Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.Cl.[CH:13]1([C:16]2[C:17]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=2)[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:29]2[CH2:30][CH2:31][N:26]([C:17]3[C:16]([CH:13]4[CH2:15][CH2:14]4)=[CH:21][C:20]([C:22]([F:25])([F:23])[F:24])=[CH:19][N:18]=3)[CH2:27][CH2:28]2)=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(C2CC2)c1
Agent: Cl
Product: O=C(c1ccc(Br)cc1F)N1CCN(c2ncc(C(F)(F)F)cc2C2CC2)CC1
Yield: 85.5 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 8 and using 4-bromo-2-fluorobenzoyl chloride (2.5 g) and 1-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazine hydrochloride (3.2 g) described in Preparation Example 76, the title compound (4.2 g) was obtained.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2([C:13]([OH:15])=[O:14])[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][O:17]C1C=CC=CC=1N>>[CH3:16][O:17][C:6]1[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=1[NH:7][C:8]([C:10]1([C:13]([OH:15])=[O:14])[CH2:11][CH2:12]1)=[O:9]
Reactant: COc1ccccc1N
Reactant: O=C(O)C1(C(=O)Nc2ccccc2)CC1
Product: COc1ccccc1NC(=O)C1(C(=O)O)CC1
Yield: 44 %

Procedure:
Following the procedure described above for the synthesis of compound 161 (Scheme 45), but replacing aniline for 2-methoxyaniline, title compound 172 was obtained in 44% yield. M/S (m/z): 236.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN.O1CCCC1.C[CH2:22][N:23](C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:23][CH3:22])=[O:5]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Br
Agent: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc([N+](=O)[O-])c1Br

Procedure:
To a solution of 2-bromo-3-nitrobenzoic acid (0.974 g, 3.96 mmol) in DMF (3 mL) was added methylamine, 2.0 m solution in tetrahydrofuran (2.97 mL, 5.94 mmol), 1,1′-dimethyltriethylamine (1.38 mL, 7.92 mmol) and (1H-benzo[d]-[1,2,3]triazol-1-yloxy)tripyrrolidin-1-ylphosphonium hexafluorophosphate(V) (2.47 g, 4.75 mmol) and the resulting mixture was stirred at rt for 2 h. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel column using DCM/EtOAc-DCM (1:1) as eluent to give 2-bromo-N-methyl-3-nitrobenzamide: LC-MS (ESI) m/z 261.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:57][NH:58][CH2:59][C:60]1[CH:75]=[CH:74][C:63]([CH2:64][N:65]2[CH2:69][CH2:68][CH:67]([NH:70][C:71](=[O:73])[CH3:72])[CH2:66]2)=[CH:62][CH:61]=1>C(Cl)Cl>[C:71]([NH:70][CH:67]1[CH2:68][CH2:69][N:65]([CH2:64][C:63]2[CH:62]=[CH:61][C:60]([CH2:59][N:58]([CH3:57])[C:21]([C:18]3[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:5]([CH3:24])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=4[CH3:9])(=[O:11])=[O:12])[CH3:14])[O:20][CH:19]=3)=[O:22])=[CH:75][CH:74]=2)[CH2:66]1)(=[O:73])[CH3:72]
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: CNCc1ccc(CN2CCC(NC(C)=O)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(NC(C)=O)C4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (80 mg, 0.22 mmol), EDCI (61 mg, 0.32 mmol), HOBt (45 mg, 0.34 mmol), DIPEA (0.08 mL, 0.45 mmol), N-(1-{4-[(methylamino)methyl]benzyl}pyrrolidin-3-yl)acetamide dihydrochloride (36 mg, 0.13 mmol) and DCM (20 mL).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.O.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[C:6]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([NH:18][C:22](=[O:24])[CH3:23])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(S(=O)(=O)c2cccc3cnccc23)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)c2cccc3cnccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.3 %

Procedure:
4-(5-Isoquinolylsulfonyl)aniline 20 mg (0.1 mmol) was dissolved in a mixture solution of acetic anhydride 2 ml and pyridine 2 ml, the mixture was stirred overnight at room temperature, water was added to the reaction solution, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated potassium hydrogensulfate and with saturated sodium hydrogencarbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give N1-[4-(5-isoquinolylsulfonyl)phenyl]acetamide 10 mg (44.3%)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Yield: 98 %

