Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]1([CH3:29])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[PH:19][C:20]1[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=1[CH3:28].[CH2:30]([O:32]C(OCC)CBr)[CH3:31].[PH2-].[K+].[K+].[K+]>C1(C)C=CC=CC=1.C1COCC1>[C:11]1([CH3:29])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[P:19]([CH2:31][CH:30]=[O:32])[C:20]1[C:21]([CH3:28])=[CH:22][C:23]([CH3:27])=[CH:24][C:25]=1[CH3:26]
Reactant: Cc1cc(C)c(Pc2c(C)cc(C)cc2C)c(C)c1
Reactant: CCOC(CBr)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Agent: [PH2-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(P(CC=O)c2c(C)cc(C)cc2C)c(C)c1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
KHMDS (35 mL of a 0.5 M solution in toluene, 17.5 mmol, Aldrich) 35 was added to a solution of dimesitylphosphine (4.1 g, 15.8 mmol) in THF (50 mL) at −78° C. After stirring for 20 min at −78° C. bromoacetaldehyde diethylacetal (2.85 mL, 19 mmol, Aldrich) was added dropwise to the solution of potassium phosphide. The solution was stirred for 5 min at −78° C., warmed to RT and stirred for 30 min at RT. Assay by 31P-NMR (crude reaction mixture) showed the formation of product (−29.5 ppm). The solvent was evaporated, the residue was flushed through a 6×3.3 cm plug of silica gel and toluene was removed (aspirator) to afford the product as a yellow oil. The product was dissolved in a mixture of degassed acetone (60 mL) and 5% aq. HCl (30 mL) and refluxed under Ar for 2.5 h. A saturated, degassed solution of NaHCO3 (100 mL) was added to the reaction mixture followed by extraction with degassed CH2Cl2 (3×50 mL). The solution was evaporated under Ar followed by filtration through a plug of silica gel (9×3.6 cm; Ar atmosphere), CH2Cl2 eluent, collecting 250 mL. Evaporation afforded product as a very air-sensitive white solid, 4.1 g (83.1%). 31P{1H} NMR (CD2Cl2): −35.6 ppm (s).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:15][NH2:16])[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[C:26](Cl)=[O:27].C(N(CC)CC)C>O1CCOCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:15][NH:16][C:26]([C:18]4[O:17][C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[CH:19]=4)=[O:27])[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(Cl)c1cc2ccccc2o1
Reactant: NCC1(c2ccc3c(c2)OCO3)CCCC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(NCC1(c2ccc3c(c2)OCO3)CCCC1)c1cc2ccccc2o1
Reaction time: 15 h
Yield: 17.9 %

Procedure:
C-(1-Benzo[1,3]dioxol-5-yl-cyclopentyl)-methylamine (43.8 mg, 0.200 mmol) and benzofuran-2-carbonyl chloride (36.1 mg, 0.200 mmol) were dissolved in 2 mL of 1,4-dioxane containing triethylamine (83.6 μL, 0.600 mmol). The reaction mixture was stirred for 15 hours, evaporated to dryness, and purified by reverse phase preparative liquid chromatography to yield the pure product (13.0 mg, 0.0358 mmol, 17.8%). ESI-MS m/z calc. 363.2, found 364.2 (M+1)+. Retention time of 4.22 minutes.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]([S:19]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)(=[O:21])=[O:20])[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][C:13]([C:16]([NH2:18])=O)=[CH:12]2)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][N:6]([S:19]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)(=[O:21])=[O:20])[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][C:13]([C:16](=[S:36])[NH2:18])=[CH:12]2)[CH3:2]
Reactant: CCOCCN(c1cccc2cc(C(N)=O)[nH]c12)S(=O)(=O)c1cccs1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CCOCCN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 70 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
A mixture of 7-[(2-ethoxyethyl)(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (4.70 g), Lawesson's reagent (3.06 g) and tetrahydrofuran (30 mL) was stirred at 70° C. for 3 hr. The reaction mixture was concentrated, and toluene was added to the residue. The obtained solid was washed with toluene to give the title compound (2.99 g, yield 58%) as crystals. melting point 182° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[CH2:6][N:7]=[C:8]=[S:9].Cl.Cl.[Cl:15][C:16]1[CH:17]=[C:18]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C@@H:27](NC(=O)C2C=CC(C)=CC=2)[CH:28]([CH3:30])[CH3:29])[CH2:22][CH2:21]1.C([NH:52][C@H](C(O)=O)C(C)C)(OC(C)(C)C)=O>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[C:18]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH:27]([C:5]2([CH:10]=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH2:4]2)[CH2:6][NH:7][C:8]([NH2:52])=[S:9])[CH:28]([CH3:30])[CH3:29])[CH2:22][CH2:21]1
Reactant: Cc1ccc(C(=O)N[C@H](CN2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)C(C)C)cc1
Reactant: COc1cccc(CN=C=S)c1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: ClCCl
Product: COC1=CC=CC(CNC(N)=S)(C(CN2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)C(C)C)C1
Reaction time: 2 h

