Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([Cl:8])=[CH:4][N:3]=1.N1C=CC=CC=1.[Br:15]Br>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:7]([Br:15])=[N:6][C:5]([Cl:8])=[CH:4][N:3]=1
Reactant: Nc1cnc(Cl)cn1
Reactant: BrBr
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Nc1ncc(Cl)nc1Br
Reaction time: 0.5 h

Procedure:
2-Amino-5-chloropyrazine (1.7 g) was dissolved in chloroform (190 ml) and pyridine (1.3 ml) was added under an argon atomosphere. The flask and its contents were protected from light and a solution of bromine (0.7 ml) in chloroform (85 ml) was added over a period of 1 hour. After stirring for 2 hours more bromine (0.07 ml) in chloroform (8.5 ml) was added. After stirring for 30 minutes, pyridine (0.2 ml) was added. The reaction mixture was stirred for a further 30 minutes then washed with water (50 ml) and the organic phase was separated. Volatile material was removed by evaporation and and the residue was purified by chromatography through a bed of silica (90 g), eluting with hexane (200 ml), followed by dichloromethane. Dichloromethane fractions containing the product were evaporated to give 2-amino-3-bromo-5-chloropyrazine (1.68 g); 1H NMR (d6 -DMSO): 6.94 (br s, 2H), 8.09 (s, 1H); mass spectrum (+ve CI): 208 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15]C)=[CH:10][CH:9]=2)([O:3][CH3:4])=[O:2].Cl.N1C=CC=CC=1>O>[C:1]([C:5]1[N:6]=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([OH:15])=[CH:10][CH:9]=2)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cc2cc(OC)ccc2c(-c2ccccc2)n1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1cc2cc(O)ccc2c(-c2ccccc2)n1
Temperature: 170 °C

Procedure:
A mixture of 3-carbomethoxy-6-methoxy-1-phenylisoquinoline (228 mg) and pyridine hydrochloride (700 mg) was heated at 170° C. for 6 hr. While still hot, H2O (15 mL) was added and the precipitate that formed was collected. The aqueous phase was extracted with EtOAc (5×) and the combined organics were dried (Na2SO4) and concentrated. The residual material was combined with the precipitate and dissolved in MeOH (20 mL) and conc. HCl (10 drops). After refluxing for 60 hr, the mixture was cooled to r.t., NH4OAc buffer was added and the mixture was extracted with EtOAc (3×). The combined organics were washed with buffer, brine, dried (MgSO4) and concentrated. Trituration of the residue with hexane/EtOAc (9:1) provided the title compound as a solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C@H:9]([OH:29])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[C@@H:12]3[CH2:28][C@@H:13]3[C:14]32[O:27][CH2:26][CH2:25][O:24]3)[CH2:6]1)(=[O:3])[CH3:2].C([O:34]O)(C)(C)C>C1(C)C=CC=CC=1.C(OCC)C>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@:7]3([O:34][C@@H:8]3[C@H:9]([OH:29])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[C@@H:12]3[CH2:28][C@@H:13]3[C:14]32[O:27][CH2:26][CH2:25][O:24]3)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OO
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=C[C@H](O)[C@H]3[C@@H]4[C@@H]5C[C@@H]5C5(OCCO5)[C@@]4(C)CC[C@@H]32)C1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@]4(C)[C@@H]([C@@H]5C[C@@H]5C45OCCO5)[C@@H]3[C@@H](O)[C@H]3O[C@]32C1
Temperature: 80 °C

Procedure:
A solution of 23.3 g of 3β-acetoxy-17,17-ethylenedioxy-15β,16β-methylene-5-androsten-7β-ol in 350 ml of toluene was combined dropwise, after adding vanadium(IV) oxide acetylacetonate, within 35 minutes with 23.3 ml of 80% tert.-butyl hydroperoxide, dissolved in 115 ml of toluene. The reaction solution was maintained at 80° C. for another 30 minutes, then cooled, diluted with diethyl ether, washed with sodium bisulfite solution, sodium bicarbonate solution, and water, and dried and evaporated, thus obtaining 24.5 g of 3β-acetoxy-5,6β-epoxy-17,17-ethylenedioxy-15β,16β-methylene-5β-androstan-7β-ol, mp 162°-163° C. (diisopropyl ether).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:22]=[CH:21][C:7]2[N:8]=[C:9]([NH:11][C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[NH:13])[S:10][C:6]=2[CH:5]=1>[OH-].[Na+].C(OCC)(=O)C>[CH3:2][O:3][C:4]1[CH:22]=[CH:21][C:7]2[N:8]3[C:9](=[N:8][C:7]4[CH:21]=[CH:22][CH:4]=[CH:5][CH:6]=4)[N:13]=[C:12]([NH:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:11]=[C:9]3[S:10][C:6]=2[CH:5]=1
Reactant: COc1ccc2nc(NC(=N)Nc3ccccc3)sc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)sc1nc(Nc3ccccc3)nc(=Nc3ccccc3)n12
Reaction time: 1 h
Yield: 33.5 %