Procedure:
In this synthesis the new (4-amino or substituted amino-3-hydroxyphenyl)-alkylnitriles of Formula (1), of this invention, where R2 is H, can be prepared by reaction of a 3-hydroxy-4-nitrobenzaldehyde of Formula (2) with a benzyl halide, such as benzyl bromide, in the presence of an inorganic base such as potassium carbonate in dimethylformamide (DMF) at room temperature for about 18 hours to produce the 3-benzyloxy-4-nitro-benzaldehyde compound of Formula (3) in about 98% yield; then reacting the compound of Formula (3) with diethyl cyanoalkylphosphonate of Formula (4) in a suspension of sodium hydride in anhydrous THF at room temperature for about 2 hours to produce 3-(3-benzyloxy-4-nitro-phenyl)-acrylonitrile of Formula (5) in about 100% yield; catalytically hydrogenating the compound of Formula (5) with 10% Pd on carbon at about 60 psi hydrogen at room temperature for about 4 hours to provide a compound of Formula (1) where R2 is H in about 100% yield.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][NH:11][S:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]1)(=[O:14])=[O:13])(=[O:8])[O:5]CC)C.C[Si](Br)(C)C.CCO.[NH4+].[OH-].O>C(Cl)(Cl)Cl>[NH:33]1[CH2:34][CH2:35][CH:30]([CH2:29][CH2:28][CH2:27][CH2:26][O:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17][CH2:16][CH2:15][S:12]([NH:11][CH2:10][CH2:9][P:4]([OH:8])(=[O:3])[OH:5])(=[O:14])=[O:13])[CH2:31][CH2:32]1
Reactant: CCOP(=O)(CCNS(=O)(=O)CCCCc1ccccc1OCCCCC1CCN(C(=O)OC(C)(C)C)CC1)OCC
Agent: C[Si](C)(C)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=P(O)(O)CCNS(=O)(=O)CCCCc1ccccc1OCCCCC1CCNCC1

Procedure:
A solution of 6-9 (0.63 g, 0.142 mmol) in CHCl3 (5 ml) at rt was treated with TMSBr (0.85 mmol) for 16 hrs. The solvent was removed and the residue was dissolved in 10% aqueous acetone and this stripped to dryness. The residue was mixed with toluene and the resulting gum was purified by flash chromatography on silica gel eluting with 4:1:1 EtOH/H2O/NH4OH to provide pure 6-11. Rf 0.38 (silica gel, 4:1:1 EtOH/NH4OH/H2O ##STR61##
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:17]([CH3:20])([O-:19])=[O:18].[OH-].[Na+]>CO.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9](/[CH:10]=[CH:20]/[N+:17]([O-:19])=[O:18])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(/C=C/[N+](=O)[O-])cc1OC1CCCC1
Reaction time: 4 h

