Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:14]=[C:13]([NH:15]C(=O)OC(C)(C)C)[CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(Cc2cccc(NC(=O)OC(C)(C)C)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(Cc2cccc(N)n2)CC1
Reaction time: 3 h

Procedure:
To a solution of tert-butyl {6-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}carbamate (103 mg, 0.337 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1.2 mL, 16 mmol) at room temperature. After 3 hours, the reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium carbonate was added to adjust to pH˜9. The mixture was then extracted with ethyl acetate (3×) and the combined organics were dried over magnesium sulfate, filtered, and concentrated to afford 6-[(4-methylpiperazin-1-yl)methyl]pyridin-2-amine that was used without further purification. MS ESI calc'd for C11H19N4 [M+H]+ 207. found 207. 1H NMR (500 MHz, CD3OD) δ 7.46-7.40 (m, 1H), 6.66 (d, J=7.2 Hz, 1H), 6.47 (d, J=8.3 Hz, 1H), 3.47 (s, 2H), 2.85-2.46 (m, 8H), 2.39 (s, 3H).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[N:8]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[O:11][C:10]2([CH3:21])[CH3:20])[CH:7]=[N:6][CH:5]=1.CCN(S(F)(F)[F:28])CC>ClCCl>[F:28][CH2:2][CH2:3][C:4]1[N:8]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[O:11][C:10]2([CH3:21])[CH3:20])[CH:7]=[N:6][CH:5]=1
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1CCO
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC1(C)OC(=O)c2ccccc2C1n1cncc1CCF
Reaction time: 0.5 h

Procedure:
To a partial suspension of 4-[5-(2-hydroxy-ethyl)-imidazol-1-yl]-3,3-dimethyl-isochroman-1-one (0.180 g, 0.616 mmol) (example 27f) in dichloromethane (10 mL) at 0° C. under nitrogen is added DAST (0.314 g, 1.848 mmol) dropwise. After 30 min, the mixture is diluted with dichloromethane and washed twice with saturated aqueous sodium bicarbonate, water and brine. The combined aqueous phase is back-extracted once with dichloromethane. The combined organic phase is dried over magnesium sulfate and filtered through a cotton plug. The residue is purified by silica gel flash chromatography (elution with dichloromethane-methanol, 99:1 to 49:1) to afford 4-[5-(2-fluoro-ethyl)-imidazol-1-yl]-3,3-dimethyl-isochroman-1-one as an oil. The material is converted to the HCl salt and triturated with methanol, to give a crystalline solid; MS (ESI) m/z 289.0 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 1.27 (s, 3 H), 1.59 (s, 3 H), 4.69-4.95 (m, 4 H), 5.73 (br. S., 1 H), 7.16 (s, 1 H), 7.53 (d, J=7.6 Hz, 1 H), 7.63 (br. S., 1 H), 7.71 (td, J=7.6, 1.1 Hz, 1 H), 7.81 (td, J=7.6, 1.3 Hz, 1H), 8.27 (dd, J=7.8, 1.3 Hz, 1 H).
Reaction SMILES: [CH2:1]([C:4]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:5]=1[O:6][CH2:7][C:8](O)=[O:9])[CH:2]=[CH2:3].S(Cl)([Cl:21])=O>>[CH2:1]([C:4]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:5]=1[O:6][CH2:7][C:8]([Cl:21])=[O:9])[CH:2]=[CH2:3]
Reactant: O=S(Cl)Cl
Reactant: C=CCc1ccc(C(F)(F)F)cc1OCC(=O)O
Product: C=CCc1ccc(C(F)(F)F)cc1OCC(=O)Cl

Procedure:
Using the procedure of Step E of Example 16, 5.2 g of the product of Step B and 40 ml of thionyl chloride were reacted to obtain 5.55 g of the expected product which was used as is for Step D.
Reaction SMILES: [CH2:1]([CH2:5][PH:6](Cl)=[O:7])[CH:2]=[CH:3][CH3:4].[O-:9][C:10]#[N:11].[Na+]>C(#N)C>[CH2:1]([CH2:5][PH:6]([N:11]=[C:10]=[O:9])=[O:7])[CH:2]=[CH:3][CH3:4]
Reactant: N#C[O-]
Reactant: CC=CCC[PH](=O)Cl
Agent: [Na+]
Solvent: CC#N
Product: CC=CCC[PH](=O)N=C=O
Reaction time: 4.5 h
Yield: 70.3 %

