Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[NH2:10][C:11]([NH2:13])=[S:12]>C(O)C>[ClH:2].[ClH:1].[N:7]1[CH:8]=[CH:9][C:4]([CH2:3][S:12][C:11](=[NH:10])[NH2:13])=[CH:5][CH:6]=1
Reactant: ClCc1ccncc1
Reactant: NC(N)=S
Agent: Cl
Solvent: CCO
Product: N=C(N)SCc1ccncc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
A suspension of 4-chloromethylpyridine hydrochloride (82 g) in gently boiling ethanol (260 cc) is added dropwise and in the course of 30 minutes to a suspension of thiourea (45.5 g) in boiling ethanol (260 cc). The reaction mixture is stirred for 1 hour 30 minutes at the boil and then cooled to 5° C. The resulting crystals are filtered off, washed twice with ethanol (60 cc in total) and dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature of about 20° C. 2-(Pyrid-4-yl-methyl)-isothiourea dihydrochloride (116 g), melting at 260° C., is thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]#[C:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].C1COCC1>CO>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]#[C:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C#CC(C)(C)C)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)C#Cc1ccc(C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.1 %

Procedure:
A mixture of methyl 2-chloro-4-(3,3-dimethylbut-1-ynyl)benzoate (330 mg, 0.0013 mol), 2N aq. NaOH (3.0 mL), THF (5 mL), and MeOH (5 mL) was stirred at rt for 5 h. The mixture was concentrated under vacuum and the residue was treated with water and acidified with 1N HCl to pH 2-3, and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), and concentrated under vacuum to give the product (305 mg, 98%) as a white solid. tR=3.56 min, 234.9 & 236.9 (M−1).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]2[C:15]3([CH2:38][O:39][C:11]=2[CH:10]=1)[C:23]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[N:17]([CH:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:16]3=[O:37])C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[C:31]1([CH:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]3([C:12]4[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]=4[O:39][CH2:38]3)[C:16]2=[O:37])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc(OCc3ccccc3)ccc12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc(O)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
A suspension of 6-(benzyloxy)-1′-(diphenylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (1.00 g, 2.0 mmol) in methanol/ethyl acetate (15/25 mL) was degassed by bubbling through nitrogen for 1 h before palladium on carbon (5%, 0.42 g, 0.2 mmol) was added. The mixture was stirred under hydrogen at ambient temperature for 16 h. The mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo. The obtained residue was recrystallized from ethyl acetate and hexane to afford 1′-(diphenylmethyl)-6-hydroxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.78 g, 95%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.42-7.25 (m, 10H), 7.16-7.10 (m, 1H), 7.07-6.92 (m, 3H), 6.54-6.48 (m, 1H), 6.44 (d, J=8.2 Hz, 1H), 6.33 (d, J=2.2 Hz, 1H), 6.20 (dd, J=8.2, 2.2 Hz, 1H), 5.65 (s, 1H), 4.99 (d, J=9.0 Hz, 1H), 4.71 (d, J=9.0 Hz, 1H); MS (ES+) m/z 420.1 (M+1).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][N:13]1[S:18]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=3)[N:29]([S:37]([CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])(=[O:39])=[O:38])[CH:28]=2)[CH2:23][CH2:22]1)(=[O:20])=[O:19])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:52]1([CH2:55]Br)[CH2:54][CH2:53]1.O>CN(C=O)C>[CH2:1]([O:8][NH:9][C:10]([C@H:12]1[CH2:17][N:16]([CH2:55][CH:52]2[CH2:54][CH2:53]2)[CH2:15][CH2:14][N:13]1[S:18]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=3)[N:29]([S:37]([CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])(=[O:39])=[O:38])[CH:28]=2)[CH2:23][CH2:22]1)(=[O:19])=[O:20])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCS(=O)(=O)n1cc(C2CCN(S(=O)(=O)N3CCNC[C@@H]3C(=O)NOCc3ccccc3)CC2)c2cc(F)ccc21
