Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cncc2c(COc3cccc(N)c3)csc12
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccccc4)c3)csc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(3-amino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (25.6 mg, 0.078 mmol) (from Example 3 supra) in THF (2 mL) were added diisopropylethyl-amine (22 mg, 0.170 mmol) (Aldrich) and then benzoyl chloride (12.5 mg, 0.085 mmol) (Aldrich). The reaction was stirred at room temperature for 30 minutes before it was concentrated to remove the solvent. The residue was diluted with EtOAc (40 mL), washed with aqueous 1N NaOH (10 mL), brine (2×10 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (hexanes/EtOAc, 60/40) to give 3-(3-benzoylamino-phenoxy-methyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield 26.0 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.O[C@H:31]1[CH2:35][CH2:34][CH2:33][C@H:32]1[C:36]([O:38][CH2:39][CH3:40])=[O:37]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([C@@H:31]5[CH2:35][CH2:34][CH2:33][C@H:32]5[C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1O
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CCOC(=O)[C@@H]1CCC[C@H]1N1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
Ethyl (1R,2R)-2-[(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]cyclopentanecarboxylate was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and ethyl (1R,2S)-2-hydroxycyclopentanecarboxylate following General Procedure J.
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:17][CH:16]3[CH:12]2[CH2:13][N:14]([C:18](=[O:29])[NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[CH2:15]3)=[CH:7][CH:6]=1)C.[OH-].[Na+]>CO.O1CCCC1>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[CH2:20][NH:19][C:18]([N:14]1[CH2:13][CH:12]2[CH:16]([CH2:17][N:11]2[C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:30])=[O:3])=[CH:6][CH:7]=2)[CH2:15]1)=[O:29]
Reactant: CCOC(=O)c1ccc(N2CC3CN(C(=O)NCc4ccc(Cl)cc4Cl)CC32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(N2CC3CN(C(=O)NCc4ccc(Cl)cc4Cl)CC32)cc1
Temperature: 60 °C
Yield: 58 %

Procedure:
To a solution of rac-4-[3-(2,4-Dichloro-benzylcarbamoyl)-3,6-diaza-bicyclo[3.2.0]hept-6-yl]-benzoic acid ethyl ester (55 mg, 123 μmol) in methanol (2 mL) and tetrahydrofuran (2 mL) was added aqueous sodium hydroxide (1 M, 2 mL) and the reaction mixture was heated to 60° C. for 1 h. The solvents were partly removed by concentration in vacuo, tetrahydrofuran (2 mL) was added and filtration afforded the title compound (30 mg, 58%) as a white solid. MS (EI) m/e: 420.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11](F)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:19]([O:23][C:24](=[O:25])[NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:11]2[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:14]=[CH:13][C:12]=2[N+:15]([O-:17])=[O:16])[CH:29]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCc1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(OCc3ccccc3)ccc2[N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 95.6 %

Procedure:
A mixture of 4-benzyloxy-2-fluoronitrobenzene (6.43 g, 26 mmols), N-tert-butoxycarbonyl-3-hydroxybenzylamine (5.78 g, 26 mmols), potassium carbonate (3.59 g, 26 mmols) and N,N-dimethylformamide (70 ml) was stirred at 100° C. for 12 hours. The reaction mixture was cooled, then poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate, and the solvent was evaporated away to give an yellow oil of tert-butyl[3-(5-benzyloxy-2-nitrophenoxy)benzyl]carbamate (11.2 g, 95.0%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[OH:16][C:17]1[CH:18]=[C:19]([CH:30]=[C:31]([OH:33])[CH:32]=1)[C:20]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Cl)=[O:21]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:16][C:17]1[CH:18]=[C:19]([CH:30]=[C:31]([OH:33])[CH:32]=1)[C:20]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:8][C:7](=[O:9])[C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=1)=[O:21]
Reactant: O=C(OCCCCCCCl)c1cc(O)cc(O)c1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: O=C(OCCCCCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)c1cc(O)cc(O)c1
Temperature: 84 °C
Yield: 62.6 %

