Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[C:8]([O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[C:7]([O:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:6][C:3]=1[CH:4]=[CH2:5].C(Cl)Cl.ClCCl.C(OCC)(=[O:33])C>>[F:1][C:2]12[O:33][C:3]1([CH:6]=[C:7]([O:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[C:8]([O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:9]2[F:10])[CH:4]=[CH2:5]
Reactant: CCOC(C)=O
Reactant: C=Cc1cc(OCOCCOC)c(OCOCCOC)c(F)c1F
Solvent: ClCCl
Product: C=CC12C=C(OCOCCOC)C(OCOCCOC)=C(F)C1(F)O2

Procedure:
Using the procedure of Stage D of Example 40, 32 g of the product of Stage E were reacted to obtain 33.5 g of the expected product with a Rf=0.14 (CH2Cl2 --AcOEt 8-2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24](OS(C(F)(F)F)(=O)=O)=[CH:23][CH:22]=1.[C:35]([C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)#[CH:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:36]#[C:35][C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)=[CH:23][CH:22]=1
Reactant: O=S(=O)(Oc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1)C(F)(F)F
Reactant: C#Cc1cccnc1
Product: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(C#Cc4cccnc4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The compound was obtained starting from 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-trifluoromethylsulfonyloxy-benzyl)-benzene and 3-ethynyl-pyridine.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1C(C2C3NN=NC=3N=C(N)N=2)=CC=N1.[H-].[Na+].[Br:26][CH2:27][C:28]1[CH:29]=[C:30]([CH:40]=[CH:41]C=1)[CH2:31]NC(=O)OC(C)(C)C>CN(C=O)C>[Br:26][CH2:27][C:28]1[CH:29]=[C:30]([CH3:31])[CH:40]=[CH:41][N:7]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CBr)c1
Reactant: C[Si](C)(C)CCOCn1nccc1-c1nc(N)nc2nn[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccnc(CBr)c1
Reaction time: 0.25 h
Yield: 138.7 %

Procedure:
A stirred solution of the 7-(1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrazol-5-yl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (330 mg, 1 mmol) in dry DMF (5 mL) was treated with NaH (40 mg, 60% in oil, 1 mmol), stirred for 15 min, treated with tert-butyl N-(3-(bromomethyl)benzyl)carbamate (300 mg, 1 mmol) and stirred for 1 h. The mixture was partitioned between EtOAc (20 mL) and H2O (20 mL), the organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; iso-hexane:EtOAc (1:1)]. The resulting yellow syrup was dissolved in MeOH (3 mL), treated with HCl (2 mL, 4-M in dioxane), stirred for 17 h and the resulting solid filtered to give the title compound (258 mg, 80%) as a cream solid.
Reaction SMILES: [CH:1]1([C:7]2[O:8][C:9]([CH3:14])=[C:10]([CH3:13])[N+:11]=2[O-])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=P(Cl)(Cl)[Cl:17]>C(Cl)Cl>[Cl:17][CH2:13][C:10]1[N:11]=[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:8][C:9]=1[CH3:14]
Reactant: Cc1oc(C2CCCCC2)[n+]([O-])c1C
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1oc(C2CCCCC2)nc1CCl

