Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13](O)=[O:14])=[C:11]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[CH:19]3)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([NH2:31])[C@H:26]1[O:30][CH2:29][CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:1]([N:8]1[C:12]([C:13]([NH:31][CH2:25][C@@H:26]2[CH2:27][CH2:28][CH2:29][O:30]2)=[O:14])=[C:11]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[CH:19]3)[N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1c(-c2ccc3[nH]ncc3c2)nnn1Cc1ccccc1
Reactant: NC[C@@H]1CCCO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC[C@@H]1CCCO1)c1c(-c2ccc3[nH]ncc3c2)nnn1Cc1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 20 mL vial, a solution of Example 149C (51 mg, 0.16 mmol) dissolved in dimethylformamide (0.5 mL) was added, followed by the addition of (S)-(+)-tetrahydrofurfurylamine (18.2 mg, 0.18 mmol) dissolved in dimethylformamide (0.9 mL). A solution of HATU (68 mg, 0.18 mmol) dissolved in dimethylformamide (0.5 mL) was added followed by a solution of diisopropylethylamine (0.087 mL, 0.5 mmol) dissolved in dimethylformamide (0.5 mL). The mixture was shaken at 50° C. overnight. The reaction was filtered through a Si-Carbonate cartridge (6 mL-1 g) supplied by Silicycle Chemical Division, and the filtrate was transferred to 20 mL vials. The reaction was checked by LC/MS and concentrated to dryness. The residue was dissolved in 1:1 DMSO/methanol and purified by reverse phase HPLC (Agilent, 5%-100% TFA/water gradient, 8 minute run). 1H NMR (300 MHz, DMSO-d6/D2O) δ ppm 1.35-1.54 (m, 1H) 1.64-1.96 (m, 3H) 3.17-3.26 (m, 1H) 3.32-3.38 (m, 1H) 3.50-3.77 (m, 2H) 3.81-4.00 (m, 1H) 5.58-5.74 (m, 2H) 7.21-7.41 (m, 5H) 7.54-7.66 (m, 1H) 7.68-7.84 (m, 1H) 8.01-8.19 (m, 2H). MS (ESI−) m/z 401 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:31])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([O:34]CC)=[O:33].[OH-].[Na+].Cl.CCOC(C)=O>CCO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:31])[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:30])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([OH:34])=[O:33]
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)NCCc3ccc(Cl)cc3)cc1)c2Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(NCCc1ccc(Cl)cc1)c1ccc(Oc2c(Cl)cc3c(c2Cl)OCCC3C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.1 %

Procedure:
Ethyl 6,8-dichloro-7-(4-(4-chlorophenethylcarbamoyl) phenoxy)chroman-4-carboxylate (26.8 g, 48.83 mmol) was dissolved in 200 proof EtOH (50 ml)-THF (170 ml). 6N NaOH solution (12.21 ml, 73.25 mmol) was added to the mixture at ambient temperature. The mixture was stirred for 1 hour at ambient temperature. The mixture was transferred to a separatory funnel. 1N HCl solution (97.66 ml, 97.66 mmol) was added to the separatory funnel and EtOAc (100 ml) was added. The mixture was shaken and stood for layer separation. The layers were separated and the organic layer was washed with water and brine (100 ml), dried over MgSO4, filtered, and concentrated to provide 28 g of foamy brown solid after drying under high vacuum. The crude solid was recrystallized from THF-hexanes to provide 22.8 g of the title compound as a white solid (89%).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([S:20]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][NH2:37]>>[CH2:24]([N:23]([CH2:26][CH3:27])[S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[F:29])[N:37]=[CH:3][CH:4]=3)=[N:8]2)[CH:15]=1)(=[O:22])=[O:21])[CH3:25]
