Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7])=[C:2]=[O:3].Cl.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C>O1CCCC1>[F:30][C:16]([F:15])([F:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]1[CH2:24][CH2:25][N:26]([C:2]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=2[C:6]([OH:8])=[O:7])=[O:3])[CH2:27][CH2:28]1
Reactant: FC(F)(F)c1ccccc1C1CCNCC1
Reactant: COC(=O)c1ccccc1N=C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)c1ccccc1NC(=O)N1CCC(c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.3 %

Procedure:
A solution of methyl 2-isocyanatobenzoate (10.00 g, 56.4 mmol) in tetrahydrofuran (30 ml) was slowly added to a solution of 4-(2-(trifluoromethyl)phenyl)piperidine hydrochloride (14.3 g, 53.8 mmol, Sigma) and triethylamine 99% (8.99 ml, 64.5 mmol) in tetrahydrofuran (120 ml) at 0° C. The mixture was removed from the cooling bath and stirred at room temperature for 15 min, at which time LC/MS analysis indicated that the reaction was complete. EtOH (75 ml) and aqueous LiOH (2N, 95 ml) were then added, and the solution was stirred for 6 h at room temperature. Subsequently, aqueous HCl (2N, 150 ml) was added, and the resulting mixture was extracted with EtOAc (2×600 ml). The EtOAc extract was dried over MgSO4 and concentrated to an off-white solid. Recrystallization from EtOAc yielded 14.0 g (66%) of 2-(4-(2-(trifluoromethyl)phenyl)piperidine-1-carboxamido) benzoic acid as a white solid, which was homogeneous by analytical high-performance liquid chromatography (>99%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([OH:8])[C:5]2[CH:9]=[CH:10][S:11][C:4]=2[CH2:3]1.[Br:12]Br.Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C>[Br:12][C:10]1[S:11][C:4]2[CH2:3][N:2]([CH3:1])[CH2:7][CH:6]([OH:8])[C:5]=2[CH:9]=1
Reactant: BrBr
Reactant: CN1Cc2sccc2C(O)C1
Agent: Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1Cc2sc(Br)cc2C(O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
6-Methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (1.2 g) prepared in Reference Example 6 was dissolved in 60 mL of acetic acid, a solution of 2.72 g of bromine in 10 mL of acetic acid was added thereto by dropping, then 0.1 mL of 33% solution of hydrogen bromide in acetic acid solution was added thereto and the mixture was stirred for 3 hours at room temperature. To the reaction solution was added 10 mL of 10% aqueous solution of sodium thiosulfate and then the reaction solution was concentrated in vacuo to evaporate acetic acid. The residue was made basic by addition of 25% aqueous ammonia with cooling followed by extracting with ethyl acetate. The organic layer was washed with water and a saturated solution of sodium chloride successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo. The residue was purified by silica gel column chromatography to give 0.74 g of the objective compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=O)=[CH:5][N:4]=[C:3]1[S:9][CH3:10].[CH3:11]O>C([O-])([O-])=O.[K+].[K+]>[C:7]([C:6]1[N:2]([CH3:1])[C:3]([S:9][CH3:10])=[N:4][CH:5]=1)#[CH:11]
Reactant: CSc1ncc(C=O)n1C
Reactant: CO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#Cc1cnc(SC)n1C
Temperature: 25 °C
Reaction time: 28 h
Yield: 72 %

Procedure:
To a mixture of 850 mg (5.44 mmol) of 3-methyl-2-methylsulfanyl-3H-imidazole-4-carbaldehyde and 1.34 g (7.00 mmol) of dimethyl 2-oxo-1-diazopropylphosphinate in 15 mL of MeOH was added 1.52 g (11.0 mmol) of K2CO3. The mixture was stirred at room temperature for 28 hours. The mixture was diluted with saturated K2CO3 (10 mL) and and extracted with CH2Cl2 (3×75 mL). The combined extracts were dried over MgSO4, concentrated, and chromatographed (0 to 100% EtOAc in hexanes) to give the 5-ethynyl-1-methyl-2-methylsulfanyl-1H-imidazole (600 mg, 72%) as a colorless liquid.
Reaction SMILES: C1([C:4]2([N:7]([CH2:40][C:41]3[CH:46]=[C:45]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:44]=[C:43]([OH:52])[CH:42]=3)[C:8](=[O:39])[CH:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][C:30]4[C:35]([Cl:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=4[Cl:38])=[CH:22][CH:21]=3)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:6][CH2:5]2)CC1.CS(O[CH2:58][CH2:59][CH2:60][S:61][CH3:62])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[CH:4]1([N:7]([CH2:40][C:41]2[CH:42]=[C:43]([O:52][CH2:58][CH2:59][CH2:60][S:61][CH3:62])[CH:44]=[C:45]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:46]=2)[C:8](=[O:39])[CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][C:30]3[C:31]([Cl:38])=[CH:32][C:33]([CH3:37])=[CH:34][C:35]=3[Cl:36])=[CH:22][CH:21]=2)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:17])[CH3:15])[CH2:6][CH2:5]1
Reactant: COCCCc1cc(O)cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2(C3CC3)CC2)c1
Reactant: CSCCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCCc1cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCCSC)c1
Temperature: 60 °C

