Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[Cl:31][C:32]1[C:37]([S:38](Cl)(=[O:40])=[O:39])=[CH:36][CH:35]=[CH:34][N:33]=1>>[Cl:31][C:32]1[C:37]([S:38]([N:11]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:9]([CH:12]=[O:13])=[CH:10]2)(=[O:40])=[O:39])=[CH:36][CH:35]=[CH:34][N:33]=1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: O=Cc1c[nH]c(-c2ccccc2)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccnc2Cl)c1

Procedure:
By a reaction under similar conditions as in Reference Example 55 and using 5-phenyl-1H-pyrrole-3-carbaldehyde (514 mg), sodium hydride (60% in oil, 180 mg), 15-crown-5 (0.90 mL) and 2-chloro-3-pyridinesulfonyl chloride (716 mg), the title compound was obtained as an amorphous form (yield 716 mg, 69%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[N:8]=[C:7]([C:9]([O:11]CC)=[O:10])[CH:6]=[N:5]1)[CH3:3].[OH-].[Na+]>CO>[CH3:3][CH:2]([N:4]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[N:5]1)[CH3:1]
Reactant: CCOC(=O)c1cnn(C(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)n1ncc(C(=O)O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
To a solution of ethyl 2-(1-methylethyl)-2H-1,2,3-triazole-4-carboxylate (670 mg) in methanol (6 ml) was added sodium hydroxide (4 ml) and the mixture was stirred at room temperature for 4 h. The methanol was removed in vacuo and water (10 ml) was added and the mixture neutralised (pH 5-6) by the addition of 2M hydrochloric acid. The aqueous layer was extracted with DCM, separated by hydrophobic frit and the organic layer evaporated in vacuo to give the title compound (455 mg) as a white solid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[S:7][S:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][S:16]Cl)=[CH:11][CH:10]=1>ClCCCl>[CH2:1]([N:3]([S:7][S:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][S:16][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:11][CH:10]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: ClSSc1ccc(SSCl)cc1
Reactant: CCNCC
Solvent: ClCCCl
Product: CCN(CC)SSc1ccc(SSN(CC)CC)cc1

Procedure:
25.0 ml (190 mmol) of diethylamine are used as initial charge in 150 ml of 1,2-dichloroethane in an inertized three-necked flask with dropping funnel, reflux condenser with hose coupling at its upper end, a tap with hose coupling and a Teflon stirrer bar, in a countercurrent of argon. 10.6 g (38.6 mmol) of 1,4-bis(chlorodisulphanyl)benzene in 50 ml of 1,2-dichloroethane are then slowly added dropwise, with stirring. The reaction mixture is stirred at room temperature for 4 hours. The resultant salt is filtered off, and the organic phase is washed three times with water and dried over sodium sulphate. After removal of the solvent on a rotary evaporator and drying in the vacuum generated by a rotary-vane pump, 1,4-bis(diethylaminodisulphanyl)benzene precipitates in the form of a yellow oil. The crude yield is 11.9 g (89%). Elemental analysis was carried out on the crude product.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[CH:29][N:28]=[C:27](Cl)[N:26]=3)[CH:20]=2)[CH2:16][CH3:17])[CH2:9]1)=O)(C)(C)C.[F:32][C:33]1[CH:34]=[C:35]([CH2:39][CH2:40][NH2:41])[CH:36]=[CH:37][CH:38]=1>>[CH2:16]([N:15]([CH2:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:41][CH2:40][CH2:39][C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([F:32])[CH:34]=3)[N:26]=2)[CH:22]=[CH:23][CH:24]=1)[CH2:14][C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1)[CH3:17]
Reactant: CCN(Cc1cccc(-c2ccnc(Cl)n2)c1)CC1CCCN(C(=O)OC(C)(C)C)C1
Reactant: NCCc1cccc(F)c1
Product: CCN(Cc1cccc(-c2ccnc(NCCc3cccc(F)c3)n2)c1)C[C@H]1CCCNC1

