Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:20]2[CH:25]=[CH:24][C:23](Cl)=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][NH:38][CH:39]=2)O1.Cl>O1CCOCC1>[NH:37]1[CH:36]=[C:35]([C:23]2[CH:22]=[CH:21][C:20]([C:11]3([C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:25][CH:24]=2)[CH:39]=[N:38]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccncc2)(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1cc(C2(c3ccc(-c4cn[nH]c4)cc3)CCNCC2)ccn1

Procedure:
4-(4-Chloro-phenyl)-3,4,5,6-tetrahydro-2H-[4,4′]bipyridinyl-1-carboxylic acid tert-butyl ester was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1, followed by treatment with 4M HCl in dioxane, to obtain the title compound. LCMS (PS-B4) Rt 4.28 min [M+H]+305. 1H NMR (Me-d3-OD) δ 2.76 (2H, br.t), 3.01 (2H, br.d), 3.24 (2H, br.t), 3.39 (2H, br.d), 7.58 (2H, d), 7.76 (2H, d), 8.17 (2H, d), 8.37 (2H, s), 8.82 (2H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH:23]([CH3:29])[C:24]([O:26]CC)=[O:25])=[N:13]2)=[O:10])=[CH:4][CH:3]=1.CO.[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH:23]([CH3:29])[C:24]([OH:26])=[O:25])=[N:13]2)=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)c1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C(=O)O)c1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product from Example 109C (1.4 g, 3.4 mmol) in THF (8 mL), water (4 mL), and MeOH (8 mL) was added 5M NaOH (3.4 mL, 17 mmol). After stirring at room temperature for 16 hours, the reaction mixture was concentrated to half the volume, diluted to 10 mL (water), washed with DCM, acidified to pH˜2 with aq 3N HCl, and filtered to obtain the precipitated product: 1H NMR (300 MHz, DMSO-d6) δ 12.72 (s, 1H), 11.60 (s, 1H), 8.33 (d, J=7.7, 1H), 8.03-7.97 (m, 2H), 7.91 (ddd, J=8.2, 6.7, 4.0, 1H), 7.41 (s, 4H), 4.40 (q, J=7.1, 1H), 3.69 (s, 2H), 1.45 (d, J=7.1, 3H); MS (ESI+) M/Z 386 (M+H)+.
Reaction SMILES: C(O)(=O)C.C(O)C.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][NH:15][C:16](=[O:43])[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=O)[CH3:25])=[C:19]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:31][CH:30]=2)[CH:18]=1.C(OCC)(=O)C>CCOCC>[CH2:36]([O:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][N:27]2[C:19]3[CH:18]=[C:17]([C:16](=[O:43])[NH:15][CH2:14][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=4)[CH:22]=[CH:21][C:20]=3[N:23]=[C:24]2[CH3:25])=[CH:30][CH:31]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(=O)Nc1ccc(C(=O)NCc2ccccn2)cc1NCc1ccc(OCc2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1nc2ccc(C(=O)NCc3ccccn3)cc2n1Cc1ccc(OCc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 7 h
Yield: 89.8 %

