Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[C:37]1(CO)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCc4ccccc4)c(C)c3C)c2cc1OC
Yield: 84.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, phenylmethanol (51 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (120 mg, yield 78%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:10]=1[C:16](=[O:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24](=[O:31])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29]I)([CH3:22])([CH3:21])[CH3:20].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:19]([O:23][C:24](=[O:31])[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][O:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]=1[C:16](=[O:18])[CH3:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(=O)c1c(O)cccc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1c(OCCCCNC(=O)OC(C)(C)C)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(2-benzyloxy-6-hydroxyphenyl)-ethanone (100 mg, 0.41 mmol) and (4-iodobutyl)-carbamic acid tert-butyl ester (Example 123, step A) (150 mg, 0.5 mmol) in DMF (5 mL) is added K2CO3 (113 mg, 0.82 mmol) and the mixture is stirred at RT for 18 h. Water is added and the mixture is extracted with EtOAc. The organic phase is washed with water and brine then is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using hexane/EtOAc (10:1) as eluent to give the title compound as a white solid.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][OH:13])=[CH:9][C:8]([O:14][CH3:15])=[CH:7][CH:6]=2.C(OCC)(=O)C>CC(C)=O.[O-2].[O-2].[Mn+4]>[SH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]=[O:13])=[CH:9][C:8]([O:14][CH3:15])=[CH:7][CH:6]=2
Reactant: COc1ccc2ncc(S)c(CO)c2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc2ncc(S)c(C=O)c2c1

Procedure:
Manganese dioxide (1.38 g, 15.89 mmol) is added at room temperature to a stirred solution of (3-mercapto-6-methoxy-quinoline-4-yl)-methanol and its corresponding dimer (500 mg) in acetone (30 mL) and the resulting suspension is heated under reflux for 8 hours. The reaction mixture is then filtered through decalite and the filtrate is concentrated to give a residue that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 2:1, v/v) to afford 3-mercapto-6-methoxy-quinoline-4-carbaldehyde and its corresponding dimer as a yellow solid (64 mg, 13% yield).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:33]([F:36])([F:35])[F:34])[C:25]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:26][C:17]=4[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.S(Cl)(Cl)=O.[Cl-].[CH3:42][O-].[Na+]>C(Cl)Cl.CO>[CH3:42][O:1][CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:33]([F:35])([F:36])[F:34])[C:25]([O:27][CH2:28][C:29]([F:30])([F:31])[F:32])=[CH:26][C:17]=4[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1
Reactant: C[O-]
Reactant: O=C1CC(c2cccc(-c3ccnc(CO)c3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COCc1cc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from 4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-(2,2,2-trifluoro-ethoxy)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 286) (255 mg, 0.50 mmol) by reaction with thionylchloride in CH2Cl2 and subsequent treatment of the corresponding crude chloride with sodium methanolate (5.4M, 1 ml) in MeOH (5 ml)/CH2Cl2 (5 ml) according to the general procedure of Example 288. Obtained as an off-white solid (94 mg, 36%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][NH:25]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[CH2:23][CH2:24][N:25]2[C:16](=[O:18])[CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=1
Reactant: Fc1cccc2c1CCN2
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)N2CCc3c(F)cccc32)nc(N2CCOCC2)cc1=O
Yield: 27.4 %

Procedure:
The product is prepared according to the procedure described in example 68, using 275 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 274 mg of 4-fluoroindoline and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 161 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 102 mg of 2-[2-(4-fluoro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pale pink powder, the characteristics of which are the following:
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].NCP(=O)(O)O.C(O)(=[O:16])C(C)C.[OH-].[Na+].[C:20]([O-:24])(=[O:23])[CH2:21][OH:22]>>[C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[C:21]([OH:16])(=[O:22])[C:20]([OH:24])=[O:23]
Reactant: O=C([O-])CO
Reactant: O=C(O)CO
Reactant: CC(C)C(=O)O
Agent: NCP(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(=O)O
Product: O=CC(=O)O
Temperature: 5 °C
Reaction time: 11.5 h