Procedure:
Intermediate 95 was coupled with 2-(3-fluoro-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 449. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.71 (s, 1H), 8.36 (t, 2H), 7.96 (d, 1H), 7.70 (m, 2H), 7.30 (s, 1H), 7.12 (d, 2H), 6.91 (s, 1H), 4.60 (s, 2H), 3.99 (s, 2H), 3.06 (m, 6H), 2.84 (m, 2H), 2.65 (t, 1H), 2.34 (m, 2H), 1.87 (m, 4H), 1.45 (t, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[CH3:31][N:28]1[CH2:27][CH2:26][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:30][CH2:29]1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CN1CCN(c2nnc3ccc(F)cn23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.6 %

Procedure:
To a solution of Intermediate A (125 mg, 0.766 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 62 mg, 1.54 mmol) and the mixture stirred at RT for 0.5 h. A solution of Intermediate 68a (180 mg, 0.766 mmol) in DMF (3 mL) was added and the mixture stirred at 60° C. for 1.75 h. The cooled mixture was diluted with water and extracted with DCM (5×25 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-20% [2M NH3 in MeOH] in DCM, to give the title compound as a pale brown gum (225 mg, 78%). LCMS (Method 3): Rt 0.44 min, m/z 379 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9](=O)[CH3:10].Cl.C([O:15][C:16](=O)[CH2:17][NH2:18])C>N1C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:16](=[O:15])[CH2:17][N:18]=[C:9]([CH3:10])[C:3]=2[CH:4]=1
Reactant: CC(=O)c1cc(Br)ccc1N
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: c1ccncc1
Product: CC1=NCC(=O)Nc2ccc(Br)cc21
Yield: 16.1 %

Procedure:
A mixture of 1-(2-amino-5-bromo-phenyl)-ethanone (8 g, 37 mmol) and glycine ethyl ester hydrogen chloride (6.7 g, 48 mmol) in pyridine was heated at reflux for 24 hrs under nitrogen. The reaction mixture was cooled, solvent removed, and residue was treated with a saturated aqueous ammonium chloride solution (200 mL). Ethyl acetate (300 mL) was added and organic layer was separated, dried (MgSO4), concentrated, and the residue purified on silica gel column (hexane:ethyl acetate/1:1) to give 7-bromo-5-methyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one as a brown solid (1.51 g, 16%). 1H NMR (DMSO-d6): δ 10.49 (s, 1H), 7.92 (d, J=2.0 Hz, 1H), 7.66 (dd, J=8.7, 2.1 Hz, 1H), 7.08 (d, J=8.7 Hz, 1H), 3.91 (s, 2H), 2.39 (s, 3H). MS (ESI) m/z 253/255 ([M+H]+); Anal. calcd for C10H9BrN2O: C, 47.46; H, 3.58; N, 11.07. Found: C, 47.58; H, 3.52; N, 10.95.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH2:16][CH2:15][NH:14][CH2:13][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CCOC(C)=O>[Cl:17][C:18]1[C:26]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([N:14]1[CH2:15][CH2:16][C:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:12][CH:11]=[N:10][C:9]=2[CH2:13]1)=[O:21]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: c1ccc(-c2ncnc3c2CCNC3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(ncnc2-c2ccccc2)C1
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a solution of Intermediate 1 (55 mg, 0.26 mmol) in DCM (3 mL) was added 2-chloro-3-(trifluoromethyl)benzoic acid (60 mg, 0.26 mmol) followed by EDCI (75 mg, 0.39 mmol), HOBt (28 mg, 0.21 mmol) and TEA (0.72 mL, 0.52 mmol). The mixture was stirred overnight and then loaded directly on a column. Chromatography on SiO2 eluting with EtOAc/Hex afforded the desired product as a colorless foam (80 mg, 73%). MS (ESI) mass calcd. C21H15ClF3N3O, 417.09. m/z found 418.2 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.16-9.03 (m, 1H), 7.82-7.77 (m, 1H), 7.65-7.46 (m, 7H), 5.16-5.02 (m, 1H), 4.61-4.42 (m, 1H), 4.09-3.97 (m, 1H), 3.52-3.38 (m, 1H), 3.11-2.83 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[CH2:6][NH:7][NH2:8].C([O:17][C:18](=O)[C:19]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[C:20]([NH2:24])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:24][C:20]1[NH:8][N:7]([CH2:6][C:5]2[CH:9]=[CH:10][C:11]([CH3:12])=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=2)[C:18](=[O:17])[C:19]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1ccc(CNN)cc1C(F)(F)F
Reactant: CCOC(=O)C(=C(N)OCC)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1ccc(Cn2[nH]c(N)c(-c3ccccc3)c2=O)cc1C(F)(F)F
Reaction time: 8 h

