Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH3:11])=[N:8][C:7]=2[CH:12]=1.[K].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.O>CN(C=O)C>[CH3:11][C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:18]3[C:14](=[O:24])[C:15]4[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:17]3=[O:19])=[CH:12][C:7]=2[N:8]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1nc2cc(CBr)ccc2o1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2cc(CN3C(=O)c4ccccc4C3=O)ccc2o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 5-(bromomethyl)-2-methylbenzo[d]oxazole (400 mg; 1.76 mmol) in anh. DMF (2 ml) was treated portionwise with phthalimide potassium salt (327 mg; 1.76 mmol), and the resulting mixture was stirred at rt, under nitrogen, for 18 h. Water was added, and the resulting precipitate was collected by filtration, and washed with water. Drying under HV afforded 2-((2-methylbenzo[d]oxazol-5-yl)methyl)isoindoline-1,3-dione as a brown solid. LC-MS (conditions E): tR=0.66 min.; [M+H]+: 293.15 g/mol.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1.[CH3:19][N:20](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:11][C:9]1[CH:10]=[C:2]([C:19]#[N:20])[C:3]2[CH:4]=[N:5][N:6]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[C:7]=2[CH:8]=1
Reactant: COc1cc(Br)c2cnn(C3CCCCO3)c2c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1cc(C#N)c2cnn(C3CCCCO3)c2c1
Temperature: 145 °C
Yield: 86 %

Procedure:
A sealed microwave vial was charged with 4-bromo-6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (1.50 g, 4.82 mmol), Zn(CN)2 (0.62 g, 5.30 mmol), Pd(PPh3)4 (0.22 g, 0.19 mmol), and DMF (13 mL). The mixture was degassed for 5 min under nitrogen and then heated in a microwave reactor at 145° C. for 25 min. The mixture was diluted with EtOAc and filtered. The filtrate was partitioned between water and EtOAc, and the layers were separated. The organic layer was washed with water (3×), dried (Na2SO4), filtered, and concentrated in vacuo. The crude mixture was purified by SiO2 chromatography to afford 6-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-4-carbonitrile as a solid (1.06 g, 86%). MS (ESI) m/z: 258.2 [M+1]+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([B:9]([OH:11])[OH:10])=[CH:5][CH:4]=1)=[O:2].O[C:13]([C:16](O)([CH3:18])[CH3:17])([CH3:15])[CH3:14].O>C1(C)C=CC=CC=1>[CH3:14][C:13]1([CH3:15])[C:16]([CH3:18])([CH3:17])[O:11][B:9]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:8][CH:7]=2)[O:10]1
Reactant: CC(C)(O)C(C)(C)O
Reactant: O=Cc1ccc(B(O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)OB(c2ccc(C=O)cc2)OC1(C)C
Yield: 93.1 %

Procedure:
A suspension of 5 g (33.3 mmol) of 4-formylphenylboronic acid and 3.93 g (33.3 mmol) of pinacol in 25 ml of toluene was refluxed on a water separator. When all the water of reaction had been removed, a clarifying filtration was carried out, and the solvent was removed by distillation until the product started to crystallize, giving 7.2 g (31 mmol) of product.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][N:9]([CH3:29])[C@H:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])[C:11]([O:13][C@H](C1C=CC=CC=1)C)=[O:12]>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:8][N:9]([CH3:29])[C@H:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])[C:11]([OH:13])=[O:12]
Reactant: C[C@H](OC(=O)[C@@H](c1ccccc1F)N(C)C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CN(C)[C@@H](C(=O)O)c1ccccc1F
Reaction time: 4 h
Yield: 84.7 %

