Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:20]=[CH:19][C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:11][CH2:12][C:6]=2[C:5]=1OS(C(F)(F)F)(=O)=O)[CH2:2][CH3:3].[NH2:29][CH2:30][C:31]1[S:32][CH:33]=[CH:34][CH:35]=1>>[CH2:1]([C:4]1[CH:20]=[CH:19][C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:15])([F:17])[F:16])[CH2:11][CH2:12][C:6]=2[C:5]=1[NH:29][CH2:30][C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)C(F)(F)F)CC2
Reactant: NCc1cccs1
Product: CCCc1ccc2c(c1NCc1cccs1)CCN(C(=O)C(F)(F)F)CC2

Procedure:
Use a method similar to the General Procedure 5-1 to couple 7-propyl-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 2-(aminomethyl)-thiophene. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 and 4:1) to give 7-propyl-6-[(2-thienyl)methylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow solid. MS (ES+) m/z: 397 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH3:11].[CH3:13][N:14]1CCCC1=O>Cl.O>[C:13]([C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH3:11])#[N:14]
Reactant: CN1CCCC1=O
Reactant: CCCCc1ccc(O)cc1Br
Agent: Cl
Solvent: O
Product: CCCCc1ccc(O)cc1C#N
Temperature: 25 °C

Procedure:
16.0 g (0.07 mol) of the 3-bromo-4-n-butylphenol prepared in Step IV was dissolved in 70 ml of N-methyl-2-pyrrolidone. 6.5 g (0.073 mol) cuprous cyanide was added to the suspension which was refluxed for four hours. The reaction mixture was cooled to room temperature and poured into a solution of 26 g ferric chloride hexahydrate dissolved in a mixed solution of 10 ml of concentrated hydrochloric acid and 47 ml of water. The resultant solution was stirred with heating for 30 minutes at 65° C. in order to decompose nitrile complexes with cuprous bromide. Next, the suspension was poured into 300 ml of cold water, and an organic layer which separated out was extracted with ether. After the organic layer was clearned with acid, alkali and water and was dehydrated with anhydrous sodium sulfate, ether in the organic layer was distilled off. The residue was distilled under vacuum (115° C./1 mmHg) to yield 8.4 g of purified 3-cyano-4-n-butylphenol. The yield was calculated to be 68.2%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]2.[C:13]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])([CH3:15])[CH3:14].N1C=CN=C1>ClCCl>[Si:17]([O:12][CH:9]1[CH2:10][C:11]2[C:2]([NH2:1])=[CH:3][CH:4]=[CH:5][C:6]=2[CH2:7][CH2:8]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:19])[CH3:18]
Reactant: Nc1cccc2c1CC(O)CC2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCc2cccc(N)c2C1

Procedure:
A mixture of the product of Example 18A (2.33 g, 14.3 mmol), tert-butylchlorodimethylsilane (2.6 g, 17.2 mmol), and imidazole (2.9 g, 42.3 mmol) was stirred in 40 mL of dichloromethane at rt overnight. The mixture was then washed several times with water and once with brine. Drying over Na2SO4, filtered and evaporation afforded the product as a dark purple oil, 2.6 g (65%). 1H NMR (DMSO-d6) δ 6.77 (dd, J=7.8, 7.4 Hz, 1H), 6.42 (d, J=7.8 Hz, 1H), 6.28 (d, J=7.4 Hz, 1H), 4.7 (br s, 2H), 4.11 (m, 1H), 2.75 (m, 3H), 2.24 (m, 1H), 1.82 (m, 1H), 1.63 (m, 1H), 0.88 (s, 9H), 0.09 (s, 6H); MS (ESI+) m/z 278 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[CH2:9])[C:5]([O:7][CH3:8])=[O:6].CO[CH2:12][N:13]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:14][Si](C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:8][O:7][C:5]([C:4]1([CH2:3][O:2][CH3:1])[CH2:9][CH2:12][N:13]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:14]1)=[O:6]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=C(COC)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCC1(C(=O)OC)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
To a stirred solution of methyl 2-(methoxymethyl)acrylate (176 mg, 1.35 mmol) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (416 μl, 1.63 mmol) in dichloromethane (2 ml) was added at 0° C. trifluoroacetic acid (21 μl, 0.27 mmol). The resulting solution was warmed to room temperature and stirred overnight. The crude product was purified by column chromatography on silica, eluted with a solution of ethyl acetate in hexanes (1:3), then 5% methanol in ethyl acetate to give the title compound (293 mg, 82%).
Reaction SMILES: [Cl:1][C:2]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:3]=1[NH:4][C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:3]=1[NH:4][C:5](=[S:27])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1cccc(NC(=O)c2ccccc2)c1Cl
Solvent: Cc1ccccc1
Product: Cc1cccc(NC(=S)c2ccccc2)c1Cl