Procedure:
31.5 g of 3-trifluoromethyl-4-methylbenzylhydrazine were added dropwise under nitrogen to a solution of 35.3 g of α-phenyl-β-amino-β-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulphonic acid in 150 ml of ethanol. After stirring overnight,the solvent was distilled off in vacuo and the residue was recrystallized from dimethylformamide.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:12]=[CH:13][C:14]([F:27])=[C:15]4[C:20]=3[N:19]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:17]=[C:16]4[O:25][CH3:26])[CH2:7][CH2:6]2)[O:4]CC1.Cl.[OH-].[Na+]>O1CCCC1>[F:27][C:14]1[CH:13]=[CH:12][C:11]([N:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)=[C:20]2[C:15]=1[C:16]([O:25][CH3:26])=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[N:19]2
Reactant: COc1cc(C(F)(F)F)nc2c(N3CCC4(CC3)OCCO4)ccc(F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(F)(F)F)nc2c(N3CCC(=O)CC3)ccc(F)c12
Temperature: 70 °C
Reaction time: 5 h
Yield: 76.8 %

Procedure:
To a solution of 8-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)-5-fluoro-4-methoxy-2-(trifluoro-methyl)quinoline (Step 3, 0.6 g, 1.56 mmol, 1 eq.) in tetrahydrofuran (20 mL) was added 2N aqueous HCl (6 mL). The resulting mixture was stirred at 70° C. for 5 hours. The reaction was cooled to room temperature, poured into 1N aqueous sodium hydroxide and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and concentrated on a rotary evaporator. The crude product was purified by flash chromatography on silica gel using hexane/ethyl acetate to give 0.41 g of the desired product as a light yellow solid; MP=171-173 C; MS (ES) m/z (relative intensity): 343 (M+H)+ (100).
Reaction SMILES: CSC.B.C[O:6][C:7](=O)[C:8]1[CH:13]=[C:12]([C@@H:14]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:15][Br:16])[CH:11]=[CH:10][C:9]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[CH2:26]([O:25][C:9]1[CH:10]=[CH:11][C:12]([C@@H:14]([O:17][Si:18]([C:21]([CH3:22])([CH3:23])[CH3:24])([CH3:19])[CH3:20])[CH2:15][Br:16])=[CH:13][C:8]=1[CH2:7][OH:6])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)c1cc([C@H](CBr)O[Si](C)(C)C(C)(C)C)ccc1OCc1ccccc1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(CO)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
Borane dimethylsulfide complex (42.4 ml of 10M solution in tetrahydrofuran, 424 mmol) was added dropwise to a solution methyl-2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)benzoate (Preparation 40) (91.0 g, 189 mmol) in tetrahydrofuran (1600 ml). The resulting mixture was then heated to reflux for 2 hours and then cooled to 0° C. before quenching with methanol (270 ml). The mixture was left to stir at room temperature for 16 hours and then the solvent removed in vacuo. The residue was partitioned between dichloromethane (500 ml) and water (500 ml). The aqueous phase was separated and extracted with dichloromethane (500 ml) and the combined organic extracts washed with brine (500 ml), dried (magnesium sulfate) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with cyclohexane:ethyl acetate (100:0 changing to 80:20, by volume) to give the title compound (68.7 g) as a colourless oil.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].FC(F)(F)S(O[C:59]1[CH:64]=[C:63]([Cl:65])[C:62]([CH2:66][CH:67]2[CH2:71][CH2:70][N:69]([CH:72]3[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73]3)[C:68]2=[O:78])=[C:61]([Cl:79])[CH:60]=1)(=O)=O.C(=[NH:95])(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])(=O)C.[Na+].Cl.NO>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[NH2:95][C:59]1[CH:64]=[C:63]([Cl:65])[C:62]([CH2:66][CH:67]2[CH2:71][CH2:70][N:69]([CH:72]3[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73]3)[C:68]2=[O:78])=[C:61]([Cl:79])[CH:60]=1
Reactant: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1C1CCCCC1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1cc(Cl)c(CC2CCN(C3CCCCC3)C2=O)c(Cl)c1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 64.1 %