Procedure:
25.1 g of the above prepared 2-cyclohexyl-4,5-dimethyl-oxazole 3-oxide (˜88.8 mmol) was dissolved in 325 ml of CH2Cl2 and treated dropwise with 9.755 ml of POCl3 (1.2 eq.). The reaction mixture was refluxed over night and then quenched by carefully pouring onto crashed ice/3N NaOH. Separation of the layers, additional extraction of the aqueous phase with CH2Cl2, washing with Na2CO3 and water, drying of the combined organic phase over sodium sulfate, evaporation of the solvents, and, finally, flash chromatography (SiO2, hexane/AcOEt=9/1) afforded 4.12 g of the title compound as yellowish oil, exhibiting in the 1H-NMR the typical signal at 4.46 ppm (2H). The other, unstable regioisomer was not isolated.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14][OH:15])=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:11]=[C:10]3[N:22]([CH2:25][CH3:26])[N:23]=[CH:24][C:9]=23)=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1.C([N+](CCC)(CCC)CCC)CC>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[O:15])=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:11]=[C:10]3[N:22]([CH2:25][CH3:26])[N:23]=[CH:24][C:9]=23)=[CH:4][CH:3]=1
Reactant: CCn1ncc2c(-c3ccc(Cl)nc3)c(CO)c(-c3ccccc3)nc21
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCn1ncc2c(-c3ccc(Cl)nc3)c(C=O)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
A mixture of [4-(6-chloro-3-pyridyl)-1-ethyl-6-phenyl-1H-pyrazolo[3,4-b]pyridin-5-yl]methanol (730 mg), 4-methylmorpholine N-oxide (352 mg) in DCM (20 ml) was added tetrapropylammonium perrutenate (70.3 mg) at room temperature and the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered through celite pad. The filtrate was washed with saturated aqueous ammonium chloride, saturated aqueous NaHCO3, water, brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a mixture of MeOH and CHCl3 (1:10) to give 4-(6-chloro-3-pyridyl)-1-ethyl-6-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (660 mg) as a yellow oil.
Reaction SMILES: C(C1C=C2C(=CC=1)N=C(C(NCC1C=CC=C(NC(=O)CCC3N=CN(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)N=3)C=1)=O)NC2=O)#N.[O:53]=[C:54]1[NH:59][C:58]([C:60]([NH:62][CH2:63][C:64]2[CH:69]=[CH:68][N:67]=[C:66]([O:70][CH2:71][CH2:72][CH2:73][C:74]3[N:78]=[CH:77][N:76](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:75]=3)[CH:65]=2)=[O:61])=[N:57][C:56]2[S:98][CH:99]=[C:100]([CH2:101][O:102][CH2:103][C:104]3[CH:114]=[CH:113][C:107]([C:108]([O:110][CH2:111][CH3:112])=[O:109])=[CH:106][CH:105]=3)[C:55]1=2>>[O:53]=[C:54]1[NH:59][C:58]([C:60]([NH:62][CH2:63][C:64]2[CH:69]=[CH:68][N:67]=[C:66]([O:70][CH2:71][CH2:72][CH2:73][C:74]3[N:78]=[CH:77][NH:76][N:75]=3)[CH:65]=2)=[O:61])=[N:57][C:56]2[S:98][CH:99]=[C:100]([CH2:101][O:102][CH2:103][C:104]3[CH:114]=[CH:113][C:107]([C:108]([O:110][CH2:111][CH3:112])=[O:109])=[CH:106][CH:105]=3)[C:55]1=2
Reactant: CCOC(=O)c1ccc(COCc2csc3nc(C(=O)NCc4ccnc(OCCCc5ncn(C(c6ccccc6)(c6ccccc6)c6ccccc6)n5)c4)[nH]c(=O)c23)cc1
Agent: N#Cc1ccc2nc(C(=O)NCc3cccc(NC(=O)CCc4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c3)[nH]c(=O)c2c1
Product: CCOC(=O)c1ccc(COCc2csc3nc(C(=O)NCc4ccnc(OCCCc5nc[nH]n5)c4)[nH]c(=O)c23)cc1

Procedure:
By a method similar to that in Step 2 of Example 32 and using, instead of 6-cyano-4-oxo-N-{[3-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propanoyl}amino)phenyl]methyl}-3,4-dihydroquinazoline-2-carboxamide, ethyl 4-{[({4-oxo-2-[({[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methyl}amino)carbonyl]-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl}methyl)oxy]methyl}benzoate, the title compound was obtained as a white powder (20.0 mg, 93%).
Reaction SMILES: [ClH:1].[CH2:2]([CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH:11]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1>>[ClH:1].[CH2:2]([CH:9]1[CH2:14][CH2:13][C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)([OH:15])[CH:11]([CH2:16][N:17]([CH3:18])[CH3:19])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(Br)c1
Reactant: CN(C)CC1CC(Cc2ccccc2)CCC1=O
Agent: Cl
Product: COc1cccc(C2(O)CCC(Cc3ccccc3)CC2CN(C)C)c1
Yield: 55 %