Procedure:
Acetic acid (4 ml) and ethanol (8 ml) are added to an N-(2-pyridylmethyl)-4-acetylamino-3-(4-benzyloxybenzylamino)benzamide (0.434 g) and the solution is stirred for seven hours at 90° C. Residue is obtained by reduced pressure condensation. By adding ethyl acetate and ether to the residue, crystallization is performed. The crystals are separated through filtration, dried and thus, 1-(4-benzyloxybenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (0.375 g) is obtained. 1H-NMR (DMSO-d6, δ): 2.59 (3H, s), 4.78 (2H, d, J=4.8 Hz), 5.01 (2H, s), 5.31 (2H, s), 6.89 (2H, d, J=8.7 Hz), 6.99 (2H, d, J=8.6 Hz), 7.21 (1H, dd, J=5.1 and 7.4 Hz), 7.29-7.42 (6H, m), 7.62 (1H, br t), 7.65-7.75 (3H, m), 7.98 (1H, s), 8.57 (1H, d, J=4.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([OH:36])[CH:34]=5)[N:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:40][CH2:41][S:42]([CH3:45])(=[O:44])=[O:43].[Na+].[I-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH2:40][CH2:41][S:42]([CH3:45])(=[O:44])=[O:43])[CH:34]=5)[N:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc2nccc(Sc3ccc(Nc4nnc(-c5ccc(Cl)cc5)c5ccccc45)cc3)c2c1
Reactant: CS(=O)(=O)CCCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)CCOc1ccc2nccc(Sc3ccc(Nc4nnc(-c5ccc(Cl)cc5)c5ccccc45)cc3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-(4-(4-chlorophenyl)phthalazin-1-ylamino)phenylthio)quinolin-6-ol (0.062 g, 0.12 mmol) in THF at 0° C., was added NaH (0.018 g, 0.73 mmol). The mixture was stirred at 0° C. for 30 minutes. 1-Chloro-2-(methylsulfonyl)ethane (0.035 g, 0.24 mmol) and trace amount of NaI were added. The mixture was stirred and warmed to RT for 15 h. The reaction was quenched with sat. NH4Cl, and extracted with DCM. The combined organic layers were washed with brine, dried, filtered and concentrated. The crude product was purified via column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-50% (90:10:1 DCM/MeOH/NH4OH-DCM) to afford 4-(4-chlorophenyl)-N-(4-(6-(2-(methylsulfonyl)ethoxy)quinolin-4-ylthio)phenyl)phthalazin-1-amine as a light yellow solid. MS: m/z=[M+H]+. 614.0 Calc'd for C32H25ClN4O3S2: 613.1.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:43])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][S:32][CH2:33][CH2:34][CH2:35][C:36]([F:42])([F:41])[C:37]([F:40])([F:39])[F:38].[BH4-].[Na+]>O1CCCC1.C(O)C.O>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:43])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][S:32][CH2:33][CH2:34][CH2:35][C:36]([F:42])([F:41])[C:37]([F:38])([F:39])[F:40]
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCCC4CSCCCC(F)(F)C(F)(F)F)[C@H]3[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCCC4CSCCCC(F)(F)C(F)(F)F)[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
500 mg of 11β-fluoro-3-hydroxy-7α-{5-[2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-trien-17-one in 5 ml of tetrahydrofuran, 2.75 ml of ethanol and 1.1 ml of water, and 100 mg of sodium borohydride is added at a bath temperature of 0° C., and it is stirred for 0.5 hour at room temperature. Then, it is added to water, extracted 3 times with ethyl acetate, washed neutral with saturated common salt solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/methanol. 441.3 mg of 11β-fluoro-7α-{5-[2-(4,4,5,5,5-pentafluoropentylthiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol is obtained as crystals with a melting point of 174-176° C. [α]D22 =-14.9° (c=0.5% in pyridine).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7](CCC(O)=O)[NH:8]2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:22]1C[O:25][CH2:24][CH2:23]1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1cc2ccc(F)cc2[nH]1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCCc1c[nH]c2cc(F)ccc12
Temperature: 20 °C
Reaction time: 15 h
Yield: 65 %