Reactant: CCN(CC)S(=O)(=O)c1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Reactant: NNc1ccccc1F
Product: CCN(CC)S(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3F)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N,N-diethyl-benzenesulfonamide (A-21) and 2-fluoro-phenylhydrazine according to the method described for example 91. MS: M=468.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][SH:10])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.[C:26]([C:28]1[C:33](Cl)=[CH:32][CH:31]=[CH:30][N:29]=1)#[N:27]>CN(C=O)C.O>[C:26]([C:28]1[C:33]([S:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:32][CH:31]=[CH:30][N:29]=1)#[N:27]
Reactant: N#Cc1ncccc1Cl
Reactant: COc1ccc(CS)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(CSc2cccnc2C#N)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirring solution of 4-methoxy-α-toluenethiol (268 mg, 1.74 mmol) in DMF (1 mL) at 0° C. was added a solution of sodium bis(trimethylsilyl)amide in THF (1.3 mL, 1M, 1.3 mmol). The resulting solution was added via cannula to a solution of 2-cyano-3-chloropyridine (200 mg, 1.45 mmol) in DMF (1 mL) at 0° C. After stirring for 2 h at 0° C., the mixture was poured into water and extracted with ethyl acetate, and the organic extracts were concentrated. The crude product was purified by column chromatography on silica gel, affording 2-cyano-3-(4-methoxybenzylthio)pyridine in quantitative yield. 1H NMR (CDCl3) δ3.80 (s, 3), 4.20 (s, 2), 6.83 (d, 2, J=10), 7.22 (d, 2, J=10), 7.34 (dd, 1, J=5, 8), 7.66 (d, 1, J=8), 8.50 (d, 1, J=5). To a solution of this compound (245 mg, 0.96 mmol) and anisole (0.52 mL, 4.8 mmol) in trifluoroacetic acid (1.5 mL) at 0° C. was added trifluoromethanesulfonic acid (0.25 mL, 2.8 mmol). The mixture was allowed to warm to room temperature, and was stirred for 1 h. The solvent was removed with a rotary evaporator, and the residue was purified by flash chromatography on silica gel, affording 117 mg (90%) of 2-cyano-3-mercaptopyridine. 1H NMR (CDCl3) δ4.15 (s, 1), 7.39 (dd, 1, J=5, 8), 7.78 (d, 1, J=8), 8.48 (d, 1, J=5).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>CO.[Pd]>[CH2:15]([N:17]([CH2:18][CH3:19])[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1)[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCNCC
Agent: [Pd]
Solvent: CO
Product: CCN(CC)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Under a nitrogen atmosphere, to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.0 g, 0.025 mol) and diethylamine (9.1 mL, 0.090 mol) in methanol (40 mL), 10% palladium on carbon (0.50 g) was added at ambient temperature. The reaction mixture was agitated under a hydrogen atmosphere at ambient temperature for 16 h. Palladium on carbon was removed by filtration with Celite and the solvent was removed under reduced pressure, then the residue was purified by chromatography on silica gel(dichloromethane/methanol) to afford tert-butyl 4-(diethylamino)piperidine-1-carboxylate as solid (6.1 g, y. 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:17][CH:16]=2)(=[O:20])=[O:19])[CH:3]=[C:4]([OH:9])[CH:5]=1
Reactant: Nc1cc(O)cc(Br)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)Nc2cc(O)cc(Br)c2)cc1
Yield: 86.8 %

Procedure:
3-Amino-5-bromophenol (0.75 g, 3.99 mmol, prepared according to WO 2011119704 A1 20110929) was treated with 4-methoxybenzene-1-sulfonyl chloride (1.61 g, 7.79 mmol) according to the method described In Preparation 15b to give 1.24 g (77% yield) of the title compound as an oil. Purity 89%.
