Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Br:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[CH2:18][OH:19])=[CH:12][CH:11]=1.N1C=CN=C1>ClCCl.Cl>[Br:9][C:10]1[CH:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[CH2:18][O:19][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])=[CH:14][CH:15]=1
Reactant: OC/C=C/c1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC/C=C/c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.4 %

Procedure:
tert-Butyl chlorodimethylsilane (1.33 g, 19.5 mmol) was added to a stirred solution of (E)-3-(4-bromo-phenyl)-prop-2-en-1-ol (3.20 g, 15.0 mmol), and imidazole (2.72 g, 18.0 mmol) in dry dichloromethane (75 ml) and the resulting mixture stirred at room temperature for 18 h, a colourless precipitate being formed. The mixture was diluted with dichloromethane (100 ml) and 1N hydrochloric acid (100 ml). The aqueous layer was separated, further extracted with dichloromethane (2×100ml) and the combined organic layers washed with brine, dried (MgSO4) and evaporated. The product was purified by column chromatography on silica gel (1% diethyl ether in n-heptane eluent) to give the colourless solid, (E)-[3-(4-bromo-phenyl)-allyloxy]-tert-butyldimethylsilane (4.39 g, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([C:29]3[NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[N:30]=3)=[O:28])[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].[CH3:45][C:46]([CH3:53])=[CH:47][CH2:48][O:49][CH2:50][CH2:51]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.CO.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([C:29]3[N:30]([CH2:51][CH2:50][O:49][CH2:48][CH:47]=[C:46]([CH3:53])[CH3:45])[C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)=[O:28])[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: CC(C)=CCOCCO
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4CCOCC=C(C)C)CC3)(c3ccccc3)C2)cc(OC)c1OC
Reaction time: 18 h

Procedure:
Combine 1-(3,4,5-trimethoxy-benzoyl)-3-[2-[4-[1H-benzoimidazole-2-carbonyl]-piperidin-1-yl]-ethyl]-3-phenyl-pyrrolidine (0.62 g, 1.0 mmol), and 2-(3,3-dimethylallyloxy)-ethanol (0.14 g, 1.0 mmol), triphenylphosphine (0.33 g, 1.27 mmol) in tetrahydrofuran (2 mL). Add dropwise diethyl azodicarboxylate ((0.2 mL, 1.27.mmol). After 18 hours, evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 10% methanol/ethyl acetate to give the title compound: Rf=0.35 (silica gel, 10% methanol/ethyl acetate).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].[C:17]1([CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:24][CH2:25]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O.C(OCC)(=O)C>[C:17]1([CH:23]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:24][CH2:25][O:10][C:3]2[C:2]([I:1])=[CH:7][C:6]([I:8])=[CH:5][C:4]=2[I:9])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCCC(c1ccccc1)c1ccccc1
Reactant: Oc1c(I)cc(I)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Ic1cc(I)c(OCCC(c2ccccc2)c2ccccc2)c(I)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A mixture of 2,4,6-triiodophenol (0.78 g, 1.65 mmol) and potassium carbonate (0.25 g, 1.82 mmol, 1.1 eq) in 5 ml of dimethylformamide was heated at 60° C. for 1 hr, cooled and then 3,3-diphenylpropyl bromide (0.5 g, 1.82 mmol) was added. After stirring for 30 minutes at room temperature the mixture was heated at 60° C. for 24 hrs. The mixture was then cooled, poured into water and the crude product was isolated by ethyl acetate extraction. The product was purified by silica gel chromatography (2.5% ethyl acetate-hexanes) followed by recrystallization from hexanes to give 0.53 g (48%) of a solid. Mp: 120°-121° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][CH:18]=O)[O:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:20]1([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH:26]([N:27]1[CH2:32][CH2:31][N:30]([CH2:18][CH2:17][CH2:16][CH2:15][CH:13]2[O:12][N:11]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH2:14]2)[CH2:29][CH2:28]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=CCCCC1CC(c2cccc([N+](=O)[O-])c2)=NO1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(C2=NOC(CCCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)C2)c1
Yield: 54.8 %

