Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([C:14]2[CH:19]=[C:18]([C:20]3[C:25]4[S:26][C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[C:24]=4[CH:23]=[CH:22][CH:21]=3)[CH:17]=[C:16]([C:33]3[C:38]4[S:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=5[C:37]=4[CH:36]=[CH:35][CH:34]=3)[C:15]=2[OH:46])=[CH:3][CH:2]=1.[CH2:47]1C[O:50][CH2:49][CH2:48]1.C(N(CC)CC)C.C(Cl)(=O)C=C>ClCCl.O>[C:49]([O:46][C:15]1[C:14]([C:4]2[C:5]3[S:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[CH:1]=[CH:2][CH:3]=2)=[CH:19][C:18]([C:20]2[C:25]3[S:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:17][C:16]=1[C:33]1[C:38]2[S:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[C:37]=2[CH:36]=[CH:35][CH:34]=1)(=[O:50])[CH:48]=[CH2:47]
Reactant: C1CCOC1
Reactant: Oc1c(-c2cccc3c2sc2ccccc23)cc(-c2cccc3c2sc2ccccc23)cc1-c1cccc2c1sc1ccccc12
Agent: C=CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)Oc1c(-c2cccc3c2sc2ccccc23)cc(-c2cccc3c2sc2ccccc23)cc1-c1cccc2c1sc1ccccc12
Reaction time: 0.5 h
Yield: 59 %

Procedure:
1.5 g of the thus obtained 2,4,6-tris(4-dibenzothiophenyl)phenol is placed in a round bottom flask; 30 mL of THF is added to form a transparent solution; after ice cooling the flask, 0.4 g of triethylamine is added; 0.30 g of acryloyl chloride is then added dropwise; after adding the whole, the temperature is returned to room temperature; and the mixture is stirred for 30 minutes. 30 mL of water is added; the mixture is vigorously stirred; and 100 mL of dichloromethane is then added, thereby separating an aqueous solution. The aqueous layer is washed with dichloromethane and then gathered with the original dichloromethane solution; and the mixture is dried upon application of magnesium sulfate. The resulting mixture is concentrated by filtration with a filter paper; and the concentrate is separated by a silica gel column (eluate: hexane/dichloromethane mixture), thereby obtaining 0.9 g (yield: 59%) of the foregoing white solid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 5.44 (dd=1.2 & 10.4 Hz, 1H), 5.63 (dd=10.4 & 17.2 Hz, 1H), 5.96 (dd=1.2 & 17.2 Hz, 1H), 7.43 to 7.69 (m, 12H), 7.82 to 7.91 (m, 3H), 8.12 (s, 2H), 8.14 to 8.21 (m, 6H)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:12]=[CH:11][C:10]=1[CH:25]=[CH:26][C:27]1[S:31][C:30]([CH:32]=O)=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([C:36]1[C:37](=[C:47]([C:50]#[N:51])[C:48]#[N:49])[O:38][C:39]([CH3:46])([C:42]([F:45])([F:44])[F:43])[C:40]=1[CH3:41])#[N:35]>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:12]=[CH:11][C:10]=1[CH:25]=[CH:26][C:27]1[S:31][C:30]([CH:32]=[CH:41][C:40]2[C:39]([CH3:46])([C:42]([F:45])([F:43])[F:44])[O:38][C:37](=[C:47]([C:48]#[N:49])[C:50]#[N:51])[C:36]=2[C:34]#[N:35])=[CH:29][CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCN(CCCCO)c1ccc(C=Cc2ccc(C=O)s2)c(OCc2ccccc2)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C(F)(F)F
Solvent: CCO
Product: CCCCN(CCCCO)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C(F)(F)F)s2)c(OCc2ccccc2)c1
Temperature: 50 °C
Yield: 73.4 %

Procedure:
In 8 ml of ethanol were dissolved 180 mg (0.39 mmol) of 5-[2-[2-benzyloxy-4-[butyl(4-hydroxybutyl)amino]phenyl]vinyl]thiophene-2-carboaldehyde and 108 mg (0.43 mmol) of 2-(3-cyano-4,5-dimethyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred with heating at 50° C. for 3 hours. The precipitate was separated by filtration, purified by silica gel column chromatography and washed with methanol to give 200 mg of a dark brown crystal having a mp of 176-178° C. (yield: 73.8%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[S:11][S:10][C:9](=O)[CH:8]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:14]>O1CCOCC1.C(#N)C>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[S:11][S:10][C:9](=[S:14])[CH:8]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1cc(-c2cnccn2)ss1