Reaction SMILES: C([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27])[CH:20]([NH:34][C:35](=[O:65])[C:36](=[N:62][O:63][CH3:64])[C:37]1[N:38]=[C:39]([NH:42]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:40][CH:41]=1)[C:19]2=[O:66])=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1>C(O)=O.O>[NH2:42][C:39]1[S:40][CH:41]=[C:37]([C:36](=[N:62][O:63][CH3:64])[C:35]([NH:34][CH:20]2[C:19](=[O:66])[N:18]3[CH:21]2[S:22][CH2:23][C:24]([CH2:25][C:26]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:27])=[C:17]3[C:15]([OH:16])=[O:14])=[O:65])[N:38]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC(=O)c3ccccc3)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O
Solvent: O=CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CC(=O)c3ccccc3)CSC12)c1csc(N)n1
Temperature: 45 °C
Yield: 36.3 %

Procedure:
The syn isomer of 2-benzhydryloxycarbonyl-7-[2-methoxyimino-2-(2-tritylaminothiazol-4yl)-acetamido]-8-oxo-3-phenacyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene (2.7 g) is dissolved in formic acid (55 cc) at 20° C. Distilled water (11 cc) is added and the mixture is heated for 15 minutes at 45° C. The mixture is cooled to 20° C., diluted with water (44 cc) and filtered. The filtrate is concentrated to dryness under reduced pressure (5 mm Hg; 0.67 kPa) at 20° C. The residue is taken up in ethanol (3×50 cc), the solvent being evaporated off each time under reduced pressure (5 mm Hg; 0.67 kPa) at 20° C. in order to remove the water and the formic acid. The final residue is taken up in a saturated solution of sodium bicarbonate (50 cc) and the aqueous phase is washed with ethyl acetate (50 cc) and acidified to pH 3 with 1N hydrochloric acid, whilst stirring, in the presence of ethyl acetate (100 cc). The organic phase is dried over magnesium sulphate and evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. This yields the syn isomer of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-2-carboxy-8-oxo-3-phenacyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene (0.54 g) in the form of a beige solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][C:23]#[N:24])=[CH:19][CH:18]=3)[CH:15]=2)[C:10]([CH3:27])=[C:9]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:34]=[N+:35]=[N-:36].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][C:23]4[NH:36][N:35]=[N:34][N:24]=4)=[CH:19][CH:18]=3)[CH:15]=2)[C:10]([CH3:27])=[C:9]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cc(-c3ccc(OCC#N)cc3)ccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cc(-c3ccc(OCc4nnn[nH]4)cc3)ccc12

Procedure:
The desired product was prepared using a procedure similar to step 6 of example 3. Thus, [4-(1-benzyl-3-methyl-2-phenyl-1H-indol-6-yl)-phenoxy]-acetonitrile (0.288 g, 0.672 mmol) was reacted with NaN3 (0.218 g, 3.360 mmol) and NH4Cl (0.180 g, 3.360 mmol) in DMF (5 ml) to give the product (0.245 g, 0.520 mmol, 77%) as a white solid, dec. 224.5-226° C. 1H NMR (DMSO-d6) δ 2.23 (s, 3H), 5.39 (s, 2H), 5.50 (s, 2H), 6.85 (d, J=7.3 Hz, 2H), 7.12 (t, J=8.4 Hz, 3H), 7.18 (t, J=7.0 Hz, 2H), 7.35-7.44 (m, 4H), 7.48 (t, J=7.2 Hz, 2H), 7.60-7.62 (m, 4H), 16.80 (broad s, 1H); IR (solid) 3020, 2910, 1605, 1520, 1480, 1460, 1340 and 1240 cm−1; [ESI(−)], m/z 470 (M−H)−; Anal. Calcd. for C30H25N5O: C, 76.41; H, 5.34; N, 14.85; Found: C, 76.33; H, 5.28; N, 14.91.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].C1(C)C(C)=CC=CC=1.[Cl:19][CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[O:10][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([CH2:20][Cl:19])=[CH:22][CH:23]=1