Procedure:
4-[3-(3-Nitrophenyl)-4,5-dihydroisoxazol-5-yl]butanal (30.0 mg, 0.114 mmol), 1-(diphenylmethyl)piperazine (26.2 mg, 0.104 mmol), molecular sieve (5 beads) and NaBH(OAc)3 (66.1 mg, 0.312 mmol) were reacted in 3 mL of methylene chloride 3 mL for about 12 hr. With the following processes the same as in Example 1, 28.4. mg (54.8%) of the target compound was obtained.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][NH2:17])=[N:14][N:15]=3)[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[NH:21][CH:22]=[N:23]2.C(O)(CC)C>>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][NH:17][C:19]4[N:27]=[CH:26][N:25]=[C:24]5[C:20]=4[NH:21][CH:22]=[N:23]5)=[N:14][N:15]=3)[N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NCc1nnc2ccc(-c3ccccc3)nn12
Solvent: CCC(C)O
Product: c1ccc(-c2ccc3nnc(CNc4ncnc5nc[nH]c45)n3n2)cc1
Temperature: 100 °C
Yield: 32.8 %

Procedure:
A 15 mL tube was charged with (6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methanamine (0.100 g, 0.444 mmol), 6-chloropurine (0.103 g, 0.666 mmol), and sec-butanol (3.00 ml, 32.4 mmol), sealed, then heated in a 100° C. oil bath for 5 hours. The reaction mixture was concentrated and the yellow residue was purified by MPLC using a 40 g RediSep column, eluting with a gradient of 3-8% MeOH/DCM over 80 minutes. N-((6-phenyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7H-purin-6-amine (0.0500 g, 32.8% yield) was isolated as the hydrochloride salt.
Reaction SMILES: C([N:11]([CH3:35])[C@H:12]([C:16]([NH:18][C@H:19]([C:32](N)=[O:33])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])(OCC1C=CC=CC=1)=O.[NH:36](C)[C@H](C(N[C@H](C(N)=O)CC1C=CC(O)=C(C(C)(C)C)C=1)=[O:42])C(C)C.[NH:61]([C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[C@H:62]([C:70]([OH:72])=O)[CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1.C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>CO.CN(C=O)C.C(OCC)(=O)C.[C].[Pd]>[NH:61]([C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[C@H:62]([C:70]([N:11]([CH3:35])[C@H:12]([C:16]([NH:18][C@H:19]([C:32]([OH:33])=[O:42])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:29])([CH3:30])[CH3:31])[CH:22]=1)=[O:17])[CH:13]([CH3:14])[CH3:15])=[O:72])[CH2:63][C:64]1[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1.[NH3:36]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)[C@@H](C(=O)N[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)OCc1ccccc1
Reactant: CN[C@H](C(=O)N[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)C(C)C
Agent: [Pd]
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)[C@@H](C(=O)N[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(=O)O)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Product: N
Reaction time: 13 h

Procedure:
A mixture of 810 mg of Z-N-Me-Val-Tyr(3-tBu)-NH2 and 300 mg of 10% palladium carbon in 50 ml of methanol was stirred under a hydrogen stream for 13 hours and a half. The reaction mixture was filtered and the filtrate was distilled off under reduced pressure. To a solution in DMF (12 ml) of 470 mg (1.35 mmol) of the resulting N-Me-Val-Tyr(3-tBu)-NH2, 390 mg (1.48 mmol) of Boc-Phe-OH and 230 mg (1.48 mmol) of HOBT, 0.23 ml (1.48 mmol) of DIC was added dropwise under cooling with ice and the mixture was stirred at room temperature for 13 hours and a half. The reaction mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent consisting of methylene chloride, methanol and aqueous ammonia at a ratio of 100:3:1) to give Boc-Phe-N-Me-Val-Tyr(3-tBu)-NH3 in the amount of 380 mg (47%).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=1.[OH-].[K+].C(O)C.Cl>O>[F:1][C:2]([F:30])([F:31])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
A mixture of 6.0 g. of ethyl 4-[15-(trifluoromethyl)pentadecylamino]benzoate, 4.0 g. of potassium hydroxide and 50 ml. of ethanol is stirred at 80° C. for 4 hours. The mixture is diluted with water and adjusted to pH 5.5 by the addition of concentrated hydrochloric acid. Cooling and filtration affords a solid which is recrystallized from acetone to yield the product as a white solid.
Reaction SMILES: [I-].[K+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]Cl)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1.C[NH:28]C1CC1.O1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][NH:28][CH2:33][CH:34]4[CH2:36][CH2:35]4)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: C1CCOC1
Reactant: CNC1CC1
Agent: [I-]
Agent: [K+]
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CNCC3CC3)n1-2