Solvent: C1COCCO1
Solvent: CC#N
Product: S=c1cc(-c2cnccn2)ss1
Temperature: 100 °C
Yield: 170.2 %

Procedure:
A mixture of 5-(pyrazin-2-yl)-1,2-dithiole-3-one (2 g.) and phosphorus pentasulphide (2.3 g.) in dioxan (35 cc.) is heated for 15 minutes at 100° C., whilst stirring. The red suspension obtained is diluted whilst hot with acetonitrile (35 cc.). The solution is decanted and the precipitate obtained is taken up with a hot mixture (2 × 50 cc.) of dioxan and acetonitrile (50:50 by volume). The combined organic phases are filtered hot, diluted with distilled water (250 cc.), and the requisite amount of a 4N aqueous ammonia solution to adjust the pH to 7. The brown precipitate formed is filtered off, washed with distilled water (2 × 25 cc.) and then with diethyl ether (2 × 10 cc.) and dried. 5-(Pyrazin-2-yl)-1,2-dithiole-3-thione (1.87 g.) melting at 200°-201° C. is thus obtained.
Reaction SMILES: CO[C:3](=[O:39])[N:4]=[C:5](SC)[C:6](=[N:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:21]=1)[C:7]1[CH:8]=[C:9]([O:17][CH3:18])[C:10]2[O:15][CH2:14][O:13][CH2:12][C:11]=2[CH:16]=1.C1COCC1.[CH3:45][O:46][C:47]([C:49]1[S:50][CH:51]=[CH:52][C:53]=1[NH:54][NH2:55])=[O:48]>C(N(CC)CC)C>[CH3:45][O:46][C:47]([C:49]1[S:50][CH:51]=[CH:52][C:53]=1[N:54]1[C:3](=[O:39])[NH:4][C:5]([CH:6]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:21]=2)[C:7]2[CH:8]=[C:9]([O:17][CH3:18])[C:10]3[O:15][CH2:14][O:13][CH2:12][C:11]=3[CH:16]=2)=[N:55]1)=[O:48]
Reactant: COC(=O)c1sccc1NN
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)c(CNC(=O)OC(C)(C)C)c1)c1cc2c(c(OC)c1)OCOC2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1sccc1-n1nc(C(Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)c2cc3c(c(OC)c2)OCOC3)[nH]c1=O
Temperature: 65 °C
Reaction time: 15 h
Yield: 87.2 %

Procedure:
To a mixture of {2-[3-(t-butoxycarbonylaminomethyl)-4-cyanophenylimino]-2-(8-methoxy-4H-benzo[1,3]-dioxin-6-yl)-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (2c))(101 mg) and THF (2.0 mL) there were added 3-hydrazinothiophene-2-carboxylic acid methyl ester (33.1 mg) and triethylamine (27.9 μL), and the mixture was stirred at 65° C. for 15 hours under a nitrogen atmosphere. The solvent in the mixture was distilled off. DMF (2.0 mL) was added to the residue, and the mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The solvent in the mixture was distilled off, and methanol (5 mL) and acetic acid (52.1 μL) were added to the residue. Sodium cyanotrihydroborate (114 mg) was then added to the mixture and the mixture was stirred overnight at room temperature. Water (25 mL) and ethyl acetate (50 mL) were added to the mixture, and after sufficiently shaking the mixture, the organic layer was separated off. The organic layer was washed twice with water (25 mL) and once with saturated aqueous sodium chloride (25 mL) in that order, and dried over anhydrous magnesium sulfate. The mixture was filtered to obtain a filtrate, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate mixture) to obtain the target compound (103 mg) as a colorless solid.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([CH2:9]O)[O:6][N:5]=1)([CH3:3])[CH3:2].[Cl-].ClC=[N+](C)C.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]2([C:29]3=[CH:30][C:31]4[O:35][CH2:34][O:33][C:32]=4[CH:36]=[C:28]3[O:27][CH2:26]2)[C:18]1=[O:37].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH:1]([C:4]1[CH:8]=[C:7]([CH2:9][N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]3([C:29]4=[CH:30][C:31]5[O:35][CH2:34][O:33][C:32]=5[CH:36]=[C:28]4[O:27][CH2:26]3)[C:18]2=[O:37])[O:6][N:5]=1)([CH3:2])[CH3:3]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: CC(C)c1cc(CO)on1
