Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:18]Br>ClCCCl>[Br:18][C:8]([CH:9]([CH3:11])[CH3:10])=[C:7]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrBr
Reactant: CC(C)C=C(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: CC(C)C(Br)=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
Into a reactor were introduced 8.81 g (39.6 mmol) of the 1,1-diphenyl-3-methylbutene and 35 mL of 1,2-dichloroethane under a nitrogen atmosphere. The contents were cooled to 0° C., and 6.33 g (39.6 mmol) of bromine was gradually added dropwise thereto. This mixture was stirred at room temperature for 1 hour. The resultant reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was recrystallized from ethanol and ethyl acetate to obtain 8.64 g (72%) of the target compound as white crystals.
Reaction SMILES: [C:1]([NH:6][C@H:7]([C:29](O)=[O:30])[CH2:8][S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.[C:33]([S:41][CH2:42][CH2:43][NH2:44])(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:1]([NH:6][C@H:7]([C:29]([NH:44][CH2:43][CH2:42][S:41][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:30])[CH2:8][S:9][C:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: NCCSC(=O)c1ccccc1
Agent: Cl
Product: CC(C)C(=O)N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCSC(=O)c1ccccc1

Procedure:
The coupling reaction of 13 (3.93 mmol) with S-benzoylcysteamine hydrochloride is carried out according to method B described in the first synthetic route (example 1). After the various treatments, the expected compound is isolated by flash chromatography on a silica gel column (eluent: AcOEt/petroleum ether 70%). 17 is collected in the form of a foam which, after trituration in hexane, provides a colorless foam (Yd=77%). Rf (CH2Cl2/ether, 6/4):0.76. [α]D20=+7.8° (c 1.03, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:13].[CH:14]#[C:15][CH2:16][CH2:17][CH2:18]CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]#[C:15][CH2:16][CH2:17][CH3:18])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:13]
Reactant: C#CCCCCC
Reactant: Oc1ccc2cc(Br)ccc2c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CCCC#Cc1ccc2c(Cl)c(O)ccc2c1
Temperature: 25 °C
Yield: 88.7 %

Procedure:
The synthesis of (S7-3) was carried out following the method described in Synthesis, No. 9, 1439 (2004). At first, 38.3 g of 1-chloro-6-bromo-2-naphthol (S1-2), 5.2 g of PdCl2(PPh3)2, 0.71 g of copper iodide and 400 ml of triethylamine were added to a reactor in nitrogen atmosphere, stirred at room temperature, added with 35.8 g of 1-heptyne (S7-2) and then refluxed for 6 hours. The reaction solution was cooled to room temperature and distilled under a reduced pressure to remove the solvent, and then the residue was added with ethyl acetate and filtered by celite. The resulting solution was washed with 1N HCl(aq) and water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under a reduced pressure. The residue was purified by silica gel column chromatography using heptane/ethyl acetate=3/1 as an eluting solvent and dried under a reduced pressure to obtain 32.3 g of 1-chloro-6-(1-pentynyl)-2-naphthol (S7-3).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([OH:18])=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[Br:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>>[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][O:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=3)=[N:10][S:11][C:12]=2[CH:17]=1
Reactant: Oc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Reactant: BrCCCCBr
Product: FC(F)(F)c1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1

Procedure:
In analogy to example 2.1, 3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-ol and 1,4-dibromobutane were converted to yield 6-(4-Bromo-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole as light yellow solid, MS: 429 (M, 1Br).
Reaction SMILES: [CH2:1]([N:8]([C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]([CH3:27])[C:21]=1[CH2:28][OH:29])[S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH2:1]([N:8]([C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]([CH3:27])[C:21]=1[CH:28]=[O:29])[S:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(C)ccc(C)c2CO)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)c2c(C)ccc(C)c2C=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.7 %