Procedure:
A mixture of (R)—((S)-1-phenylethyl) 2-(dimethylamino)-2-(2-fluorophenyl)acetate TFA salt (1.25 g, 3.01 mmol) and 20% Pd(OH)2/C (0.125 g) in ethanol (30 mL) was hydrogenated at room temperature and atmospheric pressure (H2 balloon) for 4 hours. The solution was then purged with Ar, filtered through diatomaceous earth (Celite®), and concentrated in vacuo. This gave the title compound as a colorless solid (0.503 g, 98%). 1HNMR (400 MHz, CD3OD) δ 7.53-7.63 (m, 2H), 7.33-7.38 (m, 2H), 5.36 (s, 1H), 2.86 (s, 6H). LCMS: Anal. Calcd. for C10H12FNO2: 197. found: 198 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:16]([CH3:23])[C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:7]=[C:8]([S:10]([F:15])([F:14])([F:13])([F:12])[F:11])[CH:9]=1)(=[O:3])[CH3:2].[Br-:24].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.S(=O)(=O)(O)O>CO.C1COCC1.[Br-].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>[Br:24][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([N:16]([CH3:23])[C:17](=[O:22])[C:18]([F:21])([F:19])[F:20])[CH:7]=[C:8]([S:10]([F:14])([F:15])([F:13])([F:12])[F:11])[CH:9]=1)=[O:3]
Reactant: [Br-]
Reactant: CC(=O)c1cc(N(C)C(=O)C(F)(F)F)cc(S(F)(F)(F)(F)F)c1
Agent: C[N+](C)(C)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: C1CCOC1
Product: CN(C(=O)C(F)(F)F)c1cc(C(=O)CBr)cc(S(F)(F)(F)(F)F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 164.6 %

Procedure:
N-[3-Acetyl-5-(pentafluorosulfanyl)phenyl]-2,2,2-trifluoro-N-methylacetamide (O2.075; 1.03 g) was dissolved in a mixture of methanol (20 ml) and THF (20 ml). Phenyltrimethylammonium tribromide (1.05 g) was added while stirring. After stirring at RT for 5 h, the mixture was left to stand overnight, then further phenyltrimethylammonium tribromide (100 mg) was added and the mixture was heated to 60° C. for 2 h. After cooling, the reaction mixture was added to 2 N sulfuric acid and stirred for 10 min. Then the aqueous phase was extracted three times with EA. The combined organic phases were dried over magnesium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 1.2 g of the title compound were obtained, which had sufficient purity for the next reactions.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[N:14]=[C:15]([NH2:27])[S:16][C:17]=1[C:18]1[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([S:25][CH3:26])[N:19]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:26][S:25]([C:20]1[N:19]=[C:18]([C:17]2[S:16][C:15]([NH2:27])=[N:14][C:13]=2[CH3:12])[CH:23]=[C:22]([CH3:24])[N:21]=1)=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(C)cc(-c2sc(N)nc2C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(-c2sc(N)nc2C)nc(S(C)=O)n1
Temperature: 25 °C

Procedure:
m-CPBA (57-86% purity, 6.0 g, 20-30 mmol) is added in portions to a rapidly stirring solution/suspension of 4-methyl-5-(6-methyl-2-methylsulfanyl-pyrimidin-4-yl)-thiazol-2-ylamine (6.0 g, 23.8 mmol) in dry dichloromethane (200 ml) at 0° C. After the addition (15 minutes) the reaction is allowed to warm slowly to room temperature. The mixture is cautiously added to saturated sodium bicarbonate solution (300 ml), shaken, and the organic extract is separated and dried (MgSO4). This first extract contains a 1:1 mixture of sulfoxide and sulfone. The aqueous phase is then partitioned with chloroform to extract the titled compound as yellow solid.
Reaction SMILES: [H][H].[CH2:3]([O:6][CH:7]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:25]CC3C=CC=CC=3)=[CH:13][C:14]=2[O:17]CC2C=CC=CC=2)[O:9][CH:8]1[C:33]1[CH:38]=[CH:37][C:36]([O:39]CC2C=CC=CC=2)=[C:35]([O:47]CC2C=CC=CC=2)[CH:34]=1)[CH:4]=[CH2:5]>[Pd].C(OCC)(=O)C.C(O)C>[OH:47][C:35]1[CH:34]=[C:33]([CH:8]2[CH:7]([O:6][CH2:3][CH2:4][CH3:5])[CH2:16][C:15]3[C:14]([OH:17])=[CH:13][C:12]([OH:25])=[CH:11][C:10]=3[O:9]2)[CH:38]=[CH:37][C:36]=1[OH:39]
Reactant: C=CCOC1Cc2c(OCc3ccccc3)cc(OCc3ccccc3)cc2OC1c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCOC1Cc2c(O)cc(O)cc2OC1c1ccc(O)c(O)c1
Reaction time: 2 h