Procedure:
1.960 g (9.2 mmol) 3,5-dinitrobenzoic acid was suspended in 10 ml N,N-dimethylformamide. 1.407 g (9.2 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5) (DBU) were added dropwise over a period of 10 minutes, and 0.708 g (1.9 mmol) tetrabutylammonium iodide were added. A solution of 2.3 g (8.2 mmol) 6-chlorohexyl 3,5-dihydroxybenzoate and 15 ml N,N-dimethylformamide were added and the resulting mixture was then heated to 84° C. for 22 hours. The reaction mixture was cooled and then partitioned between ethyl acetate and water. The organic phase was washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 110 g silica gel using first cyclohexane:ethyl acetate (7:3) then (3:2) as eluant yielded 2.3 g (56%) of 6-[(3,5-dinitrobenzoyl)oxy]hexyl 3,5-dihydroxybenzoate as yellow crystals.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:18][N:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:31][C:32]1[CH:37]=[CH:36][C:35](I)=[CH:34][N:33]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:31][C:32]1[N:33]=[CH:34][C:35]([C:19]2[CH:18]=[N:17][C:16]([C:8]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)=[CH:21][CH:20]=2)=[CH:36][CH:37]=1
Reactant: Brc1ccc(I)cn1
Reactant: CC1(C)OB(c2ccc(-c3nc4ccccc4n3-c3ccccc3)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Brc1ccc(-c2ccc(-c3nc4ccccc4n3-c3ccccc3)nc2)cn1
Temperature: 80 °C
Yield: 61 %

Procedure:
A mixture of 1-phenyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-1H-benzo[d]imidazole (3 mmol), 2-bromo-5-iodopyridine (1.98 g, 7 mmol) (Compound 10), Pd(PPh3)4 (0.346 g, 0.3 mmol) and potassium carbonate (0.828 g, 6 mmol) in dioxane/water (50 mL/10 mL) was degassed and heated at about 80° C. overnight. The mixture was poured into ethyl acetate (250 mL), washed with water, then brine, dried over Na2SO4, loaded on silica gel and purified by flash column (hexanes/dichloromethane 1:1 to dichloromethane to dichloromethane/ethyl acetate 9:1 to 4:1). The desired fraction was collected and concentrated, then filtered to give a light yellow solid (Compound 11) (0.78 g, in 61% yield).
Reaction SMILES: [CH2:1]=[C:2]([CH2:5][CH2:6][CH3:7])[CH:3]=[O:4].[CH2:8]([O:10][C:11](=[O:15])[CH2:12][N+:13]#[C-:14])[CH3:9]>>[CH2:8]([O:10][C:11]([CH:12]1[CH:3]([C:2]([CH2:5][CH2:6][CH3:7])=[CH2:1])[O:4][CH:14]=[N:13]1)=[O:15])[CH3:9]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: C=C(C=O)CCC
Product: C=C(CCC)C1OC=NC1C(=O)OCC

Procedure:
The starting material is manufactured as follows: Reaction of 2-methylene-pentanal with isocyanoacetic acid ethyl ester analogously to Example 1 yields 5-(penten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester. By hydrolysis of the 5-(penten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester in a manner analogous to that described in Example 15, 2-formylamino-3-hydroxy-4-propyl-4-pentenoic acid ethyl ester is obtained.Reaction of the 2-formylamino-3-hydroxy-4-propyl-4-pentenoic acid ethyl ester with thionyl bromide and subsequent treatment with trimethyl phosphite in a manner analogous to that described in Example 1 yields E-2-formylamino-4-propyl-5-dimethylphosphono-3-pentenoic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)=[CH:8][CH:7]=1)[CH:2]=[CH2:3].O.[NH2:21][NH2:22]>CO>[CH2:1]([O:4][CH2:5][C:6]1[CH:19]=[CH:18][C:9]([C:10](=[N:21][NH2:22])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH:2]=[CH2:3]
Reactant: NN
Reactant: C=CCOCc1ccc(C(=O)c2ccccc2)cc1
Solvent: CO
Solvent: O
Product: C=CCOCc1ccc(C(=NN)c2ccccc2)cc1
Yield: 20.7 %