Procedure:
To a solution of 438.7 mg of the product of Example 289 in 20 ml of acetone was added 5.33 ml (10.07 mmol) of Jones reagent and the reaction was stirred at room temperature for 18 hr. The resulting mixture was concentrated in vacuo and the residue was diluted with dichloromethane, washed with water and brine, dried over MgSO4, filtered and concnentrated in vacuo. The residue was triturated with hexane to provide 396 mg (91%) of the desired product as a white solid. Electrospray Mass Spec 410 (M+H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br-:18].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)C>[Br:18][CH2:16][C:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:10]=1)=[O:17]
Reactant: [Br-]
Reactant: CC(=O)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Agent: C[N+](C)(C)c1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution (40 mL) of the compound (9.4 g, 37 mmol) obtained in Example 38a in diethyl ether was added phenyltrimethylammonium tribromide (14 g, 37 mmol), and the mixture was stirred at room temperature for 5 hr. After confirmation of the termination of the reaction by TLC, aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a crude title compound as a colorless oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C(OC([N:18]1[CH2:23][CH2:22][CH:21]([C:24]#[N:25])[CH2:20][CH2:19]1)=O)(C)(C)C.[Br:26][C:27]1[CH:28]=[CH:29][C:30](F)=[N:31][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Br:26][C:27]1[CH:28]=[CH:29][C:30]([C:21]2([C:24]#[N:25])[CH2:20][CH2:19][NH:18][CH2:23][CH2:22]2)=[N:31][CH:32]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC1(c2ccc(Br)cn2)CCNCC1
Reaction time: 0.83 h
Yield: 70.2 %

Procedure:
1.0M Tetrahydrofuran-solution of sodium bis(trimethylsilyl)amide (19 ml) was added to 4-cyanopiperidine-1-carboxylic acid tert-butyl ester (3.23 g) at 0° C. and stirred for 50 minutes. A solution of 5-bromo-2-fluoropyridine (2.57 g) in tetrahydrofuran (5 ml) was added thereto and stirred at room temperature for 7.5 hours. An aqueous solution of potassium carbonate was added to the reaction solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. 2N Hydrochloric acid-ethanol solution (30 ml) was added to the residue and stirred for 4.5 hours. An aqueous solution of sodium bicarbonate was added to the reaction solution, extracted with ethyl acetate, and then with chloroform, washed with saturated brine dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting solid was washed with isopropylether to give 4-(5-bromopyridin-2-yl)piperidine-4-carbonitrile (2.73 g) as a pale orange solid
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH3:13])[NH2:7])[CH3:2].CCN(C1C=CC=CC=1)CC.Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:7][C:26](=[O:27])[O:28][CH:29]([CH3:31])[CH3:30])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH3:13])[CH3:2]
Reactant: CCOc1ccc(N)cc1OCC
Reactant: CC(C)OC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)c1ccccc1
Product: CCOc1ccc(NC(=O)OC(C)C)cc1OCC
Temperature: 0 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
3,4-Diethoxyaniline (1.8 g) and diethylaniline (1.5 g) were dissolved in benzene (20 ml). To the resultant solution was dropwise added isopropyl chloroformate (1.2 g) in 5 minutes under ice-cooling. After being allowed to stand at room temperatue for 3 hours, the reaction mixture was poured into ice-water and extracted with ether. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give crude crystals (2.6 g). Recrystallization from ethanol gave isopropyl N-(3,4-diethoxyphenyl)carbamate (Compound No. 13) (2.3 g) in a yield of 86%. M.P., 100°-100.5° C.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:15]2[C:11]([N:12]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=3)[CH:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH:14]=2)=[CH:10][CH:9]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:6]([C:8]1[C:15]2[C:11]([N:12]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=3)[CH:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH:14]=2)=[CH:10][CH:9]=1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)C1=CC=C2C1=CC(C(=O)OCc1ccccc1)N2Cc1ccc(Cl)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C1=CC=C2C1=CC(C(=O)OCc1ccccc1)N2Cc1ccc(Cl)c(Cl)c1
Reaction time: 24 h
Yield: 98.2 %