Procedure:
A 300-mL EZE-Seal stirred autoclave reactor (Autoclave Engineers) was charged with 100 mL of a solution containing glycolic acid (0.500M), aminomethylphosphonic acid (0.375M), isobutyric acid (0.100M, HPLC internal standard), and flavin mononucleotide (0.01 mM) at pH 8.3 (adjusted with 50% NaOH), and the solution cooled to 5° C. Frozen (-80° C.) Aspergillus nidulans FT17SYCSL/OL (26 g, 124 IU glycolate oxidase and 57,800 IU catalase) were allowed to thaw at 5° C., then washed with 2×100 mL of KH2PO4 (50 mM, pH 7.0)/FMN (0.01 mM) buffer at 5° C. and the washed cells added to the reactor with 1.4×106 units of Aspergillus niger soluble catalase (Sigma). The pH of the resulting mixture was re-adjusted to 8.3 with 50% NaOH, then stirred at 400 rpm and 5° C. under 120 psig of oxygen while bubbling oxygen through the mixture at 50 mL/min. After 11.5 hours, the yields of glyoxylic acid, oxalic acid, and formic acid were 94%, 3.5%, and 2.7%, respectively, with 1.3% recovery of glycolic acid. The final activities of glycolate oxidase and Aspergillus niger catalase were 7% and 77% of their initial values.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2].[Cl:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]#[C:26][C:27](O)=[O:28]>ClCCl.CO>[CH2:1]([N:3]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:27](=[O:28])[C:26]#[C:25][C:16]2[CH:17]=[CH:18][C:19]([C:21]([F:23])([F:22])[F:24])=[CH:20][C:15]=2[Cl:14])=[CH:11][CH:12]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)Cc1ccc(N)cc1
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)Cc1ccc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)cc1

Procedure:
Prepared analogously to Example 2.3.f. from 4-diethylaminomethylphenylamine and (2-chloro-4-trifluoromethylphenyl)propynoic acid. Yield: 72 mg (59% of theory); C21H20ClF3N2O (M=408.85); calc.: molecular ion peak (M+H)+: 409/411; found: molecular ion peak (M+H)+: 409/411; Rf value: 0.35 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[I:30][C:31]1[CH:32]=[C:33]([OH:41])[CH:34]=[C:35]([S:37]([CH3:40])(=[O:39])=[O:38])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CC(C)=O.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:41][C:33]2[CH:34]=[C:35]([S:37]([CH3:40])(=[O:39])=[O:38])[CH:36]=[C:31]([I:30])[CH:32]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: CS(=O)(=O)c1cc(O)cc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Temperature: 70 °C
Yield: 97.4 %

Procedure:
To a solution of 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (3.79 g, 8.05 mmol), 3-iodo-5-methanesulfonyl-phenol (2.0 g, 6.71 mmol) in dimethylformamide (40 mL) and acetone (80 mL) was added potassium carbonate (9.25 g, 67.1 mmol). The resulting suspension was heated at 70° C. for 24 h. Then, the reaction mixture was cooled to room temperature, diluted with EtOAc and washed with 10% HCl and water. Then, the combined organic extracts were washed with brine. The organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which was purified by using an ISCO 120 g column. The desired compound was eluted with 40% EtOAc-Hexanes. The desired fractions were combined and evaporated under reduced pressure to afford 4.5 g (97%) of title compound as a colorless oil. HR-ES(+) m/e calcd for C30H41O8SI (M+Na)+ 711.1459, found 711.1465.
Reaction SMILES: O1CCCC1.[S:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([S:22][CH2:23][C:24]([F:27])([F:26])[F:25])[CH:16]=1)C#N.[F:28][C:29]([Si](C)(C)C)([F:31])[F:30].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>C(OCC)(=O)C.CCCCCC>[F:28][C:29]([F:31])([F:30])[S:6][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([S:22][CH2:23][C:24]([F:27])([F:25])[F:26])[CH:16]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1ccc(OCCCCCSC#N)cc1SCC(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(OCCCCCSC(F)(F)F)cc1SCC(F)(F)F
Reaction time: 1 h
Yield: 77 %