Procedure:
In the manner given in Example 2, potassium iodide, 8-chloro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine in tetrahydrofuran is treated with methylcyclopropylamine to give 8-chloro-1-[(cyclopropylmethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:18]2=[CH:19][CH:20]=[N:21][CH:22]=[C:17]2[C:5]2[C:6]([OH:16])=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH3:15])[CH3:11])=[CH:9][C:4]=2[O:3]1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([O:16][C:6]1[C:5]2[C:17]3[C:18]([C:2]([CH3:1])([CH3:23])[O:3][C:4]=2[CH:9]=[C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH3:15])[CH3:11])[CH:7]=1)=[CH:19][CH:20]=[N:21][CH:22]=3)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCC(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Solvent: c1ccncc1
Product: CCCCC(C)c1cc(OC(C)=O)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
10-Acetoxy-5,5-dimethyl-8-(2-hexyl)-5H-[1]benzopyrano[3,4-d]pyridine is prepared by reacting 5,5-dimethyl-10-hydroxy-8-(2-hexyl)-5H-[1]benzopyrano[3,4-d]pyridine and acetic anhydride in the presence of pyridine according to the method of Example 12.
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2([CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1)[CH3:2].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](F)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11]3([CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[CH:3]2[CH2:1][CH3:2])=[CH:21][CH:20]=1
Reactant: Fc1ccc(Cl)cc1
Reactant: CCC1Nc2ccccc2C12CCN(C)CC2
Product: CCC1N(c2ccc(Cl)cc2)c2ccccc2C12CCN(C)CC2

Procedure:
By following the procedure of Example 1c, 2-ethyl-1'-methylspiro[indoline-3,4'-piperidine], the free base of part a, is treated with 4-chlorofluorobenzene to yield 1-(4-chlorophenyl)-2-ethyl-1'-methylspiro[indoline-3,4'-piperidine].
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[F:19][C:20]1[CH:21]=[C:22]([C:2]2[CH:3]=[CH:4][C:5]([C@H:8]3[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]3)=[CH:6][CH:7]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(I)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3cccc(F)c3)cc2)CC1
Temperature: 25 °C

Procedure:
Into a reaction vessel under an atmosphere of nitrogen, 1-iodo-4-(trans-4-pentylcyclohexyl)benzene (T26; 50.0 g), 3-fluorophenylboronic acid (T27; 21.5 g), potassium carbonate (58.0 g), Pd (Ph3P)2Cl2 (2.95 g), water (200 ml), toluene (200 ml), and Solmix A-11 (200 ml) were put and heated under reflux for 8 hours. After the reaction mixture had been cooled to 25° C., the solution was poured into water (1,000 ml) and toluene (500 ml) and mixed. The mixture was then allowed to stand to be separated into two layers of an organic layer and an aqueous layer. Extraction into an organic layer was carried out and the resulting organic layer was fractionated. The extracts were washed with water, and dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure, and the residue was purified by means of fraction-collecting column chromatography using heptane as the eluent and silica gel as the stationary phase powder. The residue was further purified by recrystallization from a mixed solvent of ethyl acetate and Solmix A-11 (volume ratio of ethyl acetate Solmix A-11=1:1) and then dried, whereby 37.3 g of 3-fluoro-4′-(trans-4-pentylcyclohexyl)biphenyl (T28) was obtained. The yield based on the compound (T26) was 82.0%.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15](I)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:36]3[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=3)[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Reactant: OB(O)c1ccncc1
Product: CCCCCCc1cccc(-c2nc(-c3ccncc3)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 7, [2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 2) was reacted with pyridin-4-yl-boronic acid to give the title compound as light yellow oil. MS: 500.3 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[N:11](CC2C=CC(OC)=CC=2OC)[CH2:10][C:9]2[S:23][N:24]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:8]=2[C:7]1=[O:32])=[O:5])[CH3:2].O=S(Cl)Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:32])=[C:8]2[C:25]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:24][S:23][C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1C(=O)c2c(-c3ccccc3)nsc2CN1Cc1ccc(OC)cc1OC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1ncc2snc(-c3ccccc3)c2c1O
Temperature: 25 °C
Yield: 71.1 %