Procedure:
To a stirred solution of 1.02 g (4.63 mmol) of 3-cyclopentoxy-4-methoxybenzaldehyde in 20 mL of methanol was added 0.3 mL (5.5 mmol) of nitromethane followed by 0.2 g (5.0 mmol) of sodium hydroxide in 5 mL of water in single portions. The mixture was stirred for 4 hours after which time the decomposing mixture was concentrated, diluted with 20 mL of water and acidified to pH 1 with concentrated hydrochloric acid. The aqueous solution was extracted with three, 10 mL portions of chloroform and the combined organic fractions were dried over magnesium sulfate and concentrated. Liquid chromatography of the crude mixture over 100 g of silica gel eluting with 5% ethyl acetate in hexane provided an analytically pure solid.
Reaction SMILES: C(=[O:3])C.[CH3:4][CH:5]1[CH2:10][CH:9]([O:11][CH2:12][C:13](Cl)=[O:14])[CH:8]([CH:16]([CH3:18])[CH3:17])[CH2:7][CH2:6]1.CO>N1C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:4][CH:5]1[CH2:10][CH:9]([O:11][CH2:12][C:13]([OH:3])=[O:14])[CH:8]([CH:16]([CH3:18])[CH3:17])[CH2:7][CH2:6]1
Reactant: CC1CCC(C(C)C)C(OCC(=O)Cl)C1
Reactant: CC=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CO
Product: CC1CCC(C(C)C)C(OCC(=O)O)C1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
Vinyl L-menthoxyacetate is prepared from acetaldehyde, L-menthoxyacetyl chloride, and pyridine catalyst. A 70 mL stainless steel high pressure reactor fitted with a Pyrex glass liner and magnetic stir bar is charged with THF (5 mL), (PPh3)2PdCl2 (0.05 mmol), CH3OH (0.5 mmol), and vinyl L-menthoxyacetate (0.5 mmol). The reactor is sealed, pressurized to 1000 psig with CO, and stirred for 24 hours at 100° C. The product mixture, isolated after removal of gas from the reactor vessel, contains a diastereomeric mixture of methyl L-menthoxyacetyl-L-lactate and methyl L-menthoxyacetyl-D-lactate. The diastereomers are separated by preparative gas chromatography using an SE-30 liquid phase column. Each diastereomer is hydrolyzed separately by treatment with 2N HCl (aq) for 2 hours at 100° C. to give pure L- and D-lactic acid, methanol, and L-menthoxyacetic acid. The L-menthoxyacetic acid is recycled to L-menthoxyacetyl chloride by treatment with thionyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16](C3C=CC=CC=3Cl)[C:3]=12.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](C2C=C(N)N(C)N=2)=[CH:28][CH:27]=1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:29]3[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=3)[C:3]=12
Reactant: Cn1nc(-c2ccccc2Cl)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: Cn1nc(-c2ccc(Cl)cc2)cc1N
Product: Cn1nc(-c2ccc(Cl)cc2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound 26 was synthesised following similar procedures outlined in Example 1 (Compound 37), starting from Step 2 using 3-(4-chlorophenyl)-1-methyl-1H-pyrazol-5-amine instead of 3-(2-chlorophenyl)-1-methyl-1H-pyrazol-5-amine.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([N:29]3[CH2:33][CH2:32][C@H:31]([N:34]4[CH:38]=[N:37][CH:36]=[N:35]4)[CH2:30]3)=[O:28])[CH2:10]2)=CC=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.C(=O)([O-])O.[Na+]>C1(OC)C=CC=CC=1.C(OCC)(=O)C>[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([C:27]([N:29]2[CH2:33][CH2:32][C@H:31]([N:34]3[CH:38]=[N:37][CH:36]=[N:35]3)[CH2:30]2)=[O:28])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@H](n4cncn4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CCOC(C)=O
Product: O=C([C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](n2cncn2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 115.6 %

Procedure:
783 mg of (2S, 4S)-4-(4-methoxybenzylthio)-2-[(3S)-3-(1-1,2,4-triazolyl)-1-pyrrolidinylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (a) above] were suspended in 1.5 ml of anisole, and 7.5 ml of trifluoroacetic acid and 0.24 ml of trifluoromethanesulfonic acid were added to the resulting suspension, whilst ice-cooling, after which the mixture was stirred at room temperature for 1.5 hours. A cycle consisting of removing the solvent by evaporation under reduced pressure, washing the residue with hexane to remove anisole, adding diethyl ether to the mixture to solidify the product and milling the product, after which the mixture was decanted was repeated several times to obtain a powder. The whole of this powder was mixed with 40 ml of ethyl acetate and with an aqueous solution of sodium hydrogencarbonate, and then the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated by evaporation under reduced pressure, to give 713 mg of the title compound, as a powder.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][CH2:12][O:13][C:14]([CH3:16])=[O:15].[N+:17]([C:20]1[CH:24]=[CH:23][N:22]([CH2:25][CH2:26][CH:27]=[O:28])[N:21]=1)([O-:19])=[O:18].O>C1COCC1>[OH:28][CH:27]([CH2:26][CH2:25][N:22]1[CH:23]=[CH:24][C:20]([N+:17]([O-:19])=[O:18])=[N:21]1)[CH2:16][C:14]([O:13][CH2:12][CH3:11])=[O:15]
Reactant: CCOC(C)=O
Reactant: O=CCCn1ccc([N+](=O)[O-])n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CC(O)CCn1ccc([N+](=O)[O-])n1
Reaction time: 0.25 h