Procedure:
A suspension of the product from part (b) (2.0 g) in a mixture of sodium hydroxide solution (1N) and ethyl acetate (200 ml) was stirred until solution was obtained. The organic phase was removed, washed with water, dried and evaporated to a gum. A solution of the gum in dry dimethyl formamide (20 ml) was added to a stirred suspension of sodium hydride (300 mg of a 50% dispersion in oil) in the same solvent (20 ml) and stirring was continued for 1 h. A solution of phenylisothiocyanate (0.72 g) in dry dimethylformamide was added at room temperature and stirring continued for a further 2 h. Methyl iodide (0.7 g) was added and the reaction mixture allowed to stand at room temperature for 16 h. Addition of water (100 ml) resulted in the precipitation of a waxy solid which was collected and crystallised from acetonitrile to give the title compound as a pale cream crystals (400 mg), mp 213°-4°.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[S:9]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)=[N:18][C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[C:2]1([N:8]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[S:9]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=4)=[N:18][C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(c1ccccc1)S(=O)(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(S(=O)(=O)N(CCC(=O)O)c3ccccc3)ccc21
Yield: 24 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-sulphonic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: 24% of theory, Rf value: 0.55 (Reverse-Phase RP-18 silica gel; methanol/5% saline solution=3:2) C25H26N6O4S (506.6) ##EQU112##
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[C:10]([C:17]([O:19]C)=[O:18])[CH:11]=[CH:12][CH:13]=2)[CH2:8]1.[OH-].[Na+].Cl>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[C:10]([C:17]([OH:19])=[O:18])[CH:11]=[CH:12][CH:13]=2)[CH2:8]1
Reactant: COC(=O)c1cccc2c1CN(c1ncccn1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cccc2c1CN(c1ncccn1)CC2
Yield: 311.6 %

Procedure:
Compound 9u (187 mg, 0.44 mmol) was refluxed with 3N aqueous NaOH (0.25 mL mg, 0.75 mmol) in THF (6 mL) overnight. Concentrated HCl solution was added to the mixture to adjust pH to 3-4. The resulting mixture was concentrated to give 9v (350 mg) as the tris-HCl salt.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([O:12]CC2C=CC=CC=2)[CH:9]=[C:8]([Cl:20])[C:3]=1[O:4][CH2:5][CH2:6][OH:7]>[Pd].C(O)C>[Cl:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([Cl:20])[C:3]=1[O:4][CH2:5][CH2:6][OH:7]
Reactant: OCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Agent: [Pd]
Solvent: CCO
Product: OCCOc1c(Cl)cc(O)cc1Cl
Yield: 95.1 %

Procedure:
A mixture of 10.3 grams (0.033 mole) of 2-(2,6-dichloro-4-(phenylmethoxy)phenoxy)ethan-1-ol and 0.4 gram (catalyst) of 10% palladium on carbon in 100 mL of ethanol was subjected to hydrogenation conditions (40 PSI) using a Parr hydrogenator. After the theoretical uptake of hydrogen, the reaction mixture was filtered and concentrated under reduced pressure, yielding 7.0 grams of the subject compound as a residue. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[F:8][C:9]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:10]=1[CH2:11][N:12]1[C:20]2[CH2:19][CH:18]([CH3:21])[NH:17][CH2:16][C:15]=2[C:14]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[N:13]1.C(OC(=O)C)(=O)C.N1C=CC=CC=1>O>[F:8][C:9]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:10]=1[CH2:11][N:12]1[C:20]2[CH2:19][CH:18]([CH3:21])[N:17]([C:3](=[O:4])[CH3:2])[CH2:16][C:15]=2[C:14]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)=[N:13]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC1Cc2c(c(-c3ccc(F)cc3)nn2Cc2ccc(F)cc2F)CN1
Solvent: O
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1Cc2c(-c3ccc(F)cc3)nn(Cc3ccc(F)cc3F)c2CC1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.9 %

