Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15].[C:20]([CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]=1)O)#[CH:21]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([O:16][CH:22]([C:20]#[CH:21])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]=1)=[O:15]
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Reactant: C#CC(O)c1cccc(Oc2ccccc2)n1
Product: C#CC(OC(=O)C(Nc1ccc(C(F)(F)F)cc1Cl)C(C)C)c1cccc(Oc2ccccc2)n1

Procedure:
Following the procedure of Example 11, 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid is reacted with α-ethynyl(6-phenoxy-2-pyridyl)methanol to yield the ester, α-ethynyl(6-phenoxy-2-pyridyl)methyl 2-(2-chloro-4-trifluoromethylphenyl-amino)-3-methylbutanoate, MS m/e 502 (M+).
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][N:28]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.ClC1C=C([N+]([O-])=O)C=CN=1>>[N+:33]([C:31]1[CH:30]=[CH:29][N:28]=[C:27]([C:24]2[O:23][C:22]([C:9](=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:26][CH:25]=2)[CH:32]=1)([O-:35])=[O:34]
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2cc([N+](=O)[O-])ccn2)o1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: O=[N+]([O-])c1ccnc(Cl)c1
Product: O=C(CCCCCCc1ccccc1)c1ncc(-c2cc([N+](=O)[O-])ccn2)o1
Yield: 66 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)-5-(4-nitropyridin-2-yl)oxazole. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (190 mg, 0.287 mmol) and 2-chloro-4-nitropyridine following General Procedure A. Flash chromatography (10% EtOAc/hexanes) yielded the title compound as a thick oil (98 mg, 66%): 1H NMR (CDCl3, 400 MHz) δ 8.91 (dd, 1H, J=5.3, 0.6 Hz), 8.33 (d, 1H, J=2.1), 7.93 (dd, 1H, J=5.3, 2.1 Hz), 7.78 (s, 1H), 7.28-7.24 (m, 2H), 7.18-7.15 (m, 3H), 4.90 (dd, 1H, J=7.3, 5.8 Hz), 2.60 (t, 2H, J=7.8 Hz), 1.96 (m, 2H), 1.62 (m, 2H), 1.36 (m, 4H), 0.92 (s, 9H), 0.12 (s, 3H), 0.03 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 166.9, 154.6, 152.2, 150.1, 149.1, 142.7, 128.3, 128.2, 127.5, 125.5, 114.8, 111.4, 68.7, 36.4, 35.9, 31.3, 29.1, 25.7, 25.7, 25.0, 18.2, −5.0, −5.1.
Reaction SMILES: [CH:1]1([NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([NH:27][S:28](=[O:41])(=[O:40])[NH:29][C:30]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[O:31])=[CH:26][C:20]=4[S:19](=[O:43])(=[O:42])[N:18]=3)[C:7]2=[O:44])[CH2:4][CH2:3][CH2:2]1.[CH3:45][Si](C=[N+]=[N-])(C)C>O1CCCC1.CO>[CH:1]1([NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([NH:27][S:28](=[O:41])(=[O:40])[N:29]([CH3:45])[C:30]([O:32][CH2:33][C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)=[O:31])=[CH:26][C:20]=4[S:19](=[O:43])(=[O:42])[N:18]=3)[C:7]2=[O:44])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NC3CCC3)c1=O)N2)OCc1ccccc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C(=O)OCc1ccccc1)S(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NC3CCC3)c1=O)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
A solution of the product of Example 465 (0.045 g, 0.07 mmol) in 1:1 tetrahydrofuran/methanol (2 ml) at −10° C. was treated dropwise with trimethylsilyl diazomethane (2.0 M in hexanes, 70 μL, 0.14 mmol), stirred at 25° C. for 16 hours and concentrated under reduced pressure to provide the title compound (0.045 g, 98% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:7]1([Mg]Cl)[CH:11]=[CH:10][CH:9]=[CH:8]1>>[CH2:2]([C:11]1[CH2:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCBr
Reactant: Cl[Mg]C1C=CC=C1
Product: CCCCCC1=CC=CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 1-bromopentane (109.8 g, 0.727 mol) was added cyclopentadienyl magnesium chloride (800 mL of 1M solution in THF, 0.8 mol) at 0° C. in 15 minutes. After stirring for an additional 2 hours at 0° C., the mixture was warmed to room temperature. After stirring overnight, the reaction was quenched with a mixture of ice and water. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum at room temperature gave a brown liquid (101.4 g, crude pentylcyclopentadiene). To the crude pentylcyclopentadiene (50 g) dissolved in THF (200 mL) was added n-BuLi (35 mL of 10 M in hexanes, 0.35 mol) at 0° C. The mixture was warmed up to room temperature and stirred overnight. The anion solution was added to benzophenone (60.7 g, 0.334 mol) dissolved in THF (280 mL) at 0° C. in 25 minutes. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched with a mixture of ice and 10% HCl aqueous solution. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum at 50° C. gave a dark red viscous oil. The oil was dissolved in heptane and filtered through silica gel. The product was collected by washing the silica gel with 5-10% CH2Cl2 in heptane. Removal of the solvent gave the desired product (74.3 g) as a dark red viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:10][C:11]([O:14][C:15]([N:17]1[CH2:21][C@H:20]([C:22](O)=[O:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])[CH3:12].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl.O>[C:11]([O:14][C:15]([N:17]1[CH2:18][CH2:19][C@@H:20]([C:22]([N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)[NH2:9])=[O:23])[CH2:21]1)=[O:16])([CH3:13])([CH3:12])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)O)C1
Reactant: NNc1ccc(F)cn1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)N(N)c2ccc(F)cn2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
To a brown solution of (5-fluoro-pyridin-2-yl)-hydrazine (590 mg, 4.64 mmol), (R)-1-N-BOC-beta proline (Manchester Organics, 1.00 g, 4.64 mmol) and HOBt.H2O (71.1 mg, 0.464 mmol) in DCM (20 mL) at RT was added EDC (1.07 g, 5.57 mmol) (CARE: exotherm to 35° C.) and the resulting solution stirred at RT for 4 h. Water (20 mL) was added and the mixture shaken. The aqueous was extracted with DCM (20 mL), then the combined organics were passed through a hydrophobic frit and concentrated in vacuo to 1 mL volume. FCC, using 1-10% MeOH in DCM, gave the title compound as a pale brown foam (1.37 g, 91%). LCMS (Method 3): Rt 2.93 min, m/z 347 [MNa+].
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][CH:4]1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O>N1C=CC=CC=1>[CH3:22][S:23]([O:1][CH2:2][CH:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5][CH:4]1[C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)(=[O:25])=[O:24]
Reactant: Cc1ccc(C2Sc3ccccc3NC(=O)C2CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(C2Sc3ccccc3NC(=O)C2COS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
3 g of 2,3-dihydro-3-hydroxymethyl-2-(p-tolyl)-1,5-benzothiazepin-4(5H)-one prepared as described in Reference Example 3 was dissolved in 15 ml of pyridine. 1.3 g of methanesulfonyl chloride was added to the solution and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and the precipitated crystals were separated by filtration and recrystallized from dichloromethane-n-hexane to obtain 3.3 g of 2,3-dihydro-3-[(methylsulfonyloxy)methyl]-2-(p-tolyl)-1,5-benzothiazepin-4(5H)-one as colorless needles having a melting point of 207° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([NH:8][C:9]2[N:10]=[CH:11][C:12]3[N:17]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:15][C:13]=3[N:14]=2)[CH:7]=1.[Cl:23][C:24]1[C:32]([C:33]2([C:36]#[N:37])[CH2:35][CH2:34]2)=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:19]([NH:18][C:16]1[S:15][C:13]2[N:14]=[C:9]([NH:8][C:6]3[CH:7]=[C:2]([NH:1][C:26](=[O:27])[C:25]4[CH:29]=[CH:30][CH:31]=[C:32]([C:33]5([C:36]#[N:37])[CH2:34][CH2:35]5)[C:24]=4[Cl:23])[CH:3]=[CH:4][C:5]=3[CH3:22])[N:10]=[CH:11][C:12]=2[N:17]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1nc2cnc(Nc3cc(N)ccc3C)nc2s1
Reactant: N#CC1(c2cccc(C(=O)O)c2Cl)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cnc(Nc3cc(NC(=O)c4cccc(C5(C#N)CC5)c4Cl)ccc3C)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
A solution of N-{5-[(5-amino-2-methylphenyl)amino][1,3]thiazolo[5,4-d]pyrimidin-2-yl}acetamide (120 mg, 382 μmol) produced in Example D35(v), 2-chloro-3-(1-cyanocyclopropyl)benzoic acid (110 mg, 500 μmol) produced in Example D19(ii) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (189 mg, 500 μmol) in pyridine (4 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→95/5), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (133 mg, 67%) as colorless crystals.