Procedure:
To a suspension of 20% palladium on carbon (80 mg) in 1:1 ethyl acetate/ethanol (15 mL) which had been stirred vigorously under 1 atmosphere of hydrogen for 10 minutes then cooled with an ice/methanol bath was added 3-Allyloxy-5,7-bis-benzyloxy-2-(3,4-bis-benzyloxy-phenyl)-chroman (200 mg). The ice bath was removed and the reaction was stirred for 2 h under 1 atmosphere of hydrogen. The mixture was filtered and concentrated, and purified by preparative reverse phase HPLC using a gradient of 5% to 100% acetonitrile/water over 10 min The appropriate fractions were frozen and lyophilized to yield 2-(3,4-Dihydroxy-phenyl)-3-propoxy-chroman-5,7-diol as a white powder.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=O)[O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:9]1[O:10][CH:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: O=c1[nH]c(-c2ccccc2)co1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Clc1nc(-c2ccccc2)co1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 15.7 %

Procedure:
To a solution of 4-phenyl-1,3-oxazol-2(3H)-one (1.00 g, 62.0 mmol) in phosphorus oxychloride (18 ml) was added pyridine (0.974 ml, 12.0 mmol), and the mixture was stirred at 100° C. for 1 hour and 20 minutes. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=9:1) to give 176 mg (15.7%) of the desired product as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C@@H:5]([C@@H:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8]([OH:10])=O)[C:4](=[O:15])[O:3]1.[F:17][C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][NH:27][C@H:26]([CH3:30])[CH2:25]2)=[N:22][CH:23]=1>>[F:17][C:18]1[CH:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:8]([C@H:7]([C@@H:5]3[O:6][C:2]([CH3:1])([CH3:16])[O:3][C:4]3=[O:15])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:10])[C@H:26]([CH3:30])[CH2:25]2)=[N:22][CH:23]=1
Reactant: C[C@@H]1CN(c2ncc(F)cn2)CCN1
Reactant: CC(C)C[C@@H](C(=O)O)[C@@H]1OC(C)(C)OC1=O
Product: CC(C)C[C@H](C(=O)N1CCN(c2ncc(F)cn2)C[C@H]1C)[C@@H]1OC(C)(C)OC1=O

Procedure:
The title compound was prepared following the procedure of Example 4 (step a), but starting from (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoic acid and 5-fluoro-2-[(3R)-3-methylpiperazin-1-yl]pyrimidine. The crude was purified by chromatography on silica using a gradient of EtOAc: cHex (0/10 to 4/6). The title compound was isolated as a yellow oil (413 mg, 75%). TLC (EtOAc:cHex 3:7) Rf=0.25; 1H NMR (DMSO-d6) δ: 8.16 (s, 2H), 4.85-5.0 (m, 0.6H), 4.41-4.52 (m, 3.4H), 4.23 (m, 0.4H), 3.46-3.67 (m, 0.6H), 2.80-3.20 (m, 4H), 1.70-1.79 (m, 1H), 1.056 (m, 3H), 1.38 (s, 6H), 1.13-1.32 (m, 2H), 0.90 (m, 6H). HPLC (Condition A) Rt: 4.26 min (HPLC purity: 96.1%). LC/MS: M+(ESI): 409.6.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[CH3:11][Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][O:15][CH2:16]Cl.CN(C=O)C.[H-].[Na+]>C(OC)(C)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:16][O:15][CH2:14][CH2:13][Si:12]([CH3:19])([CH3:18])[CH3:11])[CH:9]=[CH:10][C:3]=12
Reactant: Brc1ccnc2[nH]ccc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(Br)ccnc21
Reaction time: 4 h
Yield: 139 %