Reactant: Cc1cc(Cl)cc(Cl)c1O
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1C
Product: Cc1cc(Cl)cc(Cl)c1OC(=O)c1ccc(CCl)cc1

Procedure:
88.5 g (0.5 mole) of 2,4-dichloro-6-methylphenol, 180 ml of dry xylene, 95 g (0.5 mole) of p-chloromethylbenzoyl chloride and 0.5 ml of pyridine were refluxed for 24 hours in a weak current of nitrogen with the exclusion of moisture. After cooling, the slightly turbid (pyridine hydrochloride), orange-colored solution was filtered free of a small amount of a blackish brown resin, and the filtrate was freed of xylene at diminished pressure. The residue (165 g=100%) crystallized after two days of standing to a light brown crystal mass, which was triturated in 200 ml of ice-cold petroleum ether and suction filtered. After drying, nearly colorless crystals were obtained with a melting point of 71°-73° C. Recrystallization from petroleum ether (1:10) yielded white needles melting at 74°-75° C.; no change in the melting point was brought about by repeated recrystallization.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH2:5](Br)C.[Mg].C([O:13][C:14](=[O:23])[C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=C(Cl)[CH:16]=1)(C)(C)C>CCOCC.C1COCC1.CN1C(=O)CCC1>[CH2:21]([C:19]1[CH:20]=[C:15]([CH:16]=[C:1]([CH3:2])[N:18]=1)[C:14]([OH:13])=[O:23])[CH3:5]
Reactant: CC[Mg]Br
Reactant: CCBr
Reactant: Cc1cc(C(=O)OC(C)(C)C)cc(Cl)n1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: CCc1cc(C(=O)O)cc(C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of ethylmagnesiumbromide (freshly prepared from ethylbromide (392 mg, 3.6 mmol) and magnesium (83 mg, 3.4 mmol)) in Et2O (10 mL) is added to a cooled (−40° C.) and mechanically stirred solution of 2-chloro-6-methyl-isonicotinic acid tert-butyl ester (0.76 g, 3.34 mmol), Fe(acac)3 (21.2 mg, 0.06 mmol) and NMP (0.6 mL) in THF (60 mL). The mixture is warmed to r.t. during 0.5 h, diluted with Et2O (150 mL) and quenched with aq. KHSO4 (1 M, 40 mL). The phases are separated and the aq. phase is extracted with Et2O (2×50 mL). The combined organic extracts are dried (MgSO4), filtered and evaporated. The residue is purified by reversed phase MPLC. The obtained 2-ethyl-6-methyl-isonicotinic acid tert-butyl ester is dissolved in CH2Cl2 (10 mL). TFA (10 mL) is added and the mixture stirred at r.t. for 0.5 h. The mixture is evaporated and the residue dried in HV to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:22]([O:24]C)=[O:23])[CH2:8][CH2:7][N:6]([CH:9]2[CH2:15][CH:14]3[N:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[CH2:5][CH2:4]1.[Li+].[OH-].Cl>C1COCC1>[CH2:20]([O:19][C:17]([N:16]1[CH:11]2[CH2:12][CH2:13][CH:14]1[CH2:15][CH:9]([N:6]1[CH2:7][CH2:8][C:3]([O:2][CH3:1])([C:22]([OH:24])=[O:23])[CH2:4][CH2:5]1)[CH2:10]2)=[O:18])[CH3:21]
Reactant: CCOC(=O)N1C2CCC1CC(N1CCC(OC)(C(=O)OC)CC1)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)N1C2CCC1CC(N1CCC(OC)(C(=O)O)CC1)C2
Temperature: 25 °C
Reaction time: 168 h
Yield: 101.2 %

Procedure:
Isomer 1 of ethyl 3-[4-methoxy-4-(methoxycarbonyl)piperidin-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate (0.097 g, 0.27 mmol) was dissolved in THF (5 mL) at rt and 1 M LiOH sol. (0.3 mL) was added. The reaction mixture was stirred at rt for 7 days. The pH was carefully adjusted to pH 6 by addition of concentrated hydrochloric acid, the solvents were removed in vacuo, to give 1-[8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]oct-3-yl]-4-methoxypiperidine-4-carboxylic acid (0.093 g, 100%) as an off white solid.