Procedure:
To a solution of tert-butyl (3-{cyclopropyl[3-hydroxy-5-(3-methoxypropyl)benzyl](cyclopropyl)amino}-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from Example 70, Step 2 (1 eq.) in DMF (0.05 M) was added 3-(methylthio)propyl methanesulfonate from the previous step (1.4 eq.) and cesium carbonate (1.4 eq.). The resulting suspension was heated at 60° C. for 12 h. The reaction mixture was quenched sat. aq. NaHCO3 and then extracted with ether. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 3:2 (v/v) Hex:EtOAc→2:3 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22].[C:24]1(=[O:30])[O:29][C:27](=[O:28])[CH:26]=[CH:25]1>C(O)C.[OH-].[Na+]>[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:24](=[O:30])/[CH:25]=[CH:26]\[C:27]([OH:29])=[O:28])([OH:23])=[O:22]
Reactant: NCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: O=C1C=CC(=O)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)/C=C\C(=O)NCCCCCCCCCCCCCCCCCCCC(=O)O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
In a mixture of 85 ml of ethanol and 40 ml of 1N aqueous sodium hydroxide solution, 20-aminoeicosanoic acid (500 mg, 1.53 mmoles) was dissolved at 40° C. To the obtained solution, while maintained at 40° C., was gradually added maleic anhydride (3.75 g, 38.3 mmoles) over a period of 3 hours. The pH of the reaction mixture was kept at 8-10 during the addition. The reaction mixture was stirred for 30 minutes and then treated in the same manner as in Reference Example 4, to give N-(19-carboxynonadecyl)maleamic acid (538 mg, 83%) having the following properties.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22][OH:23]>ClCCl>[CH3:1][S:2]([O:23][CH2:22][CH2:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[F:13])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccc(F)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
Methanesulphonyl chloride (3.3 ml; 0.043 mol) and triethylamine (5.9 ml; 0.043 mol) were added to a solution of 2-(2,4-difluorophenyl)ethanol (6.4 g; 0.0426 mol) in dichloromethane (100 ml). The solution was cooled for 1 h at 0° C. and then brought to room temperature for 1 h. The reaction mixture was then treated by washing, successively, with 5N sulphuric acid (20 ml), water (50 ml), a 5% solution of NaHCO3 (50 ml) and water (50 ml). The organic phase was then dried over Na2SO4, filtered and concentrated at reduced pressure. The residue was taken up twice in CCl4, thus obtaining 6.42 g of 2-(2,4-difluorophenyl)ethyl methanesulphonate.
Reaction SMILES: C1(C(N[CH:10]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=2)[C:11]([O:13]C)=[O:12])=O)C=CC=CC=1>Cl>[C:18]1([CH2:21][C:22]([OH:24])=[O:23])[CH:17]=[CH:16][C:15]([CH2:10][C:11]([OH:13])=[O:12])=[CH:20][CH:19]=1
Reactant: COC(=O)Cc1ccc(C(NC(=O)c2ccccc2)C(=O)OC)cc1
Agent: Cl
Product: O=C(O)Cc1ccc(CC(=O)O)cc1

Procedure:
A solution of dimethyl α-[(phenylcarbonyl)amino]-1,4-benzenediacetate (1.00 g, 2.90 mmol) from the Preparation 2 above in 20 ml of 6N HCl is heated at reflux under N2 for 19 hours. The reaction mixture is cooled and extracted with a 1:1 toluene/ether solution (2×40 ml). The aqueous layer is concentrated and the residue dissolved in H2O (10 ml) and freeze-dried. A solid, 1,4-benzenediacetic acid, a-amino-, (±) is obtained (0.72 g, 76%), mp 205° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]O)=[C:11]([N+:18]([O-:20])=[O:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:41]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][Cl:41])=[C:11]([N+:18]([O-:20])=[O:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1CCO
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1CCCl
Yield: 97 %