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCS(=O)(=O)n1cc(C2CCN(S(=O)(=O)N3CCN(CC4CC4)C[C@@H]3C(=O)NOCc3ccccc3)CC2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-benzyloxy-1-{4-[5-fluoro-1-(2-trimethylsilylethane-sulfonyl)indol-3-yl]piperidine-1-sulfonyl}piperazine-2-(R)-carboxamide (424 mg, 0.68 mmol) [prepared by proceeding as described in Example 15, Steps 4 and 5, but substituting 4-(4,5,6,7-tetra-fluoroindol-3-yl)piperidinesulfamoyl chloride with 4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)indol-3-yl]piperidinesulfamoyl chloride] in DMF (3 ml) was added potassium carbonate (470 mg, 3.4 mmol) and cyclopropylmethyl bromide (101 mg, 0.75 mmol) and the suspension was vigorously stirred at RT for 24 h. Water was added and the reaction was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed (SiO2, PTLC, 50% ethyl acetate/hexanes) to give N-benzyloxy-1-{4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)indol-3-yl]piperidine-1-sulfonyl}-4-cyclopropylmethylpiperazine-2-(R)-carboxamide e as a pale yellow oil. This material was converted to N-hydroxy-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]-4-cyclopropylmethylpiperazine-2-(R)-carboxamide by proceeding as described in Example 20, Step 2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@@H:13]([S:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:12]([OH:24])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH:13]([S:15][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12](=[O:24])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)[C@H](SC(=O)c2ccccc2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1CCC(=O)C(SC(=O)c2ccccc2)C1
Yield: 83 %

Procedure:
Thiobenzoic acid S-((1R,2R,5S)-5-tert-butoxycarbonylamino-2-hydroxy-cyclohexyl) ester+(1S,2S,5R) diastereomer (8.7 g, 24.8 mmol) from Example 34 Step A was treated with 1,1-dihydro-1,1,1-triacetoxy-1,2-benziodoxol-3(1H)-one (11.02 g, 26 mmol) according to the method of Example 34 Step B. After work up and chromatography (silica, toluene/ethyl acetate=6/1) of the mixture the title compound (toluene/ethyl acetate=3/1, Rf=0.43, 7.15 g, 83% yield) was obtained as a white solid.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14]Br)[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[F:16][C:17]([F:26])([F:25])[C@H:18]1[CH2:23][CH2:22][C@H:21]([O-:24])[CH2:20][CH2:19]1.[Na+]>C1COCC1>[F:16][C:17]([F:25])([F:26])[C@H:18]1[CH2:19][CH2:20][C@H:21]([O:24][CH2:14][C@H:11]2[CH2:12][CH2:13][C@H:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:9][CH2:10]2)[CH2:22][CH2:23]1
Reactant: [O-][C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: CCCCCCC[C@H]1CC[C@H](CBr)CC1
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCC[C@H]1CC[C@H](CO[C@H]2CC[C@H](C(F)(F)F)CC2)CC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 0.11 mol of trans-4-heptylcyclohexylmethyl bromide and 80 ml of THF is added at 0° C. to a mixture of 0.1 mol of sodium (trans-4-trifluoromethylcyclohexanolate) (prepared from 0.1 mol of trans-4-trifluoromethylcyclohexanol and 0.1 mol of sodium hydride) and 200 ml of THF. The mixture is stirred at 60° C. for 3 hours, and customary work-up gives the product as a colourless solid.