Procedure:
Place Pd2(dba)3 (710 mg, 3.16 mmol), BINAP (2.95 g, 4.74 mmol), and Cs2CO3 (15.0 g, 47.0 mmol) in a dry flask. Add 3,5-dichloro-4-((1-cyclohexyl-2-oxopyrrolidin-3-yl)methyl)phenyl trifluoromethanesulfonate (Example 240) (15.0 g, 32.0 mmol), benzophenone imine (8.60 g, 47.4 mmol), and 750 mL of toluene. Heat at 100° C. overnight. Cool to room temp and filter. Remove toluene under reduced pressure. Dissolve crude imine in MeOH and add sodium acetate (5.20 g, 63.0 mmol) and hydroxylamine hydrochloride (4.40 g, 63.0 mmol). Stir at room temp for 45 min. Pour into water and extract with CH2Cl2. Dry, filter, and concentrate. Purify the residue by Biotage eluting with a mixture of EtOAc and hexanes (30:70 to 50:50) to give the title compound (7.0 g, 65%): Mass spectrum (apci) m/z=341.2 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[F:19][C:20]([F:32])([F:31])[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[CH:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:22]4[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=4[C:20]([F:19])([F:32])[F:31])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1ccc(F)cc1C(F)(F)F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(F)cc4C(F)(F)F)cc3CCC12
Yield: 37.7 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 2-trifluoromethyl-4-fluorophenylboronic acid (162 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 96 mg (38%) of the title compound as an amorphous foam. mp 70°. FDMS: m/e=391. α[D]589 =+55.81 (c=0.60, chloroform).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:27]3[CH2:32][CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][C:12]=3[F:26])[C:3]=12>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:25][C:19]1[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C@@H:27]3[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]3)[N:9]=2)=[C:12]([F:26])[CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4F)cc3F)c3c(N)ncnc32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3F)cc1F)nn2[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.3 %

Procedure:
To a solution of (R)-tert-butyl 3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (1.7 g, 3.15 mmol) in 20 ml of DCM, TFA (20 ml) was added. The reaction mixture was stirred at RT for 4 h. The mixture was washed with sat. NaHCO3 (10 mL) and concentrated to give (R)-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.1 g, 80% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28].[CH2:29](I)[CH3:30].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH2:29]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28])[CH3:30]
Reactant: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2O)c1
Reactant: CCI
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2OCC)c1
Yield: 66 %

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl and 0.423 ml (5.181 mmol) of ethyl iodide, there were added 85.8 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated overnight at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matte rand the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by silica gel column chromatography (with 20 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 100/1 and 75/1) to obtain 141.6 mg (0.3420 mmol, 66%) of 2-ethoxy-2'-hydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl as an oily product. 1H-NMR (CDCl3) δ (ppm): 1.24 (6H, t, 2CH3), 1.36 (3H, t, CH3), 2.62 (2H, t, CH2), 2.63 (2H, t, CH2), 2.94 (2H, t, CH2), 2.95 (2H, t, CH2), 4.11 (`6H, q, CH2), 4.13 (4H, q, 2CH2), 6.66 (1H, s, OH), 6.9-7.3 (6H, m, arom-H) MS (FAB): 414 (M+)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:14](=[NH:15])[C:13]3[C:16]([NH:19][CH2:20][C:21]4[CH:26]=[CH:25]C=C(OC)[CH:22]=4)=[N:17][NH:18][C:12]=3[N:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1.O1[CH2:34][CH2:33][O:32][CH2:31]C1.[OH-].[Na+]>O>[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][C:14]2[N:15]=[CH:10][N:11]=[C:12]3[NH:18][N:17]=[C:16]([NH:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:34]=[C:33]([O:32][CH3:31])[CH:22]=4)[C:13]=23)[CH:6]=[CH:7][CH:8]=1
Reactant: C1COCCO1
Reactant: COc1cccc(CNc2n[nH]c3ncn(-c4cccc(Cl)c4)c(=N)c23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Temperature: 5 °C