Procedure:
170 g (1.1 mol) of crotylmethylphosphinic acid chloride were dissolved in 300 ml of acetonitrile and heated with 73 g (1.1 mol) of sodium cyanate to 55° C. while stirring. After 4.5 hours, the precipitate was filtered off by suction and washed with acetonitrile, the filtrate was concentrated, and the residue distilled at a temperature of 76°-78° C. and at a pressure of 27 Pa. 123 g of crotylmethylphosphinic acid isocyanate (70% of theory) were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=[O:5].[OH:21][CH2:22][CH2:23][O:24][C:25]1[C:32]([CH3:33])=[CH:31][C:28]([CH:29]=O)=[CH:27][C:26]=1[CH3:34]>C(O)C.[Cu](Cl)Cl>[OH:21][CH2:22][CH2:23][O:24][C:25]1[C:32]([CH3:33])=[CH:31][C:28]([C:29]2[N:6]([C:7]3[CH:8]=[CH:9][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:12]=3)[C:4](=[O:5])[C:3]3[C:2](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:1]=2)=[CH:27][C:26]=1[CH3:34]
Reactant: Nc1ccccc1C(=O)Nc1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Agent: Cl[Cu]Cl
Solvent: CCO
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(C(F)(F)F)cc2)cc(C)c1OCCO
Temperature: 25 °C

Procedure:
To a solution of 2-amino-N-(4-trifluoromethyl-phenyl)-benzamide (0.19 g, 0.68 mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (0.16 g, 0.81 mmol) in anhydrous ethanol (15 mL) was added anhydrous copper (II) chloride (0.273 g, 2.03 mmol). The reaction mixture was stirred at reflux for 16 hours under nitrogen and then cooled to room temperature. Ethanol was evaporated under reduced pressure. The residue was taken in ethyl acetate (100 mL). The organic phase was washed with water (2×75 mL), then brine (75 mL), and dried over anhydrous Na2SO4. Solvent was evaporated; crude compound was purified by column chromatography (silica gel 230-400 mesh; 2:3:5 ethyl acetate, hexanes and CH2Cl2 as eluent) to give the title compound as a white solid. Yield: 0.17 g (55%). MP 160-161° C. 1H-NMR (400 MHz, CDCl3): δ 8.34 (d, J=8.00 Hz, 1H), 7.84-7.82 (m, 2H), 7.62-7.53 (m, 3H), 7.31 (d, J=8.40 Hz, 2H), 6.97 (s, 2H), 3.93-3.89 (m, 2H), 3.80 (t, J=5.20 Hz, 2H), 2.15 (s, 6H), 2.07 (t, J=6.40 Hz, 1H).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[C:7]([Cl:16])=[N:8][CH:9]=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>ClCCl>[Cl:16][C:7]1[C:6]([N:5]=[C:1]=[S:2])=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=1
Reactant: COC(=O)c1cnc(Cl)c(N)c1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(Cl)c(N=C=S)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 76.1 %

Procedure:
Thiophosgene (6.367 g, 55.37 mmol) in dichloromethane (10 mL) was added to a mixture of methyl 5-amino-6-chloronicotinate (8.61 g, 46.14 mmol) and sodium carbonate (9.781 g, 92.29 mmol) in dichloromethane (200 mL). The reaction mixture was stirred for four days at ambient temperature. The reaction mixture was washed with water and brine, dried, and concentrated. The residue was purified via MPLC (Biotage) eluting with 12:1 hexane:ethyl acetate to afford methyl 6-chloro-5-isothiocyanatonicotinate (8.03 g, 76.1% yield) as a white solid: 1H NMR (CDCl3) δ 3.97 (s, 3H), 8.09 (s, 1H), 8.84 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:15][C:16]3[CH:17]=[C:18]([NH2:28])[CH:19]=[C:20]4[C:26](=[O:27])[NH:25][N:24]=[CH:23][C:22]=2[C:21]=34)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[NH:15][C:16]3[CH:17]=[C:18]([NH2:28])[CH:19]=[C:20]4[C:26](=[O:27])[NH:25][N:24]=[CH:23][C:22]=2[C:21]=34)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2[nH]c3cc(N)cc4c3c2C=NNC4=O)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2[nH]c3cc(N)cc4c3c2C=NNC4=O)CC1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 29.4 %