Procedure:
To a solution of 3-(6-fluoroindolyl)propionic acid (235 mg, 1.13 mmol) in THF (5.3 mL) was added LiAlH4 (86 mg, 2.26 mmol) slowly at 0° C. under N1. The reaction mixture was warmed to 20° C. and stirred for 15 h. The reaction was quenched by addition of H2O (0.5 mL) and diluted with EtOAc. The resulting solution was dried over MgSO4, filtered through Celite and concentrated in vacuo. The residue was chromatographed to give 6-fluoro-3-(3-hydroxypropyl)indole (142 mg, 65%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C@H:13]1[O:18][C:16](=[O:17])[C@H:15]([CH:19]([CH3:21])[CH3:20])[CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Cl-].[Ca+2].[BH4-].[Na+].N>C(O)C.C1COCC1.C(OCC)C.C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C@@H:13]([OH:18])[CH2:14][C@@H:15]([CH:19]([CH3:20])[CH3:21])[CH2:16][OH:17])[CH2:22][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)OCc2ccccc2)OC1=O
Agent: N
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)[C@@H](CO)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To (2S,4S,5S) -5-benzyloxycarbonylamino-6-cyclohexyl-2-isopropyl-4-hexanolide (J. Med. Chem. 31, 1839-46 (1988), 3.88 g, 10.0 mmol) and CaCl2 (2.22 g, 20.0 retool) dissolved in a mixture of 60 mL ethanol and 60 mL THF and cooled to 0° C. was added portionwise NaBH4 (1.5 g, 40.0 mmol) resulting in vigorous gas evolution and an exotherm. The resulting solution was stirred at 0° C. for 1 hour and then at ambient temperature for 1 hour, diluted with 100 mL of diethyl ether and filtered through a plug of Celite®. The filtrate was cooled to 0° C. and quenched by the addition of 1M KHSO4 until bubbling ceased. The organic phase was washed with 2×20 mL of saturated NaHCO3 and 2×20 mL of saturated brine, dried (MgSO4) and concentrated in vacuo to a give a white solid. Recrystallization from EtOAc/hexanes gave 3.67 g (94%) of the (2S,3S,5S) -diastereomer. m.p. 113°-114° C. [α]25D =-32.0° (c=1.025, CHCl3). 1H NMR (C6D6, 300 MHz) δ0.76 (d, J=7.5Hz, 3H), 0.79 (d, J=7.5Hz, 3H), 0.75-1.74 (complex m, 18H), 1.98-2.09 (bd, J=11.1Hz, 1 H), 3.28-3.41 (m, 2H), 3.62-3.70 (m, 1H), 3.90-4.00 (m, 1H), 4.88 (d, J=9.6Hz, 1H), 5.12 (s, 2H), 7.00-7.30 (m, 5H). MS (DCI/NH3) 392 (M+H)+, 409 (M+NH4)+. Analysis calcd for C23H37NO4 : C, 70.55; H, 9.52; N, 3.58. Found: C, 70.78; H, 9.54; N, 3.56.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl.[C:17]1([C:23]2[N:27]=[C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:25][N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[NH:7][C:8]([N:31]1[CH2:32][CH2:33][N:28]([C:26]2[S:25][N:24]=[C:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:27]=2)[CH2:29][CH2:30]1)=[O:15]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: Cn1ncc(Br)c1NC(=O)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Br)c1NC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 70 °C
Reaction time: 15.5 h
Yield: 69.6 %

Procedure:
A mixture of 2,2,2-trichloroethyl (4-bromo-1-methyl-1H-pyrazol-5-yl)carbamate (289 mg, 0.822 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (184 mg, 0.747 mmol) and diisopropylethylamine (0.143 ml, 0.822 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 15.5 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 233 mg (69.7%) of the desired product as a solid.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]3[CH2:16][C:15](=[N:17][OH:18])[CH2:14]3)[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.B.N1C=CC=CC=1.Cl.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]3[CH2:16][CH:15]([NH:17][OH:18])[CH2:14]3)[CH:10]=[CH:11][CH:12]=2)=[CH:19][CH:20]=1
Reactant: ON=C1CC(c2cccc(Oc3ccc(F)cc3)c2)C1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Product: ONC1CC(c2cccc(Oc3ccc(F)cc3)c2)C1
Reaction time: 0.5 h