Procedure:
A mixture of 0.417 g (1 mmol) of 5-(3-chloro-phenyl)-1,5-dihydro-4-imino-3-(3-methoxy-benzylamino)-4H-pyrazolo[3,4-d]pyrimidine hydrochloride (Example 45, title compound II), 20 ml of dioxane, 19 ml of water and 1 ml of 1N sodium hydroxide solution is heated under reflux for 10 hours. Cooling to approx. 5° C., filtering, washing the filter residue with water and drying under a HV at 120° C. yield the title compound (see Example 45); m.p. 192-193° C.
Reaction SMILES: Cl[C:2]([S:4]Cl)=[O:3].[C:6]([NH2:14])(=[S:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(C(C)C)CC)(C)C>CC#N>[C:7]1([C:6]2[S:13][S:4][C:2](=[O:3])[N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(=S)c1ccccc1
Reactant: O=C(Cl)SCl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=c1nc(-c2ccccc2)ss1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
All the glassware were dried in the preheated oven prior to the reaction for two hours at 200° C. A 500 ml three neck round bottom flask was equipped with magnetic bar, thermometer, pressure equalizing funnel and a positive inflow of argon. The assembly was placed on to the magnetic stirrer having ice bath. Chlorocarbonyl sulfenyl chloride (9.55 grams, 72.87 mmol) was transferred to the reaction flask. 100 ml of CH3CN was also added to the flask. The mixture was cooled down to 10° C. Thiobenzamide (10 grams, 72.87 mmol) was dissolved in a separate flask using 80 ml of CH3CN and diisopropylethylamine (18.84 gm, 145.76 mmol). This solution was transferred to the pressure equalizing funnel. The thiobenzamide solution was added slowly to the reaction flask. The temperature of the flask raised to 12-15° C. The mixture was stirred for 30 min. at 5-10° C. The disappearance of the starting material and formation of two isomeric nonpolar spots was observed on TLC. The reaction mixture was filtered through a sintered funnel. The filtrate was rotaevaporated to dryness and left on high vacuum for two hours. The solid was crystallized with a mixture of hexanes and ethyl acetate in a ratio of 95:5, respectively. The upper nonpolar spot on the TLC was left behind in the mother liquor and characterized as 3,5-diphenyl-1,2,4-thiadiazole. The crystals of 3-phenyl-1,2,4-dithiazoline-5-one were light yellow in color and the recovery was 9.25 gm (65%). The yield of the crude mix was 75%. The structure of 3-phenyl-1,2,4-dithiazoline-5-one was confirmed by 1H-NMR (FIG. 1), 13C-NMR (FIG. 2), mass spectrometry (FIG. 3) and elemental analysis.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:5]([O:15][S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])[C:6]2[C:11]([C:12]=1[CH2:13]Br)=[CH:10][CH:9]=[CH:8][CH:7]=2.[CH2:34]([N:36](CC)CC)C.CN>C1COCC1>[C:30]([O:29][C@@H:23]([C:4]1[C:3]2[CH2:2][N:36]([CH3:34])[CH2:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]=1[O:15][S:16]([C:19]([F:21])([F:22])[F:20])(=[O:17])=[O:18])[C:24]([O:26][CH2:27][CH3:28])=[O:25])([CH3:32])([CH3:31])[CH3:33]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(CBr)c(CBr)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Reactant: CCN(CC)CC
Agent: CN
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c2c(c3ccccc3c1OS(=O)(=O)C(F)(F)F)CN(C)C2
Reaction time: 1 h

Procedure:
To a solution of (S)-ethyl 2-(3,4-bis(bromomethyl)-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-tert-butoxyacetate (0.1356 g, 0.219 mmol) and triethylamine (61 μL, 0.438 mmol) in anhydrous THF (10 mL) at 0° C. was added a 2M solution of methylamine in THF (109 μL, 0.219 mmol). The reaction mixture was stirred for 1 hour, then stirred overnight at room temperature. LC/MS shows some desired product. Reaction mixture was heated at 45° C. for 1.5 hours, then additional 2M solution of methylamine in THF (109 μL, 0.219 mmol) was added. After 1 hour, 2M solution of methylamine in THF (0.9 mL) was added and stirred for 45 minutes. LC/MS showed no starting material. The reaction mixture was concentrated and purified by flash column chromatography (silica gel, 30 to 100% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C22H27F3NO6S: 490.2. Found: 490.1.