Procedure:
The synthetic approach for the proposed achiral seco-CI compounds starts from the reaction of the readily available diethyl 2-(4-benzyloxy-2-nitrophenyl)malonate (4c). Treatment of diethyl 2-(4-benzyloxy-2-nitrophenyl)malonate with NaOH in ethanol (25-80° C.), preferably refluxing, followed by acidification and mild heating (25-100° C.), preferably refluxing, the solution gave the desired 4-benzyloxy-2-nitrophenylacetic acid in 95% yield. Selective reduction of the carboxylic acid with borane at 0-50° C., preferably at room temperature, in THF produced 2-(4-benzyloxy-2-nitrophenyl)ethanol in 95% yield. The alcohol was then chlorinated at 0-50° C., preferably at room temperature, with triphenylphosphine and carbon tetrachloride in CH2Cl2 to give 2-(4-benzyloxy-2-nitrophenyl)ethyl chloride in 97% yield. The 2-(4-benzyloxy-2-nitrophenyl)ethyl bromide was obtained in 92% yield after reacting 2-(4-benzyloxy-2-nitrophenyl)ethanol with triphenylphosphine and carbon tetrabromide in acetonitrile. Catalytic reduction of 2-(4-benzyloxy-2-nitrophenyl)ethyl chloride and 2-(4-benzyloxy-2-nitrophenyl)ethyl bromide at atmospheric pressure, and at 0-50° C., preferably at room temperature, using 10% Pd/C in THF afforded 2-(2-amino-4-hydroxyphenyl)ethyl chloride and 2-(2-amino-4-hydroxyphenyl)ethyl bromide, respectively. 2-(2-Amino-4-hydroxyphenyl)ethyl bromide was directly coupled at 0-50° C., preferably at room temperature, with 5-(benzofuran-2-carboxamido)indole-2-carboxylic acid in the presence of EDCI [1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride] and DMF to give compound 4-(2-bromoethyl)-3-[5-(5-benzofuran-2-carboxamido)indole-2-carboxamido]phenol in a low 2% yield for the two steps after purification by silica gel column chromatography. Similarly, coupling of 2-(2-amino-4-hydroxyphenyl)ethyl chloride with 5-(benzofuran-2-carboxamido)indole-2-carboxylic acid in the presence of EDCI gave 4-(2-chloroethyl)-3-[5-(5-benzofuran-2-carboxamido)indole-2-carboxamido]phenol in 28% yield for the two steps following column chromatography.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH2:9]Br)=[C:7]([C:11]#[N:12])[C:6]([CH2:13]Br)=[C:5]([C:15]#[N:16])[C:4]=1[CH2:17]Br)#[N:2].[P:19]([O:26]CC)([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>C1(C)C=CC=CC=1>[C:1]([C:3]1[C:8]([CH2:9][P:19]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:26])=[C:7]([C:11]#[N:12])[C:6]([CH2:13][P:19]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:26])=[C:5]([C:15]#[N:16])[C:4]=1[CH2:17][P:19]([O:20][CH2:21][CH3:22])([O:23][CH2:24][CH3:25])=[O:26])#[N:2]
Reactant: CCOP(OCC)OCC
Reactant: N#Cc1c(CBr)c(C#N)c(CBr)c(C#N)c1CBr
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1c(C#N)c(CP(=O)(OCC)OCC)c(C#N)c(CP(=O)(OCC)OCC)c1C#N)OCC

