 0.43 mmol) and 0.24 mL of N-methylpiperazine (2.2 mmol) in 5 mL of dichloromethane and 1 mL of dimethylformamide is cooled to 0° C. Sodium triacetoxyborohydride (470 mg, 2.22 mmol) is added in portions followed by a few drops of acetic acid. The resulting mixture is stirred at 0° C. for 10 minutes then at room temperature for 5.5 hours. The mixture is partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 10% methanol in ethyl acetate to 1% ammonium hydroxide in a 1:4 mixture of methanol and ethyl acetate to provide 120 mg (51%) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6 methoxy-7-{5-[(4-methylpiperazin-1-yl)methyl]-3-furyl}-3-quinolinecarbonitrile as a light yellow solid, mp 179-181° C.; 1H NMR (DMSO-d6) δ 2.15 (s, 3H), 2.23-2.36 (broad s, 4H), 2.38-2.49 (broad s, 4H), 3.54 (s, 2H), 3.87 (s, 3H), 4.06 (s, 3H), 7.01 (s, 1H), 7.33 (s, 1H), 7.74 (s, 1H), 7.94 (s, 1H), 8.10 (s, 1H), 8.28 (s, 1H), 8.43 (s, 1H), 9.82 (s, 1H); MS 552.1, 554.1 (M+H)+; HRMS calcd: 552.15638, found: 552.15599 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][Cl:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)CCCCCl
Reactant: CC(=O)N1CCc2ccccc21
Product: CC(=O)N1CCc2cc(C(=O)CCCCCl)ccc21
Yield: 45.4 %

Procedure:
Using 1-acetylindoline (1.60 g) and 5-chlorovaleryl chloride (1.70 g) according to the same method as that of Reference Example 1, the title compound (1.26 g) was obtained as colorless crystals having a melting point of 90 to 91° C.