Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[Cl:35][CH:36]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:37](Cl)=[O:38]>C(Cl)Cl>[Cl:35][CH:36]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:37]([N:16]([CH2:15][C:2]1([OH:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:4][CH2:3]1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:38]
Reactant: COc1ccc(CNCC2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CN(CC2(O)CCN(C(=O)OC(C)(C)C)CC2)C(=O)C(Cl)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.3 %

Procedure:
To a mixture of tert-butyl 4-hydroxy-4-[[(4-methoxyphenyl)methylamino]methyl]piperidine-1-carboxylate (1.06 g, 3.01 mmol) and diisopropylethylamine (1 mL, 5.74 mmol) in DCM (15 mL) at 0° C. was added 2-chloro-2-phenyl-acetyl chloride (654 mg, 3.46 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography using 0-100% EtOAc/DCM as eluent to give tert-butyl 4-[[(2-chloro-2-phenyl-acetyl)-[(4-methoxyphenyl)methyl]amino]methyl]-4-hydroxy-piperidine-1-carboxylate (1.11 g, 73%) as a pale yellow oil. ESI-MS m/z calc. 502.2. Found 503.5 (M+1)+; Retention time: 1.90 minutes (3 min run).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][C:15]([O:17][CH2:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:20])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[F:61][C:62]1[CH:67]=[CH:66][C:65]([C:68]2[S:72][C:71]([CH3:73])=[N:70][C:69]=2[C:74](O)=[O:75])=[CH:64][CH:63]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:74]([C:69]2[N:70]=[C:71]([CH3:73])[S:72][C:68]=2[C:65]2[CH:66]=[CH:67][C:62]([F:61])=[CH:63][CH:64]=2)=[O:75])[CH:10]([CH2:14][C:15]([O:17][CH2:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)=[O:20])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: CC(C)(C)OC(=O)N1CCNC(CC(=O)OCC(=O)c2ccc(F)cc2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2CC(=O)OCC(=O)c2ccc(F)cc2)c(-c2ccc(F)cc2)s1

Procedure:
(RS)-3-[2-(4-Fluorophenyl)-2-oxo-ethoxycarbonylmethyl]-piperazine-1-carboxylic acid tert-butyl ester description 110 (0.887 g) was reacted with HATU (0.932 g), diisopropylethylamine (1.30 ml) and 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (0.707 g) in dry DMF (8 ml) according to the method of description 20. Silica gel column chromatography, eluting with ethyl acetate-hexane mixtures provided the title compound as a white foam (1.168 g), mass spectrum (API+) 600 [MH+], C30H31F2N3O6S requires 599.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]([CH2:20][CH3:21])[CH2:17][CH2:16][CH:15]2[OH:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27].O>CN(C)C=O>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]([CH2:20][CH3:21])[CH2:17][CH2:16][CH:15]2[O:22][CH2:27][CH:26]=[CH2:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=CCBr
Reactant: CCN1CCC(O)c2cccc(CO[Si](C)(C)C(C)(C)C)c21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC1CCN(CC)c2c(CO[Si](C)(C)C(C)(C)C)cccc21
Reaction time: 2.5 h
Yield: 74.3 %

Procedure:
8-t-butyldimethylsilyloxymethyl-4-hydroxy-1-ethyl-1,2,3,4-tetrahydroquinoline (2.19 g) was dissolved in dimethyl formamide (15 ml), followed by addition of sodium hydride (60% in oil, 0.33 g), and allyl bromide (0.99 g) was added thereto under ice-cooling. The mixture was stirred for 2.5 hours at the same temperature. Furthermore sodium hydride (60% in oil, 0.16 g) and allyl bromide (0.48 g) were added to the reaction mixture and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture. The mixture was extracted with ethyl acetate-toluene and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography [eluent: n-hexane-ethyl acetate (6 : 1)]to give 8-t-butyldimethylsilyloxymethyl-4-allyloxy-1-ethyl-1,2,3,4-tetrahydroquinoline (1.83 g).
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:6][S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:3])[CH3:2].C(SCC(OC)CNS(CCC[I:60])(=O)=O)CCCCCCCCCCCCCCC>>[C:1]([NH:4][CH:5]([CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH2:31][I:60])(=[O:28])=[O:27])[CH2:6][S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)NC(C)=O
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)NC(C)=O