Procedure:
3-Methoxybenzyl isothiocyanate (22 mg, 0.12 mmol) was added to a solution of 1-(RS)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropylamine (40 mg, 0.12 mmol) [prepared as described in Example 1 by substituting L-N-BOC-valine with DL-N-BOC-valine] in methylene chloride (1.5 ml). The reaction mixture was stirred for 2 h and then concentrated. Purification by flash chromatography with 20:1 methylene chloride:methanol as the eluant gave 1-{1-(RS)-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-2-methylpropyl}-3-methoxybenzyl-2-thiourea (18 mg) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1.[OH2:22]>CN(C=O)C>[Si:9]([O:8][C:3]1[C:2]([F:1])=[C:7]([OH:22])[CH:6]=[CH:5][CH:4]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: O
Reactant: Oc1ccccc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(O)c1F
Reaction time: 3 h

Procedure:
To a solution of 2-fluorophenol (10.35 g, 9.2 mmol) and tert-butyldimethylsilyl chloride (101 mmol) in DMF (180 ml) was added imidazole (7.54 g, 110 mmol) in one portion. After stirring for 3 h the reaction mixture was poured into water (300 ml) and extracted with diethyl ether (3×100 ml). The combined extracts were washed with 10% aqueous citric acid (100 ml), brine (100 ml), dried (MgSO4) and concentrated under reduced pressure to afford title compound (20.63 g, quant.) as a colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](OS(C(F)(F)F)(=O)=O)[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH2:34])=[CH:28][CH:27]=1>COCCOC>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:34][CH2:33][CH2:32][C:29]2[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)[C:5]=1[N+:16]([O-:18])=[O:17]
Reactant: COc1ccc(CCN)cc1
Reactant: Nc1nc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c(-c2ccco2)n1
Solvent: COCCOC
Product: COc1ccc(CCNc2nc(N)nc(-c3ccco3)c2[N+](=O)[O-])cc1

Procedure:
From trifluoro-methanesulfonic acid 2-amino-6-furan-2-yl-5-nitro-pyrimidin-4-yl ester and 2-(4-methoxyphenyl)ethylamine in DME. ES-MS m/e (%): 356 (M+H+, 100).
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:13](=[O:15])[CH3:14])(=[O:11])C>>[CH:1](=[N:8][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:15])[CH3:14]
Reactant: N#Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCc1ccccc1
Product: ON=Cc1ccccc1

Procedure:
Also, by reaction of benzaldoxime with acetic anhydride benzaldoxime acetate is formed, which is then reduced, thus benzylamine being obtained with 91% (K. W. Rosenmund et al, Ber., 56 2258-2262 (1923)). These processes of reducing benzonitrile or benzaldoxime in the acetic anhydride solvent comprise isolating N-acetylbenzylamine and hydrolysing same to obtain benzylamine.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([O:7][CH2:8][CH:9]([CH2:29][CH:30]=C)[CH2:10][O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)C=C.N#N.[BH4-].[Na+].[CH3:36][OH:37]>C(OCC)(=O)C.CCCCCC>[OH:37][CH2:36][CH2:4][O:7][CH2:8][CH:9]([CH2:29][CH2:30][OH:1])[CH2:10][O:11][Si:12]([C:25]([CH3:28])([CH3:26])[CH3:27])([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[O+][O-]
Reactant: C=CCOCC(CC=C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CO
Agent: N#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)[Si](OCC(CCO)COCCO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72 %

