Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][S:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[C:12]1([CH:18]([CH3:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[H+].[B-:37]([F:41])([F:40])([F:39])[F:38]>C(OCC)C>[F:38][B-:37]([F:41])([F:40])[F:39].[F:1][CH2:2][S+:3]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:18]([CH3:20])[CH3:19])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1
Reactant: Cc1ccc(S(=O)CF)cc1
Reactant: CC(C)c1ccccc1
Agent: F[B-](F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [H+]
Solvent: CCOCC
Product: Cc1ccc([S+](CF)c2ccccc2C(C)C)cc1

Procedure:
1-((Fluoromethyl)sulfinyl)-4-methylbenzene (738 mg, 4.29 mmol) of example 5 was dissolved in dry diethyl ether (15 mL) under an argon atmosphere. Cumene (0.66 mL, 1.1 eq) was added to the previous solution and then the mixture was cooled to a temperature below −50° C. After stabilizing the temperature, trifluoromethanesulfonic anhydride (0.72 mL, 1 eq) was added slowly maintaining the same temperature. The mixture was stirred, at the same temperature, until the reaction was complete. HBF4 in diethyl ether solution (54%, 1.18 mL, 2 eq) was added. The resulting suspension was stirred for 30 minutes. The precipitate tetrafluoroborate salt was isolated by filtration and washed with diethyl ether at 0° C. The desired product was obtained as a slightly yellow oily solid (2.22 g) after heating at room temperature.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[CH3:25][N:26]([NH2:28])[CH3:27]>CN(C=O)C>[Cl:15][C:12]([F:14])([F:13])[C:6]1[N:5]=[C:4]([C:16]([F:17])([F:19])[F:18])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([NH:28][N:26]([CH3:27])[CH3:25])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CN(C)N
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1NN(C)C
Yield: 83.8 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 1.9 ml (0.025 mol) of unsym-dimethylhydrazine in 30 ml of DMF were reacted affording a residue which was recrystallized in hot hexane to give 4.57 g (83.8%) of product as a yellow solid; mp 97°-98° C. C14H15Cl1F5N3O4
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:7])[NH:5][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.Cl>[N+](C1C=CC=CC=1)([O-])=O>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([C:6]2[NH:5][C:4](=[O:7])[NH:3][C:2]=2[CH3:1])=[O:19])=[CH:16][CH:15]=1
Reactant: Cc1c[nH]c(=O)[nH]1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)c2[nH]c(=O)[nH]c2C)cc1

Procedure:
To 19.6g of 1,3-dihydro-4-methyl-2H-imidazol-2-one and 53.2 g of anhydrous aluminum chloride in 150 ml of nitrobenzene is added dropwise 34.2 g of p-methoxybenzoyl chloride and the mixture is poured on 500 ml of 2N-HCl and ice, washed 3 times with ethyl ether, the resulting solid is recrystallized from isopropanol-water to give the title compound. M.P. 257°-258° C. (dec.).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O-:20])=[O:19])[CH2:14]2)(=O)=O)=CC=1.[C-:21]#[N:22].[Na+]>CS(C)=O.S([O-])([O-])(=O)=O.[Fe+2]>[C:21]([CH2:12][C@@H:13]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:13]([CH3:17])([CH3:14])[CH3:12])=[O:19])[CH2:14]1)#[N:22]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCN(C(=O)[O-])C2)cc1
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](CC#N)C1
Temperature: 100 °C
Yield: 156.5 %