Procedure:
A mixture of 1-(2,4-Difluoro-benzyl)-3-(4-fluoro-phenyl)-6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (7a) (0.53 g, 1.35 mmol), acetic anhydride (5.5 ml) and pyridine (5.5 ml) was stirred at 25° C. for 16 h. The mixture was poured on 50 ml water, extracted with 150 ml ethyl acetate, the combined organic layers were washed with 3 times 0.5 N NaOH (50 ml) and once with brine, dried over MgSO4, filtrated and evaporated to dryness. The crude product was silica gel chromatography (eluting with heptane/ethyl acetate) to give 156 mg of 1-[1-(2,4-Difluoro-benzyl)-3-(4-fluoro-phenyl)-6-methyl-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (8z).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[CH:4][CH:3]=1.[CH2:16]([NH:20][CH3:21])[CH:17]([CH3:19])[CH3:18].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:16]([N:20]([CH3:21])[C:2]1[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[CH:4][CH:3]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Reactant: CNCC(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)CN(C)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 64 %

Procedure:
5 ml of (4-bromophenoxy)-t-butyldimethylsilane, 2.9 ml of isobutylmethylamine, 458.0 mg of palladium acetate, 1.2 g of 2-(di t-butylphosphino)biphenyl and 2.9 g of sodium t-butoxide were suspended in 40 ml of anhydrous toluene, and the mixture was stirred at 100° C. for 1.5 hours. The catalyst was filtered, followed by addition of water and extraction with ethyl acetate. After the extraction solution was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate/n-hexane=1/40→1/20) to give the title compound (3.83 g, 64% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[N:6][CH:7]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:9]=1)[CH3:2].[CH2:29]([O:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:58])[CH2:48][C:49]2[CH:54]=[CH:53][C:52](Br)=[C:51]([F:56])[C:50]=2[F:57])=[CH:42][C:41]=1[C:59]([F:62])([F:61])[F:60])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:29]([O:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:47](=[O:58])[CH2:48][C:49]2[CH:54]=[CH:53][C:52]([C:8]3[CH:7]=[N:6][C:5]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=4)=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=3)=[C:51]([F:56])[C:50]=2[F:57])=[CH:42][C:41]=1[C:59]([F:61])([F:60])[F:62])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OCc1ccc(OC)cc1
Reactant: O=C(Cc1ccc(Br)c(F)c1F)Nc1ccc(OCCOCc2ccccc2)c(C(F)(F)F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1cc(-c2ccc(CC(=O)Nc3ccc(OCCOCc4ccccc4)c(C(F)(F)F)c3)c(F)c2F)cnc1OCc1ccc(OC)cc1
Temperature: 110 °C
Yield: 54.5 %

Procedure:
To a solution of 3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (8.49 mg, 0.022 mmol), N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2,3-difluorophenyl)acetamide (12 mg, 0.022 mmol) and Cs2CO3 (17.96 mg, 0.055 mmol) in 1,4-dioxane (6 mL) and H2O (2 mL) stirred under a N2 atmosphere at 20° C. was added PdCl2(dppf) (0.807 mg, 1.102 μmol) in one charge. The reaction vessel was heated in 110° C. for 3 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA=2:1, Rf=0.6) to yield a brown solid of N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2,3-difluorophenyl)acetamide (10 mg, 0.012 mmol, 52.7% yield): 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J=3.0 Hz, 1H), 7.66-7.50 (m, 2H), 7.41-7.34 (m, 2H), 7.29-7.07 (m, 8H), 6.95-6.80 (m, 3H), 5.39 (d, J=4.9 Hz, 2H), 4.57 (d, J=5.0 Hz, 2H), 4.14 (d, J=4.0 Hz, 2H), 4.09-3.96 (m, 2H), 3.84-3.66 (m, 7H), 1.38 (q, J=6.4 Hz, 3H); ES-LCMS m/z 723.1 (M+H).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[N:12]1([S:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=2)(=[O:10])=[O:9])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=S(=O)(Cl)c1cccc(F)n1
Reactant: C1COCCN1
Solvent: ClC(Cl)Cl
Product: O=S(=O)(c1cccc(F)n1)N1CCOCC1