Procedure:
Ozone was bubbled through a -78 ° C. methanol (500 mL) solution of diene, 1-(2-propene-1-oxy)-2-(2-propene-1-yl)-3-(tert-butyldiphenylsilyloxy)-propane, (7.41 g, 18.80 mmol). After the disappearance of the starting material (TLC, 25% ethyl acetate/hexane), the reaction mixture was purged with N2 and sodium borohydride (2.13 g, 56.30 mmol) was added. The reaction was warmed to room temperature. After 12 hours, the reaction was concentrated. The white residue was quenched with water, and extracted with ethyl acetate (100 mL×3). The combined organic phase was washed with brine, dried, and concentrated under reduced pressure to give a residue. The residue was eluted through a short silica gel column with ethyl acetate/hexane (10% to 50% ethyl acetate gradient) and evaporation of the eluting solvent gave the 1,7-diol, 1-(2-hydroxyethoxy)-2-(2-hydroxyethyl)-3-(tert-butyldiphenylsilyloxy)-propane (5.48 g, 72% yield). Rf =0.21 (50% ethyl acetate in hexane). NMR.
Reaction SMILES: [C:1]([C:5]([C:8]([O:11][C:12](C(OC(=C(F)F)F)(F)F)([C:14]([F:17])([F:16])[F:15])[F:13])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])F.C(C(C(OC(C(OC([C:51]([O:53]C)=[O:52])(F)F)(F)F)(C(F)(F)F)F)(F)F)(F)F)(F)(F)F.[NH3:55].C(OC=C)=C>CO>[C:14]([CH:12]([O:11][C:8]([C:5]([C:1]([C:51]([O-:53])=[O:52])([F:3])[F:4])([F:6])[F:7])([F:9])[F:10])[F:13])([F:15])([F:16])[F:17].[NH4+:55]
Reactant: COC(=O)C(F)(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: N
Reactant: FC(F)=C(F)OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: C=COC=C
Solvent: CO
Product: O=C([O-])C(F)(F)C(F)(F)C(F)(F)OC(F)C(F)(F)F
Product: [NH4+]

Procedure:
Conversion of CF3CF2CF2OCF(CF3)CF2OCF═CF2 to CF3CF2CF2OCF(CF3)CF2OCF2COOCH3 (bp 91-92° C. at 133 mbar) was carried described in U.S. Pat. No. 4,987,254. The ester was reacted with aqueous ammonia and methanol was removed by distillation resulting in CF3CF2CF2OCF(CF3)CF2OCF2COONH4. All structures were confirmed by F-NMR spectra. Due to an isomer content in the vinyl ether, an isomer with the structure CF3CF2CF2OCF2CF(CF3)OCF2COOX (X═CH3, NH4) was found.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:14]1([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[PH4+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.[Pd]>[C:21]1([N:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [PH4+]
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1

Procedure:
In another embodiment, there is provided a method for forming an arylamine, comprising adding 4-bromobiphenyl and diphenylamine in toluene into a continuous plug flow reactor, the continuous plug flow reactor further comprising continuously reacting the 4-bromobiphenyl and the diphenylamine in the toluene in a presence of a base and a palladium catalyst under Buchwald conditions in the continuous plug flow reactor, adding a phosphonium-based ionic liquid with tri-t-butylphospine to the 4-bromobiphenyl and the diphenylamine in the continuous plug flow reactor, continuously reacting the 4-bromobiphenyl and the diphenylamine in the toluene and the phosphonium-based ionic liquid with the tri-t-butylphospine in the presence of the base and the palladium catalyst under Buchwald conditions in the continuous plug flow reactor until N,N-diphenyl-4-biphenylamine is produced, and collecting the N,N-diphenyl-4-biphenylamine.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.Br[CH2:29][C:30]([O:32]C(C)(C)C)=[O:31]>[OH-].[Na+]>[C:1]([C:5]1[CH:6]=[CH:7][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][C:16]2[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=2)[O:22][CH2:29][C:30]([OH:32])=[O:31])=[O:14])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)c1ccc(/C=C/C(=O)Nc2cccc(O)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(/C=C/C(=O)Nc2cccc(OCC(=O)O)c2)cc1