Procedure:
To a solution of 6-(2,4-dimethoxy-benzyl)-4-oxo-3-phenyl-4,5,6,7-tetrahydro-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (5.42 g, 11.99 mmol) in CH2Cl2 was added SOCl2 (1.31 mL, 17.98 mmol) and the mixture was stirred at r.t. After 3 h the mixture was filtered and the filter cake was washed with hexanes/CH2Cl2(4/1, 12 mL). The solid was then suspended in sat. NaHCO3 (200 mL) and the mixture extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine, water, dried over MgSO4, and concentrated in vacuo to give the title compound as yellow solid (2.56 g): MS (m/z) 301.1 (M+1).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([CH3:7])[NH:5][C:4](=[O:8])[CH2:3]1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])(=O)=O.O>C1COCC1>[Si:23]([O:1][C@@H:2]1[C@H:6]([CH3:7])[NH:5][C:4](=[O:8])[CH2:3]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: C[C@@H]1NC(=O)C[C@@H]1O
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1NC(=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
A solution of (4S,5S)-4-hydroxy-5-methylpyrrolidin-2-one (3.0 g) in THF (50 mL) was cooled to 0° C., 2,6-lutidine (4.55 mL) and tert-butyldimethylsilyl trifluoromethanesulfonate (6.6 mL) were added thereto and, after warming to room temperature, the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1→1/2) to give the title compound as a colorless solid (yield: 4.54 g, 76%).
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[F:9][C:10]([F:28])([F:27])[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2SCCC[S+]=2)=[CH:17][CH:16]=1.[Br:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1.C(N(CC)CC)C.[FH:44].[FH:45].F.C(N(CC)CC)C.BrBr>ClCCl>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][C:21]([F:45])([F:44])[C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][CH2:11][C:10]([F:9])([F:27])[F:28])=[CH:20][CH:19]=2)=[CH:32][CH:31]=1
Reactant: Oc1ccc(Br)cc1
Reactant: FC(F)(F)CCCOc1ccc(C2=[S+]CCCS2)cc1
Reactant: F
Agent: BrBr
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: FC(F)(F)CCCOc1ccc(C(F)(F)Oc2ccc(Br)cc2)cc1
Temperature: -55 °C
Reaction time: 0.75 h
Yield: 67.4 %

Procedure:
77.0 g (164 mmol) of 2-[4-(4,4,4-trifluorobutoxy)phenyl]-5,6-dihydro-4H-1,3-dithiin-1-ium trifluoromethanesulfonate, are solubilised in 750 mL of dichloromethane. The solution is cooled down to −55° C. 42.5 g (245 mmol) of 4-bromophenol and 36.5 ml (262 mmol) of triethylamine dissolved in 300 ml of dichloromethane is added to the previous solution. The solution is cooled down to −70° C. and stirred for 45 minutes. 120 ml (736 mmol) of triethylamine trihydrofluoride are added to the mixture. A solution of 8.43 ml (164 mmol) of bromine in 60 ml of dichloromethane is added at this temperature. The reaction is stirred for one hour. The reaction is quenched by addition of NaHCO3. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Chromatography of the residue on 400 g silica gel using toluene: ethyl acetate 95:5 as eluent yielded 47 g of 1-bromo-4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}-benzene.
Reaction SMILES: B(Br)(Br)Br.[ClH:5].[CH3:6][C:7]1[N:11]([C:12]2[N:17]=[C:16]([O:18]C)[CH:15]=[C:14]([CH3:20])[N:13]=2)[N:10]=[CH:9][C:8]=1[C:21](=[O:37])[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:26][CH2:25]1.O>C(Cl)Cl>[ClH:5].[CH3:6][C:7]1[N:11]([C:12]2[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([CH3:20])[N:13]=2)[N:10]=[CH:9][C:8]=1[C:21](=[O:37])[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:26][CH2:25]1
Reactant: COc1cc(C)nc(-n2ncc(C(=O)CCN3CCN(c4ccccc4C)CC3)c2C)n1
Agent: BrB(Br)Br
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: Cc1cc(O)nc(-n2ncc(C(=O)CCN3CCN(c4ccccc4C)CC3)c2C)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.9 %