Agent: C[N+](C)=CCl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC(C)c1cc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.8 %

Procedure:
To an ice-cold stirring suspension of (3-isopropylisoxazol-5-yl)methanol (0.338 g, 2.4 mmol) in N,N-dimethylformamide (20 mL) was added a solution of N-(chloromethylene)-N-methylmethanaminium chloride (0.36 g, 2.8 mmol) in N,N-dimethylformamide (10 mL). The mixture was stirred at ambient temperature for 30 min and then transferred to a suspended mixture of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.56 g, 2.0 mmol), cesium carbonate (1.95 g, 6.0 mmol) in N,N-dimethylformamide (4 mL). The reaction mixture was stirred at ambient temperature for 16 h and filtered. The solid was washed with acetone (100 mL). The filtrate was concentrated in vacuo. The residue was purified by column chromatography with ethyl acetate in hexanes (10% to 30% gradient) to give 1′-[(3-isopropylisoxazol-5-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.50 g, 60%) as a colorless solid: mp 132-136° C. (diethyl ether/hexanes); 1H NMR (300 MHz, DMSO-d6) 87.34 (ddd, J=7.7, 7.7, 1.2 Hz, 1H), 7.21 (d, J=7.5 Hz, 1H), 7.14 (d, J=7.7 Hz, 1H), 7.08 (ddd, J=7.5, 7.5, 0.8 Hz, 1H), 6.71 (s, 1H), 6.49 (s, 1H), 6.21 (s, 1H), 5.93 (d, J=1.0 Hz, 2H), 5.08 (s, 2H), 4.82 (d, J=9.4 Hz, 1H), 4.72 (d, J=9.4 Hz, 1H), 3.03 (m, 1H), 1.19 (d, J=6.9 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) δ176.4, 168.9, 166.3, 155.2, 148.3, 141.6, 141.5, 131.4, 128.8, 123.6, 123.2, 119.5, 109.1, 102.8, 101.3, 101.1, 93.2, 79.5, 57.2, 35.6, 25.8, 21.2; MS (ES+) m/z 405.3 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N:10]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:11]2)=[N:7][C:8]=1[OH:9])=O.N1CCCCC1.C(O)(=O)C.[C:34](OCC)(=[O:39])[CH2:35][C:36]([CH3:38])=[O:37]>CCO>[C:36]([C:35]1[C:34](=[O:39])[O:9][C:8]2=[N:7][C:6]([N:10]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][CH2:11]3)=[CH:5][CH:4]=[C:3]2[CH:1]=1)(=[O:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(C=O)c(O)n2)CC1
Reactant: CCOC(=O)CC(C)=O
Solvent: C1CCNCC1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)c1cc2ccc(N3CCCN(C(=O)OC(C)(C)C)CC3)nc2oc1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
To a solution of tert-butyl 4-(5-formyl-6-hydroxypyridin-2-yl)-1,4-diazepane-1-carboxylate (600 mg, 1.87 mmol) in EtOH (4 mL) were treated with piperidine (239 mg, 2.8 mmol), acetic acid (511 mg, 9.35 mmol) and ethyl acetoacetate (487 mg, 3.74 mmol) at room temperature. The reaction mixture was stirred at 90° C. for 3 hours. The mixture was concentrated, quenched with a saturated NaHCO3 solution and extracted with dichloromethane three times. The combined organic layers were combined, dried over K2CO3, filtered and concentrated. The residue was purified on silica gel with methanol (0-10%) in dichloromethane to provide tert-butyl 4-(3-acetyl-2-oxo-2H-pyrano[2,3-b]pyridin-7-yl)-1,4-diazepane-1-carboxylate (450 mg, 62%). MS m/z 388 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[N:19][C:20]4[N:21]([N:32]=[CH:33][C:34]=4[C:35](O)=[O:36])[C:22]=3[NH:23][C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=3[CH3:31])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:18]=[N:19][C:20]4[N:21]([N:32]=[CH:33][C:34]=4[C:35]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:36])[C:22]=3[NH:23][C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=3[CH3:31])=[O:16])[CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccc(C)c(Nc2c(C(=O)N3CCC(c4ccc(F)c(F)c4)CC3)cnc3c(C(=O)O)cnn23)c1
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC(c4ccc(F)c(F)c4)CC3)cnc12