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.[OH-].[Na+]>CO.C1COCC1>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([S:22]([N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[C:5]2[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=2[C:3]([OH:33])=[O:2])(=[O:24])=[O:23])=[CH:30][CH:29]=1
Reactant: COC(=O)c1cc(C)cc(C)c1N(Cc1cccc(OC)c1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(Cc2cccc(OC)c2)c2c(C)cc(C)cc2C(=O)O)cc1
Yield: 70.4 %

Procedure:
To a solution of 0.610 g (1.3 mmol) of the product of Example 103 in 6.5 mL methanol and 6.5 mL of THF was added 6.5 mL of 1N NaOH solution. The reaction mixture was refluxed for 18 hr and the organics were removed in vacuo. The resulting mixture was diluted with water, acidified with 3N HCl and extracted with EtOAc. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was triturated with ether and filtered to provide 0.417 g (79%) of the desired carboxylic acid as a white solid. Electrospray Mass Spec 456.3(M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[C:12]1[CH2:21][CH2:20][C:15]2([O:19][CH2:18][CH2:17][O:16]2)[CH2:14][CH:13]=1>CCO.[Pd]>[CH3:11][C:5]1[CH:4]=[C:3]([CH:12]2[CH2:21][CH2:20][C:15]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:14][CH2:13]2)[C:2]([CH3:1])=[CH:7][C:6]=1[NH2:8]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1C1=CCC2(CC1)OCCO2
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C2CCC3(CC2)OCCO3)c(C)cc1N
Reaction time: 14 h

Procedure:
A mixture of 8-(2,5-Dimethyl-4-nitrophenyl)-1,4-dioxaspiro[4.5]dec-7-ene (105 mg, 0.36 mmol) and Pd/C (10 mg) in EtOH was degassed and stirred under 1 atm. H2 at room temperature for 14 h. Pd/C was removed by filtration and filtrate was concentrated to provide 2,5-dimethyl-4-(1,4-dioxaspiro[4.5]decan-8-yl)aniline, which was used in the next step without further purification; ESMS m/z 262.2 (M+H+).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:13]([NH:16][C:17]([CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([CH:44]=[O:45])=[CH:40][CH:39]=1)([CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])(=[O:15])[CH3:14].Cl>O1CCCC1>[C:13]([NH:16][C:17]([CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([CH:44]([OH:45])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:40][CH:39]=1)([CH2:27][O:28][Si:29]([C:32]([CH3:33])([CH3:34])[CH3:35])([CH3:31])[CH3:30])[CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])(=[O:15])[CH3:14]
Reactant: CC(=O)NC(CCc1ccc(C=O)cc1)(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Reactant: BrCCCCc1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(=O)NC(CCc1ccc(C(O)CCCCc2ccccc2)cc1)(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Reaction time: 1.5 h
Yield: 83.2 %

Procedure:
To a solution of magnesium (0.27 g) in anhydrous tetrahydrofuran (5 ml) was dropwise added a solution of 1-bromo-4-phenylbutane (2.35 g) in anhydrous tetrahydrofuran (5 ml) under a nitrogen atmosphere, and the mixture was stirred for 1.5 hours. To this solution was dropwise added a solution of 2-acetamido-1,3-bis(tert-butyldimethylsilyloxy)-2-(2-(4-formylphenyl)ethyl)propane (1.2 g) in anhydrous tetrahydrofuran (15 ml) and the mixture was stirred for 1 hour. 3% Hydrochloric acid was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate=2:1) to give the title compound (1.27 g) as a colorless transparent oily substance.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][N:17]1[C:22]2=[C:23]3[N:28]([C:29]([C:30]4[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=4)=[C:21]2[C:20](=[O:38])[N:19]([CH3:39])[C:18]1=[O:40])[CH2:27][CH2:26][CH2:25][C:24]3=O.N1C(C)=CC=CC=1C>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:24]1[C:23]2[N:28]([C:29]([C:30]3[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=3)=[C:21]3[C:20](=[O:38])[N:19]([CH3:39])[C:18](=[O:40])[N:17]([CH3:16])[C:22]3=2)[CH2:27][CH2:26][CH:25]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CCCC3=O)c1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: Cc1cccc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CCC=C3OS(=O)(=O)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Trifluoromethanesulfonic anhydride (253 μL, 1.50 mmol) was added to an ice-cooled solution of 1,3-dimethyl-5-m-tolyl-8,9-dihydropyrimido[4,5-a]indolizine-2,4,10(1H,3H,7H)-trione (step 3) (388 mg, 1.15 mmol) and 2,6-lutidine (201 μL, 1.73 mmol) in DCM (7 mL). The solution was allowed to reach room temperature slowly and was stirred for 16 hours. A further portion of trifluoromethanesulfonic anhydride (39 μL, 0.23 mmol) was added and the solution was stirred for a further 30 minutes. The reaction mixture was diluted with dichloromethane (15 mL) and washed with water (2×8 mL) and sat brine (1×8 mL). The organic phase was dried with magnesium sulfate and the solvent was removed under vacuum, keeping the rotary evaporator water bath at 20° C. to give the title compound.