Procedure:
To solution of 9 (1.09 g, 43 mmol) in methanol (10 ml) was added hydrazine hydrate (1.08 g 20 mmol). The mixture was heated to reflux for 48 h. then concentrated in vacuo. The residue was partioned between DCM and water and the organic layer collected and concentrated to yield 10 (1.10 g, 98%) as a mixture of cis and trans isomers and as a yellow oil; δH (CDCl3) 4.03, 4.13 (2×dt, 2H, J=1.4, 5.6 Hz, OCH2CH═CH2) 4.52, 4.60 (2×s, 2H, ArCH2O), 5.20, 5.27 (ddd, 1H, J=1.4, 3.0, 10.4 Hz, OCH2CH═CHH), 5.32, 5.37 (ddd, 1H, J=1.4, 3.2, 17.3 Hz, OCH2CH═CHH), 5.45 (bs, 2H, NNH2), 5.91-6.06 (m, 1H, OCH2CH═CH2), 7.28-7.31 (m, 4H, 3-, 3′-, 5-, 5′-H), 7.46-7.55 (m, 5H, 2-, 2′-, 4′-, 6-, 6′-H) ppm; δC (CDCl3) 60.1, 71.5, 71.7 (ArCH2O, OCH2CH═CH2), 117.0, 117.3 (OCH2CH═CH2), 126.3, 126.4, 127.4, 128.0, 128.5, 128.7, 129.3 (Ar—C), 134.4, 134.6 (2×OCH2CH═CH2), 137.7, 138.1, 139.1 (Ar—C), 148.7 (C═N) ppm; νmax (thin film) 3404, 3289, 3057, 2855, 1612, 1444, 1411, 1277, 1083 cm−1; m/z (ES+) 267 ([M+H]+, 100%); found (EST+) 267.1492, C17H19N2O requires 267.1492.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:24])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH:11]=3)[S:7][C:6]=2[C:22]=1[F:23].CCOCC.[CH2:30](Br)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:1][C:2]1[C:3]([O:24][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][CH:15]=3)[S:7][C:6]=2[C:22]=1[F:23]
Reactant: CCCCCCCBr
Reactant: CCCCCCc1ccc(-c2cc3cc(O)c(F)c(F)c3s2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCC(C)=O
Product: CCCCCCCOc1cc2cc(-c3ccc(CCCCCC)cc3)sc2c(F)c1F

Procedure:
is obtained by reacting 2,3-difluoro-4-ethoxythiophenol (obtainable analogously to Reference 7 from 2,3-difluoro-4-ethoxyaniline [189751-13-1]) and 4-hexylphenacyl bromide analogously to Reference 5 to give 6,7-difluoro-2-(4-hexylphenyl)-5-ethoxybenzo[b]thiophene, ether cleavage by means of hydrobromic acid/acetic acid to give 6,7-difluoro-2-(4-hexylphenyl)-5-hydroxybenzo[b]thiophene and Williamson ether synthesis using heptyl bromide in 2-butanone in the presence of potassium carbonate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10].[OH-].[Na+].[CH2:13]([OH:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl>O.C1(C)C=CC=CC=1>[CH2:13]([O:23][C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[C:4]([CH3:9])[C:3]=1[CH3:10])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: CCCCCCCCCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCOc1cc[n+]([O-])c(C)c1C
Temperature: 25 °C
Yield: 151 %

Procedure:
15.8 g (0.1 mol, 1.0 eq.) of 4-chlor-2,3-dimethylpyridine-N-oxide, 8.0 g (0.2 mol, 2.0 eq.) of caustic soda, and 28.5 g of 1-decanol (0.18 mol, 1.8 eq.) were added to 64 mL of toluene, and the mixture was heated to reflux for 4 hours, and then cooled to room temperature. 160 mL of water was added to the reaction liquid, and then the mixture was neutralized with concentrated hydrochloric acid (7.3 g). Subsequently, the resultant was extracted with 100 mL of ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and then concentrated to dryness under reduced pressure, to obtain 42.2 g of 4-decyloxy-2,3-dimethylpyridine-N-oxide as a black brown oily matter.
Reaction SMILES: [C:1]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])[CH2:2][CH3:3].S([N:21]=[N+:22]=[N-])(C1C=CC(C)=CC=1)(=O)=O>>[N+:21](=[C:5]([C:1](=[O:4])[CH2:2][CH3:3])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N-:22]
Reactant: CCOC(=O)CC(=O)CC
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Product: CCOC(=O)C(=[N+]=[N-])C(=O)CC