Yield: 66.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 6-[4-(3,4-difluorophenyl)piperidine-1-carbonyl]-7-(2,5-dimethylphenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (100 mg, 0.20 mmol) obtained in step 4 and ethanesulfonamide (105 mg, 1.0 mmol), the title compound (79 mg, 66%) was obtained.
Reaction SMILES: [CH:1]1([CH2:4][C@@H:5]([C:7]([OH:9])=[O:8])[NH2:6])[CH2:3][CH2:2]1.O1CCOCC1.S(=O)(=O)(O)O.[CH3:21][C:22](=[CH2:24])[CH3:23]>O.C(N(CC)CC)C>[C:22]([O:8][C:7](=[O:9])[C@H:5]([CH2:4][CH:1]1[CH2:3][CH2:2]1)[NH2:6])([CH3:24])([CH3:23])[CH3:21]
Reactant: C=C(C)C
Reactant: N[C@@H](CC1CC1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@@H](N)CC1CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3.5 g (27.1 mmol) of (S)-β-cyclopropylalanine were added to a mixture of 50 mL of dioxane and 5 ml of concentrated sulfuric acid (prepared by cautious addition of the acid dropwise to dioxane at 5° C.) at room temperature. The solution was transferred into a sealing tube into which 40 ml of isobutylene were condensed at −78° C. The sealed tube was then shaken at room temperature on a shaker for 24 hours. After the sealed tube had been opened (while cooling), the reaction mixture was cautiously introduced into a stirred mixture of 30 mL of triethylamine and 50 mL of water cooled to 0° C. After removal of excess isobutylene, the product was extracted with ether (2×50 mL). Drying of the ether phases over magnesium sulfate, filtration and removal of the solvent in vacuo resulted in the crude product (pale yellow oil), which was employed without further purification in the subsequent reaction. Yield 4.2 g (84%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O1CCOCC1.O>[OH:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:2]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CCCC(CO)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.4 %

Procedure:
3-Piperidinemethanol (3.59 g, 31.2 mmol) in 1,4-dioxane (8 mL) was mixed with potassium carbonate (4.55 g, 33.0 mmol), 1 M aqueous sodium hydroxide (2 mL) and benzyl chloroformate (5.20 mL, 36.4 mmol) under cooling with ice and stirred at room temperature for one day. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous potassium hydrogen sulfate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)) to give the title compound as a colorless oil (6.41 g, yield 83%).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].COCCOC.[NH2:16][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1>CCO>[CH2:7]([O:6][C:4]([C:3]1[N:16]=[C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]2[CH:2]=1)=[O:5])[CH3:8]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1cnccn1
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)c1cn2ccncc2n1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Ethyl bromopyruvate (62.9 g) was added to the DME (258 mL) solution of 2-aminopyrazine (24.8 g) at room temperature and stirred for 2.5 h. The reaction mixture was cooled to 0° C. and stirred for 30 min to afford a pale brown precipitate. The precipitate was filtered and washed with Et2O to give pale brown crystals. The suspension of the precipitate (66.1 g) in EtOH (1.29 L) was heated at reflux temperature to turn to clear solution. After refluxing for 2 h, the reaction mixture was concentrated under reduced pressure, then mixed with CHCl3 and saturated NaHCO3aq. The mixture was filtered through a pad of Celite and the separated organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with CHCl3-MeOH (99/1˜97/3), and collected fractions were concentrated under reduced pressure followed by recrystallization from CHCl3-Et2O. The titled compound was obtained as pale pink crystals. Yield: 10.9 g, 22%).