Procedure:
A solution of 1,3,5-tricyano-2,4,6-tris(bromomethyl)benzene (1.0 g, 2.3 mmol) and P(OEt)3 (1.6 g, 14 mmol) in 60 mL of toluene was refluxed for 4 hrs. The solvent was removed in vacuo and the product was purified by column chromatography with hexane/ethyl acetate (10/1) as the eluent to obtain colorless oil. Yield, 0.97 g (69%); IR 2299 (CN), 1263 (P═O); 1H NMR δ 4.21 (q, 12H, J=7.2), 3.73 (d, 6H, J=22.1) 1.32 (t, 18H, J=7.2).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][O:11][C:12](=[O:24])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[NH:20][C:21](=[O:23])[CH3:22]>>[CH3:10][O:11][C:12](=[O:24])[C:13]1[CH:18]=[C:17]([N+:6]([O-:9])=[O:7])[C:16]([Cl:19])=[CH:15][C:14]=1[NH:20][C:21](=[O:23])[CH3:22]
Reactant: COC(=O)c1ccc(Cl)cc1NC(C)=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(Cl)cc1NC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3 mL conc. sulfuric acid and 0.40 mL of 90% nitric acid at 0° C. was added 2-acetylamino-4-chlorobenzoic acid methyl ester (1.5 g) in three portions over a period of 20 minutes. This was stirred at 0° C. for 30 minutes then allowed to warm to room temperature for an additional 1 hour. At this time the reaction was poured into 50 mL of an ice/water mixture and extracted with ethyl acetate (3×50 mL). The combined organics were washed sequentially with water (2×50 mL), 10% sodium bicarbonate (2×50 mL) and brine (50 mL) then dried over magnesium sulfate and concentrated in vacuo. Recrystallization of the crude product from methanol gave the title compound (1.02 g).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[C:5]=1[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[O:32]=[C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35](=[O:42])[N:34]1[CH2:43][CH2:44][CH2:45][C:46]1[CH:47]=[C:48]([CH:51]=[CH:52][CH:53]=1)[CH:49]=O>>[CH3:31][O:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:4]([O:3][CH3:2])[C:5]=1/[CH:6]=[CH:49]/[C:48]1[CH:47]=[C:46]([CH2:45][CH2:44][CH2:43][N:34]2[C:35](=[O:42])[C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:33]2=[O:32])[CH:53]=[CH:52][CH:51]=1
Reactant: COc1cccc(OC)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: [Br-]
Product: COc1cccc(OC)c1/C=C/c1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,6-Dimethoxybenzyltriphenylphosphonium bromide was coupled with phthalimide 29 following the method used in Example 44, except that the reaction was stirred overnight after warming up to room temperature. After concentration under reduced pressure, the residue was partitioned between EtOAc and water. The combined organics were washed with brine, dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography (7 to 60% EtOAc-hexanes gradient) gave (E)-2-(3-(3-(2,6-dimethoxystyryl)phenyl)propyl)isoindoline-1,3-dione as a light yellow oil. Yield (0.317 g, 82%): NMR (400 MHz, DMSO-d6) δ 7.79-7.84 (m, 4H), 7.42 (d, J=17.2 Hz, 1H), 7.17-7.32 (m, 5H), 7.06-7.09 (m, 1H), 6.58 (d, J=8.4 Hz, 2H), 3.83 (s, 6H), 3.61 (t, J=7.2 Hz, 2H), 2.63 (t, J=8.0 Hz, 2H), 1.88-1.96 (m, 2H).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:9][C:10]1[N:11]=[C:12]([CH:15]([C:21]2[NH:22][C:23]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=3)=[C:24]3[C:29](=[O:30])[N:28]([CH3:31])[C:27](=[O:32])[N:26]([CH3:33])[C:25]=23)[CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[S:13][CH:14]=1.N1C=CN=C1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[Si:1]([O:19][CH2:18][CH:17]([OH:20])[CH2:16][CH:15]([C:21]1[NH:22][C:23]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[CH:35]=2)=[C:24]2[C:29](=[O:30])[N:28]([CH3:31])[C:27](=[O:32])[N:26]([CH3:33])[C:25]=12)[C:12]1[S:13][CH:14]=[C:10]([Cl:9])[N:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]c(C(CC(O)CO)c3nc(Cl)cs3)c2n(C)c1=O
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]c(C(CC(O)CO[Si](C)(C)C(C)(C)C)c3nc(Cl)cs3)c2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
tert-Butyldimethylsilyl chloride (309 mg, 2.047 mmol) was added to a solution of 7-(1-(4-chlorothiazol-2-yl)-3,4-dihydroxybutyl)-5-(3-fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (817 mg, 1.706 mmol), imidazole (232 mg, 3.41 mmol) and DMAP (20.84 mg, 0.171 mmol) in DMF (15 mL). The mixture was stirred at room temperature for 50 mins. A further portion of tert-butyldimethylsilyl chloride (100 mg, 0.662 mmol) was added and the mixture stirred for a further 1 hour. The reaction mixture was diluted with EtOAc and washed with 0.1M HCl(aq) (1×) and brine (3×). The organic phase was dried over sodium sulfate and evaporated under vacuum. Purification by chromatography on silica, eluting with 0-60% EtOAc/hexane, afforded the title compound as a mixture of diastereomers.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38](Cl)=[O:39])[CH2:34][CH2:33]1>N1C=CC=CC=1>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]3[CH2:29][CH2:28][N:27]([C:38]([N:35]4[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]4)=[O:39])[CH2:26][CH2:25]3)[N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[C:22]=12
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNCC1
Agent: Cl
Solvent: c1ccncc1
Product: CN1CCN(C(=O)N2CCC(n3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 44.5 %