Procedure:
To a solution of 3-(3-(4-fluorophenoxy)phenyl)cyclobutanone oxime from above, in ethanol (50 mL) was added borane.pyridine (2.06 g, 22.2 mmol) and the resulting solution was stirred for 30 min. 6N aqueous HCl (5.05 mL, 30.3 mmol) was then added dropwise and the reaction was stirred for 30 min. It was then neutralized by the addition of 2N aqueous NaOH and the ethanol evaporated in vacuo. The resulting residue was further diluted with brine to a volume of approximately 50 mL and extracted with ethyl acetate (3×50 mL). The organics were combined, dried over MgSO4 and concentrated to afford 3-(3-(4-flurophenoxy)phenyl)-1-cyclobutylhydroxylamine which was used as is.
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11](=[S:13])[NH:10][C:9](=[O:14])[C:8]=2[CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:16]([CH2:24][CH2:25][CH2:26][CH2:27]C1C=C(S([O-])(=O)=O)C=CC=1C)[Si](C(C)(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[OH:16][CH2:24][CH2:25][CH2:26][CH2:27][N:12]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:8]([CH3:15])[C:9](=[O:14])[NH:10][C:11]1=[S:13]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1CCCCO[Si](C)(C)C(C)(C)C
Reactant: Cc1c(-c2ccccc2)[nH]c(=S)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)n(CCCCO)c(=S)[nH]c1=O
Reaction time: 1.5 h
Yield: 4.1 %

Procedure:
To 2 ml of dimethyl sulfoxide, 468 mg (2.0 mmol) of 6-phenythiothymine, 358 mg (1.0 mmol) of 4-(t-butyldimethylsiloxy)-butyl-p-toluenesulphonate and 276 mg (2.0 mmol) of potassium carbonate were added and heated to react for 4 hours at 80° C. The reaction mixture was concentrated under reduced pressure, added with methanol and filtered. The filtrate was concentrated under reduced pressure, added with 20 ml of tetrahydrofuran and 1 ml of 1N hydrochloric acid and stirred for 90 minutes. The reaction mixture was concentrated under reduced pressure and adsorbed on a silica gel column and eluted with 2% methanol/chloroform The eluate was concentrated and crystallized from acetone/hexane to obtain 12.0 mg of the target compound (Yield: 4%).
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH3:21])[C:14]#[N:15])[CH3:9].CO.C([O-])([O-])=O.[Na+].[Na+].[N:30]1[CH:35]=[CH:34][C:33]([C:36]([NH:38][NH2:39])=O)=[CH:32][CH:31]=1>CCOCC>[CH2:8]([O:10][C:11]1[CH:12]=[C:13]([C:14]2[NH:15][C:36]([C:33]3[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=3)=[N:38][N:39]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH3:21])[CH3:9]
Reactant: CCOc1ccc(C#N)cc1OCC
Reactant: NNC(=O)c1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOc1ccc(-c2nnc(-c3ccncc3)[nH]2)cc1OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Cold 4M HCl in dioxane (31.5 mmol, 8.87 mL) was added to a stirred solution of 3,4-diethoxybenzonitrile (7.84 mmol, 1.5 g) in anhydrous MeOH (23.53 mmol, 954 μl) and anhydrous ether (4 mL). The reaction was stirred at 0° C. for 1 h and then placed in the refrigerator (0-5° C.) for 48 h. The mixture was bubbled with N2 to eliminate HCl and concentrated under reduced pressure. To the crude was added anhydrous ether and the methyl 3,4-diethoxybenzimidate salt precipitated as pale orange solid in 63% yield (1.3 g). The product was used without further purification. To a stirred solution of the imidine (0.5 mmol, 130 mg) (freshly liberated from the imidate salt using a solution 1M of Na2CO3 and extracted with ether) in acetonitrile was added pyridine-4-carbohydrazide (0.55 mmol, 75.5 mg) and the reaction was refluxed for 2 h. The mixture was concentrated under reduced pressure and the crude was heated at 180° C. for 2 h. The product was purified by column chromatography using CH2Cl2:MeOH (9:1) to offer the product as a white solid in 65% yield (100 mg, 0.32 mmol). 1H NMR (400 MHz, CDCl3): δ8.71 (bs, 2H), 8.11 (d, J=5.2 Hz, 2H), 7.60 (s, 1H), 7.57 (d, J=8.4 Hz, 1H), 6.90 (d, J=8.4, 1H), 4.11 (q, J=6.8 Hz, 2H), 4.07 (q, J=6.8 Hz, 2H), 1.45 (t, J=7.0 Hz, 3H), 1.40 (t, J=7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 157.73, 150.89, 149.42, 149.14, 139.66, 121.29, 120.56, 120.06, 119.68, 113.00, 111.53, 64.82, 64.72, 14.90, 14.86. MS (EI) m/z: 311 (M+), HRMS (EI) for C17H18N4O2 (M+): calcd 311.1502, found 311.1506.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][O:12][C:13](=[O:21])[CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH3:11][O:12][C:13](=[O:21])[CH2:14][CH:15]1[CH2:16][CH2:17][N:18]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:19][CH2:20]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COC(=O)CC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)CC1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 120 °C