Reaction SMILES: [H-].[Na+].OC1C=CC(C(O)=O)=CN=1.IC.[CH3:15][N:16]1[C:21](=[O:22])[CH:20]=[CH:19][C:18]([C:23]([O:25]C)=[O:24])=[CH:17]1>CO>[CH3:15][N:16]1[C:21](=[O:22])[CH:20]=[CH:19][C:18]([C:23]([OH:25])=[O:24])=[CH:17]1
Reactant: COC(=O)c1ccc(=O)n(C)c1
Agent: O=C(O)c1ccc(O)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: Cn1cc(C(=O)O)ccc1=O
Temperature: 62 °C

Procedure:
Sodium hydride (2.87 g, 60%, 71.8 mmol) was added slowly to methanol (62.5 mL) with stirring. 6-Hydroxy-nicotinic acid (5 g, 35.9 mmol) was added slowly, and the reaction mixture was heated to 62° C. Iodomethane (8.96 mL, 143.7 mmol) was added and the reaction was stirred overnight. The mixture was then cooled to room temperature and filtered to remove undissolved starting material. The filtrate was concentrated to yield a yellow powder which NMR analysis showed contained the title compound and methyl 1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate. This mixture was used in the subsequent reaction.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[CH:37]=[CH:36][C:16]([CH2:17][S:18][C:19]2[NH:23][CH:22]([CH:24]([C:26]3[CH:35]=[CH:34][CH:33]=[C:32]4[C:27]=3[CH:28]=[CH:29][CH:30]=[N:31]4)[CH3:25])[CH2:21][N:20]=2)=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl.[Cl-].[Na+].O>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][S:18][C:19]2[NH:23][C:22]([CH:24]([C:26]3[CH:35]=[CH:34][CH:33]=[C:32]4[C:27]=3[CH:28]=[CH:29][CH:30]=[N:31]4)[CH3:25])=[CH:21][N:20]=2)=[CH:36][CH:37]=1
Reactant: COc1ccc(CSC2=NCC(C(C)c3cccc4ncccc34)N2)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CSc2ncc(C(C)c3cccc4ncccc34)[nH]2)cc1
Temperature: 25 °C
Yield: 74.1 %

Procedure:
A Swern-type reagent was formed in standard fashion: oxalyl chloride (9.15 mL as a 2M soln. in CH2Cl2) in CH2Cl2 (23 mL) was cooled to −78° C. and treated with a solution of DMSO (2.85 mL, 36.8 mmol) in CH2Cl2 (23 mL) for 30 m. To this solution was added 5-{1-[2-(4-methoxy-benzylsulfanyl)-4,5-dihydro-3H-imidazol-4-yl]-ethyl}-quinoline (Intermediate E5) (4.7 g, 12.4 mmol) in CH2Cl2 (30 mL) and stirring continued for 45 m at −78° C. Triethylamine (9 mL) was added at −78° C. and warmed to rt for 40 m. The reaction mixture was diluted with brine and CH2Cl2. The aqueous layer was extracted with ethyl acetate. The organic solution was dried over MgSO4, filtered and evaporated to dryness. Chromatography on SiO2 with 80 to 100% ethyl acetate:hexanes yielded 5-{1-[2-(4-methoxy-benzylsulfanyl)-3H-imidazol-4-yl]-ethyl}-quinoline (Intermediate E6) 3.45 g (74%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[CH3:31][O:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>>[CH3:31][O:32][C:33]1[CH:38]=[C:37]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)[NH:20][C:19]3=[O:29])[CH:36]=[CH:35][CH:34]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Product: COc1cccc(-c2ccc3nc(-n4cc(C(=O)O)cn4)[nH]c(=O)c3c2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 3-methoxyphenylboronic acid in step C. MS (ESI): mass calcd. for C19H14N4O4, 362.1; m/z found, 363.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.01 (br s, 1H), 12.91 (br s, 1H), 8.98 (s, 1H), 8.34 (s, 1H), 8.28 (s, 1H), 8.18 (d, J=6.7 Hz, 1H), 7.78 (s, 1H), 7.44 (t, J=7.9 Hz, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.29 (s, 1H), 7.00 (dd, J=8.2, 1.8 Hz, 1H), 3.86 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:2].[N-:13]=[N+:14]=[N-:15].[Na+].[Cl-].[NH4+].N([O-])=O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[NH:13]1[C:1]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=2)[C:6]([O:8][CH3:9])=[O:7])=[N:2][N:15]=[N:14]1
Reactant: COC(=O)c1cccc(C#N)c1
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2nnn[nH]2)c1
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