Procedure:
A mixture of tert-butyl ((R)-3-(4-methylbenzenesulfonyloxymethyl)pyrrolidine-1-carboxylate (Intermediate 207, 22.3 g) and sodium cyanide (6.13 g) in DMSO (100 mL) was stirred and heated at 100° C. for 4 hours. After cooling, a saturated aqueous solution of iron (II) sulphate was added and the mixture was stirred at room temperature for 8 hours. The resultant mixture was extracted with ethyl acetate, washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with an mixture of ethyl acetate and petroleum ether (20%) to give tert-butyl (S)-3-cyanomethylpyrrolidine-1-carboxylate (12.3 g) as a white solid which was used without further characterisation.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][C:10]=1[NH2:11].[CH:12]1[C:21]2[C:16](=[C:17]([CH2:22][C:23](O)=[O:24])[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1>>[CH:12]1[C:21]2[C:16](=[C:17]([CH2:22][C:23]([NH:11][C:10]3[CH:9]=[CH:8][S:7][C:6]=3[C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[O:24])[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1
Reactant: O=C(O)Cc1cccc2cnccc12
Reactant: Nc1ccsc1-c1nccs1
Product: O=C(Cc1cccc2cnccc12)Nc1ccsc1-c1nccs1

Procedure:
The title compound was prepared from 2-(thiazol-2-yl)thiophen-3-amine and 2-(isoquinolin-5-yl)acetic acid according to protocol A. Preparative HPLC gave 2-(isoquinolin-5-yl)-N-(2-(thiazol-2-yl)thiophen-3-yl)acetamide. Method[7], MS(ESI) 352.1 [M+H], Retention time=2.59 min; 1H-NMR (300 MHz, CDCl3) δ 11.32 (s, 1H), 8.26 (d, J=8.2 Hz, 1H), 8.10-8.09 (m, 1H), 8.07 (s, 1H), 7.94 (t, J=7.7 Hz, 1H), 7.35 (d, J=3.3 Hz, 1H), 7.31-7.24 (m, 4H), 7.10 (d, J=3.3 Hz, 1H), 4.33 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)c1ncoc1-c1cccc(F)c1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3cccc(F)c3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-fluoro-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 01b: tR=0.91 min; [M+H]+=395.12.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Br:10]Br>C(Cl)(Cl)(Cl)Cl>[Br:10][C:4]1[C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[S:1][CH:5]=1
Reactant: c1ccc2sccc2c1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1csc2ccccc12
Yield: 48.4 %

Procedure:
Dissolve benzo[b]thiophene (23 g, 0,170 mmol) in carbon tetrachloride (80 mL). Add, by dropwise addition, a solution of bromine (26.85 g, 0,168 mmol) in carbon tetrachloride (30 mL) and stir at room temperature for 2 days. Quench with a 1M solution of sodium thiosulfate and separate the organic phase. Extract the aqueous phase with carbon tetrachloride, combine the organic phases and dry (MgSO4). Evaporate the solvent in vacuo and purify by distillation to give 3-bromobenzo[b]thiophene as a pale yellow liquid (17.33 g, 48%); bp 64°-72° C. @ 0.02 mm Hg.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:32]=[CH:31][CH:30]=[CH:29][C:12]=3[C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]([C:26]#[N:27])[CH3:25])=[CH:19][C:18]=3[F:28])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1.C([Sn](=O)CCCC)CCC.C[Si]([N:47]=[N+:48]=[N-:49])(C)C>C1(C)C=CC=CC=1.CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:32]=[CH:31][CH:30]=[CH:29][C:12]=3[C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]([C:26]4[NH:49][N:48]=[N:47][N:27]=4)[CH3:25])=[CH:19][C:18]=3[F:28])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C#N)Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1)c1nnn[nH]1
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 27.5 %