Procedure:
To a mixture of 2-chloro-5-nitropyridine (476 mg, 3.0 mmol) and 4-piperidine acetic acid methyl ester (471 mg, 3.0 mmol) in tetrahydrofuran (10 mL) was added diisopropylethylamine (1.0 mL, 5.74 mmol). The mixture was heated in a microwave at 120° C. for 30 minutes. The mixture was evaporated to dryness and extracted with ethyl acetate and water. The organic layer was dried over sodium sulfate and solvents were evaporated. The residue was purified using flash chromatography (eluting with ethyl acetate and hexanes) to give (5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid methyl ester as a yellow solid. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[C:8](=[C:21]([NH:32][CH:33]4[CH2:38][CH2:37][N:36]([S:39]([NH2:42])(=[O:41])=[O:40])[CH2:35][CH2:34]4)[N:22](COCC[Si](C)(C)C)[N:23]=3)[N:9]=[C:10]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[C:11]=2[CH:12]=1)#[N:2].C(Cl)Cl.C(O)(C(F)(F)F)=O.N>O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[NH:23][N:22]=[C:21]([NH:32][CH:33]4[CH2:34][CH2:35][N:36]([S:39]([NH2:42])(=[O:41])=[O:40])[CH2:37][CH2:38]4)[C:8]=3[N:9]=[C:10]([C:13]3[C:14]([F:20])=[CH:15][CH:16]=[CH:17][C:18]=3[F:19])[C:11]=2[CH:12]=1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1nc2c(nc(-c3c(F)cccc3F)c3cc(C#N)ccc32)c1NC1CCN(S(N)(=O)=O)CC1
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: N#Cc1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(NC3CCN(S(N)(=O)=O)CC3)n[nH]c12
Temperature: 0 °C
Reaction time: 16 h

Procedure:
306 mg of 4-{[7-cyano-5-(2,6-difluorophenyl)-2-{[2-(trimethylsilyl)ethoxy]methyl}-2H-pyrazolo[4,3-c]isoquinolin-3-yl]amino}piperidine-1-sulphonamide are introduced into 20 ml of DCM. After cooling to 0° C. using an ice bath, 1.5 ml of TFA are added and the mixture is stirred at RT for 16 h. It is concentrated under RP and the solid obtained is taken up in 30 ml of water, neutralized with 2 ml of 7.5M aqueous ammonia solution. It is extracted with ethyl acetate, dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a DCM/methanol/NH4OH mixture (92.5/7.5/0.75 by volume). This gives 8 mg of 4-{[7-cyano-5-(2,6-difluorophenyl)-1H-pyrazolo[4,3-c]isoquinolin-3-yl]amino}piperidine-1-sulphonamide. 1H NMR: 1.61-1.73 (m, 2 H) 2.09 (m, 2 H) 2.63-2.72 (m, 2 H) 3.47 (m, 2 H) 3.67-3.76 (m, 1 H) 6.13 (d, J=7.0 Hz, 1 H) 6.70 (s, 2 H) 7.34 (t, J=7.8 Hz, 2 H) 7.65-7.74 (m, 1 H) 8.18 (broad s, 1 H) 8.28 (broad d, J=8.6 Hz, 1 H) 8.56 (d, J=8.6 Hz, 1 H) 13.05 (s, 1 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[NH:5][C:4]([CH3:10])(N)[N:3]=1.[O-]CC.[Na+].[Na].Cl.C(N)(=N)C.C(OCC)(=O)CC(OCC)=O>C(O)C>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([CH3:10])[N:3]=1
Reactant: CC1(N)N=C(O)C=C(O)N1
Agent: CC(=N)N
Agent: CC[O-]
Agent: Cl
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CCO
Product: Cc1nc(O)cc(O)n1
Reaction time: 3.5 h