Procedure:
To 100 ml of tetrahydrofuran were added 1.5 g (4.3 mmol) of 5-thiocyanatopentyl-{4-methyl-3-(2,2,2-trifluoroethylthio)phenyl}ether and 1.8 g (13 mmol) of trifluoromethyltrimethylsilane. Thereto was added, at 0° C., 5 ml (5.0 mmol) of a tetra-n-butylammonium fluoride-tetrahydrofuran (1 mol/liter) solution. A reaction was carried out for 1 hour. After confirmation of the completion of the reaction, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane:ethyl acetate=10:1), to obtain 1.3 g (yield: 77%) of an intended product.
Reaction SMILES: Br[CH2:2]C1C=CC(F)=CC=1.Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19].[O:20]=[C:21]1[NH:25][CH2:24][CH2:23][N:22]1[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][N:34]=1)[C:29]([O-:31])=[O:30]>>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[CH2:11][N:25]1[CH2:24][CH2:23][N:22]([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][N:34]=2)[C:29]([O:31][CH3:2])=[O:30])[C:21]1=[O:20]
Reactant: O=C([O-])c1ccnc(N2CCNC2=O)c1
Reactant: Fc1ccc(CBr)cc1
Reactant: Fc1ccc(CBr)c(F)c1
Product: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3F)C2=O)c1
Yield: 64 %

Procedure:
Following the procedure as described in Preparation 17, making variations as required to replace 1-(bromomethyl)-4-fluorobenzene with 1-(bromomethyl)-2,4-difluorobenzene to react with 2-(2-oxoimidazolidin-1-yl)isonicotinate, methyl 2-(3-(2,4-difluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate was obtained as a colorless solid in 64% yield: 1H NMR (300 MHz, CDCl3) δ 8.85 (s, 1H), 8.36 (d, J=5.1 Hz, 1H), 7.46-7.31 (m, 2H), 6.89-6.79 (m, 2H), 4.51 (s, 2H), 4.04 (t, J=8.1 Hz, 2H), 3.92 (s, 3H), 3.44 (t, J=8.1 Hz, 2H); MS (ES+) m/z 347.9 (M+1).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([NH2:7])[C:4]([Cl:8])=[CH:3][CH:2]=1.[O-:9][C:10]#[N:11].[K+]>O.C(O)(=O)C>[Cl:8][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[NH:7][C:10]([NH2:11])=[O:9]
Reactant: Nc1ccccc1Cl
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1ccccc1Cl
Temperature: 15 °C
Yield: 70.4 %

Procedure:
O-chloroaniline (50 g) was added in water (400 g) and acetic acid (200 g), followed by cooling to 15° C. Then, a solution of potassium cyanate (63.6 g) and water (300 g) was added dropwise at not more than 15° C. over 40 minutes. The mixture was heated to 30° C., filtered and then washed with cold water to obtain a white crystal. This crystal was recrystallized from a solution of ethanol (350 g) and water (100 g) to obtain 47.1 g of o-chlorophenylurea as a white needle crystal.
Reaction SMILES: Cl[C:2]1([CH2:9][CH:10](O)[CH2:11][CH3:12])[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH2:3]1.C1(C)C=CC=CC=1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.[OH-:26].[Na+]>O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:9][CH2:10][CH:11]([OH:26])[CH2:12][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)=[CH:3][CH:4]=1
Reactant: CCC(O)CC1(Cl)C=CC(Cl)=CC1
Reactant: c1c[nH]cn1
Reactant: [OH-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: OC(CCc1ccc(Cl)cc1)Cn1ccnc1
Temperature: 94 °C
Reaction time: 1 h