Procedure:
Benzyl 4-tert-butoxycarbonyl-1-(3,4dichlorobenzyl)cyclopenta[b]pyrrole-2-carboxylate (0.7 g) was dissolved in methylene chloride (10 mL) and TFA (3 mL) was added. Stirring was continued for 24 hours and the solvents were removed in vacuo to afford a pale oil. The oil slowly solidified on standing to afford the title product (0.61 g, 98%), NMR d(DMSO) 2.40 (4H, m), 3.70 (1H, t), 5.10 (2H, s), 5.40 (2H, AB d), 6.70 (1H, s), 6.90 (1H, d), 7.30 (6H, m), 7.50 (1H, d); M/z (−) 444, 442 (M-H+).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]([S:31](=[O:34])(=[O:33])[NH2:32])=[CH:27][CH:26]=4)[CH2:23][CH2:22][C:21]([C:35]([O:37]C)=[O:36])=[CH:20][C:19]=3[CH:39]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:26]=[CH:27][C:28]([S:31](=[O:33])(=[O:34])[NH2:32])=[CH:29][CH:30]=4)[CH2:23][CH2:22][C:21]([C:35]([OH:37])=[O:36])=[CH:20][C:19]=3[CH:39]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3c2ccc(S(N)(=O)=O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3c2ccc(S(N)(=O)=O)cc2)cc1
Yield: 90.5 %

Procedure:
In methanol (50 ml) and THF (15 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.34 g). To the solution was added 1N sodium hydroxide solution (10 ml), and the mixture was refluxed for 2 hours, concentrated, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-(4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.3 g) as yellow crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1.C([Li])CCC.[B:26](OC)([O:29]C)[O:27]C.C(OC1C=CC(B(O)O)=CC=1)CCCCCCC>C1COCC1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([B:26]([OH:29])[OH:27])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: COB(OC)OC
Reactant: CCCCCCCCCCCCOc1ccc(Br)cc1
Agent: CCCCCCCCOc1ccc(B(O)O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOc1ccc(B(O)O)cc1

Procedure:
Quantities: compound 30 (15.00 g, 0.047 mol) in anhydrous THF (150 ml), n-butyllithium (20 ml, 2.5M in hexane, 0.050 mol), trimethyl borate (9.79 g, 0.094 mol) in anhydrous THF (50 ml). The experimental procedure was as described for the preparation of compound 33.
Reaction SMILES: [CH2:1]([NH:7][C:8](=O)[CH3:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:11][N:12](C)[C:13](Cl)=O>C1(C)C=CC=CC=1>[CH3:11][N:12]([CH3:13])[C:8](=[N:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH3:9]
Reactant: CCCCCCNC(C)=O
Reactant: CN(C)C(=O)Cl
Solvent: Cc1ccccc1
Product: CCCCCCN=C(C)N(C)C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
To a solution of N-hexyl acetamide (15.0 g, 105 mmol) in 15 mL of dry toluene was slowly added 11.2 g (104.9 mmol) of dimethylcarbamyl chloride. The solution was refluxed under a nitrogen atmosphere for 24 h. The volatile materials were removed on a rotary evaporator and then in vacuo at room temperature. The residue was dissolved 30 mL of chloroform and stirred vigorously with a solution of 4.2 g sodium hydroxide in 40 mL of water for 30 min. Calcium carbonate (4.2 g) was added and stirring was continued for another 30 min. The organic phase was separated and the aqueous phase was extracted with dichloromethane (25 mL×3). The combined organic phases were dried (calcium carbonate) and the solvent was removed on a rotary evaporator. The residue was distilled at 52-54° C./0.25 Torr (lit. bp 125° C./30 Torr (see Oszczapowicz, J.; Raczynska, E. J. Chem. Soc., Perkin Trans. 2 1984, 1643-1666)) product to yield 8.7 g (49%) of liquid (purity 99% by GC). IR (neat) 2955, 2926, 2856 (C—H), 1626 (N═C) cm−1. 1H NMR 3.18 (t, 2H, JHH 7.5 Hz, —CH2—N═), 2.87 (s, 6H, —N—(CH3)2); 1.87 (s, 3H, —N═C(CH3)—N); 1.49 (m, 2H, —CH2—CH2—N═); 1.25-1.4 (m, 6H, CH3—(CH2)3—); 0.88 (t, 3H, JHH 7.2 Hz, CH3). 13C NMR 158.79; 50.32; 38.07; 32.49; 32.00; 27.38; 22.80; 14.17; 12.45.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.[F:21][C:22]1[CH:36]=[CH:35][C:25]2[C:26]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][O:28][C:24]=2[CH:23]=1>CN(C)C=O.C(O)C>[F:21][C:22]1[CH:36]=[CH:35][C:25]2[C:26]([CH:29]3[CH2:30][CH2:31][N:32]([CH2:3][C@@H:2]([OH:1])[CH2:4][O:5][C:6]4[CH:11]=[CH:10][CH:9]=[C:8]([C:12]5[C:20]6[C:15](=[N:16][CH:17]=[CH:18][CH:19]=6)[O:14][N:13]=5)[CH:7]=4)[CH2:33][CH2:34]3)=[N:27][O:28][C:24]=2[CH:23]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: c1cc(OC[C@H]2CO2)cc(-c2noc3ncccc23)c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@@H](COc1cccc(-c2noc3ncccc23)c1)CN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
The title compound is prepared from a mixture of (R)-3-(3-oxiranylmethoxy-phenyl)-isoxazolo[5,4-b]pyridine in dimethylformamide and ethanol and 6-fluoro-3-piperidine-4-yl-benzo[d]isoxazole (Table No. 1, SM 8) in ethanol essentially as described above in Example 102. Purity by LC/MS=100%, [M+H]+=489.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([N:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.Br[CH2:37][C:38]([NH2:40])=[O:39]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([N:23]5[CH2:24][CH2:25][N:26]([CH2:37][C:38]([NH2:40])=[O:39])[CH2:27][CH2:28]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: NC(=O)CBr
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1N1CCNCC1
Product: NC(=O)CN1CCN(N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
2-{4-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]piperazin-1-yl}acetamide was prepared from ((5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-piperazin-1-yl-1,3-thiazolidine-2,4-dione (Example 351) and 2-bromoacetamide following General Procedure S.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH:18]=3)[CH:13]=2)[C:8]=1[Br:26])[CH3:2].[C:28]([CH2:32][C:33](Cl)=[O:34])([CH3:31])([CH3:30])[CH3:29].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[S:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[C:18]=3[C:33](=[O:34])[CH2:32][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:13]=2)[C:8]=1[Br:26])[CH3:2]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCOC(=O)COc1ccc2cc(-c3cc4ccccc4s3)ccc2c1Br
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1ccc2cc(-c3sc4ccccc4c3C(=O)CC(C)(C)C)ccc2c1Br
Temperature: 25 °C
Yield: 6.5 %