Procedure:
This compound was synthesised from ethyl propionylacetate (CAS 4949-44-4) and polymer-bound tosylazide using similar protocol as described in Intermediate 1-7. Crude material (0.9 g, 95%) was taken directly to next step.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[N:16]1[CH:21]=[C:20]([C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)[CH:19]=[N:18][CH:17]=1>CO>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:20]3[CH:19]=[N:18][CH:17]=[N:16][CH:21]=3)=[CH:29][CH:28]=2)[CH:8]=1
Reactant: O=Cc1ccc(-c2cncnc2)cc1
Reactant: COC(=O)CCc1cccc(CN)c1
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1cccc(CNCc2ccc(-c3cncnc3)cc2)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, of Preparation 44, and 4-pyrimidin- 5-yl-benzaldehyde, of Preparation 26, using the method described in Example 1, Step A except the mine was formed in MeOH at reflux over 2 h. 1H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 8.92 (s, 2H), 7.55 (m, 4H), 7.25 (m, 3H), 7.11 (d, 1H), 3.87 (s, 2H), 3.81 (s, 2H), 3.66 (s, 3H), 2.95 (t, 2H), 2.63 (t, 2H); MS 362 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:14]=[O:15])=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])=[O:4].CC(=CC)C.[Cl-].[Na+].[O:23]1CCOCC1>O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]([OH:23])=[O:15])=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13])=[O:4]
Reactant: COC(=O)c1sc(C=O)cc1C(F)(F)F
Reactant: C1COCCO1
Agent: CC=C(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1sc(C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of 5-Formyl-3-trifluoromethyl-thiophene-2-carboxylic acid methyl ester (2.05 g, 8.61 mmol) in dioxane (40 ml) was added 2-methyl-2-butene (9 ml) and a solution of Na2ClO2 (2.34 g, 25.92 mmol) and NaH2PO4 (2.82 g) in water (9 ml). The mixture was stirred at rt for 1.5 h. The solution was saturated with sodium chloride, then successively extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford the desired product (2.61 g, 100% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][NH2:16].C(O[CH:20](O)[C:21]([F:24])([F:23])[F:22])C>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:13])([F:14])[F:12])=[CH:4][C:3]=1[NH:15][N:16]=[CH:20][C:21]([F:24])([F:23])[F:22]
Reactant: CCOC(O)C(F)(F)F
Reactant: Cc1cc(Cl)c(NN)cc1SCC(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: Cc1cc(Cl)c(NN=CC(F)(F)F)cc1SCC(F)(F)F
Yield: 67.8 %

Procedure:
A mixture of 4.1 g of 2-chloro-4-methyl-5-(2,2,2-trifluoroethylthio)phenylhydrazine, 2.3 g of trifluoroacetaldehyde ethyl hemiacetal, 0.1 g of p-toluenesulfonic acid monohydrate and 50 ml of ethanol was refluxed with heating for 6 hours. The obtained reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with toluene. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 3.6 g of trifluoroacetaldehyde {2-chloro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}hydrazone.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([OH:9])=O.ClC(OCC(C)C)=O.[N+:18]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])([O-:20])=[O:19].C(=O)(O)[O-].[Na+]>O1CCCC1.C(N(CC)CC)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([NH:24][C:23]1[CH:25]=[CH:26][CH:27]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=1)=[O:9]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: COCCOCC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCOCC(=O)Nc1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
5 g of (2-methoxyethoxy)-acetic acid is dissolved in 500 ml of tetrahydrofuran. 9.7 ml of triethylamine and 5.6 ml of isobutyl chloroformate are added at 0° C., and it is stirred for 30 minutes at 0° C. 5.0 g of 3-nitroaniline is added, and it is stirred for another 15 hours at room temperature. The reaction mixture is mixed with semi-saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic solution is washed with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation and, after purification by chromatography on silica gel, 7.5 g of the title compound is obtained.
Reaction SMILES: [F:1][CH:2]([F:20])[CH:3]([N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])[CH2:4][C:5](=[CH2:8])[CH2:6]Br.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K]>CN(C)C=O>[F:1][CH:2]([F:20])[CH:3]([N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])[CH2:4][C:5](=[CH2:8])[CH2:6][N:25]1[C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]2[C:21]1=[O:31]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=C(CBr)CC(C(F)F)N1C(=O)c2ccccc2C1=O
Agent: [K]
Solvent: CN(C)C=O
Product: C=C(CC(C(F)F)N1C(=O)c2ccccc2C1=O)CN1C(=O)c2ccccc2C1=O