Reaction SMILES: C1COC2C=CC(NC3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=CC=2O1.Cl[C:28]1[N:33]=[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH:42]([CH3:44])[CH3:43])=[CH:37][CH:36]=2)[C:31]([F:45])=[CH:30][N:29]=1.[NH2:46][C:47]1[CH:48]=[CH:49][C:50]2[O:54][CH:53]([C:55]([O:57][CH3:58])=[O:56])[CH2:52][C:51]=2[CH:59]=1>>[F:45][C:31]1[C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH:42]([CH3:44])[CH3:43])=[CH:37][CH:36]=2)=[N:33][C:28]([NH:46][C:47]2[CH:48]=[CH:49][C:50]3[O:54][CH:53]([C:55]([O:57][CH3:58])=[O:56])[CH2:52][C:51]=3[CH:59]=2)=[N:29][CH:30]=1
Reactant: CC(C)Oc1ccc(Nc2nc(Cl)ncc2F)cc1
Reactant: COC(=O)C1Cc2cc(N)ccc2O1
Agent: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Product: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(OC(C)C)cc4)n3)ccc2O1

Procedure:
In a manner similar to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(4-isopropoxyphenyl)-4-pyrimidineamine and 5-amino-2,3-dihydro-2-(methoxycarbonyl)benzofuran were reacted to yield 5-fluoro-N2-(2,3-dihydro-2-(methoxycarbonyl)benzofuran-5-yl)-N4-(4-isopropoxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.87 (d, 1H, J=3.0 Hz), 7.47-7.42 (m, 3H), 7.12 (dd, 1H, J=2.4 and 8.4 Hz), 6.87 (d, 2H, J=9.6 Hz), 6.80 (d, 1H, J=8.7 Hz), 6.63 (d, 1H, J=2.4 Hz), 5.21 (dd, 1H, J=6.3 and 10.5 Hz), 4.53 (2q, 1H, J=5.7 Hz), 3.80 (s, 3H), 3.52 (dd, 1H, J=10.5 and 15.9 Hz), 3.35 (dd, 1H, J=6.3 and 15.9 Hz), 1.34 (d, 6H, J=5.7 Hz); 19F NMR (CDCl3): −47664; LCMS: ret. time: 23.78 min.; purity: 95%; MS (m/e): 439 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:66]=[CH:65][C:6]([CH2:7][O:8][C:9]([C:11]2[N:12]3[C@H:15]([S:16][CH2:17][C:18]=2[CH2:19]Cl)[C@H:14]([NH:21][C:22](=[O:63])/[C:23](/[C:57]2[N:58]=[C:59]([NH2:62])[S:60][CH:61]=2)=[N:24]\[O:25][C@H:26]([C:41]([O:43][CH:44]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])[C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34](=[O:36])[CH3:35])=[C:29]([O:37][C:38](=[O:40])[CH3:39])[CH:28]=2)[C:13]3=[O:64])=[O:10])=[CH:5][CH:4]=1.[I-:67].[Na+].O>CC(C)=O>[CH3:1][O:2][C:3]1[CH:66]=[CH:65][C:6]([CH2:7][O:8][C:9]([C:11]2[N:12]3[C@H:15]([S:16][CH2:17][C:18]=2[CH2:19][I:67])[C@H:14]([NH:21][C:22](=[O:63])/[C:23](/[C:57]2[N:58]=[C:59]([NH2:62])[S:60][CH:61]=2)=[N:24]\[O:25][C@H:26]([C:41]([O:43][CH:44]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])[C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34](=[O:36])[CH3:35])=[C:29]([O:37][C:38](=[O:40])[CH3:39])[CH:28]=2)[C:13]3=[O:64])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)/C(=N\O[C@H](C(=O)OC(c4ccccc4)c4ccccc4)c4ccc(OC(C)=O)c(OC(C)=O)c4)c4csc(N)n4)C(=O)N23)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C2=C(CI)CS[C@@H]3[C@H](NC(=O)/C(=N\O[C@H](C(=O)OC(c4ccccc4)c4ccccc4)c4ccc(OC(C)=O)c(OC(C)=O)c4)c4csc(N)n4)C(=O)N23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a solution of the product obtained in Step 6 (14 g) in acetone (210 ml) was added sodium iodide (4.85 g) in total darkness and the mixture was stirred at room temperature for one hour. The reaction mixture was then poured into water (300 ml) and extracted twice with ethyl acetate (500 ml). The combined organic layer was washed with 5% sodium thiosulfate solution (200 ml) and brine (200 ml), and dried over anhydrous sodium sulfate. The dried solution was concentrated under reduced pressure, giving 15.1 g of the objective compound as yellow crystals.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:9]=1[OH:15].Cl(O)(=O)(=O)=O>C(OCC)(=O)C.C(OC(=O)C)(=O)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:10](=[O:14])[CH3:11])[C:9]=1[O:15][C:9](=[O:15])[CH3:8]
