Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([C@H:7]2[C@H:12]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]4[O:23][CH2:22][O:21][C:19]=4[CH:20]=3)[CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:5][CH:4]=[C:3](F)[CH:2]=1.[OH-].[K+].C1(NC(=O)[O-])C=CC=CC=1.[CH3:37][S:38]([OH:41])(=[O:40])=[O:39]>C1(C)C=CC=CC=1>[CH3:37][S:38]([OH:41])(=[O:40])=[O:39].[CH2:8]1[C@@H:7]([C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=2)[C@H:12]([CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][O:21][C:19]=3[CH:20]=2)[CH2:11][NH:10][CH2:9]1
Reactant: Fc1ccc([C@@H]2CCNC[C@H]2COc2ccc3c(c2)OCO3)cc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])Nc1ccccc1
Agent: [K+]
Solvent: Cc1ccccc1
Product: c1ccc([C@@H]2CCNC[C@H]2COc2ccc3c(c2)OCO3)cc1

Procedure:
A round bottom flask was charged with unpurified paroxetine base (8.6 g) in toluene (20 ml) which had been prepared by potassium hydroxide hydrolysis of a phenylcarbamate derivative, and a solution of methanesulfonic acid (1.9 ml) in toluene (10 ml) was added dropwise. The resulting clear solution was placed into a separating funnel and extracted with water (30 ml). The aqueous phase was separated, residual toluene removed by evaporation at reduced pressure and the remaining clear solution (25 ml) was further diluted with water (40 ml). The water was removed by freeze drying to afford amorphous paroxetine methanesulfonate.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[CH:3]=1.O.[NH2:13][NH2:14]>C(O)(C)C>[NH:13]([C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[CH:3]=1)[NH2:14]
Reactant: Cn1c(Cl)cc(=O)n(C)c1=O
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: Cn1c(NN)cc(=O)n(C)c1=O

Procedure:
A mixture of Step 1 intermediate (17 g, 97.34 mmol) and hydrazine hydrate (119 ml) in isopropyl alcohol (280 ml) were refluxed for 1 h. The excess of solvent was removed under reduced pressure, solid obtained was filtered, washed with methanol (25 ml) and dried to obtain 8.1 g of the product as white solid; 1H NMR (300 MHz, DMSO-d6): δ 3.09 (s, 3H), 3.21 (s, 3H), 4.37 (br s, 2H), 5.10 (s, 1H), 8.02 (br s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][OH:18])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29](Cl)=[S:30])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:19][CH3:20])[CH2:16][CH2:17][OH:18])=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[S:30])=[CH:24][CH:23]=1
Reactant: S=C(Cl)Oc1ccc(Cl)cc1
Reactant: CCN(CCO)CCCCOc1ccc2c(c1)CCN2
Product: CCN(CCO)CCCCOc1ccc2c(c1)CCN2C(=S)Oc1ccc(Cl)cc1

Procedure:
In analogy to example 7.8, 2-{[4-(2,3-Dihydro-1H-indol-5-yloxy)-butyl]-ethyl-amino}-ethanol and chloro-thioformic acid (4-chloro-phenyl)ester were converted to yield 5-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butoxy}-2,3-dihydro-indole-1-carbothioic acid O-(4-chloro-phenyl)ester as yellow viscous oil, MS: 449 (MH+, 1Cl).
Reaction SMILES: N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].I[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1.[CH2:30]([OH:34])/[CH:31]=[CH:32]/[CH3:33]>[Cu]I.C1(C)C=CC=CC=1>[CH2:30]([O:34][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)/[CH:31]=[CH:32]/[CH3:33]
Reactant: COc1ccc(I)cc1
Reactant: C/C=C/CO
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: C/C=C/COc1ccc(OC)cc1
Temperature: 110 °C
Reaction time: 22 h
Yield: 85.8 %