Procedure:
In a manner analogous to that of Example 183, palladium (10% on activated carbon) (0.186 g) was added to a solution of Intermediate 220(a) of Example 220 (0.61 g, 1.60 mmol) in 9:1 methanol:N,N-dimethformamide (50 mL). The reaction mixture was purged with H2 and stirred at room temperature under H2 (1 atm.) for 6.5 hours. The mixture was filtered, and the filtrate evaporated. The resulting residue was dissolved in methanol and loaded onto a silica gel plug. The plug was then loaded onto a silica gel column and eluted with 50:3 dichloromethane:methanol to give Intermediate 222(a) (0.18 g, 0.470 mmol) as a yellow solid in 29% yield.
Reaction SMILES: [Na].[CH:2]1([CH2:8][CH2:9][CH2:10]Br)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O.[CH2:13]([OH:16])[CH2:14][OH:15]>C1(C)C(C)=CC=CC=1>[CH:2]1([CH2:8][CH2:9][CH2:10][O:15][CH2:14][CH2:13][OH:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: BrCCCC1CCCCC1
Reactant: OCCO
Agent: [Na]
Solvent: Cc1ccccc1C
Solvent: O
Product: OCCOCCCC1CCCCC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 82.5 %

Procedure:
85 ml of xylene are added to a solution of 15.75 g of sodium in 182.2 g of ethylene glycol. The mixture is heated to 100° C., and a solution of 140.5 g of 3-cyclohexylpropyl bromide in 70 ml of xylene is added dropwise within 3 hours. When the addition has ended, the mixture is boiled for 4 hours under reflux, cooled, and then 500 ml of water are added. The mixture is extracted with twice 500 ml of petroleum ether, the combined organic phases are dried over sodium sulphate and the remaining oil is purified by chromatography on silica gel (migrating agent: 80:20 petroleum ether/ethyl acetate). 105.3 g of 2-(3-cyclohexylpropyloxy)-ethanol are obtained.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[CH:17]=[C:16]([C:18]3[CH:32]=[CH:31][C:21]([CH2:22][N:23]4[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]4)=[CH:20][C:19]=3[F:33])[O:15][C:11]2=[C:12](Cl)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCCCC=1>CCO.[Pd]>[CH2:1]([C:8]1[CH:9]=[C:10]2[CH:17]=[C:16]([C:18]3[CH:32]=[CH:31][C:21]([CH2:22][N:23]4[CH2:24][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:26]4)=[CH:20][C:19]=3[F:33])[O:15][C:11]2=[CH:12][N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CN(Cc2ccc(-c3cc4cc(Cc5ccccc5)nc(Cl)c4o3)c(F)c2)C1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: COC(=O)C1CN(Cc2ccc(-c3cc4cc(Cc5ccccc5)ncc4o3)c(F)c2)C1
Temperature: 85 °C

