Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[CH2:13][CH2:12][CH2:11]3)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Cl.[CH:20]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)([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.C=O.[C:41](=O)([O-])O.[Na+]>C(O)C>[CH:20]([N:33]1[CH2:38][CH2:37][N:36]([CH2:41][CH:13]2[CH2:12][CH2:11][C:10]3[C:15](=[CH:16][CH:17]=[C:8]([N:2]4[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]4)[CH:9]=3)[C:14]2=[O:18])[CH2:35][CH2:34]1)([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
Reactant: O=C1CCCc2cc(N3CCCCC3)ccc21
Reactant: O=C([O-])O
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1c2ccc(N3CCCCC3)cc2CCC1CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 240 h

Procedure:
In 50 ml. of ethanol was dissolved a mixture of 2 g. of 6-piperidino-3,4-dihydro-1(2H)-naphthalenone hydrochloride, 4 g. of 1-benzhydrylpiperazine hydrochloride and 4 g. of a 37% aqueous solution of formalin. The solution was allowed to stand at room temperature for 10 days, after which it was neutralized with aqueous sodium hydrogen carbonate and extracted with chloroform. The extract was dried and the solvent was distilled off under reduced pressure, whereby 2-[(4-benzhydryl-1-piperazinyl)methyl]-6-piperidino-3,4-dihydro-1(2H)-naphthalenone was obtained as an oil. This oil was dissolved in 50 ml. of methanol and the solution was stirred with 3 g. of sodium borohydride at room temperature for 30 minutes. The reaction mixture was diluted with 500 ml. of water and extracted with chloroform. The extract was dried and the solvent was distilled off under reduced pressure. By the above procedure there was obtained 2-[(4-benzhydryl-1-piperazinyl)methyl]-6-piperidino-1,2,3,4-tetrahydro-1-naphthalenol as an oil. This oily product was dissolved in 50 ml. of 20% ethanolic HCl and the solution was heated under reflux for 2 hours. After cooling, the crystals were collected by filtration, whereby 2.7 g. of 3-[(4-benzhydryl-1-piperazinyl)methyl]-7-piperidino-1,2-dihydronaphthalene hydrochloride was obtained as colorless prisms melting at 195°-199° C.(decomposition).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[Cl:34][CH2:35][C:36]([NH:38]O)=[NH:37]>C(OCC)(=O)C.CN(C=O)C>[Cl:34][CH2:35][C:36]1[N:38]=[C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[O:7][N:37]=1
Reactant: N=C(CCl)NO
Reactant: O=C(O)c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cccc(-c2nc(CCl)no2)c1
Temperature: 135 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
DMF (10 ml) was added to a mixture of 3-fluorobenzoic acid (710 mg, 5.07 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (972 mg, 5.07 mmol), 1-hydroxybenzotriazole hydrate (HOBt) (685 mg, 5.07 mmol) and 2-chloro-N-hydroxy-acetamidine (500 mg, 4.61 mmol) at room temperature and then stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with water (3 times) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. DMF (14 ml) was added to the residue and the resulting solution was heated at 135° C. for 3.5 h to effect cyclization to oxadiazole. After cooling the reaction mixture was washed with water (3 times) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. 