Procedure:
To a solution of 6-fluoropyridine-2-sulphonyl chloride (1.96 g) in chloroform (40 cm3) at 0° C. was added a solution of morpholine (1.74 g) in chloroform (20 cm3). The reaction was quenched in water (100 cm3) and the product extracted into chloroform (3×50 cm3). The combined organic layers were washed with water, dried over anhydrous magnesium sulphate and the solvent evaporated under reduced pressure to give the title compound which was used without further purification.
Reaction SMILES: [CH2:1]([C:4]1[C:5](=[O:10])[NH:6][CH:7]=[CH:8][CH:9]=1)[CH2:2][CH3:3].CC(C)([O-])C.[K+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[O:27][CH3:28].O>CN(C=O)C>[CH3:28][O:27][C:19]1[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=1[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:1][CH2:2][CH3:3])[C:5]1=[O:10]
Reactant: CCCc1ccc[nH]c1=O
Reactant: COc1cc([N+](=O)[O-])ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cccn(-c2ccc([N+](=O)[O-])cc2OC)c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
500 mg (3.65 mmol) of the product from example 51A are dissolved in 7.3 ml of DMF and cooled to 0° C. To this are added 613 mg (5.47 mmol) of potassium tert-butoxide, and the mixture is left to stir at RT for 30 min. Then 624 mg (3.65 mmol) of 1-fluoro-2-methoxy-4-nitrobenzene are added. The mixture is stirred at RT for 6 h, water is added and the mixture is extracted four times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated. Purification is effected by preparative HPLC. The resulting product fraction is purified further by chromatography on silica gel (eluent: dichloromethane, then 10:1 dichloromethane/methanol). This affords 158 mg (15% of theory) of the desired compound as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:6]=[C:5]2[CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Cl-].[Na+].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>[C:28]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:6]=[C:5]3[CH:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C2CCN(C)CC2)c2cc(Br)ccc21
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: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C2CCN(C)CC2)c2cc(-c3ccccc3)ccc21
Temperature: 25 °C
Yield: 21.4 %

Procedure:
A mixture of 5-bromo-3-(1-methylpiperidin-4-yl)-1-(triisopropylsilyl)-indole (0.600 g, 1.34 mmol), phenylboronic acid (0.171 g, 1.40 mmol), tetrakis(triphenylphosphine)palladium(0) (0.077 g, 0.067 mmol), and 2M aqueous sodium carbonate solution (2 mL) in toluene (15 mL) was heated at reflux overnight. The solution was allowed to cool to room temperature, diluted with ethyl acetate and brine, the organic phase was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel (flash) chromatography (dichloromethane:methanol:aqueous ammonium hydroxide 4.5:0.5:0.2) to give 0.128 g of 5-phenyl-3-(1-methylpiperidin-4-yl)-1-(triisopropylsilyl)-indole (22%) as an oil, which was desilylated by dissolving in 1 mL of tetrahydrofuran and treating with tetrabutylammonium fluoride (1M solution in tetrahydrofuran, 4 mL) with stirring at room temperature for 3 hours. The mixture was concentrated in vacuuo, and the resulting oil was purified by silica gel (flash) chromatography (eluting with 500 mL dichloromethane, followed by dichloromethane:methanol:aqueous ammonium hydroxide 4.5:0.5:0.1) to give the title compound (0.045 g) as an amorphous white solid. FDMS m/e=289 (M+). EA calculated for C20H22N2: C, 82.72; H, 7.64; N, 9.65. Found: C, 82.19; H, 7.37; N, 9.75.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn].[Cl-].[CH2:26]([C:33]1[O:34][C:35]([CH3:39])=[C:36]([CH3:38])[CH:37]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl.CN(C)C=O>[CH2:26]([C:33]1[O:34][C:35]([CH3:39])=[C:36]([CH3:38])[C:37]=1[C:7]([C:6]1[CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:13][CH3:14])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:9])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1cc(Cc2ccccc2)oc1C
Reactant: COc1c(C(C)C)cc(C(=O)O)cc1C(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Sn]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc1C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
At ambient temperature, to a stirred suspension containing 3,5-diisopropyl-p-anisic acid (1.95 g, 8.23 mmol, RN-1 17439-59-5) and oxalyl chloride (0.8 mL, 9.20 mmol) in CH2Cl2 (22.5 mL) was added N,N-dirnethylformamide (2 drops). After 2h, the reaction was cooled to −78° C. To the reaction was added tin (TV) chloride (1.05 mL) followed by a solution of 2-benzyl4,5-dimethylfuran (1.8 g, 9.68 mmol) in CH2Cl2 (10.0 mL). After the additions were complete, the reaction was allowed to warm to ambient temperature and stirred for 24 h. The reaction was quenched into crushed ice (100 g), diluted with sat. aq. KH2PO4 (100 mL) and extracted with ether. The combined ethereal extracts were washed with sat aq. NaHCO3 (2×60 mL), with brine (1×60 ml), dried (Na2SO4) and concentrated. The crude product was purified on Biotage KP-Sil eluting with 1% EtOAc/pet. ether to give 2.07 g, (62%) of the title compound as an oil; 1H NMR (DMSO-d6)67 1.17 (d, 12 H), 1.81 (s, 3 H), 2.19 (s, 3 H), 3.29 (septet, 2 H), 3.74 (s, 3 H), 3.84 (s, 2 H), 7.01-7.03 (m, 2 H), 7.16-7.25 (m, 3 H), 7.47 (s,2H). mass spectrum (EI), m/z 404 (M+). Anal. Calcd. for C27H32O3 .0.6H2O: C, 78.07; H, 8.06; N, 0.00. Found: C, 78.04; H, 7.93; N, −0.02.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19]([S:21]Cl)=[O:20]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[O:14][C:19](=[O:20])[S:21][N:15]=2)=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: O=C(Cl)SCl
Solvent: Cc1ccccc1
Product: O=c1oc(-c2ccc(OCc3ccccc3)cc2)ns1
Temperature: 90 °C