Reaction SMILES: C1(C)C=CC(S([NH:10][C:11]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][C:12]=2/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])(=O)=O)=CC=1.Br[CH2:30][C:31]([C:33]1[CH:38]=[C:37]([CH2:39][CH3:40])[CH:36]=[CH:35][N:34]=1)=[O:32]>>[CH3:18][O:17][C:15](=[O:16])[CH2:14][C:13]1[C:12]2[C:11](=[CH:22][CH:21]=[C:20]([O:23][C:24]([F:25])([F:26])[F:27])[CH:19]=2)[NH:10][C:30]=1[C:31]([C:33]1[CH:38]=[C:37]([CH2:39][CH3:40])[CH:36]=[CH:35][N:34]=1)=[O:32]
Reactant: CCc1ccnc(C(=O)CBr)c1
Reactant: COC(=O)/C=C/c1cc(OC(F)(F)F)ccc1NS(=O)(=O)c1ccc(C)cc1
Product: CCc1ccnc(C(=O)c2[nH]c3ccc(OC(F)(F)F)cc3c2CC(=O)OC)c1

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-2-p-toluenesulfonylamino-5-(trifluoromethoxy)cinnamate (step 2 of Example 145) and 2-bromoacetyl-4-ethylpyridine (Preparation is described in Example 57).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O.ClCCl.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:25]2[S:24][CH:28]=[CH:27][CH:26]=2)[CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Reactant: OB(O)c1cccs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Cc2cccs2)c1
Yield: 25.3 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(thiophen-2-ylmethyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.080 g; 0.230 mmol), thiophen-2-ylboronic acid (0.031 g; 0.241 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride, complex with dichloromethane (0.018 g; 0.023 mmol), sodium carbonate (0.049 g; 0.461 mmol), sodium iodide (0.069 g; 0.461 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 25% ethyl acetate in dichloromethane) furnished 0.023 g (25%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1)=[O:3].[Cl:11][C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[CH:16][C:17]=1[Cl:18].C([O-])([O-])=O.[K+].[K+].S1(CCCC1)(=O)=O.[OH-].[Na+]>O>[Cl:18][C:17]1[CH:16]=[CH:15][C:14]([O:19][C:7]2[CH:8]=[CH:9][C:4]([S:2]([CH3:1])=[O:3])=[CH:5][CH:6]=2)=[CH:13][C:12]=1[Cl:11]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CS(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: CS(=O)c1ccc(Oc2ccc(Cl)c(Cl)c2)cc1
Temperature: 170 °C
Yield: 79.7 %

Procedure:
A mixture of 16.14 g (0.102 mole) of 4-fluorophenyl methyl sulfoxide, 33.18 g (0.204 mole) of 3,4-dichlorophenol, 28.15 g (0.204 mole) of anhydrous K2CO3 and 150 ml of sulfolane was heated at 170° C. for 4 hrs and cooled. The reaction mixture was poured into a solution of 20% aqueous NaOH and 500 ml of water. The homogeneous solution was extracted with diethyl ether. The organic layer was washed with water, dried (Na2SO4) and solvent removed in vacuo leaving 24.5 g (79.8% yield) of product. Recrystallization from ethanol followed by column chromatography using silica gel as the support and chloroform as the eluent afforded purified 1,2-dichloro-4-(4-(methylsulfinyl)phenoxy)benzene, mp 92°-93.5° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[CH2:7][CH2:8][C:2]1=2.[OH-].[K+].C(O)(=[O:14])C.C(O)(=O)C.IC1C=CC=CC=1>CO>[OH:14][CH:7]1[CH2:8][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[C:6]1=[O:9]
Reactant: O=C1CCc2sccc21