Procedure:
The base of compound (36) was reacted with 1-bromo-3-methoxy-benzene corresponding to the conditions described in Example 1. The base obtained was purified with 7:1 ether/methanol via a silica gel column and was taken up in ether. After adding trimethylchlorosilane/water, compound (35) was obtained in a yield of 55% theoretical.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:13]([CH3:14])[N:12]=[C:11]([C:15]([O:17]C)=[O:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([O:8][C:9]1[N:13]([CH3:14])[N:12]=[C:11]([C:15]([OH:17])=[O:16])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)n(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nc(C(=O)O)cc1OCc1ccccc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 90.8 %

Procedure:
A mixture of methyl 5-(benzyloxy)-1-methyl-1H-pyrazole-3-carboxylate (15.8 g, 64.0 mmol) and 8 M sodium hydroxide solution (20 mL) in tetrahydrofuran (100 mL) and methanol (100 mL) was stirred at 40° C. for 4 h. Solvent was removed and 6 M hydrochloric acid solution added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a solid (13.5 g, 91%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([S:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)=[C:11]([CH:22]([CH3:24])[CH3:23])[N:10]=[C:9]1[CH2:25][O:26]CC1C=CC(OC)=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CO>[CH2:1]([N:8]1[C:12]([S:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)=[C:11]([CH:22]([CH3:24])[CH3:23])[N:10]=[C:9]1[CH2:25][OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(COCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2Cc2ccccc2)cc1
Agent: Cl
Solvent: CO
Product: CC(C)c1nc(CO)n(Cc2ccccc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 60 °C
Yield: 91.9 %

Procedure:
To 25 ml of methanol was dissolved 1.41 g (2.67 mmol) of 1-benzyl-5-(3,5-dichlorophenylthio)-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (17f), followed by addition of 12.5 ml of 6N-hydrochloric acid at room temperature with stirring, and the mixture was stirred under heating at 60° C. for 3 hour. This reaction mixture was concentrated under reduced pressure, the residual solution was neutralized with a saturated aqueous solution of sodium bicarbonate to be weakly basic, and was extracted with methylene chloride. The extract was rinced with water, and then, was dried over magnesium sulfate, arid the solvent was concentrated under reduced pressure. The residue was crystalized from n-hexane and collected by filtration to give 1.0 g (yield 92%) of [1-benzyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1H-imidazol-2-yl]methanol (Compound I-16). mp 121-124° C.
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH:11](Cl)[CH3:12].CON(C)[C:17]([C:19]1[CH:34]=[CH:33][C:22]2[N:23]([CH2:30][CH:31]=[CH2:32])[C:24](=[O:29])[N:25]([CH2:26][CH:27]=[CH2:28])[C:21]=2[CH:20]=1)=[O:18].O>C1COCC1>[CH2:30]([N:23]1[C:22]2[CH:33]=[CH:34][C:19]([C:17](=[O:18])[CH:11]([C:4]3[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=3[Cl:2])[CH3:12])=[CH:20][C:21]=2[N:25]([CH2:26][CH:27]=[CH2:28])[C:24]1=[O:29])[CH:31]=[CH2:32]
Reactant: C=CCn1c(=O)n(CC=C)c2cc(C(=O)N(C)OC)ccc21
Reactant: COc1ccc(C(C)Cl)c(Cl)c1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: C=CCn1c(=O)n(CC=C)c2cc(C(=O)C(C)c3ccc(OC)cc3Cl)ccc21
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 52.8 %