Procedure:
2-Acetamido-3-(3-chloropropylsulfonylamino)-1-hexadecylthiopropane IIIg2 is allowed to react and worked up by the same procedure as described in (5). m.p. 75°-76° C. The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]1([CH2:14][CH:15]([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[CH2:16][NH2:17])[CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:17][CH2:16][CH:15]([C:18]1[CH:19]=[N:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=1)[CH2:14][CH:11]1[CH2:12][CH2:13]1)=[O:6]
Reactant: NCC(CC1CC1)c1ccc(C(F)(F)F)nc1
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(NCC(CC1CC1)c1ccc(C(F)(F)F)nc1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and 3-cyclopropyl-2-(6-trifluoromethyl-pyridin-3-yl)-propylamine. LCMS (MH+): m/z=382.9, tR (minutes, Method C)=1.24
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[BrH:16].O.[CH3:18][C:19](O)=O>>[Br:16][CH:19]([C:11]1[CH:10]=[CH:9][C:8]([O:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:13][CH:12]=1)[CH3:18]
Reactant: Br
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CC(=O)O
Agent: C=O
Solvent: O
Product: CC(Br)c1ccc(Oc2ccccc2)cc1
Temperature: 60 °C

Procedure:
Into 100 mL of glacial HOAc was dissolved 34 g (0.2 Mole) of diphenyl ether. To the stirred solution was added 6.78 g (0.22 Mole) paraformaldehyde and 40 mL of 31% solution of HBr in HOAc. The reaction was heated 48 hours at 60° C. and then poured into cold water with stirring. The mixture was extracted with EtOAc and the resulting organic layer was washed with water, dried over Na2SO4, and evaporated under vacuum to give 50 g of crude 1-bromethyl-4-phenoxybenzene as an oil, which was used in the subsequent reaction without additional purification.
Reaction SMILES: [S:1]1(=[O:11])(=[O:10])[C:5]2=[CH:6][S:7][CH:8]=[C:4]2[C:3](=O)[NH:2]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:13].O>N1C=CC=CC=1>[S:1]1(=[O:11])(=[O:10])[C:5]2=[CH:6][S:7][CH:8]=[C:4]2[C:3](=[S:13])[NH:2]1
Reactant: O=C1NS(=O)(=O)c2cscc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: O
Product: O=S1(=O)NC(=S)c2cscc21
Temperature: 80 °C
Reaction time: 0.42 h
Yield: 40 %

Procedure:
To a mixture of 5.6 g (0.03 mole) of thieno[3,4-d]isothiazol-3(2H)-one1,1-dioxide in 50 ml of dry pyridine is added 5.6 g (0.016 mole) of phosphorus pentasulfide portionwise over 3 minutes. The viscous mixture is slowly heated in an oil bath under an atmosphere of nitrogen. The temperature of the oil bath is slowly increased to 80° C. after 30 minutes. The temperature of the oil bath is then kept at 80° C. for 25 minutes, the internal temperature reading 63° C. The solution is cooled to 50° C. and is added dropwise over 5 minutes to 200 ml of water and cooled in an ice bath. The precipitate which forms is collected and discarded. The filtrate is cooled in ice and acidified with concentrated hydrochloric acid to pH 1. The precipitate which forms is collected to yield 40% of material. In another experiment, a sample is recrystallized from water to obtain an analytical sample, m.p. 196°-8° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C@H:5]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[N:6]=[CH:7]2.[CH3:21][Mg]Cl>C(OCC)C>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C@H:5]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[NH:6][C@H:7]2[CH3:21]
Reactant: C[Mg]Cl
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1Cc2c(Br)cccc2C=N1
Solvent: CCOCC
Product: C[C@@H]1N[C@@H](CO[Si](C)(C)C(C)(C)C)Cc2c(Br)cccc21
Temperature: -78 °C
Reaction time: 8 h
Yield: 106.4 %

Procedure:
Dissolve (3R)-5-bromo-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3,4 dihydroisoquinoline (3.4 g, 9.59 mmol) in diethyl ether (160 mL). Cool to −78° C. on a dry ice-acetone bath. Add methylmagnesium chloride (26.9 mL, 80.6 mmol, 3M in THF) dropwise. Warm the reaction mixture slowly to room temperature and stir overnight. Quench with saturated ammonium chloride solution slowly. Extract with dichloromethane and dry over sodium sulfate, filter, and concentrate under reduced pressure. Combine with the crude product from a substantially same reaction run with 1.73 mmol of (3R)-5-bromo-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3,4 dihydroisoquinoline. Purify the combined residues by silica gel chromatography eluting with ethyl acetate: hexanes (5-65% gradient) to give the title compound (3.78 g, 10.2 mmol). MS (m/z): 370 (M+1).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[S:15]([OH:18])(=[O:17])=[O:16].O>ClCCl>[C:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc(Cc2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(O)c1ccc(Cc2ccccc2)cc1