Procedure:
A solution of (±)-2-(benzo[1,3]dioxol-5-yloxy)-N-[4-(1-cyano-ethoxy)-2-fluoro-benzyl]-nicotinamide (1.5 g, 3.5 mmol) in anhydrous toluene (5 mL) was transferred to a small pressure flask. Dibutyltin oxide (0.53 g, 2.1 mmol) and trimethylsilyl azide (1.7 mL, 21 mmol) were added. The tube was sealed and placed behind a blast shield. The reaction was stirred 15 min at 55° C., then warmed to 110° C. with stirring over night. The black reaction mix was cooled to 0–5° C., the pressure flask opened, and the residue taken up in methanol. Solvents were removed in vacuo and the residue taken up in ethyl acetate. The organic solution was washed twice with saturated aqueous sodium carbonate. The aqueous phases were pooled and acidified with concentrated hydrochloric acid, and extracted twice with ethyl acetate. The pooled organic phases were dried (MgSO4), concentrated, and loaded onto a silica gel column as a brown oil. Purification by column chromatography (5% methanol/dichloromethane) afforded product as a white solid (0.46 g, 28%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:12][O:13][CH2:14][CH2:15]Br>CS(C)=O>[CH3:12][O:13][CH2:14][CH2:15][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Oc1cccc2cccnc12
Reactant: COCCBr
Solvent: CS(C)=O
Product: COCCOc1cccc2cccnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
To 8-hydroxyquinoline (9.47 g, 0.065 mol) in dimethyl sulfoxide (50 ml) was added 2 -methoxyethyl bromide (8.96 g, 0.065 mol). The mixture was stirred at room temperature for two hours, and turned a dark red. The solvent was removed under vacuum, and the residue dissolved in water. The aqueous solution was extracted several times with ethyl acetate, and the ethyl acetate solution was then washed well with water, dried, and the solvent removed; the residual oil weighed 7.45 g. This was purified on a silica gel column, eluted with heptane:ethyl acetate, with increasing proportions of the latter. There was isolated 8-methoxyethoxyquinoline (7.11 g) as a light blue oil. NMR: (CDCl3) δ 3.51 (s, 3, OMe), 4.01 (tr, 2, CH2), 4.48 (tr, 2, CH2), 7.20 (m, 1, beta-pyridine-H), 7.45 (m, 3, Ar), 8.15 (dd, 1, gamma-pyridine-H), 8.98 (dd, 1, alpha-pyridine-H). Anal. Calcd. for C12H13NO2 : C, 70.92; H, 6.45; N, 6.89. Found: C, 70.80; H, 6.49; N, 6.90.
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].N1C=CN=C1.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.CCOC(C)=O>[Si:20]([O:1][CH2:2][C@H:3]1[O:4][C@@H:9]([OH:10])[C@@H:7]([OH:8])[CH:5]1[OH:6])([C:16]([CH3:19])([CH3:18])[CH3:17])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](OC[C@H]1O[C@@H](O)[C@@H](O)C1O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.7 %

Procedure:
To a stirred solution of D-arabinose (50 g, 0.33 mol) in DMF (500 mL) was added imidazole (45 g, 0.66 mol) and tert-butylchlorodiphenylsilane (109 g, 0.4 mol). After being stirred at room temperature for 2 hours, the resulting solution was diluted with EtOAc (2000 mL), washed with water, brine and dried over Na2SO4. The organic layer was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 1:11 EtOAc in petroleum ether) to afford 33 g of (2R,3S,5R)-5-[[tert-butyl(diphenyl)silyl]oxymethyl]tetrahydrofuran-2,3,4-triol (compound 25a).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH:2]([CH3:4])[CH3:3].[CH3:7][CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][CH2:10][N:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].Cl>C1COCC1>[OH:14][C:12]1([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH:8]([CH3:7])[CH2:13]1
Reactant: CC1CC(=O)CCN1C(=O)OC(C)(C)C
Reactant: CC(C)C[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)CC1(O)CCN(C(=O)OC(C)(C)C)C(C)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Under an argon atmosphere, in a 50-mL pear-shaped evaporating flask was weighed a solution of lanthanum chloride lithium chloride complex in THF (15.6 mL) and cooled to 0° C. To the solution was added dropwise a solution of isobutylmagnesium chloride in THF (3.5 mL) and stirred at 0° C. for 3 hours. A solution of tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (1 g) in THF (2.0 mL) was further added dropwise. The reaction solution was stirred at 0° C. for 1 hour, heated to 25° C., poured to hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution and dried over anhydrous magnesium sulphate. The filtrate was concentrated and the resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=9:1→3:1) to give the titled compound (450 mg) having the following physical properties.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:22][CH2:23][CH3:24])[C:8]3[O:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][C:12](=[O:21])[C:9]=3[CH:10]=2)[N:5]=[C:4]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:3]=1.[Se](=O)=[O:31]>C(O)(=O)C>[CH:1]([C:2]1[C:11]2[C:6](=[C:7]([CH2:22][CH2:23][CH3:24])[C:8]3[O:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][C:12](=[O:21])[C:9]=3[CH:10]=2)[N:5]=[C:4]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:3]=1)=[O:31]
Reactant: O=[Se]=O
Reactant: CCCc1c2nc(C(=O)OCC)cc(C)c2cc2c(=O)cc(C(=O)OCC)oc12
Solvent: CC(=O)O
Product: CCCc1c2nc(C(=O)OCC)cc(C=O)c2cc2c(=O)cc(C(=O)OCC)oc12
Reaction time: 2 h
Yield: 70.9 %

