Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.[Li]CCCC.[CH2:16]([CH:19]1[CH2:24][CH2:23][CH:22]([CH:25]2[CH2:32][C:27]3([CH2:30][C:29](=O)[CH2:28]3)[CH2:26]2)[CH2:21][CH2:20]1)[CH2:17][CH3:18]>C1COCC1>[CH2:16]([CH:19]1[CH2:20][CH2:21][CH:22]([CH:25]2[CH2:32][C:27]3([CH2:30][C:29](=[C:3]4[S:8][CH2:7][CH2:6][CH2:5][S:4]4)[CH2:28]3)[CH2:26]2)[CH2:23][CH2:24]1)[CH2:17][CH3:18]
Reactant: CCCC1CCC(C2CC3(CC(=O)C3)C2)CC1
Reactant: C[Si](C)(C)C1SCCCS1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC1CCC(C2CC3(CC(=C4SCCCS4)C3)C2)CC1
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
15.5 g (80.3 mmol) of 2-trimethylsilyl-1,3-dithiane are dissolved in 150 ml of THF, and 51 ml (80.3 mmol) of n-BuLi (15 percent in hexane) are rapidly added dropwise at −70° C. The batch is subsequently allowed to thaw to 0° C. over the course of 4 hours, stirred for 10 minutes without cooling and re-cooled to −70° C., and a solution of 17.0 g (72.5 mmol) of 6-(4-n-propylcyclohexyl)spiro[3.3]heptan-2-one 5 in 50 ml of THF is added drop-wise. The batch is left to stir overnight at room temperature, hydrolysed using saturated sodium hydrogencarbonate solution and extracted with dichloromethane. The combined organic phases are washed with water and dried over sodium sulfate. The solvent is removed under reduced pressure, and the crude product is recrystallised from n-heptane. The dithioacetal 6 is obtained as colourless flakes.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18]([S:23][CH3:24])=[N:19][CH:20]=2)[NH:15][C:14]1=[O:25].[CH2:26]([O:28][C:29]([CH:31]1[CH2:36][CH2:35][CH:34](O)[CH2:33][CH2:32]1)=[O:30])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH2:26]([O:28][C:29]([CH:31]1[CH2:36][CH2:35][CH:34]([N:15]2[C:16]3=[N:17][C:18]([S:23][CH3:24])=[N:19][CH:20]=[C:21]3[CH2:22][N:13]([C:3]3[C:2]([F:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=3[F:12])[C:14]2=[O:25])[CH2:33][CH2:32]1)=[O:30])[CH3:27]
Reactant: COc1cc(OC)c(F)c(N2Cc3cnc(SC)nc3NC2=O)c1F
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(N2C(=O)N(c3c(F)c(OC)cc(OC)c3F)Cc3cnc(SC)nc32)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
To a 250-mL dry, round-bottomed flask was added 3-(2,6-Difluoro-3,5-dimethoxy-phenyl)-7-methylsulfanyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidine (1.5 g, 4.08 mmol), ethyl-4-hydroxycyclohexanecarboxylate (2.11 g, 12.23 mmol), triphenylphosphine (3.21 g, 12.23 mmol), and tetrahydrofuran (50 mL), and the solution was blanketed with a nitrogen atmosphere. The solution was then cooled to 0° C., and diisopropylazodicarboxylate (2.41 mL, 12.23 mmol) was added dropwise. The solution was then warmed to room temperature and stirred overnight. The crude mixture was then concentrated in vacuo and taken up in dichloromethane, washed with water, dried over sodium sulfate, and concentrated. The crude was purified by flash silica chromatography eluting with 3:2 hexane/ethyl acetate to yield the title compound (1.17 g, 55% yield): LRMS: 523.2 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]3[NH:13][C:14](=[O:19])[O:15][C:16]([CH3:18])([CH3:17])[C:11]=3[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:22][N:23](C=O)C>[C-]#N.[Zn+2].[C-]#N.[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>[CH3:17][C:16]1([CH3:18])[O:15][C:14](=[O:19])[NH:13][C:12]2[CH:20]=[CH:21][C:9]([C:4]3[CH:3]=[C:2]([CH:7]=[C:6]([F:8])[CH:5]=3)[C:22]#[N:23])=[CH:10][C:11]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(Br)c3)cc21
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21
Temperature: 85 °C

Procedure:
A mixture of 6-(3-bromo-5-fluorophenyl)-4,4-dimethyl-2H-benz[d][1,3]oxazin-2-one (1 g, 2.8 mmol), zinc cyanide (0.2 g, 1.7 mmol), and tetrakis(triphenylphosphine)-palladium (0) (0.2 g, 0.17 mmol) in dry DMF (20 mL) was degassed to remove oxygen and was then heated at 85° C. under a blanket of nitrogen for 6.5 hours. The reaction solution was cooled to room temperature and poured onto a cold saturated aqueous ammonium chloride solution (100 mL). The white precipitate appeared and was collected on a filter. The white solid was washed with distilled water (3×20 mL) and dissolved in a mixture of ethyl acetate (10 mL) and methanol (10 mL). The solution was applied on a pad of silica gel and eluted with a mixture of ethyl acetate and hexane (1:1). After solvent was removed, 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluorobenzonitrile was obtained as a white solid (0.7 g, 84%): mp 253-254° C.; 1H-NMR (DMSO-d6) δ 10.4 (s, 1H, D2O exchangeable), 8.13 (s, 1H), 7.92 (m, 1H), 7.82 (m, 1H), 7.73 (m, 2H), 6.98 (d, 1H, J=8.2 Hz), 1.68 (s, 6H); 19F-NMR (DMSO-d6) 5-112.25 (m, 1F); MS (EI) m/z 296 (M+, 65%); Anal. Calcd. For C17H13FN2O2: C, 68.91; H, 4.42; N, 9.45. Found: C, 68.85; H, 4.58; N, 9.14.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(NC(C)C)(C)C.[CH3:42][O:43][C:44](=[O:62])[CH2:45][C:46]1[C:47]([CH3:61])=[N:48][N:49]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([NH2:59])=[CH:55][C:54]=2[F:60])[C:50]=1[CH3:51].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:42][O:43][C:44](=[O:62])[CH2:45][C:46]1[C:47]([CH3:61])=[N:48][N:49]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([NH:59][C:10]([C:2]3[NH:1][C:9]4[C:4]([CH:3]=3)=[CH:5][CH:6]=[CH:7][CH:8]=4)=[O:12])=[CH:55][C:54]=2[F:60])[C:50]=1[CH3:51]