3-Chloromethyl-5-(3-fluoro-phenyl)-[1,2,4]oxadiazole (383 mg, 35% yield over 2 steps, yellow oil) was obtained by flash chromatography on silica gel, using 5% ethyl acetate in hexane. 1H NMR (CDCl3), δ (ppm): 7.96 (d, 1H), 7.86 (m, 1H), 7.54 (m, 1H), 7.33 (m, 1H), 4.68 (s, 2H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:19])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[NH:31][C:32]([NH:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][C:36]=1[CH3:50])=[O:33].FC1C=CC(C(F)(F)F)=CC=1NC(NC1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1)=O>>[NH2:11][C:9]1[C:10]2=[C:2]([C:38]3[CH:39]=[CH:40][C:35]([NH:34][C:32]([NH:31][C:22]4[CH:23]=[C:24]([C:27]([F:29])([F:30])[F:28])[CH:25]=[CH:26][C:21]=4[F:20])=[O:33])=[C:36]([CH3:50])[CH:37]=3)[C:3]([CH3:19])=[C:4]([CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:5]2[N:6]=[CH:7][N:8]=1
Reactant: Cc1c(Br)c2c(N)ncnn2c1CN1CCOCC1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)Nc1cc(C(F)(F)F)ccc1F
Agent: CC1(C)OB(c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)OC1(C)C
Product: Cc1cc(-c2c(C)c(CN3CCOCC3)n3ncnc(N)c23)ccc1NC(=O)Nc1cc(C(F)(F)F)ccc1F
Yield: 16 %

Procedure:
The title compound was prepared in a manner similar to the procedure described for the preparation of Example 117 Step 4, using the product of step 1, Example 119 (5-bromo-6-methyl-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine) in place of 5-bromo-6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine and Intermediate AAH (1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea) in place of Intermediate AAN (1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-urea) 28 mg (16%) of the desired product was isolated. 1H-NMR (DMSO-d6) δ 9.41-9.40 (m, 1H), 8.67 (dd, J=2.1, 7.2 Hz, 1H), 8.58 (s, 1H), 8.01 (d, J=8.1 Hz, 1H), 7.85 (s, 1H), 7.53-7.46 (m, 1H), 7.39-7.35 (m, 1H), 7.22 (s, 1H), 7.18-7.15 (m, 1H), 3.80 (s, 2H), 3.53-3.50 (m, 4H), 2.41-2.39 (m, 4H), 2.31 (s, 3H), 2.09 (s, 3H); MS [M+H]+=558.1; LCMS RT=2.59.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]34[CH2:28][CH:23]5[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]5)[CH2:20]3)[CH2:26]4)[CH:13]=2)=[CH:8][CH:7]=1.[H-].[Na+].[CH2:32](Cl)[O:33][CH2:34][CH2:35][O:36][CH3:37].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37])=[C:14]([C:19]34[CH2:28][CH:23]5[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]5)[CH2:20]3)[CH2:26]4)[CH:13]=2)=[CH:10][CH:11]=1
Reactant: COCCOCCl
Reactant: COC(=O)/C=C/c1ccc(-c2ccc(O)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCOc1ccc(-c2ccc(/C=C/C(=O)OC)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
A solution of (E)-3-(3′-adamantan-1-yl-4′-hydroxybiphenyl-4-yl)-acrylic acid methyl ester (120 mg, 0.309 mmol) in 1 ml of anhydrous DMF, was dropped into a 1 ml suspension of NaH (14.8 mg, 0.371 mmol, 60% in mineral oil) in anhydrous DMF (0.3 ml) at 0° C. The resulting red solution was stirred at RT for 30 min, then MEM-Cl (46 mg, 0.371 mmol) was added. After stirring overnight at RT, iced water was added and the mixture was extracted several times with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated under vacuo. The resulting crude product was purified on silica gel (acetone:hexane 15:85) to obtain (E)-3-[3′-adamantan-1-yl-4′-(2-methoxyethoxymethoxy)-biphenyl-4-yl]-acrylic acid methyl ester (123 mg, 84%).