Procedure:
A mixture of diethyl 6-methyl-4-oxo-10-propyl-4H-pyrano[3,2-g]quinoline-2,8-dicarboxylate (19 g), selenium dioxide (20.99 g), and glacial acetic acid (950 ml) was heated on a steam bath with stirring for 2 hours. The resulting suspension was cooled, filtered and poured into brine (8 l). The resulting precipitate was filtered off and the crude product dissolved in CH2Cl2, filtered and evaporated to dryness to give 20.5 g of the crude product (20.5 g). This product was chromatographed using 25:1 CH2Cl2 : ethyl acetate as the solvent, yielding 13.95 g of required product (71%).
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:15]=[CH:16][C:2]([O:17][C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=[O:22])=[CH:3][CH:4]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(O)c1cccc(O)c1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cccc(Oc2ccc(C(=O)c3ccc(F)cc3)cc2)c1
Temperature: 120 °C
Reaction time: 48 h
Yield: 48.8 %

Procedure:
A mixture of 4,4'-difluorobenzophenone (25.2 g, 115.5 mmol), 3-hydroxybenzoic acid (8.0 g, 57.9 mmol), and anhydrous potassium carbonate (16.0 g) in dry dimethylsulfoxide (120 ml, distilled under reduced pressure from calcium hydride) was stirred at 120° C. under nitrogen for 48 hours. At the end of this period the reaction mixture was poured into water, and the suspension thus obtained was filtered through Celite. The clear filtrate was cooled, then carefully acidified with conc. hydrochloric acid until strongly acidic. The white precipitate that formed was filtered and recrystallized from aqueous ethanol. Two recrystallizations gave 9.5 g (48%) of 3-[4-(4-fluorobenzoyl)phenoxy]benzoic acid with m.p. 158.5°-160° C. A sample with m.p. 159°-161.5° C. could not be purified further by recrystallization.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:32])[NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16]([NH:18][C:19]2[CH:31]=[CH:30][C:22]([O:23][CH2:24][C:25]([O:27]CC)=[O:26])=[CH:21][CH:20]=2)=[O:17])[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[CH2:1]([NH:8][C:9](=[O:32])[NH:10][C:11]1[S:12][CH:13]=[C:14]([C:16]([NH:18][C:19]2[CH:31]=[CH:30][C:22]([O:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:21][CH:20]=2)=[O:17])[N:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1ccc(NC(=O)c2csc(NC(=O)NCc3ccccc3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)COc1ccc(NC(=O)c2csc(NC(=O)NCc3ccccc3)n2)cc1
Yield: 91.2 %