Procedure:
98 g (0.4 mol) of the compound from Example V and 162 g (0.4 mol) of Lawesson's reagent were boiled in 1 l of toluene overnight, and the mixture was concentrated and purified on SiO2 (cyclohexane/ethyl acetate=8:2)
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.Cl.[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1>>[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:11]([C:10]4[CH:9]=[CH:8][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:16])=[CH:15][CH:14]=4)=[O:13])[CH2:31][CH2:32]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Agent: Cl
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2)CC1
Yield: 52.5 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (241 mg) described in Preparation Example 16 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (254 mg) described in Preparation Example 82 and by the reaction and treatment in the same manner as in Example 86, the title compound (231 mg) was obtained.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33].CC(C)=O>C(O)C>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCO
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 75.6 %

Procedure:
Fluvastatin methyl ester (2.0 g) was added to a solution of NaOH (1 eq.) in ethanol (15 ml). The mixture was stirred at about 70EC for 1.75 h, after which the starting material was not detected by HPLC. Then, acetone (40 ml) was dripped into the solution and the mixture was cooled slowly to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with acetone (20 ml) and dried at 50EC in a vacuum oven for 24 h to obtain 1.54 g (75.6%) of fluvastatin sodium Form VI.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][CH2:13][CH2:14][OH:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H][H]>[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C#CCCO)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(CCCCO)cc1OC
Yield: 93.2 %

Procedure:
A mixture of 2.0 g of 4-(3,4-dimethoxyphenyl)-3-butyn-1-ol and 0.2 g of 10% palladium on carbon in 40 mL of ethanol was stirred in a hydrogen atmosphere for 4 hours. After filtration, the filtrate was concentrated under reduced pressure to give 1.9 g of 4-(3,4-dimethoxyphenyl)butan-1-ol as an oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:12])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[S:8].[CH:13](Br)([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:13]([O:1][C:2]1[C:3]([CH3:12])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[S:8])([CH3:15])[CH3:14]
Reactant: CC(C)Br
Reactant: COC(=S)c1cnc(C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=S)c1cnc(C)c(OC(C)C)c1
Temperature: 60 °C

Procedure:
A mixture of methyl 5-hydroxy-6-methylthionicotinoate (3 g), isopropyl bromide (2.1 mL) and anhydrous potassium carbonate (3 g) in dry dimethylformamide (35 mL) is stirred and heated at 60±5° C. for 18 hours. After cooling the solvent is removed in vacuo and the residue partitioned between ethyl acetate and water. The organic phase is washed with brine and dried (MgSO4). Evaporation gives a brown oil which is purified by flash chromatography (pentane/ethyl acetate 4:1 v/v as eluent on silica) to give methyl 5-isopropyloxy-6-methylthionicotinoate (2.36 g) as a pale yellow oil. [Elemental analysis: —C, 54.40; H, 6.24; N, 5.88%. calculated: —C, 54.75; H, 6.27; N, 5.81%.].
Reaction SMILES: C(=O)([O-])[O-].[K+].[OH:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([CH2:15][CH2:16][CH3:17])[CH:14]=1)[CH:10]=[O:11].[K+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>C(C(C)=O)C>[CH:10]([C:9]1[CH:8]=[C:7]([CH:14]=[C:13]([CH2:15][CH2:16][CH3:17])[CH:12]=1)[O:6][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:11]
Reactant: COC(=O)CBr
Reactant: CCCc1cc(O)cc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1cc(C=O)cc(OCC(=O)OC)c1