Procedure:
To a solution of 56.7 g (0.26 mol) of 1-chloro-4-chlorophenyl-2-butanol (J. of Medicinal Chemistry, 1978. Vol. 21. No. 8. p. 842) in 200 ml of toluene 36.2 g (0.9 mol) of sodium hydroxide dissolved in 100 ml of water, 6.4 g (0.028 mol) of benzyltriethyammonium chloride and 35.2 g (0.51 mol) of imidazole (III) are added. The reaction mixture is heated at 93-95° C. for one hour then the temperature is returned to about 60° C., the phases are separated and to the organic layer water (100 ml) is added. The mixture is first stirred at 22-25° C. for 1 hour then at 0-5° C. for two hours. The crystals are separated by filtration, washed with water (2×35 ml) of 0-5° C. to yield 74 g of wet (1-[4-(4-chlorophenyl)-2-hydroxy-n-butyl]-imidazole) which is dried at maximum 50° C. in vacuo to give 61.6 g (95%) of the product. Recrystallization from ethyl acetate gives 52.4 g (85%) of dry product melting at 104-106° C.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:13][N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20].C(N(CC)CC)C>O1CCCC1>[C:1]([O:13][N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)ON1C(=O)CCC1=O
Reaction time: 15 h
Yield: 70.1 %

Procedure:
A solution of decanoyl chloride (5.0 g) in tetrahydrofuran (20 ml) was dropwise added to a mixture of N-hydroxysuccinimide (3.06 g) and triethylamine (3.7 ml) in tetrahydrofuran (30 ml) with stirring under ice-cooling. The mixture was stirred at the same temperature for one hour and then at ambient temperature for 15 hours. A precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 ml). The solution was washed with water (50 ml), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to give N-decanoyloxysuccinimide as a crystal (4.95 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:48][C:49]1[S:50][C:51]2[CH:57]=[C:56]([O:58][S:59]([C:62]3[CH:67]=[CH:66][C:65]([NH:68][CH2:69][CH2:70][N:71]([CH:75]([CH3:77])[CH3:76])[CH:72]([CH3:74])[CH3:73])=[CH:64][CH:63]=3)(=[O:61])=[O:60])[CH:55]=[CH:54][C:52]=2[N:53]=1>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([C:12](=[O:14])[NH:48][C:49]2[S:50][C:51]3[CH:57]=[C:56]([O:58][S:59]([C:62]4[CH:67]=[CH:66][C:65]([NH:68][CH2:69][CH2:70][N:71]([CH:75]([CH3:77])[CH3:76])[CH:72]([CH3:73])[CH3:74])=[CH:64][CH:63]=4)(=[O:61])=[O:60])[CH:55]=[CH:54][C:52]=3[N:53]=2)[CH2:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: CC(C)N(CCNc1ccc(S(=O)(=O)Oc2ccc3nc(N)sc3c2)cc1)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(CCNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)C4CN(C(=O)OC(C)(C)C)C4)sc3c2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 27.4 %

Procedure:
68 mg of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester, 256 mg of HBTU and 235 μl of DIEA are added to a solution of 4-(2-diisopropylamino-ethylamino)benzenesulfonic acid 2-aminobenzothiazol-6-yl ester (inter-mediate 34) (100 mg, 0.225 mmol) in 5 ml of dimethylformamide. The solution obtained is stirred for 20 hours at room temperature. After addition of 50 ml of water, the reaction medium is extracted with 3 times 25 ml of ethyl acetate. The extracts are dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 700 mg of crude oil. This oil is purified by elution in a 95/5 dichloromethane/methanol mixture at a flow rate of 10 ml/minute, on 20 g of silica, to give 39 mg of 3-{6-[4-(2-diisopropylaminoethylamino)-benzenesulfonyloxy]benzothiazol-2-ylcarbamoyl}azetidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.O(CCCCCCCBr)C1C=CC=CC=1>>[C:1]1([S:7][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][Br:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCCCBr
Reactant: Sc1ccccc1
Agent: BrCCCCCCCOc1ccccc1
Product: BrCCCCCCCSc1ccccc1
Yield: 46 %

Procedure:
7-Phenylthioheptyl bromide was prepared from thiophenol (4.40 g, 40 mmol) and 1,7-dibromoheptane (10.32 g, 40 mmol) as described above for 7-phenoxyheptyl bromide. Yield: 46% bp; 132°-136° C./0.05 torr; 1H-NMR: 1.30-1.85 (m, 10H), 2.90 (t, 2H), 3.35 (t, 2H), 7.25 (s, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=O)=[CH:16]1.CO>C(O)(=O)C>[CH3:13][C:5]1([CH3:14])[C:4]2[C:8](=[CH:9][C:10]3[NH:11][C:24]([C:17]4[C:18]5[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=5)[NH:15][CH:16]=4)=[N:1][C:2]=3[CH:3]=2)[NH:7][C:6]1=[O:12]
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Solvent: CO
Solvent: CC(=O)O
Product: CC1(C)C(=O)Nc2cc3[nH]c(-c4c[nH]c5ccccc45)nc3cc21