Procedure:
To 33.6 g (0.2 mol) of diphenylmethane in 100 g of dichloromethane at room temperature, 23.4 g (0.2 mol) of chlorosulfonic acid was added dropwise. The solution was ripened for 2 hours, whereupon 50 g of water was added. This reaction mixture was used in the subsequent reaction without isolation.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C@@H:10]3[CH2:12][C@H:11]3[CH2:13][NH:14][C:15](=[O:18])[CH2:16][CH3:17])[C:4]=2[CH2:3][CH2:2]1.[I:19]I>C(O)(=O)C.C(Cl)Cl>[I:19][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[C:9]=1[C@@H:10]1[CH2:12][C@H:11]1[CH2:13][NH:14][C:15](=[O:18])[CH2:16][CH3:17]
Reactant: CCC(=O)NC[C@@H]1C[C@H]1c1cccc2c1CCO2
Reactant: II
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC(=O)NC[C@@H]1C[C@H]1c1c(I)ccc2c1CCO2
Reaction time: 1.5 h
Yield: 26.9 %

Procedure:
To a solution of 0.12 g (0.6 mmol) (trans)-N-[[2-(2,3-dihydrobenzofuran-4-yl)cyclopropyl]methyl]propanamide and 0.27 g (0.6 mmol) of lead IV tetraacetate in 1 mL acetic acid was added 0.075 g (0.25 mmol) iodine. The solution was allowed to stir for 1.5 h and was diluted with methylene chloride. The resulting solution was washed with water and saturated sodium bicarbonate solution and dried. The solution was concentrated in vacuo and the residue purified by chromatography on silica eluting with ethyl acetate-hexane, 3:7 containing 0.2% methanol to give the product (25 mg, 11%, mp 148-149° C.).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[N:11]=1.[CH3:21][O:22][C:23]1[C:26](=O)[C:25](=[O:28])[C:24]=1[O:29]C>CO>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:26]2[C:25](=[O:28])[C:24](=[O:29])[C:23]=2[O:22][CH3:21])[N:11]=1
Reactant: NCCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reactant: COc1c(OC)c(=O)c1=O
Solvent: CO
Product: COc1c(NCCCCCc2csc(NC(N)=NCC(F)(F)F)n2)c(=O)c1=O
Yield: 40.6 %

Procedure:
To 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(5-aminopentyl)thiazole (0.4 g.) in methanol (1.5 ml.) was added 1,2-dimethoxycyclobutene-3,4-dione (0.2 g.). After 2.5 hours at room temperature the mixture was evaporated to dryness, and the residue purified by preparative thin layer chromatography using methanol/chloroform 1:9 v/v as developing solvent. The appropriate band was isolated to give 1-[5-(2-[2-(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)pentylamino]-2-methoxycyclobutene-3,4-dione (0.22 g.) which was dissolved in propargylamine (1 g.) and the mixture allowed to stand at room temperature overnight. The mixture was then evaporated to dryness, and the residue purified by preparative thin layer chromatography using chloroform/methanol/aqueous ammonia 90:10:1 v/v/v as developing solvent. The product from this purification was treated in methanol/acetone with excess maleic acid and the resulting salt precipitated by the addition of diethyl ether to give 1-[5-(2-[2-(2,2,2-trifluoroethyl)guanidino]thiazol-4-yl)pentylamino]-2-propargylaminocyclobutene-3,4-dione hydrogen maleate. The n.m.r. spectrum in d 6 dimethylsulphoxide using tetramethylsilane as internal standard (δ=0) included the following resonances (δ):1.5 (multiplet, 6H); 3.3 (singlet, 1H); 3.5 (multiplet, 2H); 4.1 (quartet, 2H); 4.8 (quartet, 2H); 6.6 (singlet, 1H).
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[OH:7][C:8]1[C:12]2[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=2[O:10][C:9]=1[C:19]([O:21][CH3:22])=[O:20].BrC(C)C>CS(C)=O>[CH3:22][O:21][C:19]([C:9]1[O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[C:8]=1[O:7][CH:2]([CH3:3])[CH3:1])=[O:20]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1oc2ccc(OC)cc2c1O
Agent: [K+]
Solvent: CC(C)Br
Solvent: CS(C)=O
Product: COC(=O)c1oc2ccc(OC)cc2c1OC(C)C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 46 %