Procedure:
The first intermediate, 4,6-dihydroxy-2-methylpyrimidinamine, is synthesized by preparing sodium ethoxide in situ from sodium and an hydrous ethanol under a nitrogen blanket. Acetamidine hydrochloride and diethyl malonate are added and the reaction mixture heated to boiling for 2 to 5 hours to afford 4,6-dihydroxy-2-methylpyrimidine.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.Cl.[CH3:27][C@@H:28]1[CH2:32][CH2:31][C@@H:30]([CH3:33])[NH:29]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[CH3:27][C@@H:28]1[CH2:32][CH2:31][C@@H:30]([CH3:33])[N:29]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: C[C@@H]1CC[C@@H](C)N1
Reactant: O=C(c1ccc(-c2ccc(OCCCCl)cc2)cc1)N1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCC(C)=O
Product: C[C@@H]1CC[C@@H](C)N1CCCOc1ccc(-c2ccc(C(=O)N3CCOCC3)cc2)cc1
Temperature: 25 °C
Yield: 70 %

Procedure:
The product from Example 10E (30 mg, 0.084 mmol), (2R,5R)-2,5-dimethylpyrrolidine hydrochloride (50 mg, 0.5 mmol) (purchased from Toronto Research Chemicals, TRC), 75 mg of potassium carbonate and 75 mg of potassium iodide in 5 mL of 2-butanone were heated at 80° C. for 72 hours. The mixture was allowed to cool to ambient temperature, filtered and the filtrate was evaporated under reduced pressure. The residue was purified by HPLC chromatography (C18 reverse phase Water's 25 mm module prep column, 10 to 95% acetonitrile/0.1% TFA in water, 10 minute linear gradient, flow rate 40 mL/minute) to provide the title compound (70% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:35][CH3:36])=[C:5]([CH:32]=[CH:33][CH:34]=1)[C:6]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1>ClCCl>[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50]([O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:5]2[CH:32]=[CH:33][CH:34]=[C:3]([O:2][CH3:1])[C:4]=2[O:35][CH3:36])(=[O:52])=[O:51])=[CH:46][CH:45]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cccc(C(OCCOCCOCCOCCO)(c2ccccc2)c2ccccc2)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(OCCOCCOCCOCCOS(=O)(=O)c2ccc(C)cc2)(c2ccccc2)c2ccccc2)c1OC
Temperature: 0 °C

Procedure:
Compound 2 (5.0 g, 10.06 mmol) was dissolved in 50 mL of anhydrous dichloromethane and cooled to 0° C. Triethylamine (1.82 mL, 13.1 mmol) was added, followed by p-toluenesulfonyl chloride (1.92 g, 10.06 mmol) as a solid, with stirring. The reaction was stored in the refrigerator overnight. TLC Analysis indicated the reaction was approximately 80% complete. An additional 0.5 equivalents of triethylamine and 0.5 equivalents of p-toluenesulfonyl chloride were added, and the reaction was stirred at room temperature overnight. The reaction was filtered through Celite and concentrated. The residue was purified by flash chromatography using 300 mL of silica gel (wet-packed onto column using 5% triethylamine in hexane) eluting with 25-50-75% ethyl acetate in hexane containing 5% triethylamine, and then ethyl acetate containing 5% triethylamine. 5.7 g (87%) of 3 was collected as an orange oil. 1H NMR (300 MHz, CDCl3) d 7.75 (d, 2H), 7.44-7.12 (m, 11H), 6.78 (d, 4H), 4.12-4.09 (m, 2H), 3.73 (s, 6H), 3.66-3.54 (m, 13H), 3.22 (t, J=3.87 Hz, 2H), 2.41 (s, 3H).