Procedure:
300 mg of boron tribromide was added to 3 ml of methylene chloride and the obtained solution was cooled. Into the solution was dropped a solution of 470 mg of 1-[5-methyl-1-(4-methoxy-6-methyl-2-pyrimidinyl)-4-pyrazolyl]-3-[4-(2-methylphenyl)-1-piperazinyl]-1-propanone hydrochloride in 100 ml of methylene chloride. After stirring at room temperature for 72 hours, water was added and the mixture was extracted with methylene chloride twice. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (silica gel 800 g, chloroform:methanol=10:1-5:1). Then the obtained product was converted into hydrochloride by adding a 1N hydrochloric acid/ethanol solution and recrystallized from ethanol to thereby give 150 mg of the title compound.
Reaction SMILES: [F:1][C:2]1([F:14])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][C:3]1([F:13])[F:12].C([Li])CCC.[Br:20]C(F)(F)C(F)(F)Br.[Cl-].[Na+]>O1CCCC1.O>[Br:20][C:11]1[C:5]2[O:4][C:3]([F:12])([F:13])[C:2]([F:1])([F:14])[O:7][C:6]=2[CH:8]=[CH:9][CH:10]=1
Reactant: FC1(F)Oc2ccccc2OC1(F)F
Reactant: FC(F)(Br)C(F)(F)Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: FC1(F)Oc2cccc(Br)c2OC1(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin (5.00 g, 24.0 mmol) in dry tetrahydrofuran (150 mL) is cooled to -78° C. under a nitrogen atmosphere. A solution of n-butyllithium (10.6 mL, 26.4 mmol of a 2.5M solution in hexanes) is added dropwise while maintaining the reaction temperature below -65° C. The reaction mixture is stirred at -78° C. for 30 min and then 1,2-dibromotetrafluoroethane (3.16 mL, 26.4 mmol) is added dropwise. After this addition is complete, the reaction mixture is allowed to come to room temperature. A small mount of water is slowly added to the mixture which is then poured into water. The aqueous mixture is saturated with sodium chloride and is extracted with diethyl ether. The combined organic extracts are dried (MgSO4), filtered, and concentrated under reduced pressure to afford the title compound of Step A.
Reaction SMILES: [CH2:1]([C:4]1[CH:27]=[CH:26][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][C:15]([C:21]([O:23]C)=[O:22])=[CH:14][C:13]=3[CH:25]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[S:18](=[O:19])(=[O:20])[CH2:17][CH2:16][C:15]([C:21]([OH:23])=[O:22])=[CH:14][C:13]=3[CH:25]=2)=[CH:26][CH:27]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1ccc(Oc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Temperature: 65 °C
Reaction time: 20 h
Yield: 65.9 %

Procedure:
Into a solution of methyl 7-(4-propylphenoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.40 g) in THF-methanol (10-5 ml) was added at room temperature a 1 M aqueous solution of potassium carbonate (3.0 ml), and the resulting mixture was stirred at 65° C. for 20 hours. After cooling to room temperature, 1 N hydrochloric acid (10 ml) was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with hexane to obtain 7-(4-propylphenoxy)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (254 mg) as light yellow crystals.