Procedure:
A solution of 12.3g (0.11 mole) of potassium tert-butoxide in 100 ml of dimethyl sulfoxide (under a nitrogen atmosphere) is cooled in a cold water bath and treated dropwise with a solution of 16.6 g (0.075 mole) of 3-hydroxy-5-methoxy-2-benzofuran carboxylic acid, methyl ester. The mixture is stirred for 45 minutes after completion of the addition, and 7.0 ml (9.2 g; 0.075 mole) of 2-bromopropane is added in one portion. After stirring for 24 hours at room temperature, the reaction mixture is added to 1.5 kg of ice/water and stirred an additional hour. The precipitated product is filtered and washed with water. The crude yield is 9.0 g (46% yield). A sample recrystallized from aqueous methanol yields analytically pure 5-methoxy-3-(1-methylethoxy)-2-benzofurancarboxylic acid methyl ester, mp 66°-68° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](Br)=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[CH:7]2>CO.C(O)(=O)C.C(Cl)Cl.[Pd]>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[CH:7]2
Reactant: Cn1ccc2c(Br)ccc(N)c2c1=O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cn1ccc2cccc(N)c2c1=O
Reaction time: 24 h
Yield: 23 %

Procedure:
A solution of 8-amino-5-bromo-2-methylisoquinolin-1(2H)-one (Compound 123A, 2.83 g, 10.0 mmol) in a mixture of methanol (120 mL) and acetic acid (5 mL) was hydrogenated over 5% Pd/C (500 mg) under pressure for 24 h. Another batch of 5% Pd/C (400 mg) was added to the reaction mixture and the hydrogenation was continued for a further 24 h. TLC (5% MeOH in CH2Cl2) showed the reaction was complete. The catalyst was filtered off and the filtrate was evaporated to dryness to give a residue, which was purified by column chromatography on silica gel (5% MeOH in CH2Cl2) to afford the title compound as a solid (0.40 g, 23%). 1H NMR (CDCl3, 300 MHz): δ=3.50 (s, 3H), 6.32 (d, J=7.5 Hz, 1H), 6.48 (br, 2H), 6.54 (d, J=7.8 Hz, 1H), 6.67 (d, J=7.8 Hz, 1H), 6.91 (d, J=7.5 Hz, 1H), 7.29 (d, J=7.8 Hz, 1H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][NH:12][C:13](=[O:33])[C:14]1[CH:19]=[C:18]([CH:20]=[O:21])[C:17]([F:22])=[C:16]([F:23])[C:15]=1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=1[F:32])(C(C)(C)C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.O>[F:23][C:16]1[C:15]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[C:14]([CH:19]=[C:18]([CH:20]=[O:21])[C:17]=1[F:22])[C:13]([NH:12][O:11][CH2:10][CH2:9][OH:8])=[O:33]
Reactant: CC(C)(C)[Si](C)(C)OCCONC(=O)c1cc(C=O)c(F)c(F)c1Nc1ccc(I)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 72 %

Procedure:
N-[2-(Tert-butyldimethylsilanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-5-formyl-benzamide (37.1 g as a crude product containing the desilylated product) prepared in Step E was dissolved in a mixed solvent of tetrahydrofuran (200 ml) and water (16 ml). To this solution, p-toluenesulfonic acid monohydrate (1.76 g, 9.25 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and evaporated under reduced pressure. The resultant residue was triturated with ethyl acetate to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide (16.0 g, 72% yield in two steps) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[O:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH3:19])[CH:13]=2)=[CH:10][CH:9]=[CH:8][N:7]=1.[F:24][C:25]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:26]=1[C:27](Cl)=[O:28].C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:23][C:22]1[CH:21]=[CH:20][C:4]([O:5][C:6]2[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH3:19])[CH:13]=3)=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:3][C:2]=1[NH:1][C:27](=[O:28])[C:26]1[CH:30]=[C:31]([C:34]([F:35])([F:36])[F:37])[CH:32]=[CH:33][C:25]=1[F:24]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Reactant: CNc1cc(-c2cccnc2Oc2ccc(Cl)c(N)c2)ccn1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CNc1cc(-c2cccnc2Oc2ccc(Cl)c(NC(=O)c3cc(C(F)(F)F)ccc3F)c2)ccn1
Temperature: 75 °C
Reaction time: 48 h