Procedure:
3.1 g. 5,6-Diamino-3,3-dimethylindolin-2-one and 2.5 g. indole-3-aldehyde are stirred for 4 days at ambient temperature in 150 ml. methanol and 4 ml. glacial acetic acid. The solvent is then removed in a vacuum and the residue is purified by column chromatography on silica gel. The appropriate fractions are combined, the solvent is removed in a vacuum, the residue (3.7 g. of a yellow oil) is dissolved in methanol, dichloromethane added thereto until turbidity commences and then left to crystallise. There are obtained 3.1 g. of the title compound; m.p. 243°-245° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[C:10]([CH:24]=O)[N:9]=2)[CH:7]=1.[CH3:27][NH:28][CH3:29].O1CCCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH3:27][N:28]([CH2:24][C:10]1[N:9]=[C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[CH3:26])[CH:17]=[C:16]2[C:11]=1[CH:12]=[C:13]([NH:18][C:19]([CH:21]1[CH2:22][CH2:23]1)=[O:20])[N:14]=[CH:15]2)[CH3:29]
Reactant: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(C=O)n1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(F)cc1-c1cc2cnc(NC(=O)C3CC3)cc2c(CN(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a slurry of N-(7-(5-fluoro-2-methylphenyl)-5-formyl-2,6-naphthyridin-3-yl)cyclopropanecarboxamide (30 mg, 0.08 mmol) in methylene chloride (0.5 mL) was added a 2.0M solution of dimethylamine in tetrahyrdofuran (0.052 mL, 0.1 mmol) and the reaction mixture was stirred at room temperature. After 1 hour, sodium triacetoxyborohydride (27 mg, 0.13 mmol) was added, and the reaction mixture was stirred for another 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% ammonium hydroxide over 14 min) to afford the title compound as a pale yellow solid (22 mg, 70%). 1H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 9.28 (s, 1H), 8.96 (s, 1H), 8.03 (s, 1H), 7.41-7.28 (m, 2H), 7.18 (td, J=8.5, 2.8 Hz, 1H), 3.92 (s, 2H), 2.36 (s, 3H), 2.25 (s, 6H), 2.14-2.07 (m, 1H), 0.87 (m, 4H). LCMS (Method E): RT=3.929 min, M+H+=379.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][C:13]([C:17](Cl)=[O:18])=[C:14]([CH3:16])[N:15]=3)[S:10][C:3]=12.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][C:13]([C:17]([N:24]4[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]4)=[O:18])=[C:14]([CH3:16])[N:15]=3)[S:10][C:3]=12
Reactant: CN1CCNCC1
Reactant: Cc1nc(-c2cc3nccc(Cl)c3s2)sc1C(=O)Cl
Solvent: ClCCl
Product: Cc1nc(-c2cc3nccc(Cl)c3s2)sc1C(=O)N1CCN(C)CC1
Yield: 70.1 %

Procedure:
A solution of 2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazole-5-carbonyl chloride, (0.28 g, 0.85 mmol), dry dichloromethane (1.5 mL), and 1-methylpiperazine (0.21 mL, 1.87 mmol) was stirred at room temperature for four hours. A gas discharge and immediate solution were noted. The reaction mixture was evaporated directly onto silica gel and purified through silica gel chromatography to afford [2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazol-5-yl]-(4-methyl-piperazin-1-yl)-methanone (0.234 g) in 70% yield. C17H17ClN4OS2: APCI 393.2/395.2 (pos.); 1H NMR (d6-DMSO): δ 8.68 (d, 1H, J=5.4 Hz), 8.32 (s, 1H), 7.64 (d, 1H, J=5.4 Hz), 3.6–3.4 (bm, 4H), 2.38 (s, 3H), 2.4–2.2 (bm, 4H), 2.17 (s, 3H) ppm.