Reactant: Oc1cccc(CCCCCCBr)c1O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1cccc(CCCCCCBr)c1OC(C)=O
Reaction time: 1.5 h
Yield: 191.5 %

Procedure:
To 1.0 g (3.8 mmol) of 1-(6-bromohexyl)-2,3-dihydroxybenzene in 150 mL of ethyl acetate and 15 mL of acetic anhydride was added 0.03 mL of 70% perchloric acid. The solution was left at room temperature for 1.5 hours and then was washed with sodium bicarbonate solution. After drying, the organic layer was concentrated to give 1.3 g of 1-(6-bromohexyl)-2,3-bis(acetyloxy)benzene as an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][SH:7].[OH-].[K+].Cl.Cl[CH2:12][CH2:13][NH2:14].C1(C)C=CC=CC=1>O>[NH2:14][CH2:13][CH2:12][S:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1cccs1
Reactant: NCCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: NCCSCc1cccs1
Reaction time: 3 h

Procedure:
The crude product from (a) was taken up under nitrogen in a solution of 128 g of potassium hydroxide (2.3 moles) in 150 ml of water. A solution of 88.2 g (0.76 mole) of 2-chloroethyl amine hydrochloride in 100 ml of water was then added dropwise with stirring at 323° K. After 3 hours on a steam bath, the reaction mixture was taken up with 200 ml of toluene, the toluene phase was washed with 200 ml of water, dried with sodium chloride, concentrated and fractionated in vacuo.
Reaction SMILES: Cl[C:2]1[N:3]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:4](=[O:17])[C:5]2[CH:10]=[N:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.C([Sn](CCCC)(CCCC)[C:30]1[S:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1)CCC>C1(C)C=CC=CC=1.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>[S:31]1[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=[C:30]1[C:2]1[N:3]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:4](=[O:17])[C:5]2[CH:10]=[N:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2s1
Reactant: O=c1c2cnn(-c3ccccc3)c2nc(Cl)n1-c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=c1c2cnn(-c3ccccc3)c2nc(-c2nc3ccccc3s2)n1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A reaction tube charged with 6-chloro-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (20.0 mg, 0.056 mmol) and Pd(PPh3)4 (6.5 mg, 0.0056 mmol) is purged with nitrogen. A solution of 2-tributylstannanyl-benzothiazole (47.6 mg, 0.112 mmol) in anhydrous toluene (1.0 mL) is added via syringe. The reaction mixture is heated at 100° C. for 2 days. After removal of the solvent, the residue is purified by preparative LCMS to provide the title compound; 1H NMR (CDCl3, 400 MHz) δ 8.36 (s, 1H), 8.21 (d, 2H), 7.90 (t, 1H), 7.69 (t, 1H), 7.59 (t, 2H), 7.46-7.40 (m, 5H), 7.24 (d, 2H); HPLC-MS calculated for C24H14ClN5OS (M+H+) 456.1. Found 456.1.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[BH4-].[Na+].CO.O>C(O)(C)(C)C>[CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][OH:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CO
Product: Cc1c(CO)cccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 91.8 %

Procedure:
39.0 g (0.2 mol) of methyl 2-methyl-3-nitrobenzoate was dissolved in 600 ml of tert-butanol, and 19.0 g of sodium borohydride was added thereto. Under refluxing, 150 ml of methanol was dropwise added thereto over a period of 1 hour. The refluxing was continued further for 1 hour to complete the reaction. The reaction mixture was left to cool, and then water was added thereto. The solvent was distilled off under reduced pressure. To the residue, water and chloroform were added, and the organic layer was separated and dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain 30.7 g of 2-methyl-3-nitrobenzyl alcohol.