Procedure:
A mixture of methyl 1-(4-(5-benzyl-7-chlorofuro[2,3-c]pyridin-2-yl)-3-fluorobenzyl)azetidine-3-carboxylate (0.320 g, 0.69 mmol), cyclohexene (1.00 mL, 9.9 mmol), palladium (10 wt. % on activated carbon, 0.320 g, 3.0 mmol) in EtOH (6.0 mL) was prepared in a sealed tube and heated under N2 to 85° C. for 4 h. The mixture was filtered through Celite, and the filtrate evaporated purified by flash chromatography using EtOAc/hexanes to give title compound. 1H NMR (300 MHz, CDCl3) δ ppm 8.82 (s, 1H), 7.96 (t, J=7.7 Hz, 1H), 6.99-7.38 (m, 9H), 4.25 (s, 2H), 3.72 (s, 3H), 3.65 (s, 2H), 3.48-3.59 (m, 2H), 3.33-3.39 (m, 3H). MS (ESI) m/z: Calculated; 430.2 Observed: 431.2 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[N:6][C:7]=1Cl.[I:13][Si](C)(C)C.[I-].[Na+]>C(#N)CC>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[N:6][C:7]=1[I:13]
Reactant: COC(=O)c1cnc(Cl)c(Br)c1
Reactant: C[Si](C)(C)I
Agent: [I-]
Agent: [Na+]
Solvent: CCC#N
Product: COC(=O)c1cnc(I)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a mixture of methyl 5-bromo-6-chloro-3-pyridinecarboxylate (1 g, 3.99 mmol) in propionitrile (30 ml) was added iodotrimethylsilane (0.689 ml, 3.99 mmol) and then sodium iodide (1.795 g, 11.98 mmol). The mixture was stirred at room temperature for 30 min. Solvent was evaporated and the obtained solid was dissolved in H2O. pH was adjusted to basic with 2M NaOH and DCM was added. The organic phase was extracted, dried over Na2SO4, filtered and concentrated to give 1.2 g (79%) of desired compound as a yellow solid.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[C:21]([CH2:25]O)[CH:22]=[N:23][CH:24]=2)=[CH:15][CH:14]=1>ClCCl>[Cl:3][CH2:25][C:21]1[CH:22]=[N:23][CH:24]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][C:11]([F:28])([F:27])[F:10])=[CH:14][CH:15]=2)[CH:20]=1
Reactant: OCc1cncc(-c2ccc(OC(F)(F)F)cc2)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(-c2cncc(CCl)c2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
136 mg (0.083 ml, 1.14 mmol) thionyl chloride were added drop by drop at 0° C. to a solution of 0.1 ml N,N-dimethylformamide (DMF) and 153 mg (0.57 mmol) [5-(4-Trifluoromethoxy-phenyl)-pyridin-3-yl]-methanol in 10 ml dichloromethane and stirred for 2 h at 0° C. The mixture was poured on ice/sodium bicarbonate solution and the organic phase separated. The water phase is extracted with dichloromethane. The combined organic phases were washed with water, dried (sodium sulphate), evaporated and the obtained material (156 mg, 89%) used without further purification.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23](B3OC(C)(C)C(C)(C)O3)=[CH:22][N:21]=2)[CH2:16][CH2:15]1>>[CH3:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]2[N:21]=[CH:22][C:23]([C:2]3[C:10]4[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=4)[NH:4][N:3]=3)=[CH:24][CH:25]=2)[CH2:18][CH2:19]1
Reactant: O=Cc1ccc2c(I)n[nH]c2c1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: CN1CCN(c2ccc(-c3n[nH]c4cc(C=O)ccc34)cn2)CC1

Procedure:
According to the procedure example A12A, except substituting 3-iodo-1H-indazole-6-carbaldehyde and 1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)pyridin-2-yl)piperazine (67 mg, 0.22 mmol), the title compound was obtained as a beige solid (57 mg, 99%). 1H NMR (400 MHz, CD3OD) δ ppm 10.11 (s, 1H), 8.73 (d, J=2.3 Hz, 1H), 8.16 (dd, J=8.8, 2.3 Hz, 1H), 8.14 (s, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.05 (d, J=8.8 Hz, 1H), 3.83-3.78 (m, 4H), 3.01 (t, J=5.0 Hz, 4H), 2.67 (s, 3H); MS ESI 322.1 (100) [M+H]+, calcd for [C18H19N5O+H]+ 322.16.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][C:5]([C:10]1[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=3)[NH:12][CH:11]=1)=[CH:6]2.I.CS[C:25]([C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)=[NH:26]>C(O)C.[Pd]>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][C:5]([C:10]1[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:25]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)=[NH:26])[CH:17]=3)[NH:12][CH:11]=1)=[CH:6]2
Reactant: CSC(=N)c1cccs1
Reactant: CN1C2C=C(c3c[nH]c4ccc([N+](=O)[O-])cc34)CC1CC2
Agent: [Pd]
Agent: I
Solvent: CCO
Product: CN1C2C=C(c3c[nH]c4ccc(NC(=N)c5cccs5)cc34)CC1CC2
Reaction time: 14 h
Yield: 43.8 %