Procedure:
To a 0° C. mixture of (6-benzo[b]thiophen-2-yl-1-bromo-naphthalen-2-yloxy)-acetic acid ethyl ester (5.18 g, 11.7 mmol) in chloroform (270 mL) was added t-butylacetyl chloride (2.0 mL, 14 mmol) and tin (IV) chloride (2.1 mL, 18 mmol). It was refluxed for 23 hours. During reflux, more t-butylacetyl chloride (9.0 mL, 66 mmol) in four portions and tin (IV) chloride (8.4 mL, 71 mmol) in four portions were added. It was then allowed to cool to ambient temperature and poured into ice water. It was diluted with additional chloroform and washed with water and brine. It was then dried with anhydrous magnesium sulfate, filtered and solvent evaporated. The residue was purified by flash chromatography using (1) 100% chloroform, (2) 25–60% methylene chloride in hexane. It was then purified by HPLC using 90% acetonitrile (0.1% trifluoroacetic acid) in water as the mobile phase. Evaporating the solvent and extracting with ethyl acetate, washing with water and brine, drying with anhydrous magnesium sulfate, filtering, concentrating and drying in vacuo at ambient temperature for two hours yielded {1-bromo-6-[3-(3,3-dimethyl-butyryl)-benzo[b]thiophen-2-yl]-naphthalen-2-yloxy}-acetic acid ethyl ester as an amber semi-solid (0.412 g, 6.53%); mass spectrum (+EI, [M+H]+) m/z 539/541. 1H NMR (500 MHz, DMSO-d6): δ8.26 (d, 1H, J=8.81 Hz), 8.07–8.14(m, 3H), 7.91–7.93 (m, 1H), 7.76 (dd, 1H, J=8.81 Hz and 1.97 Hz), 7.45–7.53 (m, 3H), 5.12 (s, 2H), 4.19 (q, 2H, J=7.15 Hz), 2.33 (s, 2H), 1.20–1.25 (m, 3H), 0.76 ppm (s, 9H). Elemental Analysis for C28H27BrNO4S: Calcd: C, 62.34; H, 5.04; N, 0.00; Found: C, 57.16; H, 4.37; N, 0.00.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([CH2:9][O:10][C:11]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:12]=3[CH:13]=[C:14]([C:20](O)=[O:21])[NH:15]4)=[CH:7][O:8][C:4]=2[CH:3]=1.[ClH:25].Cl.Cl.[C@H:28]1([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]2)[C@@H:37]2[N:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:31][CH2:30][CH2:29]1>>[ClH:1].[ClH:25].[C@H:28]1([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([NH:45][C:20]([C:14]3[NH:15][C:16]4[C:12]([CH:13]=3)=[C:11]([O:10][CH2:9][C:6]3[C:5]5[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][C:4]=5[O:8][CH:7]=3)[CH:19]=[CH:18][CH:17]=4)=[O:21])[CH2:41][CH2:40]2)[C@@H:37]2[N:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:31][CH2:30][CH2:29]1
Reactant: NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Reactant: O=C(O)c1cc2c(OCc3coc4cc(Cl)ccc34)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cc(Cl)ccc34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(6-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (117) (preparation see below) and amine 61 analogously to the method described in example 1.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:13][CH2:14][CH3:15])=[O:12]>C1(C)C=CC=CC=1>[CH2:14]([O:13][C:11](=[O:12])/[CH:16]=[CH:1]/[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:15]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCCc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/CCc1ccccc1