Procedure:
A mixture of 1,1-difluoro-2-phthalimido-4-methylene-5-bromo-pentane (impure, evaluated 67 mmoles) prepared as in Step C above, and potassium phthalimide (13.9 g, 75 mmoles) is heated at 75° C. in dry N,N-dimethylformamide (DMF) (100 mL) for 3 hours. After removal of the DMF under vacuum, the residue is dissolved in chloroform and extracted with 1 N potassium hydroxide and three times with water. Work-up as described in Example 1(D) affords a colored oil (30 g, containing solvents) which is chromatographed on silica gel (petroleum ether/ether acetate: 70/30). The oil obtained (11.3 g) is crystallized from chloroform/ether/petroleum ether to give 1,1-difluoro-2,5-diphthalimido-4-methylene-pentane slightly contaminated (about 15%) by 1,1-difluoro-2,5-diphthalimido-4-methyl-3-pentene (7.9 g of mixture, yield based on 1,1-difluoro-2-phthalimido-4-methyl-4-pentene: 29%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[CH2:8][S:9][CH2:10][CH2:11][NH2:12])[CH3:3].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:31]=[CH:32][CH:33]=1)[CH2:21][C:22]1[C:23](=[O:30])[NH:24][C:25](SC)=[N:26][CH:27]=1>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[CH2:8][S:9][CH2:10][CH2:11][NH:12][C:25]1[NH:24][C:23](=[O:30])[C:22]([CH2:21][C:20]2[CH:31]=[CH:32][CH:33]=[C:18]([O:17][CH3:16])[CH:19]=2)=[CH:27][N:26]=1)[CH3:1]
Reactant: CN(C)Cc1cccc(CSCCN)c1
Reactant: COc1cccc(Cc2cnc(SC)[nH]c2=O)c1
Solvent: c1ccncc1
Product: COc1cccc(Cc2cnc(NCCSCc3cccc(CN(C)C)c3)[nH]c2=O)c1

Procedure:
Reaction of 2-(3-dimethylaminomethylbenzylthio)ethylamine by heating under reflux for 40 hours in dry pyridine with 5-(3-methoxybenzyl)-2-methylthio-4-pyrimidone gives 2-[2-(3-dimethylaminomethylbenzylthio)ethylamino]-5-(3-methoxybenzyl)-4-pyrimidone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[CH3:37][N:38]([CH3:48])[C:39](=[O:47])[CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:44]3[CH2:43][CH2:42][N:41]([CH2:40][C:39]([N:38]([CH3:48])[CH3:37])=[O:47])[CH2:46][CH2:45]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([C:32]#[N:33])([CH3:30])[CH3:31])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CN(C)C(=O)CN1CCNCC1
Product: CCOc1cc(C(C)(C)C#N)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(C)C)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl}-piperazin-1-yl)-N,N-dimethyl-acetamide was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12j) and N,N-dimethyl-2-piperazin-1-yl-acetamide (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 675.3 [(M+H)+]
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].S(O[CH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1)(=O)(=O)C>CN(C=O)C>[C:46]([O:45][C:43]([N:40]1[CH2:41][CH2:42][CH:37]([CH2:36][O:17][C:11]2[CH:10]=[C:9]3[C:14]([C:5]([O:4][C:3]4[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:2]=4[F:1])=[CH:6][CH:7]=[N:8]3)=[CH:13][C:12]=2[O:15][CH3:16])[CH2:38][CH2:39]1)=[O:44])([CH3:49])([CH3:47])[CH3:48]
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
To a solution of the 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-hydroxyquinoline (609 mg, 1.8 mmol) in DMF (9 mL) was added K2CO3 (1.24 g, 9.0 mmol) and N-Boc-4-piperidinemethanol mesylate (732 mg, 2.5 mmol). The mixture was then stirred at 80° C. for 2.5 h. After it was cooled to it, the mixture was loaded directly to a Biotage column, and eluted with solvents (hexanes:EtOAc=1:3). The resulting product, 4-[4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester, was obtained as a solid (556 mg, 56%).