Procedure:
A solution of 3-(4-phenoxyphenyl)-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.300 g, 0.780 mmol) in pyridine (5 mL) at 0° C. was treated with 4-methyl-1-piperazinecarbonyl chloride hydrochloride (0.127 g, 0.780 mmol). The reaction mixture was stirred for 5 min at 0° C., after which the ice bath was removed, and the reaction stirred at room temperature over night. An additional equivalent of 4-methyl-1-piperazinecarbonyl chloride hydrochloride (0.127 g, 0.780 mmol) was added and stirred for 2 h. Solvent was removed under reduced pressure. Dichloromethane (10 mL) and sodium bicarbonate (5 mL) saturated aqueous solution were added to the solid. The layers were separated using an Empore extraction cartridge. The organic layer was removed under reduced pressure to give 0.417 g of crude material. The crude product was purified by flash chromatography on silica gel eluting 8% methanol in dichloromethane, 15% methanol in dichloromethane, and then 20% methanol in dichloromethane as eluent to give 0.178 g (45%) of 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino(4-methylpiperazino)methanone. A hot solution of 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino(4-methylpiperazino)methanone (0.178 g, 0.347 mmol) in ethyl acetate was treated with a hot solution of maleic acid (0.081 g, 0.693 mmol) in ethyl acetate. Upon cooling of the solvent a precipitate formed, was filtered under nitrogen, and dried under high vacuum to give 0.124 g of 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino(4-methylpiperazino)methanone bis-maleate.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH:11]=[C:12]2[NH:24][C:23](=[S:25])[NH:22][C:13]2=[N:14][C:15]=1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.I[CH3:27]>CN(C=O)C>[F:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH:11]=[C:12]2[N:24]=[C:23]([S:25][CH3:27])[NH:22][C:13]2=[N:14][C:15]=1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: Fc1cnccc1-c1cc2[nH]c(=S)[nH]c2nc1-c1cccnc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc2cc(-c3ccncc3F)c(-c3cccnc3)nc2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
To a suspension of sodium hydride 60% (0.098 g, 2.45 mmols) in DMF (5 mL) a suspension of 6-(3-fluoropyridin-4-yl)-5-pyridin-3-yl-1,3-dihydro-2H-imidazo[4,5-b]pyridine-2-thione (0.6 g, 1.86 mmols) in DMF (15 mL) was added dropwise, at 0° C., under argon. The solution was allowed to stir for 30 minutes at 0° C. and then iodomethane (0.116 mL, 1.86 mmol) in DMF (1 mL) was added dropwise. The reaction mixture was warmed up to room temperature and stirred for 2.5 hours. The mixture was concentrated and purified by silica gel flash chromatography (150:40:5 dichloromethane/methanol/ammonia) to give the title compound (0.34 g, 54% of yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.[NH2:17][C:18]1[C:22]([C:23]#[N:24])=[CH:21][NH:20][N:19]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[N:20]=[CH:21][C:22]([C:23]#[N:24])=[C:18]3[N:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1cccc(F)c1
Reactant: N#Cc1c[nH]nc1N
Product: N#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(F)c3)nc12
Yield: 46 %

Procedure:
Reaction of 1-(3-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (234 mg, 1.0 mmol), prepared from commercially available 3-fluoro-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light yellow solid (141 mg, 46%). MS (ISP) 306.9 [(M+H)+]; mp 199° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]3[CH2:19][CH2:20][O:21][CH2:22][CH:23]=3)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pt](=O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(C3=CCOCC3)cc2C1
Agent: O=[Pt]=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(C3CCOCC3)cc2C1
Reaction time: 16 h
Yield: 38 %

Procedure:
To a stirred solution 0.81 mmol 5-chloro-6-(3,6-dihydro-2H-pyran-4-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A61(a)) in 40 ml methanol was added 0.41 mmol platinum(IV) oxide and the mixture was stirred under an atmosphere of hydrogen for 16 h. The reaction mixture was then filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a white solid (38% yield). MS (m/e): 284.3 ({37Cl}[M+H−Me2C═CH2]+, 49%), 282.3 ({35Cl} [M+H−Me2C═CH2]+, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CCOC(C)=O.[H][H]>[Pd].CO>[OH:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C=CC(=O)O)cc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(CCC(=O)O)cc1O
Yield: 99 %

Procedure:
The mixture of 3-(3-Hydroxy-4-methoxy-phenyl)-acrylic acid (3 g), 10% Pd/C (0.5 g), EtOAc (50 ml) and MeOH (50 ml) was shaken in Parr apparatus for 5 hs under 30-40 psi of hydrogen. Then the solution was passed through a celite pad and was concentrated to give 3-(3-Hydroxy-4-methoxy-phenyl)-propionic acid (3 g). LC-MS: m/e 197 (MH+).