Procedure:
A 1M suspension of Rieke magnesium in THF (1.3 ml) was added to THF (2 ml). The mixture was cooled to −10° C., and a solution of 2-chloro-1-(1-chloro-ethyl)-4-methoxy-benzene (136 mg) in THF (2 ml) was added. The mixture was stirred for 15 min. A solution of 1,3-diallyl-2-oxo-2,3-dihydro-1H-benzoimidazole-5-carboxylic acid methoxy-methyl-amide (100 mg) in THF (2 ml) was added at −10° C. The mixture was stirred overnight at room temperature. Water was added and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and then concentrated to an oil. The residue was purified by flash chromatography (SiO2, 0 to 100% EtOAc/heptane) to give the title compound (72 mg) as a light yellow foam. MS (m/e)=411.2 [M+H+].
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]1[CH:29]=[C:28]([OH:30])[C:27]([F:31])=[CH:26][C:18]=1[C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[O:20]>CS(C)=O>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[O:30][C:28]1[C:27]([F:31])=[CH:26][C:18]([C:19]([NH:21][S:22]([CH3:25])(=[O:23])=[O:24])=[O:20])=[C:17]([F:16])[CH:29]=1)#[N:5]
Reactant: CS(=O)(=O)NC(=O)c1cc(F)c(O)cc1F
Reactant: N#Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)NC(=O)c1cc(F)c(Oc2ccccc2C#N)cc1F
Temperature: 120 °C
Reaction time: 5 h
Yield: 9.9 %

Procedure:
To 2-fluorobenzonitrile (12.1 mg, 0.100 mmol) was added potassium carbonate (27.6 mg, 0.200 mmol) and a solution of 2,5-difluoro-4-hydroxy-N-(methylsulfonyl)benzamide (Preparation 34, 32.7 mg 0.130 mmol) in dimethyl sulfoxide (1.0 mL). The reaction mixture was shaken at 120° C. for 5 hours. The reaction mixture was purified on an HPLC column (DIKMA Diamonsil(2) C18 200*20 mm*5 um, acetonitrile-water (0.225% formic acid) gradient) to afford the title compound (3.50 mg, 9.93 μmol).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2=[CH:9][S:10][CH:11]=[C:4]2[S:3]1(=[O:13])=[O:12].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23].C(N(CC)CC)C.Cl>CS(C)=O>[OH:8][C:7]1[N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]2[C:5](=[CH:9][S:10][CH:11]=2)[C:6]=1[C:22](=[O:23])[NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[Cl:14]
Reactant: CN1C(=O)Cc2cscc2S1(=O)=O
Reactant: O=C=Nc1ccccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1C(O)=C(C(=O)Nc2ccccc2Cl)c2cscc2S1(=O)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1 g (4.6 mmol) of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[3,4]-1,2-thiazine 1,1-dioxide are stirred at room temperature for 3 hours under nitrogen with 0.71 g (4.6 mmol) of o-chlorophenylisocyanate and 0.47 g (4.6 mmol) of triethylamine in 10 ml of absolute dimethylsulfoxide. Thereafter, the mixture is poured into 40 ml of 2-N hydrochloric acid and 25 g of ice and stirred for 20 minutes. The separated precipitate is filtered off under suction and washed neutral with water. The precipitate is dissolved in 200 ml of methylene chloride, the turbid solution is dried over sodium sulfate, stirred with 0.3 g of active carbon and filtered. The filtrate is extracted with five 100 ml portions of saturated sodium carbonate solution, each of the aqueous phases being re-extracted with a small amount of methylene chloride. The combined aqueous phases are acidified to pH 1 with concentrated hydrochloric acid. The separated product is extracted with two 150 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate. The solvent is distilled off, whereby the product crystallizes out. For purification, the product is recrystallized from ca 30 ml of methanol. There is obtained 3-hydroxy-2-methyl-4-(2-chlorophenylcarbamoyl)-2H-thieno[3,4-e]-1,2-thiazine 1,1-dioxide of melting point 152°-155° C.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:27]4[C:22](=[C:23]([O:28][CH2:29][CH2:30][CH2:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:24]=[CH:25][CH:26]=4)[CH:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=[O:5])C.O[Li].O>C1COCC1.CO.O>[CH3:35][S:32]([CH2:31][CH2:30][CH2:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:22]=1[CH:21]=[CH:20][N:19]2[C:17]1[CH:16]=[CH:15][N:14]=[C:13]([NH:12][CH:9]2[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)[N:18]=1)(=[O:34])=[O:33]
Reactant: CCOC(=O)C1CCC(Nc2nccc(-n3ccc4c(OCCCS(C)(=O)=O)cccc43)n2)CC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CS(=O)(=O)CCCOc1cccc2c1ccn2-c1ccnc(NC2CCC(C(=O)O)CC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a suspension of 4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-yl-amino}-cyclohexanecarboxylic acid ethyl ester (35.4 g, 70 mmol) in THF (180 mL) and MeOH (200 mL) was added a solution of LiOH-H2O (14.69 g) in H2O (150 mL). The resulting mixture was briefly heated in a steam bath and stirred at RT with a mechanical stirrer for 1 h to provide a light yellow solution. The reaction mixture was concentrated in vacuo and diluted with cold H2O and the pH was adjusted to 6 with 10% HCl. The resulting solid was filtered, washed several times with cold H2O and finally with EtOH at 0° C. The resulting solid product was then dried in vacuo to provide 4-{4-[4-(3-methanesulfonyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclo-hexanecarboxylic acid (32.2 g, 97.4%).
Reaction SMILES: [CH3:1][CH:2]([CH2:14][CH3:15])[CH2:3][NH:4][CH2:5][C:6]1[S:10][C:9](B(O)O)=[CH:8][CH:7]=1.Br[C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:29]1[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.O>[CH2:38]([S:35]([N:32]1[CH2:31][CH2:30][CH:29]([C:20]2[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=[C:17]([C:9]4[S:10][C:6]([CH2:5][NH:4][CH2:3][CH:2]([CH3:1])[CH2:14][CH3:15])=[CH:7][CH:8]=4)[CH:18]=3)[NH:22][CH:21]=2)[CH2:34][CH2:33]1)(=[O:37])=[O:36])[CH3:39]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CCC(C)CNCc1ccc(B(O)O)s1
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: C1COCCO1
Solvent: O
Product: CCC(C)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Temperature: 150 °C
Reaction time: 0.13 h
Yield: 20 %