Procedure:
To a solution of 4-benzyloxybenzamide (0.25 g, 1.10 mmol) in toluene (15 ml) was added chlorocarbonylsulfenyl chloride (0.18 ml, 2.20 mmol) and the resulting reaction mixture was refluxed at 90° C. overnight. After the completion of the reaction (TLC monitoring), the mixture was concentrated, added diethyl ether and washed twice with water, twice with 5% NaHCO3, again with water, and was then dried (Na2SO4), concentrated under vacuum to give the product (crude yield 0.310 g, 98%) that was used as such for the next step.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@H:9]2[CH2:11][C@H:10]2[NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)=[O:14])[CH:6]=[CH:7][CH:8]=1)#[CH:2].C(OCC)(=[O:25])C.C([O-])([O-])=O.[K+].[K+]>OS(O)(=O)=O.O.C(O)(=O)C.[Hg](OC(C)=O)OC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([C@H:9]2[CH2:11][C@H:10]2[NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)=[O:14])[CH:6]=[CH:7][CH:8]=1)(=[O:25])[CH3:2]
Reactant: CCOC(C)=O
Reactant: C#Cc1cccc([C@H]2C[C@H]2NC(=O)Nc2ccc(Cl)cn2)c1
Agent: CC(=O)O[Hg]OC(C)=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1cccc([C@H]2C[C@H]2NC(=O)Nc2ccc(Cl)cn2)c1

Procedure:
A solution of (+,−)-N-(cis-2-(3-Ethynylphenyl)-cyclopropyl)-N′-(5-chloropyrid-2-yl)-urea of Example 22(130 mg, 0.42 mmole), H2SO4 (10 drops), H2O (10 drops) and Hg(OAc)2 (100 mg) in acetic acid (4 mL) was stirred at room temperature for 30 min. The reaction mixture was then poured into an ethyl acetate and saturated K2CO3 solution. The organic layer was dried (MgSO4) and the solvent was evaporated to give a residue which was purified on silica gel using 1:1 acetone: and hexanes as the eluent providing 43 mg of the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([NH:13][NH2:14])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].Cl.C(OC(N1CCC(NN)CC1)=O)(C)C.[Cl:30][C:31]1[C:36]([CH:37]=O)=[C:35](Cl)[N:34]=[CH:33][N:32]=1.ClC1N=CN=C2N(C3CCC(C4ON=C(C(C)C)N=4)CC3)N=CC=12>>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([N:13]2[C:35]3=[N:34][CH:33]=[N:32][C:31]([Cl:30])=[C:36]3[CH:37]=[N:14]2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: O=Cc1c(Cl)ncnc1Cl
Reactant: CC(C)OC(=O)N1CCC(NN)CC1
Agent: CC(C)c1noc(C2CCC(n3ncc4c(Cl)ncnc43)CC2)n1
Agent: Cl
Product: CC(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1

Procedure:
4-(4-Chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid isopropyl ester was prepared from the reaction of 4-hydrazino-piperidine-1-carboxylic acid isopropyl ester (Intermediate 10) and 4,6-dichloro-pyrimidine-5-carbaldehyde (Intermediate 16) using the procedure described for 4-chloro-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 23). The product was purified by flash chromatography eluting with 40% ethyl acetate/hexanes to give 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid isopropyl ester as a white solid. Mass spectrum M+=323.0.