Procedure:
Lithium bis(trimethylsilyl)amide (10 ml. of a 1M solution in THF) was cooled to -75° under argon and freshly distilled EtOAc (0.88 g.) was added over 5 minutes. Crude 3-(3-nitropyrazol-1-yl)propionaldehyde (1.75 g.) in dry THF (10 ml.) was added at -75° over 10 minutes and the mixture was kept at -75° for a further 15 minutes then allowed to warm to 20° . Water (200 ml.) was added and the mixture was extracted with EtOAc (3×60 ml.). The extracts were dried (MgSO4) and evaporated in vacuo to give crude ethyl 3-hydroxy-5-(3-nitropyrazol-1-yl)valerate as an oil (2.41 g.) which was used in the next stage without further purification. The n.m.r. spectrum in CD3OD included the following resonances: 7.76 (d, 1H): 6.86 (d, 1H); 4.36 (t, 2H); 4.1 (q, 2H); 3.9 (m, 1H); 2.47 (d, 2H); 2.1 (m, 2H); 1.24 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:33])[N:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=2)[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40]O)=[CH:38][CH:37]=1>>[CH3:34][O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][O:23][C:22]([C:21]2[N:12]([N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH3:33])[C:13](=[O:32])[C:14]3[C:19]([C:20]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:18][C:17]([Cl:31])=[CH:16][CH:15]=3)=[O:24])=[CH:38][CH:37]=1
Reactant: COc1ccc(CO)cc1
Reactant: CN(C(=O)OCc1ccccc1)n1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: COc1ccc(COC(=O)c2c(-c3ccccc3)c3cc(Cl)ccc3c(=O)n2N(C)C(=O)OCc2ccccc2)cc1

Procedure:
The present compound was synthesized by a method similar to that in Example 200 and using 2-[(benzyloxycarbonyl)(methyl)amino]-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (200 mg) and 4-methoxybenzyl alcohol. A colorless powder (110 mg). HPLC analysis (Agilent 1100 system): purity 96% (retention time: 4.30 min). MS (ESI+): 583 (M+H), 585.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH2:10])[S:5][C:6]=1[CH3:7].[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])[S:5][C:6]=1[CH3:7]
Reactant: Cc1cc(CCN)sc1C
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCCc1cc(C)c(C)s1
Yield: 79 %

Procedure:
In close analogy to the procedure described above, 2-(4,5-Dimethyl-thiophen-2-yl)-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:31][CH2:30][C:17]3([CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1>C(Cl)Cl>[N:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:31][CH2:30][C:17]3([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:16][CH2:15]2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccncc1)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(N2CCC3(CCNCC3)CC2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium tert-butylate (4 mmol) was added to a solution of 4-bromopyridine hydrochloride (1.9 mmol) in dry toluene (10 ml) under argon, followed by 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (1.6 mmol) in toluene (5 ml). Argon was added to the mixture for 15 min, then (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.123 mmol) and tris(dibenzylidene acetone)dipalladium (0.041 mmol) were added. The mixture was heated at 90° C. for 4 h and the reaction progress was monitored by thin-layer chromatography. On completion of the reaction the mixture was diluted with ethyl acetate (100 ml) and extracted with water and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated to small volume. The crude product was purified by column chromatography (3% methanol in DCM). Yield: 45% 2. TFA (13 eq.) was added to a DCM solution (10 ml/mmol) of tert-butyl 9-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (1 eq.) at 0° C. and the mixture was stirred for 2 h at RT. The solvent was removed and the product was dried under vacuum. The crude product was used in the following stage with no further purification. Yield: quantitative
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[CH3:41][O:42][CH2:43][CH2:44][CH2:45][NH2:46].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C.C(O)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:33]3[CH:34]=[CH:35][C:36]([CH2:39][NH:46][CH2:45][CH2:44][CH2:43][O:42][CH3:41])=[CH:37][CH:38]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][C:20]=4[F:29])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(-c3ccc(C=O)cc3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Reactant: COCCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COCCCNCc1ccc(-n2nc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4F)c(OC)c3)c3c(N)ncnc32)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 10 %