Procedure:
In a sealed tube, [2-(3-Amino-4-chloro-phenoxy)-[3,4′]bipyridinyl-2′-yl]-methyl-amine (300 mg, 0.918 mmol) and 2-Fluoro-5-trifluoromethyl-benzoyl chloride (0.180 mL, 1.19 mmol) were dissolved in 2.0 mL chloroform. The solution was heated to 75° C. and stirred for 48 h. The reaction was then cooled to RT, quenched with triethylamine (0.128 mL, 0.918 mmol), and concentrated in vacuo to yield the title compound as a crude light yellow solid. MS m/z (M+H)+=517; Calc'd 516.87 for C25H17ClF4N4O2.
Reaction SMILES: [C:1]1([CH:7]([CH3:10])[CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11](O)[CH:12]=[CH2:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1C=CC=CC=1.O>[CH3:10][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:13][CH:12]=[CH2:11])[CH:8]=[O:9]
Reactant: C=CCO
Reactant: CC(C=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: C=CCC(C)(C=O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 2-phenylpropionaldehyde (9.90 mL, 74.5 mmol), allyl alcohol (20.4 mL, 300 mmol) and p-toluene sulfonic acid (0.8560 g, 4.5 mmol) in benzene (37 mL) was heated to reflux for 19 hours and a Dean-Stark trap was used to collect the water formed. The mixture was cooled to room temperature and saturated aqueous NaHCO3 (5 mL) and H2O (5 mL) were added. The phases were separated and the organic layer was washed a second time with saturated aqueous NaHCO3 (5 mL) and H2O (5 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. A solution of the resultant yellow residue in p-xylene (150 mL) was heated to reflux for 24 hours. The solution was cooled to room temperature and concentrated under reduced pressure. The resultant aldehyde (13.0 g) was used in the next reaction without further purification.
Reaction SMILES: N[CH2:2]CNCCN.[C:8](O)(=O)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[OH2:18]>>[CH3:2][O:18][C:10]1[CH:9]=[CH:8][C:13]([OH:15])=[CH:12][CH:11]=1.[C:13]([OH:15])(=[O:14])[C:12]([CH3:2])=[CH2:11]
Reactant: O=C(O)CCCCC(=O)O
Reactant: O
Reactant: NCCNCCN
Product: C=C(C)C(=O)O
Product: COc1ccc(O)cc1
Temperature: 150 °C
Reaction time: 20 h

Procedure:
A cylindrical reaction vessel equipped with a thermometer, stirrer, water separator and cooling pipe (condenser) was charged with 6,000 parts of diethylenetriamine, 7,309 parts of adipic acid, and the mixture was stirred and blended in a nitrogen atmosphere. The cock portion of the water separator was charged with 2 parts of methoquinone as an antigelling agent. The reaction vessel had an outside diameter of 30 cm (heated on an oil bath), a height of 50 cm and a capacity (A) of 0.03 m3 and had a structure such that a connecting pipe having an inside diameter of about 2 cm could be connected thereto at a site 10 cm distant from the central axis of the reaction vessel. The condenser used was a commercially available glass-made Dimroth condenser (condenser pipe length 40 cm; product of Shibata Kagaku Kikai Kogyo). The byproduct water separator and connecting pipe used was a commercially available volumetric water receptacle (capacity 25 ml, equipped with a cock; product of Shibata Kagaku Kikai Kogyo). With this water separator, when the cock is closed, the amount of the byproduct water can be read from marked lines provided on the side glass face, so that it functions also as a level gauge. Thus, the amount of the byproduct water can be checked by reading the marked line indicating the liquid level and, upon arrival of the level at the maximum value-indicating marked line, the byproduct water can be discharged out of the system by turning on the bottom cock; thereafter, the amount of the byproduct water newly formed can be read. The reaction mixture was heated to 150° C. and the reaction was conducted for 20 hours while removing the byproduct water formed by the polycondensation, to give 11,332 parts of a polycondensate (the byproduct water amounting to 1,977 parts) Then, 17 parts of hydroquinone methyl ether and 701 parts of methacrylic acid were charged into the vessel and the amidation reaction was carried out at a reaction temperature of 150° C. As a result of 10 hours of amidation reaction, 160 parts of byproduct water was separated in the byproduct water separator to give 11,890 parts of an amidation product (M9), namely a polyamide polyamine. During the reaction, methacrylic acid contained in the byproduct water would not gelate but the cock could be turned on from time to time to discharge the water; the amount of the byproduct water thus could be monitored.