Procedure:
To a CEM microwave tube containing the crude (5-{[(2-methylbutyl)amino]methyl}-2-thienyl)boronic acid (43 mg, 0.188 mmol) was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), dioxane (1.5 mL), H2O (0.5 mL) and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol). The reaction was heated in a CEM microwave for 30 min at 150° C. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with 3 mL MeOH), eluting in sequence with H2O (3 mL), MeOH (9 mL) and a 2 M solution of NH3/MeOH (6 mL). The NH3/MeOH fraction was dried under a stream of nitrogen at 40° C., and the crude product was taken up in dimethyl sulfoxide (1 mL) and purified on an Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2×50 mm) eluting at 20 mL per min for 1 min with 10% CH3CN/H2O (0.1% TFA) then a linear gradient of 10% CH3CN/H2O (0.1% TFA) to 95% CH3CN/H2O (0.1% TFA) over 8 min and holding at the final concentration for 30 sec. The fractions containing product were filtered through a 2 g Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies) to remove TFA and concentrated under a stream of nitrogen at 50° C. to give 16.2 mg of the title compound (17%).
Reaction SMILES: [Si:1]([CH2:8][CH2:9][CH2:10][NH:11][CH2:12][CH2:13][NH2:14])([O:6][CH3:7])([O:4][CH3:5])[O:2][CH3:3].[Si:15](CCCCl)([O:20][CH3:21])([O:18][CH3:19])[O:16][CH3:17]>CO>[CH3:3][O:2][Si:1]([CH:8]([Si:15]([O:20][CH3:21])([O:18][CH3:19])[O:16][CH3:17])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13][NH2:14])([O:4][CH3:5])[O:6][CH3:7]
Reactant: CO[Si](CCCNCCN)(OC)OC
Reactant: CO[Si](CCCCl)(OC)OC
Solvent: CO
Product: CO[Si](OC)(OC)C(CCNCCN)[Si](OC)(OC)OC
Temperature: 200 °C

Procedure:
In a manner similar to that shown in examples 1 and 2 above, 44 gms. of (CH3O)3Si(CH2)3NH(CH2)2NH2 and 40 gms. of (CH3O)3Si(CH2)3Cl were mixed together and warmed to 140° C. whereupon the reaction exothermed to 200° C. The reaction mass was heated at 140° C. for about 2 hours and then cooled and diluted using 168 gms. of CH3OH. After removal of HCl as an ethylenediamine salt, the crude product was distilled to recover a center cut boiling at 160° C. at 0.5 mm Hg, d425 =1.048, ND25 =1.4462.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:17]1(C)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1([Li])C=CC=CC=1.O>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:10]([OH:11])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ccccc1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(O)c2ccccc2)cc1OC1CCCC1
Temperature: 25 °C