Reaction SMILES: [BrH:1].[OH:2][C:3]1[CH:4]=[C:5]([CH:10]([OH:28])[CH2:11][NH:12][C:13]([CH3:27])([CH3:26])[CH2:14][NH:15][C:16](=[O:25])[CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:7][C:8]=1[OH:9].[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].Br>FC(F)(F)C(O)=O>[BrH:1].[C:29]([O:28][CH:10]([C:5]1[CH:6]=[CH:7][C:8]([O:9][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[C:3]([O:2][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[CH:4]=1)[CH2:11][NH:12][C:13]([CH3:26])([CH3:27])[CH2:14][NH:15][C:16](=[O:25])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(CNC(=O)COc1ccccc1)NCC(O)c1ccc(O)c(O)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: Br
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CNC(=O)COc1ccccc1)NCC(OC(=O)C(C)(C)C)c1ccc(OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c1

Procedure:
A solution of 1-(3,4-dihydroxyphenyl)-2-[1,1-dimethyl-2-(2-phenoxyacetamido)ethylamino]ethanol hydrobromide (0.8 g.) in trifluoroacetic acid (5.4 ml.) was treated with pivaloyl chloride (1.12 ml.) and the mixture was heated under reflux for 40 minutes. The mixture was then evaporated and the residue was dissolved in ether. The solution obtained was treated with ethereal hydrogen bromide until just acid, where upon an oily solid separated. Trituration of this material with ether (20 ml.) gave the triester, 1-[3,4-bis(pivaloyloxy)phenyl]-2-[1,1-dimethyl-2-(2-phenoxyacetamido)ethylamino]ethyl pivaloate hydrobromide, as a solid (0.6 g.) m.p. 106°-110° C., NMR δ: 8.8 (2H, broad singlet, N+H2); 8.45 (1H, triplet, NHCO); 7.8-6.8 (8H, complex, aromatic protons); 5.43 (1H, broad, =CHO); 3.58 (2H, singlet, CHHD 2OPh); 4.0-3.0 (complex, CH2NH); 1.3-1.2 (33H, broad singlet, C.CH3).