Procedure:
To a solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine (6.2 g, 0.031 mol) and [β-(trimethylsilyl)ethoxy]methyl chloride (6.7 mL, 0.038 mol) in DMF (62 mL, 0.80 mol) was added sodium hydride (1.5 g, 0.038 mol) at 0° C., and the resulting solution turned opaque. The mixture was stirred for additional 4 h, then diluted with methyl tert-butyl ether (MTBE). The organic layer was separated and washed with water (×2) and brine aqueous solution successively. The organic phase was dried and concentrated in vacuo to give 14.1 g of a product as a pale orange oil. The oil was purified by column chromatography eluting with 5-20% ethyl acetate/hexanes to give the purified product as a colorless oil (9.66 g, 94% yield).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[C:12]([CH2:13]O)=[CH:11][CH:10]=[CH:9][N:8]=1.[ClH:15]>C(Cl)Cl>[ClH:3].[CH3:5][O:6][C:7]1[C:12]([CH2:13][Cl:15])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: COc1ncccc1CO
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: COc1ncccc1CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
51 ml of thionyl chloride (696.67 mmol) were added dropwise to 17 g of 2-methoxy-3-picolyl alcohol.HCl (96.76 mmol) suspended in 60 ml of DCM, the solution was stirred at room temperature for 1 h, the solvent and excess thionyl chloride were removed under reduced pressure, and the residue was codistilled 4 times with methanol under reduced pressure and subsequently extracted by stirring with ether. 15.2 g of is 2-methoxy-3-picolyl chloride hydrochloride (81%) were obtained as a white crystalline salt.
Reaction SMILES: [OH:1][C:2]1([CH2:14][CH2:15][OH:16])[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[OH:1][C:2]1([CH2:14][CH2:15][O:16][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CCO)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2(O)CCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
Under cooling with a cryogen (−10° C. to 0° C.), to a solution of tert-butyl 3-hydroxy-3-(2-hydroxyethyl)pyrrolidine-1-carboxylate (4.72 g) in pyridine (10 mL) was added p-toluene sulfonylchloride (1.68 g), followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure, and 1 M hydrochloric acid was added thereto, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane: EtOAc) to obtain tert-butyl 3-hydroxy-3-(2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)pyrrolidine-1-carboxylate (3.25 g) as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:13]([CH3:16])([O-:15])=[O:14].CN(C)C(=N)N(C)C>C(OCC)C.Cl>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH:5]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[CH2:16][N+:13]([O-:15])=[O:14]
Reactant: COC(=O)C=Cc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CCOCC
Product: COC(=O)CC(C[N+](=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 300 g of cinnamic acid methyl ester, 500 g of nitromethane and 39 g of tetramethylguanidine is allowed to stir at room temperature for 72 hours. The solution is diluted with diethyl ether and aqueous hydrochloric acid solution (1 N, 1 liter) is added. The organic layer is separated dried over anhydrous magnesium sulfate, and evaporated to give 4-nitro-3-phenylbutanoic acid methyl ester.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>>[C:14]1([S:20]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][Br:1])=[CH:9][CH:8]=2)(=[O:11])=[O:12])(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NS(=O)(=O)c1ccc(CCBr)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=S(=O)(NS(=O)(=O)c1ccc(CCBr)cc1)c1ccccc1