Reaction SMILES: B.CSC.O=[C:6]1[CH:11]([CH2:12][C:13](O)=[O:14])[S:10](=[O:17])(=[O:16])[C:9]2[S:18][C:19]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:20][C:8]=2[NH:7]1.CO>C(COC)OC>[OH:14][CH2:13][CH2:12][CH:11]1[S:10](=[O:16])(=[O:17])[C:9]2[S:18][C:19]([S:21](=[O:23])(=[O:24])[NH2:22])=[CH:20][C:8]=2[NH:7][CH2:6]1
Reactant: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)C(CC(=O)O)C(=O)N2
Agent: B
Solvent: CSC
Solvent: CO
Solvent: COCCOC
Product: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)C(CCO)CN2
Reaction time: 24 h

Procedure:
Borane-dimethylsulfide (9.5 ml, 10M, 95 mmol) was added to a solution of (2,3-dihydro-2,4,4-trioxo-6-sulfamoyl-1H-thieno-[2,3-b][1,4]thiazin-3-yl)acetic acid (3.25 g, 9.5 mmol) in dimethoxyethane (325 ml) and the resulting solution was heated under reflux for 24 hours. Methanol (100 ml) was added to the cooled reaction mixture, and after stirring for an additional 24 hours, the mixture was evaporated to a thick oil. The oil was partitioned between water and ethyl acetate and the organic layer was washed with brine and dried over sodium sulfate. Removal of the solvent and recrystallization of the residue from water gave 1.5 g. Chromatographic purification over silica gel eluting with CHCl3 /MeOH/NH4OH (70:30:3) gave 3-(2-hydroxyethyl)-2,3-dihydro-4,4-dioxo-6-sulfamoyl-1H-thieno[2,3-b][1,4]thiazine, mp 158°-160° C.
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([CH2:31][CH:32]=C)[C@@H:12]([CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11](=[O:22])[N:10]([C@@H:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:34]=O.CSC>CO>[C:1]([O:5][C:6]([C@@:8]1([CH2:31][CH:32]=[O:34])[C@@H:12]([CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11](=[O:22])[N:10]([C@@H:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH3:24])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=O
Reactant: C=CC[C@@]1(C(=O)OC(C)(C)C)CN([C@H](C)c2ccccc2)C(=O)[C@@H]1COCc1ccccc1
Solvent: CSC
Solvent: CO
Product: C[C@H](c1ccccc1)N1C[C@@](CC=O)(C(=O)OC(C)(C)C)[C@@H](COCc2ccccc2)C1=O

Procedure:
A solution of (3S,4S)-3-allyl-4-benzyloxymethyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (6.76 g, 15.0 mmol) in methanol (150 mL) was bubbled with oxygen for five minutes. After bubbling with ozone for 1.5 hours with stirring under cooling with dry ice-methanol, ozone was removed by bubbling with nitrogen. Dimethyl sulfide (5.64 mL, 76.8 mmol) was added under cooling, and the mixture was stirred for 19 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→80:20→75:25→66:34→50:50) to give 4.58 g of the title compound as a transparent oil.
Reaction SMILES: CN(C)CC[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH:11]([CH:22]([CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20]C)=[O:9].[CH3:44][NH:45][CH3:46].[CH2:47](O)C>>[CH3:44][N:45]([CH3:47])[CH2:46][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH:11]([CH:22]([CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:9].[CH2:33]([CH:22]([CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:11]([OH:10])[CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CNC
Reactant: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)C(CCC/C=C\CCCCC)OC(=O)CCCCCN(C)C
Reactant: CCO
Product: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)C(CC/C=C\CCCCC)OC(=O)CCCCN(C)C
Product: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)C(O)CC/C=C\CCCCC

Procedure:
Using an analogous procedure to that described for the synthesis of (6Z,16Z)-12-((Z)-dec-4-enyl)docosa-6,16-dien-11-yl 6-(dimethylamino)hexanoate 11, (6Z,15Z)-11-((Z)-dec-4-enyl)henicosa-6,15-dien-10-yl 5-(dimethylamino)pentanoate 19 was obtained as a colorless oil (0.2 g, 24%) from 5.6 M dimethylamine in ethanol (10 mL) and (6Z,15Z)-11-((Z)-dec-4-enyl)henicosa-6,15-dien-10-ol 17 (0.35 g, 0.7 mmol). 1H NMR (400 MHz, CDCl3) δ 5.40-5.28 (m, 6H), 4.97-4.88 (m, 1H), 2.35-2.24 (m, 4H), 2.24-2.19 (m, 6H), 2.08-1.93 (m, 12H), 1.70-1.55 (m, 3H), 1.55-1.45 (m, 5H), 1.45-1.13 (m, 25H), 0.93-0.82 (m, 9H). Rf 0.4 (10% MeOH—CH2Cl2).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])C=O.[CH2:14]([Li])CCC.CS[S:21][CH3:22].[Cl-].[NH4+]>C1COCC1>[CH3:13][O:12][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([CH3:14])[C:9]=1[O:10][CH3:11])[CH:22]=[S:21]
Reactant: COc1cc(C=O)cc(Br)c1OC
Reactant: CSSC
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C=S)cc(C)c1OC
Reaction time: 1.33 h

Procedure:
3-Bromo-4,5-dimethoxybenzaldehyde (4.9 g) in THF (30 ml) was added over 10 minutes and the mixture cooled to 31 75° . Further n-butyllithium (20 ml) was then added, and the mixture stirred at -75° for 80 minutes, before adding dimethyldisulphide (2.7 g) by syringe. The mixture was stirred for 1.5 hours, allowing the temperature to rise to ambient, then treated with an aqueous solution of ammonium chloride (50 ml) and the organic layer separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers washed with brine, and dried over NaSO4. Crude product was purified by chromatography on silica, eluting with 10% ethyl acetate in hexane, to give 3,4-dimethoxy-5-methylthiobenzaldehyde (3.4 g): NMR (CDCl3): δ2.49 (s, 3H); 3.94 (s, 3H); 3.96 (s, 3H); 7.25 (d, 1H); 7.28 (d, 1H); 9.89 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[S:14][C:13]([C:15](=[O:17])[CH3:16])=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19].ClC1C=C(C=CC=1)C(OO)=[O:26]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([C:10]1[S:14][C:13]([C:15](=[O:17])[CH3:16])=[CH:12][C:11]=1[N+:18]([O-:20])=[O:19])=[O:26]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)c1cc([N+](=O)[O-])c(S(=O)c2ccc(Cl)cc2Cl)s1
Temperature: 25 °C
Reaction time: 10 h
Yield: 66.3 %

Procedure:
To a solution of 1-[5-(2,4-Dichlorophenylsulfanyl)-4-nitro-2-thienyl]ethanone (200 mg, 0.58 mmol) as prepared in example 2 in dichloromethane (5 mL), m-chloroperoxybenzoic acid (198 mg, 1.14 mmol) was added slowly at 0° C. The mixture was stirred at ambient temperature for 10 hours. After this time the mixture was diluted with dichloromethane (25 mL) and washed with aqueous sodium bicarbonate solution (10 mL×3), then water (10 mL×2) and brine (5 mL). The organic phase was dried (Na2SO4), concentrated under vacuum to afford a yellow solid as the title product (0.14 g, 67% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.65 (1H, s), 7.96 (1H, d), 7.63 (2H, m), 2.66 (3H, s). MS m/z: 362.10 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[F:9][C:10]1[CH:20]=[CH:19][C:13]([C:14](OCC)=[O:15])=[CH:12][CH:11]=1.C[Si](C)(C)N[Si](C)(C)C.[Li]>O1CCCC1.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:14]([C:13]2[CH:19]=[CH:20][C:10]([F:9])=[CH:11][CH:12]=2)=[O:15])[CH:3]=1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: Cc1cc(Br)ccn1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Cc1cc(Br)ccn1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