Procedure:
A mixture of 3-hydroxy-5-propyl-benzaldehyde potassium carbonate (0.7 g) and methyl bromoacetate (0.8 ml) in methyl ethyl ketone (6 ml) were heated at 70° for 4 hours. The reaction was filtered and evaporated. Flash chromatography of the residue using 30% ether in hexane afforded the title compound.
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:14][O:15][CH3:16])[NH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11])([CH3:4])[CH3:3].CC(C)([O-])C.[K+].[C:23]([O:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]1[CH:43]=[CH:42][C:39]([CH2:40][N:8]2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[N:6]=[C:7]2[CH2:14][O:15][CH3:16])=[CH:38][CH:37]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: COCc1nc(C(C)(C)O)c(C(=O)OC)[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COCc1nc(C(C)(C)O)c(C(=O)OC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 93.9 %

Procedure:
Following a procedure similar to that described in Example 82(a), but using 230 mg of methyl 4-(1-hydroxy-1-methylethyl)-2-methoxymethylimidazole-5-carboxylate [prepared as described in Preparation 42(v)], 119 mg of potassium t-butoxide and 420 mg of 4-[2-(t-butoxycarbonyl)phenyl]benzyl bromide and then purifying the product by column chromatography through silica gel using a 1:2 by volume mixture of hexane and ethyl acetate as the eluent, 468 mg of the title compound were obtained as a syrup.
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[N:8]=2)=[CH:4][CH:3]=1.FC(F)(F)S(O)(=O)=O.[CH2:31]=[C:32]([CH3:34])[CH3:33]>ClCCl>[C:32]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[N:8]=2)=[CH:21][CH:22]=1)([CH3:34])([CH3:33])[CH3:31]
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1Cc1ccc(O)cc1
Reactant: C=C(C)C
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1Cc1ccc(OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
To a solution of 0.6 g of 5-(4-hydroxybenzyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole in 10 ml of dichloromethane at -70° C. was added 0.29 g of trifluoromethanesulfonic acid and 2.1 g of isobutene was bubbled in a few minutes. After 1 hour of stirring at the same temperature, triethyamine was added to the solution and then the reaction mixture was warmed gradually to room temperature. The reaction mixture was poured into iced water and the organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to afford 0.55 g of 5-(4-t-butoxybenzyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole. nD22.8 1.5458
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])([CH3:4])([CH3:3])[CH3:2].I[C:21]1[CH:26]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:24]=[CH:23][C:22]=1[CH2:31][CH2:32][CH3:33]>>[C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[C:18][C:23]1[CH:24]=[C:25]([S:27]([CH3:30])(=[O:28])=[O:29])[CH:26]=[CH:21][C:22]=1[CH2:31][CH2:32][CH3:33])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1ccc(S(C)(=O)=O)cc1I
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Product: CCCc1ccc(S(C)(=O)=O)cc1C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-cyano-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 46) and 2-iodo-4-(methylsulfonyl)-1-propylbenzene (Intermediate 62), the title compound was obtained after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]Cl)=[CH:7][CH:6]=1)=[O:4].[C:13]([O:17][C:18]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C:21]1=[O:26])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:20]2([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:25][CH2:24][CH2:23][CH2:22][C:21]2=[O:26])=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)C1CCCCC1=O
Reactant: COC(=O)c1ccc(SCl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(SC2(C(=O)OC(C)(C)C)CCCCC2=O)cc1
Reaction time: 0.25 h
Yield: 56.7 %

Procedure:
A solution 10.8 g (53.2 mmol) of 4-methoxycarbonylphenylsulphenic acid chloride in 20 ml of methylene chloride (analytically pure) is added dropwise to a solution of 11.4 g (57 mmol) of 2-tert.butoxycarbonylcyclohexanone and 7.5 g (75 mmol) of triethylamine in 150 ml of methylene chloride. When the dropwise addition has ended the mixture is subsequently stirred for 15 mins. and is then diluted with methylene chloride and the organic phase is washed with 2N sulphuric acid and a saturated bicarbonate solution, dried with sodium sulphate and concentrated by evaporation. 20.5 g of a crude product are thus obtained, which is chromatographed on 2 kg of silica gel (Merck Si 60, 0.04-0.063 nm) using petroleum ether/ether 8:20 as the mobile solvent. A fraction is thus obtained which, after being concentrated by evaporation, yields 11 g of a solid product.
Reaction SMILES: [N-]=[N+]=[N-].[Na+].Br[CH:6]([CH3:20])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=1)=[O:8].[N-:21]=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:43]1([CH3:53])[CH:48]=[CH:47][C:46]([S:49]([OH:52])(=[O:51])=[O:50])=[CH:45][CH:44]=1>O1CCCC1>[C:43]1([CH3:53])[CH:44]=[CH:45][C:46]([S:49]([OH:52])(=[O:50])=[O:51])=[CH:47][CH:48]=1.[NH2:21][CH:6]([CH3:20])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:10]=1)=[O:8]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(Br)C(=O)c1ccc(F)c(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(N)C(=O)c1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.3 %