Procedure:
A mixture of N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide (Intermediate 2) (0.075 g, 0.14 mmol), 3-methoxypropylamine (0.024 g, 0.27 mmol), and sodium triacetoxyborohydride (0.087 g, 0.41 mmol) in dichloroethane (1.4 mL) was shaken at room temperature for 3 days. Additional portions of 3-methoxypropylamine (0.1 mL, 1 mmol) and sodium triacetoxyborohydride (0.085 g, 0.40 mmol) were added and the mixture was shaken for 3 days. Acetic acid (0.1 mL) was added and the reaction mixture was shaken for 4 days. An additional portion of sodium triacetoxyborohydride (0.100 g, 0.470 mmol) was added and the reaction mixture was shaken for 16 h. 1N NaOH (1 mL) was added and the reaction mixture was concentrated, dissolved in DMF (2 mL), filtered through a syring-tip Acrodisc filter, and purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 20-80% acetonitrile—0.05 M ammonium acetate over 25 min, 21 mL/min); the fraction eluting from 18.0-19.7 min was collected, concentrated, and lyopholized to afford N1-{4-[4-amino-1-(4-{[(3-methoxypropyl)amino]methyl}phenyl)-1H-pyrazolo [3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide as a white solid (0.009 g, 0.014 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.93 (1H, s), 8.33-8.38 (2H, m), 8.18-8.20 (2H, m), 7.97-8.01 (1H, m), 7.87-7.91 (1H, m), 7.73-7.76 (1H, m), 7.54-7.64 (5H, m), 7.31-7.45 (2H, m), 3.95 (3H, s), 3.85-3.89 (2H, m), 3.38 (2H, s), 2.55-2.68 (2H, m), and 1.70-1.74 (2H, m); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile—0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 10.58 min. MS: MH+624.2.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].O[C:7]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]=[CH:9][N:8]=1>C1(C)C=CC=CC=1>[Cl:3][C:7]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]=[CH:9][N:8]=1
Reactant: Cc1ncnc(O)c1Cl
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ncnc(Cl)c1Cl

Procedure:
50 ml of POCl3 was added dropwise to a solution of 14.5 g (0.1 mol) of 4-hydroxyl-5-chloro-6-methylpyrimidine in 50 mL of toluene, the mixture was refluxed for 5-7 h after addition. After the reaction was over by Thin-Layer Chromatography monitoring, the reaction mixture was concentrated under reduced pressure to remove toluene and extra POCl3, and then poured into ice water. The water phase was extracted with ethyl acetate (3×50 ml), the organic phases were emerged, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified through silica column to give 14.43 g as yellow liquid with yield of 88.5%.
Reaction SMILES: OC1C=CC(C(N[C@H](C(N[C@H](C(O)=O)CC2C=CC=CC=2)=O)C)=O)=CC=1.C(N(CC)CC)C.[CH2:34]([O:36][C:37](=[O:47])[C@H:38]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[NH2:39])[CH3:35].Cl.[C:49]([NH:59][C@H:60]([C:62](O)=[O:63])[CH3:61])([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50]>ClCCl>[CH2:34]([O:36][C:37](=[O:47])[C@H:38]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[NH:39][C:62](=[O:63])[C@H:60]([CH3:61])[NH:59][C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50])[CH3:35]
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C[C@H](NC(=O)c1ccc(O)cc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
Synthesis of p-hydroxybenzoyl-L-alanyl-L-phenylalanine: 0.1 g (0.1 mol) of triethylamine was added to a suspension of 23.0 g (0.1 mol) of L-phenylalanine ethyl ester·HCl in 500 ml of dichloromethane, and to this mixture in an ice bath was added 22.3 g (0.1 mol) of carbobenzoxy-L-alanine, and then 19.2 g (0.1 mol) of 1-ethyl-3(3-dimethyaminopropyl) carbodiimide·HCl was added to the mixture. This mixture was stirred for three hours. This reaction mixture was washed with a 0.1% aqueous solution of Na2CO3 three times and with a 0.1 N HCl solution three times, and then with distilled water three times. Thereafter, the mixture was dried over anhydrous sodium sulfate, and dichloromethane was removed from the mixture under reduced pressure to obtain carbobenzoxy-L-alanyl-L-phenylalanine ethyl ester. This ester was dissolved in 260 ml of 25% HBr in glacial acetic acid, and this solution was stirred for one hour. To this solution was added 5 l of absolute ethyl ether to produce a precipitate. The precipitate was filtered and washed with ethyl ether to obtain L-alanyl-L-phenylalanine ethyl ester·HBr.