Procedure:
A test tube was charged with CuI (20 mg, 0.10 mmol, 0.10 equiv), 1,10-phenanthroline (36 mg, 0.20 mmol, 0.20 equiv), Cs2CO3 (652 mg, 2.0 mmol, 2.0 equiv), 4-iodoanisole (234 mg, 1.0 mmol, 1.0 equiv), trans-2-buten-1-ol (171 μL, 2.0 mmol, 2.0 equiv) and toluene (0.5 mL). The test tube was sealed and the reaction mixture was stirred at 110° C. for 22 h. The resulting suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel, eluting with diethyl ether. The filtrate was concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (2×20 cm; pentane:diethyl ether 30:1) provided 153 mg (86% yield) of the title compound as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:9]=O)=[N:5][CH:6]=[CH:7][N:8]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1/[CH:18]=[CH:19]/[CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C.C(OCC)(=O)C>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1/[CH:18]=[CH:19]/[CH:20]1[CH2:21][CH2:22][N:23]([CH2:9][C:4]2[C:3]([O:2][CH3:1])=[N:8][CH:7]=[CH:6][N:5]=2)[CH2:24][CH2:25]1
Reactant: Fc1ccccc1/C=C/C1CCNCC1
Reactant: COc1nccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1nccnc1CN1CCC(/C=C/c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
After dissolving 186 mg of 3-methoxypyrazine-2-carboxaldehyde and 230 mg of (E)-4-[2-(2-fluorophenyl)vinyl]piperidine in 3 ml of 1,2-dichloroethane, 0.08 ml of acetic acid and 373 mg of sodium triacetoxyborohydride were added and the mixture was stirred overnight at room temperature. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture and extraction was performed with ethyl acetate. The extract was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (296 mg, 82% yield).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:36]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1)[CH2:8][S:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([S:20][CH2:21][C:22]2[CH:27]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:25]=[C:24]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:23]=2)[CH:19]=1)[C:13](OC)=[O:14])([CH3:4])([CH3:3])[CH3:2].Cl>C1(C)C=CC=CC=1>[C:32]([C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:25]=1)[CH2:21][S:20][C:18]1[CH:17]=[C:12]([CH:11]=[C:10]([S:9][CH2:8][C:7]2[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:38]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:36]=2)[CH:19]=1)[CH2:13][OH:14])([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)c1cc(SCc2cc(C(C)(C)C)cc(C(C)(C)C)c2)cc(SCc2cc(C(C)(C)C)cc(C(C)(C)C)c2)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(CSc2cc(CO)cc(SCc3cc(C(C)(C)C)cc(C(C)(C)C)c3)c2)cc(C(C)(C)C)c1
Reaction time: 2 h
Yield: 10 %

Procedure:
Methyl 3,5-bis(3,5-di-tertiary-butylbenzylthio)benzoate (52.0 g, 86.0 mmol) was dissolved in 300 ml of toluene. To this, was added dropwise a 70% solution of sodium dihydrobis(2-methoxyethoxy)aluminate in toluene (52 g, 180.0 mmol), maintaining the temperature at 35° C. or below and the resulting mixture was stirred for 2 hours under the same conditions. After completion of the reaction, the reaction mixture was poured into 500 ml of a cold 10% hydrochloric acid solution, followed by stirring for 10 minutes. The toluene layer was separated, dried over anhydrous magnesium sulfate and then concentrated. The resulting residue was then purified by means of chromatography with dichloromethane, giving 4.96 g of 3,5-bis(3,5-di-tertiary-butylbenzylthio)benzyl alcohol as a viscous substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[S:10][C:11]([CH3:16])=[CH:12][C:13]=1[C:14]#[N:15].Cl>C(O)(C)C>[CH3:16][C:11]1[S:10][C:9]2[NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=[C:14]([NH2:15])[C:13]=2[CH:12]=1
Reactant: Cc1cc(C#N)c(Nc2ccccc2N)s1
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N