1.00 g (6.21 mmol) of the compound from Example 47A are initially charged in 18 ml of dry DMF. 2.42 g (37.23 mmol) of sodium azide and 1.99 g (37.23 mmol) of ammonium chloride are then added. The reaction mixture is stirred at 120° C. for 2.5 h. After cooling to RT the mixture is poured into a mixture of 30 ml of ice-water and 10 ml of ethyl acetate. 2.57 g (37.23 mmol) of sodium nitrite are added to this mixture to destroy excess azide. By addition of 6 N hydrochloric acid, the pH is then adjusted to 1-2 and the mixture is stirred at RT for 30 min. The mixture is extracted three times with in each case 20 ml of a 1:1 mixture of ethyl acetate and THF. The precipitate formed is filtered off with suction and dried under reduced pressure. In order to isolate more product, the separated organic phase is washed in each case once with in each case 10 ml of water and saturated aqueous sodium chloride solution. After drying over magnesium sulfate the solvent is removed on a rotary evaporator. Both solids are combined and used for the next step.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH:19]=[O:20])=[C:11]2Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH:19]=[O:20])=[C:11]2[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1c(Cl)n(S(=O)(=O)c2ccccc2)c2ccccc12
Reactant: C1CNCCN1
Product: O=Cc1c(N2CCNCC2)n(S(=O)(=O)c2ccccc2)c2ccccc12
Yield: 45 %

Procedure:
1-Benzenesulfonyl-2-chloro-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 1-benzenesulfonyl-2-(piperazin-1-yl)-1H-indole-3-carboxaldehyde (45% yield). ESI/MS 370 (M+H); RT=2.59 min.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:22])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][C:19](O)=[O:20])([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:26])=O>C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([CH3:22])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][C:19]([Cl:26])=[O:20])([CH3:17])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(CC(=O)O)O2
Solvent: c1ccccc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(CC(=O)Cl)O2
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
In a dry flask, a solution of 15.32 g. (50 mmol.) of (±)-(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl)acetic acid in 100 ml. of benzene was heated under N2 to 50°C. as 21.15 ml. (0.25 mol.) of oxalyl chloride was added over 20 minutes. The solution was stirred at 50°C. for another 20 minutes, cooled and stripped of solvent to produce (±)-(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl)acetyl chloride. To a solution of this acid chloride in 200 ml. of dry toluene was added 15 g. of sodium acetate and 1.5 g. of 10% by weight palladium on 90% by weight carbon and 0.30 ml. of quinoline. This mixture was hydrogenated in a Parr apparatus. After 12 hours, the uptake of H2 (about 55 mmole) had virtually ceased. The catalyst was removed by filtration and the filtrates were stripped of solvent. The residue was taken up in ether, washed with 2N aqueous HCl, saturated aqueous sodium bicarbonate solution and saturated brine, dried over sodium sulfate and stripped of solvent to give 15.4 g. of light yellow solid which was chromatographed on 1 kg. of 0.063-0.2 mm silica gel. Elution with 95:5 parts by volume benzene-ethyl acetate gave 11.0 g. of light yellow resin. The material from two such reactions was combined and crystallized from acetone-petroleum ether (b.p. 30°-60°C.) to give (±)-(6-acetoxy-2,5,7,8-tetramethylchroman-2yl)-acetaldehyde as a white powder, sint 66.5°C., m.p. 68°-70°C.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]([S:13][CH3:14])[C:9]([F:12])([F:11])[F:10])(=O)=O.[F:15][C:16]([F:28])([F:27])[CH2:17][CH2:18][S:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])(=[O:21])=[O:20].[H-].[Na+].Cl>CS(C)=O>[F:12][C:9]([F:10])([F:11])[CH:8]([S:13][CH3:14])[CH2:7][CH2:6][CH:22]([S:19]([CH2:18][CH2:17][C:16]([F:27])([F:28])[F:15])(=[O:21])=[O:20])[C:23]([O:25][CH3:26])=[O:24]
Reactant: CSC(CCOS(C)(=O)=O)C(F)(F)F
Reactant: COC(=O)CS(=O)(=O)CCC(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(CCC(SC)C(F)(F)F)S(=O)(=O)CCC(F)(F)F