Procedure:
A solution of compound 89 (0.25 g, 0.882 mmol) in dry ethanol (10 mL) was treated with Pd—C (0.025 g) and purged with hydrogen gas. The reaction was stirred under hydrogen atm. (balloon pressure) for overnight (14 h). The solid was filtered off using celite bed and washed with ethanol (2×5 mL). The combined ethanol layer was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.5 g, 1.764 mmol) at room temperature and stirred for 24 h. Ethanol was evaporated and crude material was basified with sat. NaHCO3 solution (20 mL) and product was extracted into CH2Cl2 (2×25 mL). The combined CH2Cl2 layer was washed with brine (15 mL) and dried (Na2SO4). The solvent was evaporated and crude was purified by column chromatography on silica gel (2 M NH3 in methanol: CH2Cl2, 1:9) to obtain compound 90 (0.14 g, 44%) as a solid. mp 93-95° C.; 1H NMR (DMSO-d6) δ 1.60-1.65 (m, 1H), 1.84-1.90 (m, 1H), 2.02-2.26 (m, 4H), 2.41 (s, 3H), 2.83-2.89 (m, 1H), 3.46-3.55 (m, 1H), 6.20 (brs, 2H), 6.67 (d, 1H, J=7.8 Hz), 7.10 (s, 1H), 7.23-7.31 (m, 3H), 7.60-7.72 (m, 2H), 10.99 (s, 1H); ESI-MS m/z (%): 363 (MH+, 65), 182 (100), 119 (48); ESI-HRMS calculated for C21H23N4S (MH+), Calculated: 363.1633; Observed: 363.1637.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:11]=1)[N:8]=[CH:7][C:6]([C:16]#[N:17])=[C:5]2[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(O)(=O)C>[Br:25][C:21]1[CH:20]=[C:19]([NH:18][C:5]2[C:4]3[C:9](=[C:10]([CH2:12][N:13]([CH3:14])[CH3:15])[CH:11]=[C:2]([NH:1][C:26](=[O:28])[CH3:27])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:16]#[N:17])[CH:24]=[CH:23][CH:22]=1
Reactant: CN(C)Cc1cc(N)cc2c(Nc3cccc(Br)c3)c(C#N)cnc12
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(CN(C)C)c2ncc(C#N)c(Nc3cccc(Br)c3)c2c1

Procedure:
To a stirred mixture of 6-amino-4-[(3-bromophenyl)amino]-8-dimethylaminomethyl-3-quinolinecarbonitrile (0.20 g, 0.50 mmol) and 1.5 ml of acetic acid at 25° C. was added 0.14 ml (1.5 mmol) of acetic anhydride. After 60 m volatile matter was evaporated off under vacuum. The residue was stirred with sodium bicarbonate solution. The resulting solid was filtered off, washed with water, dried, and recrystallized from isopropanol-hexane to give a light yellow solid, mp 162-167° C.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1.O>CN(C)C=O>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[S:1][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)=[N:17][CH:18]=1
Reactant: Oc1ccccc1S
Reactant: Clc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(Oc2ccccc2Sc2ccc(Cl)cn2)nc1

Procedure:
To a mixture of 3.0 grams (0.023 mole) of 2-mercaptophenol and 7.0 grams of potassium carbonate stirring in 50 ml of dimethylformamide, 9.0 grams of 2,5-dichloropyridine is added and the stirred mixture heated at 130° overnight. After pouring into excess H2O, the aqueous mixture is extracted with ethyl ether (200 ml) and the extract washed with H2O, saturated NaHCO3, and brine, dried (MgSO4), filtered, and the solvent evaporated to give the crude product which is recrystallized from 1-chlorobutane.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:37]4[CH:36]=[CH:35][C:34]([O:33][CH3:32])=[CH:39][CH:38]=4)(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(OC)cc4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 4-methoxy-benzenesulfonyl chloride. Purity (ELSD, based on MW=591.7)=94%.
Reaction SMILES: C(O[C:4](=[O:25])[C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:6]=1[NH:15][C:16](=[O:24])[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])C.CN(C)C=O.[H-].[Na+].[H][H]>C1(C)C=CC=CC=1.[Cl-].[Na+].O.O.C(O)(=O)C>[CH2:22]([O:21][C:19]([C:18]1[CH2:17][C:16](=[O:24])[NH:15][C:6]2[CH:7]=[C:8]([O:13][CH3:14])[C:9]([O:11][CH3:12])=[CH:10][C:5]=2[C:4]=1[OH:25])=[O:20])[CH3:23]
Reactant: CCOC(=O)CCC(=O)Nc1cc(OC)c(OC)cc1C(=O)OCC
Reactant: [H][H]
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(O)c2cc(OC)c(OC)cc2NC(=O)C1
Temperature: 80 °C
Reaction time: 7 h
Yield: 57.8 %