Procedure:
As an additional variation of the reaction sequence, the 4-(2-bromoethyl) benzenesulfonamide produced as in Example I was reacted with benzenesulfonyl chloride and sodium hydroxide and then acidified to produce N-benzenesulfonyl-4-(2-bromoethyl) benzenesulfonamide. Recrystallization of a small portion from toluene gave a white solid, having a melting point of 148°-150° C. and a neutralization equivalent of 405 (theory 404).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([S:27](=[O:30])(=[O:29])[NH2:28])=[CH:23][C:19]=1[C:20](O)=[O:21]>>[C:14]([C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:20]([C:19]3[CH:23]=[C:24]([S:27]([NH2:28])(=[O:30])=[O:29])[CH:25]=[CH:26][C:18]=3[Cl:17])=[O:21])[CH2:10][CH2:9]2)=[C:2]([F:1])[CH:3]=1)(=[O:16])[CH3:15]
Reactant: NS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(N)(=O)=O)ccc3Cl)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure described for example K/step 2 from 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone and 2-Chloro-5-sulfamoyl-benzoic acid (CAS: 97-04-1; Basu; D.-G.; J.Indian Chem. Soc.; 16; 1939; 100, 106) (42%, white solid), MS (m/e): 438.1 (M−H, 100%)
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].B1([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:28]=2)OC(C)(C)C(C)(C)O1>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([S:33](=[O:35])(=[O:34])[NH2:36])[CH:28]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Reactant: CC1(C)OB(c2cccc(S(N)(=O)=O)c2)OC1(C)C
Product: Nc1ncc(-c2cccc(S(N)(=O)=O)c2)cc1C(=O)Nc1ccncc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with benzenesulfon-amide-3-boronic acid pinacol ester gives “A78”; method 1: HPLC/MS: 1.13 min, [M+H]=370;
Reaction SMILES: C(O[CH2:6][C@H:7]([CH3:19])[CH2:8][CH2:9][CH2:10][C@H:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])(C)(C)C.[BrH:20]>>[Br:20][CH2:6][C@H:7]([CH3:19])[CH2:8][CH2:9][CH2:10][C@H:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: Br
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)COC(C)(C)C
Product: CC(C)CCC[C@@H](C)CCC[C@@H](C)CBr

Procedure:
A mixture of 1 g. (3.7 mmoles) of (2R,6R)-(+)-1-tert. butoxy-2,6,10-trimethylundecane and 10 ml. of 48% aqueous HBr was stirred and heated at reflux for 5.75 hours. The resulting mixture was cooled and worked up by ether extraction in the manner of Example 1 giving 0.9 g. of crude product. This material was chromatographed on 30 g. of silica gel. Elution with 49:1 parts by volume hexane-ether gave the (2R,6R)-(-)-1-bromo-2,6,10-trimethylundecane which was evaporatively distilled yielding 0.748 g. (73.4%) of a colorless oil, b.p. 83°-85° C. (bath temperature) (0.15 mm Hg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[CH2:11]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccccc1
Reactant: NC(=O)c1ccccc1N
Solvent: O
Product: NC(=O)c1ccccc1NCc1ccccc1

Procedure:
To a hot solution of 20 g Na OHin 1250 ml water was added 68 g 2-aminobenzamide followed by 58 ml benzyl chloride. The mixture was refluxed 20 minutes, cooled and the solid filtered and washed with water. The product was recrystallized from 95% alcohol to give 62 g, m.169-73°.
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:5]([CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:4][C:3]=1[CH2:12][C:13]1[C:14]([O:44][CH3:45])=[CH:15][C:16]([O:42][CH3:43])=[C:17]([C@@H:19]2[O:36][C@H:35]([CH2:37][O:38]COC)[C@@H:30]([O:31]COC)[C@H:25]([O:26]COC)[C@H:20]2[O:21]COC)[CH:18]=1.O>CO>[CH:2]1[C:11]2[C:5]([CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:4][C:3]=1[CH2:12][C:13]1[C:14]([O:44][CH3:45])=[CH:15][C:16]([O:42][CH3:43])=[C:17]([C@@H:19]2[O:36][C@H:35]([CH2:37][OH:38])[C@@H:30]([OH:31])[C@H:25]([OH:26])[C@H:20]2[OH:21])[CH:18]=1
Reactant: COCOC[C@H]1O[C@@H](c2cc(Cc3cc4cccccc-4c3)c(OC)cc2OC)[C@H](OCOC)[C@@H](OCOC)[C@@H]1OCOC
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1cc(OC)c([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1cc2cccccc-2c1
Yield: 31.1 %