Procedure:
To a round-bottomed flask equipped with magnetic stirring was added (2E)-3-[4-(tert-butyl)phenyl]-N-(3-hydroxyphenyl)prop-2-enamide, Example 23, (120 mg, 0.407 mmol), THF (10 mL), tert-butyl bromoacetate (60 uL, 0.407 mmol, Aldrich) and 5 N NaOH (10 mL). The reaction mixture was stirred at 25° C. overnight. The mixture was extracted with EtOAc (20 mL), the organic extract washed with water (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was treated with trifluoroacetic acid (10 mL), stirred at 25° C. for 2 h, then concentrated in vacuo. Purification by silica gel chromatography (1:2 hexane:EtOAc) provided the title product as an off-white solid. MP 166-172° C. MS (ESI, pos. ion) m/z: 354 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][NH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[O:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:13][N:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(=O)NNC(=O)CNC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nnc(CNC(=O)OC(C)(C)C)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
A solution of compound 7 (59 g, 200 mmol) and triethylamine (42 ml, 0.57 mol) in carbon tetrachloride (60 ml) is added to a stirred, room temperature of triphenylphosphine (63 g, 0.24 mol) in methylene chloride (900 ml). The reaction mixture is stirred for 30 minutes and then refluxed for 12 hours. After cooling to room temperature, the volatiles are removed in vacuo and the resulting residue is filtered through silica using methylene chloride:ethyl acetate (9:1) as the eluent. After removing the volatiles in vacuo, the crude product is purified by flash column chromatography over silica gel using methylene chloride:ethyl acetate (19:1) as the eluent. 24 g (44%) Of compound 8 is obtained as orange oil, which solidifies to a yellow solid on standing.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH:35]=[N:36][O:37][CH3:38])=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:39][O:40]C(=O)C)(=O)C.O.[OH-].[Li+]>C1COCC1.CO.O>[CH3:38][O:37][N:36]=[CH:35][CH2:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C:21]2[CH:20]=[C:19]([C@H:8]3[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:39][OH:40])[O:7]3)[CH:24]=[CH:23][C:22]=2[Cl:25])=[CH:28][CH:29]=1
Reactant: CON=CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CON=CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(2-(methoxyimino)ethoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (100 mg, 0.161 mmol) in THF (0.6 mL), methanol (0.8 mL) and water (0.3 mL) was added lithium hydroxide monohydrate (13.5 mg, 0.322 mmol) at 0° C. The reaction was stirred at r.t. for 1 h. Volatiles were evaporated in vacuo and the residue obtained was purified by column chromatography (silica gel, 1:9 MeOH:DCM) to provide the title compound (70 mg, 96.2%) as white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]([CH3:13])[CH:10]=[CH:11][N:12]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=1.[CH3:23][N:24]1[CH2:29][CH2:28][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][NH:37][C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:26][CH2:25]1.C(N(CC)CC)C>S(Cl)(Cl)=O>[CH3:23][N:24]1[CH2:25][CH2:26][C:27]2([C:40]3[C:32](=[CH:33][C:34]4[CH2:35][CH2:36][N:37]([C:20]([C:17]5[CH:18]=[CH:19][C:14]([C:3]6[CH:4]=[CH:5][C:6]([C:8]7[N:9]([CH3:13])[CH:10]=[CH:11][N:12]=7)=[CH:7][C:2]=6[CH3:1])=[CH:15][CH:16]=5)=[O:22])[C:38]=4[CH:39]=3)[O:31][CH2:30]2)[CH2:28][CH2:29]1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Reactant: Cc1cc(-c2nccn2C)ccc1-c1ccc(C(=O)O)cc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2nccn2C)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCN(C)CC2)CO4)cc1
Reaction time: 72 h
Yield: 40.7 %

Procedure:
2'-Methyl-4'-(1-methylimidazol-2-yl)biphenyl-4-carboxylic acid (D90, 310 mg, 1.06 mmol) was heated at reflux in thionyl chloride (10 ml) for 30 minutes, cooled, evaporated in vacuo and the orange residue redissolved in dry THF (10 ml). 1'-Methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D8, 260 mg, 1.06 mmol) and triethylamine (0.15 ml, 1.06 mmol) were added and the mixture stirred for 72 hours. The mixture was evaporated in vacuo, the residue partitioned between H2O and CHCl3 (4 times) and the organics combined, dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by flash silica-gel chromatography with 2% MeOH/CHCl3 as eluant to yield the title compound as a pale yellow gum (224 mg, 41%) which was converted to the hydrochloride salt.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]([C:13]2[CH:18]=[CH:17][C:16](B3[O:23][C:22]([CH3:25])(C)C(C)(C)O3)=[CH:15][CH:14]=2)[N:3]=1.I[C:29]1[C:37]2[C:32](=[N:33][CH:34]=[N:35][C:36]=2[NH2:38])[N:31]([C@H:39]2[CH2:44][CH2:43][C@H:42]([N:45]3[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]3)[CH2:41][CH2:40]2)[N:30]=1.O.[C:53](=[O:56])([O-])[O-:54].[Na+].[Na+]>COCCOC.O>[C:22]([OH:54])(=[O:23])[CH3:25].[C:53]([OH:54])(=[O:56])[CH3:1].[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]([C:13]2[CH:14]=[CH:15][C:16]([C:29]3[C:37]4[C:32](=[N:33][CH:34]=[N:35][C:36]=4[NH2:38])[N:31]([C@H:39]4[CH2:40][CH2:41][C@H:42]([N:45]5[CH2:46][CH2:47][N:48]([CH3:51])[CH2:49][CH2:50]5)[CH2:43][CH2:44]4)[N:30]=3)=[CH:17][CH:18]=2)[N:3]=1
Reactant: CC1=NN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(c2ccccc2)C1
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)O
Product: Cc1cc(-c2ccccc2)n(-c2ccc(-c3nn([C@H]4CC[C@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)n1
Temperature: 25 °C