Reactant: COC(=O)Cc1c(C)nn(Cc2ccc(N)cc2F)c1C
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nn(Cc2ccc(NC(=O)c3cc4ccccc4[nH]3)cc2F)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.3 %

Procedure:
To a solution of indole-2-carboxylic acid (80 mg, 0.50 mmol) in N,N-dimethylformamide (1.5 mL) are added TBTU (139 mg, 0.43 mmol) and N,N-diisopropyl amine (0.126 mL, 0.74 mmol). Subsequently [1-(4-amino-2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl]acetic acid methyl ester (120 mg, 0.41 mmol) is added. The mixture is stirred at room temperature for 12 hours. After that an aqueous solution of K2CO3 (2 M, 0.5 mL) is added. The obtained mixture is flushed through Al2O3 with dichloromethane/methanol (9:1, 10 mL). The solvent is removed in vacuo to yield 82.3 mg of (1-(2-fluoro-4-[(1H-indole-2-carbonyl)amino]benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester (ESI mass spectrum: [M+H]+=435; Retention time HPLC: 0.41 min (method N). b) (1-(2-Fluoro-4-[(1H-indole-2-carbonyl)amino]benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid methyl ester (82 mg, 0.19 mmol) is dissolved in methanol (0.5 mL). An aqueous solution of NaOH (4M, 0.3 mL) is added and the mixture is stirred at room temperature for 2 hours. The resulting mixture is diluted with methanol/water, the solid is filtered off and after evaporation the residue is purified by HPLC (Gilson, XRS Pursuit, methanol/H2O+0.1% conc. NH3). The fractions containing the title compound are concentrated and lyophilized to yield 15 mg of the title compound (ESI mass spectrum: [M+H]+=421; Retention time HPLC: 1.04 min (method G)).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:57]=[CH:56][C:12]([C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:48][C:49]([O:51]C(C)(C)C)=[O:50])[C:24](=[O:47])[C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:46])[CH2:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=4[C:42]([F:45])([F:44])[F:43])=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:48][C:49]([OH:51])=[O:50])[C:24](=[O:47])[C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:46])[CH2:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=4[C:42]([F:44])([F:45])[F:43])=[CH:27][CH:26]=3)=[CH:20][CH:21]=2)=[O:14])=[CH:56][CH:57]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4C(F)(F)F)cc3)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)O)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4C(F)(F)F)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
Prepared using General Procedures 8: To 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-6 (555 mg, 0.702 mmol) in DCM (3 mL) was added TFA (3 mL). The reaction was stirred at room temperature for 2 h then purified by chromatography (EA/hexanes+1% acetic acid) to provide 385 mg (74%) of 2-(N-(4-((4-(heptyloxy)benzoyl)oxy)benzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetic acid 3. LCMS-ESI (m/z) calculated for C40H41F3N2O8: 734; no m/z observed, tR=11.42 min (Method 2). 1H NMR (400 MHz, DMSO) δ 12.83 (s, 1H), 10.35 (s, 1H), 8.14-8.01 (m, 2H), 7.65 (d, J=8.3 Hz, 2H), 7.54-7.29 (m, 5H), 7.29-7.16 (m, 4H), 7.14-7.01 (m, 2H), 4.69 (s, 1H), 4.61 (s, 1H), 4.08 (t, J=6.5 Hz, 2H), 4.00 (s, 1H), 3.94 (s, 1H), 3.86 (s, 2H), 3.83 (s, 3H), 1.81-1.68 (m, 2H), 1.48-1.22 (m, 8H), 0.92-0.81 (t, J=6.8 Hz, 3H).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[NH2:6][C:7]1[CH:15]=[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][N:9]2[N:8]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[NH2:6][C:7]1[C:15]([Cl:4])=[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][N:9]2[N:8]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Nc1cc2n(n1)CCCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Nc1nn2c(c1Cl)CCCC2
Reaction time: 1 h

Procedure:
5 g (37 mmol) sulfuryl chloride was added dropwise to 5.08 g (37 mmol) 2-amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine, dissolved in 30 ml methylene chloride, with ice-cooling. The mixture was stirred for 1 hour, then added to saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated. Purification was carried out by silica gel column chromatography to ethyl acetate/hexane).