Procedure:
10% aqueous solution of hydrochloric acid (0.5 ml) was added to a solution of (1S)-1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2,4-dimethoxyphenyl]-2,3,4,6-tetrakis-O-(methoxymethyl)-D-glucitol (0.09 g) in methanol (2.0 ml) and the mixture was refluxed with heating for 30 minutes. The reaction mixture was poured into ice-cooled water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain (1S)-1,5-anhydro-1-[5-(azulen-2-ylmethyl)-2,4-dimethoxyphenyl]-D-glucitol (0.02 g).
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][N:12]([C:14]2[C:18]([NH:19][C:20]([C:22]3[N:23]=[C:24]([CH3:27])[O:25][CH:26]=3)=[O:21])=[CH:17][N:16]([CH3:28])[N:15]=2)[C:11](=[O:29])[CH2:10]1)(C(C)(C)C)(C)C>C1COCC1.O>[OH:8][C@@H:9]1[CH2:13][N:12]([C:14]2[C:18]([NH:19][C:20]([C:22]3[N:23]=[C:24]([CH3:27])[O:25][CH:26]=3)=[O:21])=[CH:17][N:16]([CH3:28])[N:15]=2)[C:11](=[O:29])[CH2:10]1
Reactant: Cc1nc(C(=O)Nc2cn(C)nc2N2C[C@@H](O[Si](C)(C)C(C)(C)C)CC2=O)co1
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(C(=O)Nc2cn(C)nc2N2C[C@@H](O)CC2=O)co1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42.9 %

Procedure:
To a solution of N-(3-((4S)-4-((tert-butyl(dimethyl)silyl)oxy)-2-oxopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-methyl-1,3-oxazole-4-carboxamide (32 mg) in THF (2.0 mL) was added 1M tetra-n-butylammonium fluoride THF solution (0.15 mL), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (10 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH2:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].CCCCCC.C([Li])CCC.Cl[Si:20]([CH:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1)([CH3:22])[CH3:21]>C1COCC1>[CH2:1]([C:3]1[CH:7]=[CH:6][CH:5]([Si:20]([CH:23]2[CH:27]=[CH:26][CH:25]=[CH:24]2)([CH3:22])[CH3:21])[CH:4]=1)[CH3:2]
Reactant: C[Si](C)(Cl)C1C=CC=C1
Reactant: CCC1=CC=CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC1=CC([Si](C)(C)C2C=CC=C2)C=C1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Ethylcyclopentadiene in an amount of 7.52 g (80 mmol) was dissolved in 100 ml of THF, and the solution was cooled to −78° C. A 1.58 M hexane solution of n-butyllithium in a volume of 56 ml (92 mmol) was added thereto dropwise. The mixture was stirred at room temperature for 2 hours and was added dropwise to 50 ml of THF containing 110 mmol of the chloro(cyclopentadienyl)dimethylsilane at −78° C. The temperature was gradually increased, and the mixture was stirred at room temperature for 24 hours and was concentrated under reduced pressure. Insolubles were removed by filtration. The filtrate was washed with hexane and was distilled under reduced pressure. The distillate was subjected to silica gel column chromatography, and 0.86 g of (3-ethylcyclopentadienyl)(cyclopentadienyl)dimethylsilane was obtained. The compound was identified by GC-MS. GC-MS: 216 (MS).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=O)=[CH:12][CH:11]=2)[CH:2]=1.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH2:30][CH2:31][N:32]([C:14]([C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:20][CH:19]=2)=[O:16])[CH2:33][CH2:34]1
Reactant: CCOC(=O)c1ccc(-n2cnc3cccnc32)cc1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(-n4cnc5cccnc54)cc3)CC2)c(C)c1
Yield: 73.2 %

Procedure:
Using ethyl 4-(imidazo[4,5-b]pyridin-3-yl)benzoate (300 mg) described in Preparation Example 77 and 1-(2,4-dimethylphenyl)piperazine (214 mg) and by the reaction and treatment in the same manner as in Example 109, the title compound (338 mg) was obtained.