Procedure:
A mixture of 2-((2-aminophenyl)amino)-5-methylthiophene-3-carbonitrile, prepared as described in the previous step, (22.9 g, 100 mmol) in isopropanol (150 mL) and aqueous hydrochloric acid (50 mL, 18%) was heated at 80° C. for 3 hrs. The resulting suspension was filtered and the filter cake was dried to give the title compound as a red solid. 1H NMR (400 MHz CDCl3) δ 7.14-7.12 (t, 1H), 7.7.12-7.10 (t, 1H), 6.95-6.93 (d, J=8 MHz, 1H), 6.81-6.79 (d, J=8 MHz, 1H), 6.70 (s, 1H), 2.30 (s, 3H).
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([OH:37])[C:5]=2[N:4]=1.Br[CH2:40][CH2:41][CH2:42][OH:43].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:38][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH2:40][CH2:41][CH2:42][OH:43])[C:5]=2[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(O)cccc43)n2)CC1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OCCCO)cccc43)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A mixture of 0.60 g (1.1 mmol) of tert-butyl 4-[4-[2-(difluoromethyl)-4-hydroxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperazine-1-carboxylate, 0.47 g (3.3 mmol) of 3-bromo-1-propanol, and 0.80 g (5.5 mmol) of powdered K2CO3 in 20 mL dry DMF was stirred at room temperature for 8 hrs. Dilution with water gave 0.66 g, (99% yield) of tert-butyl 4-[4-[2-(difluoromethyl)-4-(3-hydroxypropoxy)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate: 1H NMR (CDCl3) δ 7.94 (dd, J=8.4. 0.7 Hz, 1H), 7.49 (t, JHF=53.4 Hz, 1H), 7.34 (t, J=8.1 Hz, 1H), 6.92 (dd, J=8.0, 0.6 Hz, 1H), 4.47 (t, J=5.9 Hz, 2H), 3.98 (t, J=5.4 Hz, 2H), 3.87 (m, 8H), 3.79 (m, 4H), 3.54 (m, 4H), 3.30 (m, exchangeable with D2O, 1H), 2.14 (pentet, J=5.8 Hz, 2H), 1.50 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.[NH2:16][CH2:17][C:18]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[O:19].C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[CH3:8][C:7]1[C:2]([NH:16][CH2:17][C:18]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[O:19])=[N:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][C:6]=1[CH3:9]
Reactant: CCCN(CCC)C(=O)CN
Reactant: Cc1nc(-c2ccccc2)nc(Cl)c1C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCN(CCC)C(=O)CNc1nc(-c2ccccc2)nc(C)c1C
Temperature: 150 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
A mixture of 4-chloro-5,6-dimethyl-2-phenylpyrimidine (1.0 g), 2-amino-N,N-dipropylacetamide (0.87 g) and triethylamine (0.55 g) is refluxed with stirring at 150° C. for three hours. To the reaction mixture are added water and chloroform, and the chloroform layer is collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from a mixture of diethyl ether and n-hexane to give the desired compound (1.3 g), m.p. 79-80° C.
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([C:8]1[C:17]2[C:12](=[C:13]([N+:18]([O-])=O)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)([O-])=O>>[NH2:5][C:8]1[C:17]2[C:12](=[C:13]([NH2:18])[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1cccc2c([N+](=O)[O-])cccc12
Solvent: O=[N+]([O-])O
Product: Nc1cccc2c(N)cccc12

Procedure:
The invention also provides a process for the production of 1,5-diisocyanatonaphthalene in which naphthalene and/or 1-nitronaphthalene is reacted with nitric acid in the presence of a zeolite, the resulting 1,5-dinitronaphthalene is then hydrogenated to form 1,5-diaminonaphthalene and the resulting 1,5-diaminonaphthalene is phosgenated to form 1,5-diisocyanatonaphthalene.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH2:11][C:10](=[O:12])[N:9]([CH2:13][CH3:14])[C:8]2=[O:15])=[C:4]([Cl:18])[CH:3]=1.[CH:19]1([N:22]2[CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27](B4OC(C)(C)C(C)(C)O4)[CH:28]=3)[C:23]2=[O:40])[CH2:21][CH2:20]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[Cl:18][C:4]1[CH:3]=[C:2]([C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[C:23](=[O:40])[N:22]([CH:19]2[CH2:21][CH2:20]2)[CH2:30]3)[CH:17]=[CH:16][C:5]=1[CH2:6][N:7]1[CH2:11][C:10](=[O:12])[N:9]([CH2:13][CH3:14])[C:8]1=[O:15]
Reactant: CCN1C(=O)CN(Cc2ccc(Br)cc2Cl)C1=O
Reactant: CC1(C)OB(c2ccc3c(c2)CN(C2CC2)C3=O)OC1(C)C
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCN1C(=O)CN(Cc2ccc(-c3ccc4c(c3)CN(C3CC3)C4=O)cc2Cl)C1=O
Yield: 33.6 %