Procedure:
243 mg of ethyl (4-{[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino}-phenoxy)-acetate are stirred in 4.3 ml of ethanol and 0.8 ml of 1N NaOH for 4.5 hrs. at RT. For the working up, the mixture is stirred into ethyl acetate/dilute hydrochloric acid, the organic phase is separated, washed with water and sodium chloride solution, dried over sodium sulphate dried and evaporated in a vacuum. Crystallization from ether gives 208 mg of [4-[[2-(3-benzyl-ureido)-thiazole-4-carbonyl]-amino]-phenoxy]-acetic acid, m.p. 208° C., MS: 427 (M+H)+.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[CH:16][C:17]4[S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][C:20]([C:26]([OH:28])=O)=[CH:19][C:18]=4[CH:29]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:52]1[CH2:71][O:70][C:54]2([CH2:59][CH2:58][CH:57]([N:60]([CH2:62][C:63]3[CH:69]=[CH:68][C:66]([NH2:67])=[CH:65][CH:64]=3)[CH3:61])[CH2:56][CH2:55]2)[O:53]1>CN(C=O)C.C(N(CC)CC)C>[CH2:71]1[CH2:52][O:53][C:54]2([CH2:55][CH2:56][CH:57]([N:60]([CH2:62][C:63]3[CH:64]=[CH:65][C:66]([NH:67][C:26]([C:20]4[CH2:21][CH2:22][S:23](=[O:24])(=[O:25])[C:17]5[CH:16]=[CH:15][C:14]([C:11]6[CH:12]=[CH:13][C:8]([N:5]7[CH2:6][CH2:7][O:2][CH2:3][CH2:4]7)=[CH:9][CH:10]=6)=[CH:29][C:18]=5[CH:19]=4)=[O:28])=[CH:68][CH:69]=3)[CH3:61])[CH2:58][CH2:59]2)[O:70]1
Reactant: O=C(O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2S(=O)(=O)CC1
Reactant: CN(Cc1ccc(N)cc1)C1CCC2(CC1)OCCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(N5CCOCC5)cc4)ccc3S(=O)(=O)CC2)cc1)C1CCC2(CC1)OCCO2
Reaction time: 1 h
Yield: 39.4 %

Procedure:
To a solution of 7-(4-morpholinophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid hydrochloride (200 mg) and 1-hydroxybenzotriazole (0.12 g) in DMF (5 ml) was added at room temperature 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.18 g), and the mixture was stirred for 1 hour. To the mixture was added a solution of 4-[N-(4,4-ethylenedioxycyclohexyl)-N-methylaminomethyl]aniline (0.19 g) and triethylamine (0.2 ml) in DMF (3 ml), and the mixture was stirred for 64 hours. The mixture was concentrated under reduced pressure, and to the residue was added water. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with column chromatography (ethanol/ethyl acetate=1:1) to give yellow crystals of N-[4-[N-(4,4-ethylenedioxycyclohexyl)-N-methylaminomethyl]phenyl]-7-(4-morpholinophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 15) (119 mg).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)=O.[Cl-].[OH:18][NH3+:19].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]([F:16])([F:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)=[N:19][OH:18]
Reactant: COc1ccc(C(=O)C(F)(F)F)cc1OC
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=NO)C(F)(F)F)cc1OC
Temperature: 0 °C
Yield: 95.2 %

Procedure:
2.9 g (9.7 mmol) of 2,2,2-trifluoro-1-(3,4-dimethoxyphenyl)-ethanone are dissolved in 12 ml of ethanol at 80° C. To the solution are added dropwise 0.83 g (12.0 mmol) of hydroxylammonium chloride and 1.2 g (15.0 mmol) of sodium acetate dissolved in 6 ml of water. The reaction mixture is refluxed for 7.5 hours, poured into ice water, and extracted with ether. The organic phase is washed with water and brine, dried over MgSO4, and concentrated, yielding 2.3 g of 2,2,2-trifluoro-1-(3,4-dimethoxyphenyl)-ethanone oxime. The crude product is used in the next reaction step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[O:5][CH2:6][CH2:7][N:8]([CH3:10])[CH3:9].[CH3:14][C:15]1([CH3:36])[C:19]([CH3:21])([CH3:20])[O:18][B:17](C2C=CC(OC3C=CC=CC=3)=CC=2C)[O:16]1>>[CH3:9][N:8]([CH3:10])[CH2:7][CH2:6][O:5][C:4]1[CH:11]=[CH:12][CH:13]=[C:2]([B:17]2[O:18][C:19]([CH3:21])([CH3:20])[C:15]([CH3:36])([CH3:14])[O:16]2)[CH:3]=1
Reactant: CN(C)CCOc1cccc(Br)c1
Reactant: Cc1cc(Oc2ccccc2)ccc1B1OC(C)(C)C(C)(C)O1
Product: CN(C)CCOc1cccc(B2OC(C)(C)C(C)(C)O2)c1