Under a stream of nitrogen, 5.0 g (29.07 mmol) of 4-bromo-2-picoline and 10.2 g (60.95 mmol) of ethyl 4-fluorobenzoate are placed in a round-bottomed flask and dissolved in 50 mL of anhydrous tetrahydrofuran. The mixture is cooled to 0° C. and 70 mL (70 mmol) of a lithium hexamethyldisilazane solution (1M in tetrahydrofuran) are added dropwise. After addition, the mixture is stirred at room temperature for 2 hours, cooled to 5° C., and 100 mL of water are then gradually added. The medium is then diluted with 250 mL of ethyl acetate and 100 mL of water. The organic phase is separated out and the aqueous phase is extracted twice with 100 mL of ethyl acetate. The organic phases are then combined, dried over sodium sulfate and filtered. 15 g of silica are then added to the filtrate, and the resulting mixture is stirred and then concentrated under reduced pressure. The powder obtained is used as a solid deposit for a chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (9/1). 7.5 g (88%) of compound are obtained in the form of a yellow powder.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]([CH2:12]Cl)[N:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2.[CH3:14][C:15]1[N:20]=[C:19]([SH:21])[N:18]=[C:17]([OH:22])[CH:16]=1>CC(C)=O.C(=O)([O-])[O-].[Ag+2]>[Cl:2][C:3]1[N:4]([CH2:12][S:21][C:19]2[N:18]=[C:17]([OH:22])[CH:16]=[C:15]([CH3:14])[N:20]=2)[N:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Cc1cc(O)nc(S)n1
Reactant: ClCn1nc2ccccc2c1Cl
Agent: [Ag+2]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: Cc1cc(O)nc(SCn2nc3ccccc3c2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.9 %

Procedure:
3-chloro-2-(chloromethyl)-2H-indazole hydrochloride (285 mg, 1.0 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (142 mg, 1.0 mmol), and silver carbonate (550 mg, 2.0 mmol) were mixed in acetone (20 mL). The mixture was stirred at room temperature overnight. The solid was filtered. The solution was evaporated, and the crude product was purified by column chromatography to provide the titled final product (15 mg, 5% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.34 (s, 3H), 6.05 (s, 1H), 6.22 (s, 2H), 7.25 (t, 1H), 7.48 (t, 1H), 7.67 (d, 1H), 7.74 (s, 1H); M+ 307.
Reaction SMILES: [CH2:1]([C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CCOCC.C1(C)C(S(O)(=O)=O)=CC=CC=1.C(Cl)(Cl)Cl>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:10][C:4]1([CH2:1][C:2]#[CH:3])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: C1=COCCC1
Reactant: C#CCC1(O)CCCCC1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: C#CCC1(OC2CCCCO2)CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A solution of 2.9 g (21 mmol) of (prop-2-ynyl)cyclohexanol in 10 ml of dry ether was stirred under argon as 0.24 ml (26 mmol) of dihydropyran was added followed by about 5 mg of toluenesulfonic acid. After one hour, tlc (CHCl3, silica gel) analysis indicated that significant starting material remained. Another 0.2 ml of dihydropyran and about 5 mg of toluenesulfonic acid were added. Twice more at one hour intervals, 0.2 ml portions of dihydropyran along with a small amount of toluenesulfonic acid were added to the reaction mixture. It was left to stir under argon at room temperature for 15 hours. Potassium carbonate was then added to the mixture and it was stirred for several minutes before it was washed with water. The wash solution was back extracted with ether and the combined extracts were then washed with brine, dried (Na2SO4) and evaporated in vacuo to yield 4.6 g of 1-(tetrahydropyran-2-yloxy)-1-(prop-2-ynyl)cyclohexane) having the following spectral characteristics: nmr (CDCl3) δ 1.0-2.5 (19H, m), 3.6 (2H, broad m) and 4.65 ppm (1H, broad s); ir (CHCl3) 980, 1030, 1050, 1070, 1120, 1150, 1270, 1450, 2120, (weak) 2760, 2930 and 3300 cm-1.