Procedure:
1-(4-Bromo-2-chlorobenzyl)-3-ethylimidazolidine-2,4-dione (2C5) (0.106 mmol, 35 mg), 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (1A5) (106 mmol, 31.6 mg), tris(dibenzylidineacetone)dipalladium (0.005 mmol, 4.8 mg), tricyclohexylphosphine (0.013 mmol, 3.6 mg) and potassium phosphate (0.317 mmol, 67 mg) were dissolved in dioxane (2 ml) and water (1 ml) and the mixture was heated at 120° C. in the microwave for 30 min. The sample was concentrated and partitioned between DCM and water and the organic layer collected and dried using a hydrophobic fritted tube before concentration. Purification using basic semi-prep HPLC afforded 1-(2-chloro-4-(2-cyclopropyl-1-oxoisoindolin-5-yl)benzyl)-3-ethylimidazolidine-2,4-dione (Example 2a) 15.1 mg (33%); 1H NMR (400 MHz, CDCl3) δ 7.90 (d, 1H) 7.62 (m, 2H) 7.56 (s, 1H) 7.51 (d, 1H) 7.43 (d, 1H) 4.76 (s, 2H) 4.39 (s, 2H) 3.85 (s, 2H) 3.61 (q, 2H) 2.98 (m, 1H) 1.25 (t, 3H) 0.96-89 (m, 4H); LCMS m/z (M+H) 424.0.
Reaction SMILES: Cl.C[N:3](C)CCCN=C=NCC.[CH2:13]([N:16]1[C:20]([CH2:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:19][C:18]([C:28]([OH:30])=O)=[N:17]1)[CH2:14][CH3:15].ON1C2C=CC=CC=2N=N1.[OH-].[NH4+]>CN(C)C=O.O>[CH2:13]([N:16]1[C:20]([CH2:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:19][C:18]([C:28]([NH2:3])=[O:30])=[N:17]1)[CH2:14][CH3:15]
Reactant: CCCn1nc(C(=O)O)cc1CC1CCOCC1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1nc(C(N)=O)cc1CC1CCOCC1
Reaction time: 2 h
Yield: 83.5 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.06 g, 21.2 mmol) was added to a solution of 1-propyl-5-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazole-3-carboxylic acid (4.88 g, 19.3 mmol) and 1-hydroxybenzotriazole (2.87 g, 21.2 mmol) in N,N-dimethylformamide (DMF) (24.4 mL) at room temperature. The mixture was stirred for two hours, cooled in an ice bath, and treated with concentrated ammonium hydroxide (3.9 mL). A precipitate formed, and the mixture was stirred 30 minutes at 0° C. Water (100 mL) was added, and the mixture was stirred for an additional ten minutes. The precipitate was isolated by filtration, washed with water, and dried on the vacuum filter funnel to provide 4.05 g of 1-propyl-5-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazole-3-carboxamide as white crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2OS(C(F)(F)F)(=O)=O)[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH2:4][CH2:3]1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1([CH3:25])[C:6]([C:7]2[CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[CH:14]=[CH:15][C:16]=2[C:28]2[CH:29]=[C:30]([C:33]([F:35])([F:36])[F:34])[CH:31]=[CH:32][C:27]=2[F:26])=[CH:5][CH2:4][CH2:3]1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1F
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C2=CCCC2(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2F)c(C2=CCCC2(C)C)c1
Temperature: 90 °C
Reaction time: 17 h
Yield: 53 %

Procedure:
To a stirred solution of 66.61 (0.7595 g, 2.007 mmol) in DMF (5 mL) at 23° C. was added 2-fluoro-5-(trifluoromethyl)phenylboronic acid (commercially available from Aldrich Chemical Company, Inc.) (0.8352 g, 4.017 mmol) and potassium carbonate (0.8357 g, 6.047 mmol) followed by tetrakis(triphenylphosphine)palladium (0.2364 g, 0.2046 mmol). The mixture was heated to 90° C. After 17 hours, LCMS-showed that the reaction was complete. The mixture was cooled to room temperature and then diluted with water. After extracting three times with EtOAc, the mixture was concentrated in vacuo and then purified on silica gel (0%-10% EtOAc/hexane) to afford 66.53A as a clear oil that was used without further purification (414.2 mg, 53% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:13]2[CH2:15][CH2:14]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[CH2:6][CH2:5]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([CH:13]2[CH2:15][CH2:14]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[S:25])[CH2:6][CH2:5]2
Reactant: O=C1CCc2c(ccc(Br)c2C2CC2)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: S=C1CCc2c(ccc(Br)c2C2CC2)N1
Temperature: 100 °C

Procedure:
To a stirred solution of 6-bromo-5-cyclopropyl-3,4-dihydroquinolin-2(1H)-one (147-6; 0.8 g, 0.0030 mol) in toluene (10 mL) was added Lawesson's reagent (1.2 g, 0.003 mol). Reaction mass was refluxed at 100° C. for 12 h. The reaction mixture was concentrated and directly purified by silica gel column chromatography to obtain title compound. MS (M+1): 284.0.
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.Cl.Cl.[CH3:43][O:44][C:45](=[O:54])[C@H:46]([CH2:48][C:49]1[N:53]=[CH:52][NH:51][CH:50]=1)[NH2:47].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)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:47][C@@H:46]([CH2:48][CH:49]4[CH:50]=[N:51][CH:52]=[N:53]4)[C:45]([O:44][CH3:43])=[O:54])=[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: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COC(=O)[C@H](CC1C=NC=N1)NCc1ccc(-n2nc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4F)c(OC)c3)c3c(N)ncnc32)cc1
Temperature: 25 °C
Reaction time: 72 h