Procedure:
Add sodium azide (640.94 mg; 1.05 equiv; 9.76 mmoles) in one portion to a solution of 2-Bromo-1-(4-fluoro-3-trifluoromethyl-phenyl)-propan-1-one (2.78 g; 1.00 equiv; 9.30 mmoles) in tetrahydrofuran (15 mL). Stir the mixture at room temperature overnight. Filter the solids and wash with THF. Add the crude azide (1.00 equiv; 9.30 mmoles; 2.43 g) to a solution of triphenylphosphine (1.06 equiv; 9.86 mmoles; 2.61 g) and p-Toluenesulfonic Acid (2.2 equiv; 20.47 mmoles; 3.56 g) in tetrahydrofuran (15 mL) under 20° C. Stir the mixture overnight. Filter the solid, then wash with THF to obtain 920 mg (24%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:22]=[CH:21][C:20]([CH:23]5[CH2:25][CH2:24]5)=[CH:19][N:18]=4)[CH2:13][CH2:12]3)([CH3:10])[CH2:7][C:6]=2[CH:26]=1.CC1(C)C(C)(C)OB([C:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[CH:23]1([C:20]2[CH:19]=[N:18][C:17]([N:14]3[CH2:15][CH2:16][CH:11]([C:8]4([CH3:10])[CH2:7][C:6]5[CH:26]=[C:2]([C:35]6[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=6)[CH:3]=[CH:4][C:5]=5[O:9]4)[CH2:12][CH2:13]3)=[N:22][CH:21]=2)[CH2:25][CH2:24]1
Reactant: CC1(C2CCN(c3ncc(C4CC4)cn3)CC2)Cc2cc(Br)ccc2O1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)CC(C)(C2CCN(c4ncc(C5CC5)cn4)CC2)O3)CC1
Temperature: 100 °C
Yield: 68.3 %

Procedure:
To a degassed solution of 2-(4-(5-bromo-2-methyl-2,3-dihydrobenzofuran-2-yl)piperidin-1-yl)-5-cyclopropylpyrimidine (424 mg, 1.02 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (380 mg, 1.23 mmol), and K2CO3 (424 mg, 3.07 mmol) in dioxane (6 mL) and water (2 mL) was added Pd(Ph3P)4 (59.1 mg, 0.051 mmol). Upon completion of addition, the reaction mixture was heated in 100° C. oil bath for 3 hours. After this time, the reaction mixture was cooled to room temperature, diluted with water, and extracted with CH2Cl2 (3×5 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated to yield a residue. The residue was purified by column chromatography (silica gel, hexanes/EtOAc gradient 0 to 50% EtOAc) to afford Compound 11F as a white solid (360 mg, 0.697 mmol, 68% yield). 1H NMR (500 MHz, CDCl3) δ ppm 8.11 (s, 2 H), 7.15 (s, 1 H), 7.13 (d, J=8.5 Hz, 1 H), 6.65-6.71 (m, 1 H), 5.88 (br. s., 1 H), 4.75-4.87 (m, 2 H), 4.05 (br. s., 2 H), 3.73 (t, J=6.2 Hz, 1 H), 3.62 (t, J=5.5 Hz, 2 H), 3.16 (d, J=15.7 Hz, 1 H), 2.74-2.87 (m, 2 H), 2.39-2.54 (m, 2 H), 1.86-1.96 (m, 2 H), 1.76-1.84 (m, 1 H), 1.67-1.74 (m, 1 H), 1.61 (m, 1 H), 1.49 (s, 9 H), 1.37-1.41 (m, 3 H), 1.23-1.36 (m, 1 H), 0.84-0.92 (m, 2 H), 0.54-0.60 (m, 2 H). LC/MS (m/z)=517 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH2:18][CH2:19][N:20]3C(=O)C4C(=CC=CC=4)C3=O)(=[O:16])=[O:15])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NN.O>>[C:31]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:9][CH2:10][N:11]([S:14]([CH2:17][CH2:18][CH2:19][NH2:20])(=[O:16])=[O:15])[CH2:12][CH2:13]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCS(=O)(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: NN
Solvent: O
Product: NCCCS(=O)(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
Batch size: 149 (27.8 mmol) 2-[3-(4-diphenylmethyl-piperazin-1-yl-sulfonyl)-propyl)-isoindolin-1,3-dione and 2.8 ml (55.6 mmol) hydrazine.hydrate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].CC(C)=O.C(=O)=O.[Li]CCCC.[C:22]([N:26]1[C:30]2[NH:31][C:32](=[O:44])[CH2:33][CH:34]([C:35]3[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=3[F:43])[C:29]=2[C:28]([CH:45]2[CH2:48][C:47](=[O:49])[CH2:46]2)=[N:27]1)([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([N:26]1[C:30]2[NH:31][C:32](=[O:44])[CH2:33][CH:34]([C:35]3[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=3[F:43])[C:29]=2[C:28]([CH:45]2[CH2:48][C:47]([C:2]3[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=3)[C:5]#[N:6])([OH:49])[CH2:46]2)=[N:27]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)n1nc(C2CC(=O)C2)c2c1NC(=O)CC2c1cc(F)c(F)cc1F
Reactant: N#Cc1cccc(Br)c1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(C)(C)n1nc(C2CC(O)(c3cccc(C#N)c3)C2)c2c1NC(=O)CC2c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.9 %