Reaction SMILES: [NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([N+:12]([O-:14])=[O:13])([S:8][CH2:9][CH2:10][CH3:11])[C:4]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:3]1[NH:22][C:23]([NH:25][C:26]([O:28][CH3:29])=[O:27])=[S:24].[CH3:30]C(C)=O.[OH-].[Na+].CI>O>[NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([N+:12]([O-:14])=[O:13])([S:8][CH2:9][CH2:10][CH3:11])[C:4]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:3]1[NH:22][C:23](=[N:25][C:26]([O:28][CH3:29])=[O:27])[S:24][CH3:30]
Reactant: CC(C)=O
Reactant: CCCSC1([N+](=O)[O-])C=CC(=N)C(NC(=S)NC(=O)OC)=C1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: CCCSC1([N+](=O)[O-])C=CC(=N)C(NC(=NC(=O)OC)SC)=C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
A mixture of 1-imino-(4-nitro)phenylmethyl-2-(3-carbomethoxythioureido)-4-propylthiobenzene (4.3 g; 0.01 mole) acetone (50 ml), water (25 ml) and 50% aqueous sodium hydroxide (0.8 g; 0.01 mole) is stirred at room temperature for 15 min. and is cooled to 12° C. To the mixture there is added methyl iodide (1.4 g; 0.01 mole) and it is stirred at 13° C. to 20° C. for 2 hrs. The suspension that forms is vacuum filtered and the filter cake is washed with acetone and dried to afford 1-imino(4-nitro)phenylmethyl-2-(3-carbomethoxy-S-methylisothioureido)-4-propylthiobenzene (3.5 g; 78%), m.p. 135°-137° C. dec.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:18]([O:20][CH3:21])=[O:19])[C:7](=[CH:12][C:13]=1[C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]([O:10][CH3:11])=[O:9])([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]([C:18]([O:20][CH3:21])=[O:19])[C:7](=[CH:12][C:13]=1[C:14]([CH3:17])([CH3:15])[CH3:16])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C(C)(C)C)cc1C(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)c(C(C)(C)C)cc1C(=O)OC
Reaction time: 16 h

Procedure:
Dimethyl 4-nitro-5-t-butylphthalate (42 g.) was mixed with 0.2 g. of 5% Pd/C and, while kept under argon, 200 ml. of methanol was added. Rapid stirring under 30 psi of hydrogen gave complete reduction after 20 hours at 35° C. The mixture was filtered through Celite, and the methanol removed under reduced pressure. The residue was dissolved in 250 ml. of hot benzene, filtered, and mixed with 500 ml. of hexane. After standing 3 hours at room temperature and 16 hours at -10° C., the crystalline product was filtered off. After drying, 35.8 g. (95%) of solid dimethyl 4-amino-5-t-butylphthalate remained, m.p. 120°-122° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][P:16]([O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:35][C:34]=1[C:43]([CH3:46])([CH3:45])[CH3:44])[O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][C:19]=1[C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:4])([CH3:3])[CH3:2].C([OH:50])(C)C>O>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:12])[CH3:13])[CH:8]=[CH:7][C:6]=1[O:15][P:16]([O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:35][C:34]=1[C:43]([CH3:46])([CH3:45])[CH3:44])([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:25])([CH3:26])[CH3:27])=[CH:20][C:19]=1[C:28]([CH3:31])([CH3:30])[CH3:29])=[O:50])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(OP(Oc2ccc(C(C)(C)C)cc2C(C)(C)C)Oc2ccc(C(C)(C)C)cc2C(C)(C)C)c(C(C)(C)C)c1
Reactant: CC(C)O
Solvent: O
Product: CC(C)(C)c1ccc(OP(=O)(Oc2ccc(C(C)(C)C)cc2C(C)(C)C)Oc2ccc(C(C)(C)C)cc2C(C)(C)C)c(C(C)(C)C)c1
Temperature: 57.5 °C

Procedure:
tris(2,4-Di-tert.butylphenyl)phosphite (5146 g; Irgafos® 168, Ciba Specialty Chemicals) and isopropanol (IPA, 7890 g) are mixed in a reaction vessel and heated to 55-60° C. At this point the mixture is a slurry of approximately 39.0% solids. The peroxide (549 g, 50 weight-% solution of H2O2 in water, 1 equivalent) is added for 2-3 hours while maintaining the pot temperature (reaction is exothermic). After the peroxide addition, the mixture is maintained for 1 hour at 60° C. The reaction mass is homogeneous and the completeness of reaction is checked by LC (>97.0% conversion). Water (1355 g) is added, and the reaction mass is seeded to induce crystallization. Cooling slowly in 2 steps to 45° C. and then to 20° C. completes crystallization. The product is filtered (25μ screen), then dried at 70° C. under full vacuum with a nitrogen sweep.