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), L-histidine methyl ester dihydrochloride (0.046 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 ), L-histidine methyl ester dihydrochloride (0.100 g, 0.59 mmol) and sodium triacetoxyborohydride (0.085 g, 0.40 mmol) were added and the reaction mixture was shaken for 2 days. 1N NaOH (1 mL) was added and the brown precipitate was collected by filtration. The filtrate was extracted with dichloromethane (5 mL) and the organic extract was concentrated and combined with the aforementioned brown solid. The crude mixture was 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 18.9-20.5 min was collected, concentrated, and lyopholized to afford methyl (2S)-2-({4-[4-amino-3-(4-{[2-fluoro-4-(trifluoromethyl)benzoyl]amino}-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]benzyl}amino)-3-(4H-4-imidazolyl)propanoate as a white solid. (0.029 g, 0.041 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.94 (1H, s), 8.35-8.38 (2H, m), 8.13 (2H, d, J=8.0 Hz), 7.99-8.02 (1H, m), 7.90 (1H, d, J=10.8 Hz), 7.75 (1H, d, J=8.4 Hz), 7.51 (1H, s), 7.39-7.45 (5H, m), 6.78 (1H, bs), 3.96 (3H, s), 3.82 (1H, d, J=14.0 Hz), 3.59 (3H, s), 3.47 (1H, t, J=6.4 Hz), 2.80-2.89 (2H, m), and 1.91 (3H, s); 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 11.15 min. MS: MH+704.2.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)(O)[O-].[Na+].[C:21](Cl)(Cl)=[S:22]>C(Cl)(Cl)Cl.O>[N:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:10][CH:11]=1)=[C:21]=[S:22]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(OCCn2ccnc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: S=C=Nc1ccc(OCCn2ccnc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 116.8 %

Procedure:
To an ice-cooled stirred biphasic solution of 4-[2-(1H-imidazol-1-yl)ethoxy]benzenamine (1.00 g; 4.92 mmol) and sodium bicarbonate (2.07 g; 24.6 mmol) in chloroform (100 mL) and water (50 mL) was added a solution of thiophosgene (452 μL; 5.90 mmol) in chloroform (10 mL) over 5 min. The mixture was stirred at ice-bath temperature for 20 min, and then the aqueous and organic phases were separated and the aqueous phase extracted with chloroform (50 mL). The combined chloroform layers were washed with brine, then dried over magnesium sulfate and concentrated under reduced pressure to give 1-[2-(4-isothiocyanatophenoxy)ethyl]-1H-imidazole (1.41 g) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([CH3:13])[C:5]2[N:6]([CH3:10])[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1.[N-:14]=[N+:15]=[N-:16].[Na+].[Na].O=C1O[C@H]([C@H](CO)O)C(O)=C1O.C(O)C>[Cu]I.O>[N:14]([C:2]1[CH:12]=[C:11]([CH3:13])[C:5]2[N:6]([CH3:10])[C:7]([CH3:9])=[N:8][C:4]=2[CH:3]=1)=[N+:15]=[N-:16]
Reactant: Cc1cc(Br)cc2nc(C)n(C)c12
Reactant: [N-]=[N+]=[N-]
Agent: [Cu]I
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(N=[N+]=[N-])cc2nc(C)n(C)c12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
0.59 g (2.50 mmol) 5-bromo-1,2,7-trimethyl-1H-benzimidazole, 0.32 g (4.9 mmol) sodium azide, 75 mg (0.50 mmol) trans-(1R,2R)—N,N′-bismethyl-1,2-cyclohexane-diamine, 50 mg (0.30 mmol) copper(I) iodide and 50 mg (0.30 mmol) L-ascorbic acid sodium salt were added to 2.0 ml of a mixture of ethanol and water (EtOH/water=7/3) and the mixture was stirred for 1 h at 100° C. Then the EtOH was distilled off and the residue was mixed with water. The precipitate formed was suction filtered, washed with water and diethyl ether and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][CH2:14][N:15]=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]
Reactant: COc1ccc(CCCCN=[N+]=[N-])c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CCCCN)c(OC)c1
Yield: 64.6 %

Procedure:
Amine 79 was prepared by typical procedure A from azide 78 (4.06 g, 0.017 mol) and LiAlH4 (13 mL of a 1.0 M solution in THF). The material was purified by column chromatography (silica gel, 2:1:0.1 chloroform/ethanol/concentrated ammonium hydroxide) to provide 79 (2.3 g, 64%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.53 (m, 4H), 2.53 (m, 2H), 2.73 (m, 2H), 3.80 (s, 6H), 6.43 (m, 2H), 7.52 (m, 1H).