Procedure:
A mixture of 3-methyl-5-phenyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4,5-dihydro-1H-pyrazole (0.102 g, 0.000283 mol), trans-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.104 g, 0.000236 mol), tetrakis-(triphenylphosphine)palladium (0.016 g, 0.000014 mol) and sodium carbonate monohydrate (0.073 g, 0.00055 mol) was heated in a mixture of ethylene glycol dimethyl ether (5 mL) and water (3 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield trans-3-[4-(3-methyl-5-phenyl-1H-1-pyrazolyl)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate (0.094 g, 0.000141 mol) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.23 (s, 1H), 7.64 (d, 2H), 7.37 (m, 7H), 6.49 (s, 1H), 4.63 (m, 1H), 2.6-2.2 (br, 9H), 2.30 (s, 3H), 2.13 (s, 3H), 2.05 (m, 6H), 1.91 (s, 6H), 1.46 (m, 2H); RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 14.10 min. MS: MH+ 548.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:27])[C:15](=[O:26])[CH2:16][NH:17][C:18]2[C:23](Cl)=[CH:22][N:21]=[N:20][C:19]=2[Cl:25])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O-:29].[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:27])[C:15](=[O:26])[CH2:16][NH:17][C:18]2[C:23]([O:29][CH3:28])=[CH:22][N:21]=[N:20][C:19]=2[Cl:25])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: CN(C(=O)CNc1c(Cl)cnnc1Cl)C1CCN(Cc2ccccc2)CC1
Agent: [Na+]
Solvent: CO
Product: COc1cnnc(Cl)c1NCC(=O)N(C)C1CCN(Cc2ccccc2)CC1
Yield: 30.9 %

Procedure:
A solution of Compound 139 (10 mg) and sodium methoxide (1.3 mg) in methanol (1 mL) was stirred overnight under reflux. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by amino-coated silica gel (Fuji Sylysia Chemical Ltd., NH-DM1020) column chromatography (ethyl acetate:hexane=1:9 to 1:1) to give 3.0 mg (30% yield) of the desired product as a white amorphous.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][OH:15].[H-].[Na+].O>O1CCOCC1.C(OCC)(=O)C>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:11]([O:10][CH3:9])[CH:12]=2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: COc1cccc(CO)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cccc(COc2cncc(Cl)n2)c1
Reaction time: 8 h
Yield: 114.4 %

Procedure:
To a solution of 2,6-dichloropyrazine (444 mg, 3.00 mmol) and 3-methoxybenzyl alcohol (455 mg, 3.30 mmol) in dioxane (5 mL) was added NaH (55% in oil, 144 mg, 3.30 mmol) at room temperature. The reaction mixture was stirred overnight. Water (0.5 mL) and ethyl acetate (10 mL) were added and the mixture was stirred for 15 min and then filtered. The filtrate was dried over K2CO3 and concentrated to give an oil (0.86 g) that was used directly in the next step. MS m/z 250 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH2:29]([C:31]1[C:36]([NH:37][S:38]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)(=[O:40])=[O:39])=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1)[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>>[NH2:1][C:2]1[C:3]([C:34]2[CH:35]=[C:36]([NH:37][S:38]([C:41]3[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=3)(=[O:40])=[O:39])[C:31]([CH2:29][CH3:30])=[N:32][CH:33]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: CCc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(=O)(=O)c1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1ncc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1NS(=O)(=O)c1ccc(OC)cc1
Yield: 54.6 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (180 mg, 0.41 mmol) was treated with N-(2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-methoxybenzenesulfonamide (250 mg, 0.60 mmol), 2M cesium carbonate (410 μl, 0.82 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (30 mg, 0.04 mmol) according to the method described in Example 3 to give 146 mg (55% yield) of the title compound as a solid. Purity 100%.