Reaction SMILES: [CH2:1]([S:3]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:16][CH2:17][CH2:18][OH:19])(=[O:5])=[O:4])[CH3:2].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].C([O-])(O)=O.[Na+]>C1COCC1.C(OCC)(=O)C>[CH3:27][S:28]([O:19][CH2:18][CH2:17][CH2:16][C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([NH:6][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:8]=2)[NH:12][CH:11]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CCS(=O)(=O)Nc1ccc2[nH]cc(CCCO)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCS(=O)(=O)Nc1ccc2[nH]cc(CCCOS(C)(=O)=O)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
To a solution of 3-(5-ethanesulfonylamino-1H-indol-3-yl)propanol (0.59 g, 2.1 mmol) in 20 mL of THF at 0° C. was added triethylamine (0.58 mL, 4.2 mmol) followed by the dropwise addition of methanesulfonyl chloride (0.24 mL, 3.1 mmol). The reaction was stirred for 30 minutes at 0° C. The reaction was poured into a mixture of saturated NaHCO3 and ethyl acetate. The organic phase was separated and the aqueous phase reextracted with three portions of ethyl acetate. The combined organic layers were washed with a saturated NaCl solution, dried over anhydrous K2CO3, filtered, and concentrated in vacuo to yield 3-(5-ethanesulfonylamino-1H-indol-3-yl)propyl methanesulfonate (0.75 g, >99%) which was used without further purification.
Reaction SMILES: CS(C)=O.[C:5](Cl)(=[O:9])[C:6](Cl)=O.[CH2:11]([N:13]([CH2:16][CH3:17])[CH2:14]C)[CH3:12]>ClCCl>[CH3:14][N:13]1[CH2:16][CH2:17][CH:12]([CH2:6][CH:5]=[O:9])[CH2:11]1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CN1CCC(CC=O)C1
Temperature: 25 °C

Procedure:
Dimethylsulphoxide (0.36 ml) was added dropwise to a solution of oxalyl chloride (0.33 ml) in dry dichloromethane (8 ml) at -72°, with stirring under nitrogen. The solution was stirred at -72° for 5 min then a solution of the compound of stage (i) (325 mg) in dry dichloromethane (5 ml) was added in a stream over 3 min. The solution was stirred at -72° for 15 min then triethylamine (1.75 ml) was added. The mixture was then warmed to room temperature over 1 h. The solvent and excess triethylamine were evaporated to give the crude title compound which was used immediately in the next step.
Reaction SMILES: [CH3:1][O-:2].[Na+].C([O:6][C:7]([C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:11]([C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][N:21]=2)[N:10]=1)=[O:8])C.O>CO.C1(C)C=CC=CC=1.[Cu]Br>[CH3:1][O:2][C:23]1[CH:24]=[CH:25][C:20]([N:11]2[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[CH:13][C:9]([C:7]([OH:6])=[O:8])=[N:10]2)=[N:21][CH:22]=1
Reactant: CCOC(=O)c1cc(-c2ccccn2)n(-c2ccc(Br)cn2)n1
Reactant: C[O-]
Agent: [Cu]Br
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-n2nc(C(=O)O)cc2-c2ccccn2)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.5 %

Procedure:
In an argon atmosphere at room temperature, sodium methoxide (1.74 g) and copper(I) bromide (0.231 g) were added to the above-obtained 1-(5-bromo-2-pyridyl)-5-(2-pyridyl)pyrazole-3-carboxylic acid ethyl ester (3.00 g) in a mixture of methanol (30 mL) and toluene (30 mL). The resultant mixture was refluxed under heat for 47 hours, and then cooled in air. Water (50 mL) was added to the reaction mixture, followed by stirring at room temperature for 1.5 hours. The reaction mixture was partitioned by use of water, acetic acid (10 mL), and methanol-chloroform (1:10) solvent mixture. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, to thereby give the title compound as a solid (1.68 g, 71%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[F:14][C:15]1[CH:16]=[C:17]([OH:22])[CH:18]=[CH:19][C:20]=1[F:21]>>[F:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[F:21])[O:22][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11]
Reactant: Oc1ccc(F)c(F)c1
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Product: O=Cc1ccc(Oc2ccc(F)c(F)c2)c(C(F)(F)F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 4-fluoro-3-(trifluoromethyl)benzaldehyde and 3,4-difluorophenol.