Procedure:
Prepared from [2-(3-bromo-phenoxy)-ethyl]-dimethyl-amine according to general Method I for borylation described above for preparation of 4,4,5,5-tetramethyl-2-(2-methyl-4-phenoxy-phenyl)-[1,3,2]dioxaborolane.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:15])[CH2:13][CH3:14]>>[CH3:14][CH2:13][C:12]([C:7]1[CH:8]=[C:9]([N+:1]([O-:4])=[O:2])[CH:10]=[CH:11][C:6]=1[Cl:5])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: CCC(=O)c1ccccc1Cl
Product: CCC(=O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
31 ml of 100% nitric acid (dl.52) are introduced into the reaction vessel, and 6 g of o-chloropropiophenone are added dropwise at -10° C. in the course of 15 minutes in such a way that the reaction temperature is between -5° C. and -10° C. To complete the reaction, stirring is continued at 0° C. for 45 minutes. The reaction mixture is subsequently poured onto 300 g of ice, and the aqueous mixture is extracted twice using 200 ml portions of diethyl ether. The organic phase is washed with 100 ml of water, twice with 100 ml portions of 2N potassium hydrogen carbonate solution and finally with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is recrystallised from diisopropyl ether/n-hexane; m.p.: 55°-56° C.
Reaction SMILES: [C:1]([NH:7][NH:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])(=O)[CH2:2][CH2:3][CH:4]=[CH2:5].O.C([O-])(O)=O.[Na+]>O=P(Cl)(Cl)Cl>[CH2:2]([C:1]1[O:10][C:9]([NH:11][C@H:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]([CH3:15])[CH3:14])=[N:8][N:7]=1)[CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCC(=O)NNC(=O)N[C@H](C(=O)OC)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: C=CCCc1nnc(N[C@H](C(=O)OC)C(C)C)o1
Temperature: 0 °C

Procedure:
Methyl N-[(2-pent-4-enoylhydrazino)carbonyl]-L-valinate (from Step 3) was heated at 80° C. for 2 h in POCl3 (0.1 M solution). The mixture was cooled at 0° C. and water was carefully added. Solid NaHCO3 was added until the mixture reached pH 7, then the mixture was extracted with EtOAc and the organic layer dried over Na2SO4 to obtain a pale yellow oil. 1H NMR (400 MHz, DMSO-d6) δ: 8.42 (d, J 15.7, 1H), 5.88-5.78 (m, 1H), 5.08 (d, J 17.2, 1H), 5.01 (d, J 10.3, 1H), 4.04 (dd, J 7.1, 14.2, 1H), 3.64 (s, 3H), 2.75 (t, J 7.3, 2H), 2.39 (m, 2H), 2.13-2.06 (m, 1H), 0.94 (d, J 3.9, 3H), 0.92 (d, J 3.9, 3H). MS (ES+) C12H19N3O3 requires: 253 found: 254 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][O:4]C1CCCCO1.[ClH:11].[C:12]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[O:24][C@H:25]2[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27][CH2:26]2)[CH:17]=[N:16][CH:15]=1)#[N:13]>>[ClH:11].[C:12]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[O:24][C@H:25]2[CH2:30][CH2:29][C@H:28]([NH:31][CH2:2][CH2:3][OH:4])[CH2:27][CH2:26]2)[CH:17]=[N:16][CH:15]=1)#[N:13]
Reactant: BrCCOC1CCCCO1
Reactant: N#Cc1cncc2cccc(O[C@H]3CC[C@H](N)CC3)c12
Agent: Cl
Product: N#Cc1cncc2cccc(O[C@H]3CC[C@H](NCCO)CC3)c12

Procedure:
According to the method of Example 144, an alkylation reaction with 2-(2-bromoethoxy)tetrahydro-2H-pyran and a deprotection reaction were performed by using the compound of Example 134 to obtain the title compound.