Procedure:
To a stirring solution of 3-bromobenzonitrile (3.7 g, 20.4 mmol) in 50 mL of THF at −78° C. (acetone/CO2 bath) was added a solution of n-BuLi (8.2 mL, 20.4 mmol, 2.5 M in hexanes). After 15 min, a solution of 1-tert-butyl-3-(3-oxo-cyclobutyl)-4-(2,4,5-trifluoro-phenyl)-1,4,5,7-tetrahydro-pyrazolo[3,4-b]pyridin-6-one (2.0 g, 5.1 mmol in 10 mL of THF) was added. After one hr, the reaction mixture was quenched cold by the addition of a saturated NH4Cl solution, and was then allowed to warm to room temperature. The reaction mixture was diluted with CH2Cl2, and the layers were separated. The organic layer was dried over MgSO4, filtered through a pad of diatomaceous earth, and concentrated under reduced pressure to give a tan solid. Purification of this material was accomplished by MPLC using a 35 g ISCO cartridge on a Biotage® system eluting with a gradient of 25-50% EtOAc/hexanes. The product-containing fractions were collected and concentrated to yield the title compound (0.98 g, 40% yield) as a tan solid. Rf=0.29 (50% EtOAc/hexanes).
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][O:8][N:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:10]([C:12]1[CH2:13][N:14]([CH3:19])[C:15](=[O:18])[C:16]=1[OH:17])=[O:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:9]([C:10]([C:12]2[CH2:13][N:14]([CH3:19])[C:15](=[O:18])[C:16]=2[OH:17])=[O:11])[O:8][CH2:7][C:6]([OH:28])=[O:5])=[CH:26][CH:25]=1
Reactant: CN1CC(C(=O)N(Cc2ccc(F)cc2)OCC(=O)OC(C)(C)C)=C(O)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CC(C(=O)N(Cc2ccc(F)cc2)OCC(=O)O)=C(O)C1=O
Temperature: 22 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
A solution of [(4-fluorobenzyl)-(4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)-aminooxy]-acetic acid tert-butyl ester (0.041 g, 0.104 mmol) in dichloromethane (4 ml) was treated with trifluoroacetic acid (1 ml) and the resulting mixture was stirred at 22° C. for 2 h. The solvent was evaporated in vacuo and the residue was recrystallized from a mixture of ethyl acetate and hexane to give 0.027 g (80% yield) of the tittle material as white crystals; mp 147–150° C. 1HNMR 400 MHz (DMSO-d6) δ (ppm): 2.95 (3H, s, NCH3), 4.14 (2H, s, CH2), 4.62 (2H, s, CH2), 4.92 (2H, s, CH2), 7.17 (2H, m, aromatics), 7.36 (2H, m, aromatics), 11.4 (1H, broad s, OH), 13.1 (1H, broad s, OH). HRMS (ES+) calculated for C15H16FN2O6, [M+H]+: 339.099240. found: 339.100624.