Procedure:
A solution of 4,5-dimethoxy-2-[(4-ethoxy-1,4-dioxobutyl)amino]benzoic acid ethyl ester (5.940 g, 16 mmol) and N,N-dimethylformamide (7.5 ml) in toluene (60 ml) was added dropwise to a stirred suspension of powdered sodium hydride (80%, 2.57 g, 85.7 mmol) under argon in toluene (70 ml). After the hydrogen evolution had ceased, the mixture was stirred for 7 hours at 80° C. under argon, then cooled to 20° C. and acetic acid (5 ml) and water (40 ml) added dropwise in succession. Brine (100 ml) was added and the organic phase dried (magnesium sulphate) and evaporated to give the title compound as a white solid, (2.842 g, 55% yield), mp 218° C.; 1H-NMR (DMSO-d6, 300 MHz): δ (ppm)=12.7 (br s; 1 H), 7.96 (s; 1H), 7.3 (s; 1H), 6.49 (s; 1H), 4.32 (q; 2H), 3.95 and 3.93 (s; 6H), 3.1 (s; 2H), 1.38 (t; 3H).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[C:6]([CH3:27])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([OH:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[C:9]=1[CH3:10].[OH-].[Na+].O.Cl>O1CCOCC1>[OH:26][CH:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[C:9]([CH3:10])=[C:5]([CH2:4][C:3]([OH:28])=[O:2])[C:6]([CH3:27])=[N:7]2)=[CH:13][CH:14]=1)[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(C(O)Cc3ccccc3)cc2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nn(Cc2ccc(C(O)Cc3ccccc3)cc2)c(C)c1CC(=O)O
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
{1-[4-(1-Hydroxy-2-phenyl-ethyl)-benzyl]-3,5-dimethyl-1H-pyrazol-4-yl}-acetic acid methyl ester (intermediate 15.1.2, 110 mg, 0.29 mmol) was dissolved in 3 ml dioxane and aqueous NaOH solution (0.58 ml, 1 M) was added. After stirring for 2.5 h at 60° C. and dilution with water, aqueous HCl solution (0.61 ml, 1 M) was added. The mixture was extracted with ethyl acetate, and the organic layer was dried with MgSO4 and evaporated under reduced pressure. The residue was lyophilized.
Reaction SMILES: [NH4+:1].[OH-].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1>O1CCCC1>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH2:1])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: [NH4+]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(S(N)(=O)=O)cc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
25 ml of 25% NH4OH were added dropwise while cooling in an ice bath to a solution of 7.3 g of p-methoxybenzenesulfonyl chloride in 50 ml of tetrahydrofuran. Subsequently, the reaction mixture was stirred vigorously for 30 minutes at 70° C. (bath temperature). Thereafter, the tetrahydrofuran was distilled. The residue was extracted with ethyl acetate. There was obtained p-methoxybenzenesulfonamide which was converted into the potassium salt as described in Example 50.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[N:6][C:7](S(C)(=O)=O)=[N:8][CH:9]=2)[N:4]([CH3:15])[N:3]=1.[CH2:16]([CH2:18][NH2:19])[OH:17].O.C(OCC)(=O)C>CN1CCCC1=O>[Cl:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([NH:19][CH2:18][CH2:16][OH:17])=[N:8][CH:9]=2)[N:4]([CH3:15])[N:3]=1
Reactant: Cn1nc(Cl)c2cnc(S(C)(=O)=O)nc21
Reactant: NCCO
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1nc(Cl)c2cnc(NCCO)nc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of 3-chloro-6-methanesulfonyl-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (131 mg, 0.5 mmol) in 1-methyl-2-pyrrolidinone (5 mL) was added ethanolamine (150 mg, 2.5 mmol, 5 eq) and the reaction mixture was heated to 50° C. After 1 hour, water (20 mL) was added, followed by ethyl acetate (20 mL). The layers were separated. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The resulting yellow residue was purified by column chromatography (50% ethyl acetate-hexane) to give 2-(3-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-ethanol (100 mg, 87% yield); LC/MS (m/e)=228.2 (MH+), Rt=1.44 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)([O-:3])=[O:2].[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>>[Cl:23][CH2:22][CH2:21][CH2:20][N:8]1[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: O=[N+]([O-])c1ccc2[nH]c3ccccc3c2c1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc2c(c1)c1ccccc1n2CCCCl

Procedure:
The compound was synthesized by mixing 3-nitrocarbazole (0.5 g, 0.0024 mol), NaH (0.06 g, 0.0026 mol) and 1-bromo-3-chloropropane (0.41 g,