Reactant: CC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: Ic1ccccc1
Solvent: CO
Product: O=C1c2ccsc2CC1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5,6-dihydro-cyclopenta[b]thiophen-4-one (36.8 g, 0.266 mol) in MeOH (1000 mL) was added at about 5° C. to a solution of potassium hydroxide 85% (52.7 g, 0.798 mol) in MeOH (500 mL). Between 0° C. and 5° C. iodobenzene diacetate (94.4 g, 0.293 mol) was added in portions and the mixture was allowed to come to room temperature. The mixture was stirred overnight at room temperature. The mixture was evaporated and a 20% solution of potassium carbonate (500 mL) was added. The mixture was extracted for times with DCM dried with sodium sulphate and evaporated under reduced pressure. The residue was dissolved in 1,4-dioxane (400 mL) and water (150 mL) and concentrated hydrochloric acid (150 mL) was added. The mixture was stirred for two hours at room temperature. The mixture was neutralized by the addition of potassium carbonate and extracted four times with dichloromethane. The organic phase was dried with sodium sulphate and evaporated under reduced pressure. The product was crystallized with ether ethyl acetate and the mother liquid was purified by silica gel chromatography with toluene and acetone. Yield: 33.5 g=81.6%.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH3:6].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41]([CH:46]=O)=[CH:40]2.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Cl:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][C:41]([CH:46]=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:40]2
Reactant: O=Cc1cc2cc(Cl)ccc2[nH]1
Reactant: CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCC=Cc1cc2cc(Cl)ccc2[nH]1
Reaction time: 0.5 h

Procedure:
To the cold suspension of Pentyl-triphenyl-phosphonium bromide in THF was added LiHMDS in THF and the mixture was stirred for 30 minutes. A solution of 5-Chloro-1H-indole-2-carbaldehyde in THF was added to the reaction mixture and stirred for 3 hours. The reaction mixture was treated with saturated ammonium chloride and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[C:5]([C:14]([O:16]CC)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[OH-].[Na+]>C1COCC1.CO.O>[C:1]([C:3]1[C:4]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)#[N:2]
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1-c1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.1 %

Procedure:
To a solution of ethyl 4-cyano-3-(2,4-dichlorophenyl)-5-morpholin-4-ylthiophene-2-carboxylate (0.060 g, 0.15 mmol) in THF/MeOH/water (2:1:2) (5 mL) was added sodium hydroxide (0.061 g, 1.5 mmol). The reaction mixture was allowed to stir at rt for 20 h and was concentrated. The residue was acidified with 1N HCl and was extracted with EtOAc. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated to give 4-cyano-3-(2,4-dichlorophenyl)-5-morpholin-4-ylthiophene-2-carboxylic acid (0.034 g, 62%). LCMS: (FA) ES+ 382.9. 1H NMR (400 MHz, d6-DMSO) δ: 7.75 (d, 1H), 7.50 (dd, 1H), 7.39 (d, 1H), 3.79-3.74 (m, 4H) and 3.61-3.55 (m, 4H).