Reaction SMILES: Cl.[C:2]([NH:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].[OH-].[K+].[CH3:10][N:11]=[C:12]=[O:13]>O1CCCC1.C(Cl)(Cl)Cl>[CH3:10][NH:11][C:12]([N:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[NH2:7])=[O:13]
Reactant: CN=C=O
Reactant: CC(C)(C)NN
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CNC(=O)N(N)C(C)(C)C
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of 6.23 g t-butylhydrazine hydrochloride (0.050 moles) in 50 mL tetrahydrofuran was degassed, then stirred under nitrogen as, first, one equivalent of powdered potassium hydroxide and then, dropwise, 2.85 g methyl isocyanate in 25 mL tetrahydrofuran were added. The solution was stirred overnight. The mixture was filtered to remove the residual solid impurity which was washed several times with tetrahydrofuran. The combined filtrates were evaporated to yield a white product which was taken up in chloroform and dried. Removal of the solvent yielded 5.80 g (79.9%) white crystalline N-methyl-1-t-butylhydrazinecarboxamide (m.p. 127°-9° C.). This structure was confirmed by NMR analysis.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[C:11]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)#[CH:12].N>>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[N:8][CH:9]=3)[CH:12]=2)[CH:14]=1
Reactant: ON=C(Cl)c1cncnc1
Reactant: C#Cc1cccnc1
Agent: N
Product: c1cncc(-c2cc(-c3cncnc3)no2)c1

Procedure:
The titled compound was prepared as the bishydrochloride salt according to Method CB using the product of Example 44B (79 mg, 0.5 mmol) and 3-ethynylpyridine (Aldrich, 52 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.70 (ddd, J=8.1, 4.9, 0.8 Hz, 1H), 7.96 (s, 1H), 8.37 (ddd, J=8.2, 1.9, 1.7 Hz, 1H), 8.77 (dd, J=4.7, 1.7 Hz, 1H), 9.17 (dd, J=2.2, 0.8 Hz, 1H), 9.34 (s, 2H), 9.36 (s, 1H) ppm; MS (DCI/NH3) m/z 225 (M+H)+.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCN(C(C)C)C(C)C>CS(C)=O>[CH2:29]([NH:36][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:17][CH:18]=3)[NH:13][N:12]=2)[CH:8]=[CH:7][N:6]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)c1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(CNc2nccc(-c3n[nH]c4nc(NCCN5CCOCC5)ncc34)n2)cc1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
To the solution of [3-(2-methanesulfonyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 11 supra) (220 mg, 0.54 mmol) and benzyl-amine (70 mg, 0.65 mmol) in DMSO (15 mL) was added DIPEA (84 mg, 0.65 mmol). The mixture was heated at 130° C. with stirring under N2 for 4 hours. The solvent was removed under reduced pressure. The residue was first purified by column chromatography (silica gel, dichloromethane:MeOH, 50:1 to 30:1), then by prep-HPLC. Concentrated HCl was added to the fractions with product and concentrated under reduced pressure to give [3-(2-benzylamino-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine; hydrochloride. (Yield 40 mg, 17.1%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:22][C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([F:30])[CH:29]=1)[NH2:26].C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:22][C:23]1[CH:24]=[C:25]([NH:26][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])[CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: O=C(O)c1ccccn1
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1cc(F)cc(F)c1)c1ccccn1
Reaction time: 72 h
Yield: 69.1 %

Procedure:
Picolinic acid (13.0 g, 106 mmol) was added to a solution of 1,1'-carbonyldiimidazole (17.11 g, 106 mmol) in dry dimethylformamide (100 mL) and the reaction stirred for 1 hour, before introduction of 3,5-difluoroaniline (15.0 g, 116 mmol). After 3 days, the reaction mixture was poured into saturated sodium bicarbonate solution (1 L) and extracted with ether (2×500 mL). The organic layers were dried and concentrated to give a solid, which was recrystallized from a mixture of ether and petroleum ether to give N-(3,5-difluorophenyl)-2-pyridinecarboxamide (17.15 g, 69%) m.p. 111°-113° C.