Temperature: 60 °C
Reaction time: 120 h
Yield: 26.1 %

Procedure:
To a solution of 5.0 g of 4,4,4-trifluoro-3-methylthio-butyl methanesulfonate and 4.6 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 50 ml of dimethyl sulfoxide was added 0.8 g of sodium hydride (60% in oil) at room temperature. The reaction mixture was heated to 60° C., stirred at the same temperature for 5 days, and then allowed to stand to cool to nearly room temperature. To the reaction mixture was added 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 2.00 g of methyl 6,6,6-trifluoro-5-methylthio-2-(3,3,3-trifluoropropylsulfonyl)hexanoate (hereinafter referred to as the present compound (27)).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1.[I:19]I.O>C1COCC1>[I:19][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2cc(I)ccc2c1
Temperature: -75 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (2.5 M in hexanes, 92 mL, 230 mmol) is added via dropping funnel to a solution of 2-bromo-6-methoxy-naphthalene (49.5 g, 209 mmol) in anhydrous THF (2 L) at −75° C. at such a rate that the temperature is kept below −70° C. (over 45 min). The resulting yellow solution is stirred for 15 min at −75° C. A solution of iodine (58.3 g, 230 mmol) in anhydrous THF (100 mL) is added via a fresh dropping funnel until the red iodine colour persists (addition over 45 min, max. temp. −68° C.). The mixture is warmed to rt. and water (1.3 L) is added. The mixture is extracted with dichloromethane (2 L) with brine (500 mL) being added to aid the separation. The aqueous fraction is back-extracted with dichloromethane (1 L). The combined organic fractions are reduced in vacuo to approx. 1 L, washed with saturated aqueous sodium metabisulphite (100 mL), then brine (200 mL), dried (Na2SO4), filtered and solvent removed in vacuo. The crude residue is recrystalised from IMS (1.9 l) washing with ice-cold IMS (2×150 mL) and dried in a vacuum oven at 70, ° C. to give a light cream crystalline solid. 46.45 g, 78%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([C:19]2[N:23](COCC[Si](C)(C)C)[C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[N:21][C:20]=2[Cl:38])(O)[CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].Cl.C(=O)([O-])O.[Na+]>C(O)C>[Cl:38][C:20]1[N:21]=[C:22]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[NH:23][C:19]=1/[C:10](/[C:4]1[CH:5]=[CH:6][C:7]([S:8][CH3:9])=[C:2]([Cl:1])[CH:3]=1)=[CH:11]/[CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CSc1ccc(C(O)(CC2CCOCC2)c2c(Cl)nc(-c3ccccn3)n2COCC[Si](C)(C)C)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CSc1ccc(/C(=C\C2CCOCC2)c2[nH]c(-c3ccccn3)nc2Cl)cc1Cl
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
To a solution of 1-[3-chloro-4-(methylsulfanyl)phenyl]-1-(4-chloro-2-(pyridin-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanol (1.47 g) in ethanol (40 mL) was added 3M hydrochloric acid (40 mL), and the mixture was stirred at 80° C. for 1.5 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-80:20, volume ratio) to give the title compound (1.10 g, yield 100%) as a colorless amorphous solid. MS: 446 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].S(=O)(=O)(O)O.[C:24](=O)(O)[O-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O:14][CH3:24])=[O:13]
Reactant: COc1ccccc1Sc1ccccc1C(=O)O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccccc1Sc1ccccc1OC
Temperature: 25 °C

Procedure:
Dissolve 115 gm of the acid of Step A in 3.5 1. of methanol and add slowly 25 cc of sulfuric acid. Stir under reflux for 72 hours. Cool the reaction mixture to room temperature.and add 100 gm of sodium bicarbonate in portions. Stir for an additional hour, filter and strip the filtrate to dryness. Dissolve the residue in methylene chloride and wash the solution three times with water. Dry the solution and strip to an oil which solidifies. (m.p. 82°-84° C.).