Procedure:
A solution of dihydrocinnamaldehyde (6.73 g, 50.2 mmol) and (carboethoxymethylene)triphenylphosphorane (17.84 g, 50.2 mmol) in toluene (250 mL) was refluxed for 18 h. It was then cooled to r.t and concentrated in vacuo. The residue was taken up in ether (250 mL) and the triphenylphosphine oxide was filtered off. The filtrate was concentrated to afford the intermediate trans-ethyl-(5-phenyl)-2-pentenoate (32.1).
Reaction SMILES: [F:1][C:2]1([C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[CH:7]([O:8]C(=O)C)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13].[CH:21](=[N:27]/O)/[C:22]1[O:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1.CC(C)=O>[F:1][C:2]1([C:14]([O:16][CH2:17][CH:18]([CH3:19])[CH3:20])=[O:15])[CH:7]([O:8]/[N:27]=[CH:21]\[C:22]2[O:26][CH:25]=[CH:24][CH:23]=2)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13]
Reactant: O/N=C\c1ccco1
Reactant: CC(=O)OC1NC(=O)NC(=O)C1(F)C(=O)OCC(C)C
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC(C)COC(=O)C1(F)C(=O)NC(=O)NC1O/N=C\c1ccco1
Temperature: 60 °C
Reaction time: 16 h
Yield: 40.3 %

Procedure:
In 45 ml of pyridine-acetone (pyridine:acetone=2:1) were dissolved 11.6 g (40 mmol) of isobutyl 5-fluoro-6-acetoxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate and 6.1 g (54.9 mmol) of (Z)-furfuraldoxime, and the solution was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in 150 ml of ethyl acetate. The solution was washed three times with 50-ml portions of water, and the ethyl acetate layer was dried and the solvent was evaporated under reduced pressure. The residue was recrystallized three times from ethyl acetate-hexane to give 5.5 g of isobutyl 5-fluoro-6-(Z)-furfurylideneaminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate. m.p. 159°-160° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8](O)[CH:7]=[C:6]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1.O=P(Cl)(Cl)[Cl:25]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([Cl:25])[CH:7]=[C:6]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2nc(O)cc(Nc3ccc(Cl)c(Cl)c3)c2c1
Product: COc1ccc2nc(Cl)cc(Nc3ccc(Cl)c(Cl)c3)c2c1
Yield: 61 %

Procedure:
Prepared using general procedure 3; 6-Methoxy-2-hydroxy-4-(3,4-dichlorophenyl)aminoquinoline (1.05 g, 3.13 mmol) and 26 mL of POCl3 were heated to 120° C. for 4 h. Isolation afforded 0.685 g of material (1.94 mmol, 61%).