Procedure:
A solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (10.00 g, 45.40 mM) in dried tetrahydrofuran (50 ml) was cooled to −78° C. A toluene solution of phenyllithium (49.94 mM) was dropped into this solution and the resultant mixture was stirred at that temperature for 5 hours. Water was added to the solution obtained, which was then warmed to room temperature and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, then the solvent was removed in vacuo to obtain a crude product of α-(3-cyclopentyloxy-4-methoxyphenyl)benzylalcohol (13.56 g) as a yellow oil. The crude product (10.00 g) of α-(3-cyclopentyloxy-4-methoxyphenyl)benzylalcohol was dissolved in dried methylene chloride (110 ml) thus obtained, manganese dioxide (16.00 g) was added to the solution, then the solution was vigorously stirred at room temperature for 2 days. The undissolved material in the solution was removed by filtration through Celite and the filtrate was concentrated in vacuo to obtain a residue as a yellow solid. The residue was purified by flash chromatography (SiO2: eluted by 20% ethyl acetate/hexane). The solvent was removed in vacuo and the resultant product was dried to obtain 3-cyclopentyloxy-4-methoxybenzophenone 9.20 g (yield 92.6%) as a light yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]2=[CH:11][C:10]=1[CH3:20])=[O:8].[N+](=[CH2:23])=[N-]>C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([C:9]1[N:13]2[CH2:14][CH2:15][CH:16]([C:17]([O:19][CH3:23])=[O:18])[C:12]2=[CH:11][C:10]=1[CH3:20])=[O:8]
Reactant: Cc1cc2n(c1C(=O)c1cccn1C)CCC2C(=O)O
Reactant: C=[N+]=[N-]
Solvent: ClCCl
Product: COC(=O)C1CCn2c1cc(C)c2C(=O)c1cccn1C
Temperature: 25 °C

Procedure:
A solution of 200 mg. of 5-(N-methyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid in 5 ml. of methylene chloride is treated with an excess of ethereal diazomethane, and the reaction mixture is maintained at room temperature for 30 minutes. The solvents and excess reagent are eliminated under reduced pressure and the residue crystallized from ethyl acetate-methanol, to yield methyl 5-(N-methyl-2-pyrroyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:6]([CH3:7])=[CH:5][CH2:4][CH:3]1[CH2:8][CH:9]=[O:10]>[Pd]>[CH3:11][C:2]1([CH3:1])[CH:6]([CH3:7])[CH2:5][CH2:4][CH:3]1[CH2:8][CH:9]=[O:10]
Reactant: CC1=CCC(CC=O)C1(C)C
Agent: [Pd]
Product: CC1CCC(CC=O)C1(C)C

Procedure:
510 g of 2-(2,2,3-trimethylcyclopent-3-en-1-yl) acetaldehyde at 85% (2.85 moles) were hydrogenated with 20 g of 5% Pd on carbon (50% wet) with 10 g of soda ash at 60 psi and 50°-60° C. The crude product was distilled from 22 g of boric anhydride affording 324 g of purified product, containing pinocamphone as a 10-15% impurity. BP 48° C./0.6 mmHg; 1H-NMR (300 MHz), δ0.54 (3H, s), 0.87 (3H, d, J=6.6 Hz), 0.88 (3H, s), 1.1-1.4 (2H, m), 2.25 (1H, m), 2.50 (1H, m), 2.55 (1H, m), 2.70-2.95 (3H, br m), 9.76 (1H, br s); 13C-NMR (75 MHz), δ14.01, 14.73, 25.54, 28.34, 30.35, 42.62, 44.84, 45.03, 45.75, 203.83; IR (Neat), 2980, 2720, 1730, 1470, 1390, 1370 cm-1 ; MS (m/e), 139 (M+ -15), 97, 69 (Base).