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([C:21]4([CH2:25][C:26]#[N:27])[CH2:24][NH:23][CH2:22]4)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.C(N(CC)C(C)C)(C)C.[CH:39]1([S:42](Cl)(=[O:44])=[O:43])[CH2:41][CH2:40]1>O1CCCC1>[CH:39]1([S:42]([N:23]2[CH2:22][C:21]([CH2:25][C:26]#[N:27])([N:19]3[CH:20]=[C:16]([C:15]4[C:10]5[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:28])([CH3:1])[CH3:29])[C:11]=5[N:12]=[CH:13][N:14]=4)[CH:17]=[N:18]3)[CH2:24]2)(=[O:44])=[O:43])[CH2:41][CH2:40]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(S(=O)(=O)C5CC5)C4)c3)ncnc21
Temperature: 2.5 °C
Reaction time: 0.17 h
Yield: 81.4 %

Procedure:
To a oven dried 2 L round bottom flask equipped with the overhead stirring, a nitrogen inlet, a septa and a thermocouple was charged anhydrous tetrahydrofuran (THF, 800 mL), {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (16, 38.6 g, 94.2 mmol) and N,N-diisopropylethylamine (DIEA, 22.0 mL, 126 mmol, 1.34 equiv) at room temperature. The resulting solution was then cooled to 0-5° C. before being charged with cyclopropanesulfonyl chloride (14.3 mL, 134 mmol, 1.42 equiv) portion wise over eight minutes via syringe at 0-5° C. After 10 minutes, the ice bath was removed and the reaction mixture was allowed to warm gradually to room temperature. When HPLC showed that the reaction was complete after 22 h, the reaction mixture was concentrated under reduced pressure to remove about 400 mL of solvent. The residue was treated with ethyl acetate (EtOAc, 500 mL) and the resulting solution was washed with 20% aqueous sodium chloride solution (NaCl, 300 mL). The aqueous layer was back extracted with ethyl acetate (EtOAc, 150 mL). The combined organic fractions were dried over magnesium sulfate (MgSO4) and concentrated under reduced pressure to yield the crude product (25) as an amber oil. The crude product was then purified by flash column chromatography (SiO2, 50% to 70% ethyl acetate/hexane gradient elution) to afford {1-(cyclopropylsulfonyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (25, 39.4 g, 48.4 g theoretical, 81.4% yield) as a light yellow oil, which solidified upon standing at room temperature in vacuum. For 25: 1H NMR (DMSO-d6, 300 MHz) δ 8.98 (s, 1H), 8.78 (s, 1H), 8.50 (s, 1H), 7.81 (d, 1H, J=3.8 Hz), 7.20 (d, 1H, J=3.6 Hz), 5.63 (s, 2H), 4.66 (d, 2H, J=9.5 Hz), 4.28 (d, 2H, J=9.3 Hz), 3.69 (s, 2H), 3.52 (t, 2H, J=7.8 Hz), 2.84 (m, 1H), 1.01 (m, 4H), 0.82 (t, 2H, J=8.4 Hz), −0.12 (s, 9H) ppm; C23H31N7O3SSi (MW, 513.69), LCMS (EI) m/e 514 (M++H) and 536 (M++Na).
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[P:27](OCl)([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[O:28]>C1COCC1>[C:1]([CH:3]([P:27]([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[O:28])[N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2]
Reactant: CCOP(=O)(OCl)OCC
Reactant: CC(C)(C)OC(=O)N1CCN(CC#N)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(C#N)N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
In a 100 ml 3 necked round bottom flask, intermediate tert-butyl 4-(cyanomethyl)piperazine-1-carboxylate (7 g) was taken in dry THF (125 ml) under nitrogen. lithium bis trimethylsilyl amide (10.8 g) was added dropwise at −78° C. and stirred for 1 hr, then diethyl chloro phosphate (5.84 g) in 5 ml dry THF was added drop wise to the above reaction mixture. Reaction mixture was stirred at −78° C. for 1 hour. TLC was checked no starting material and the reaction mixture was quenched with saturated ammonium chloride (250 ml) and ethyl acetate was added. The organic layer was washed with brine, dried and concentrated. The crude product was purified by column chromatography using 230-400 silica gel 2.5% methanol\chloroform as eluent to give compound tert-butyl 4-(cyano(diethoxyphosphoryl)methyl)piperazine-1-carboxylate as yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH3:12])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.[CH2:15](Br)[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:17]([N:10]1[C:9]2[C:8](=[O:11])[N:7]([CH3:12])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=[C:2]1[Cl:1])[CH:16]=[CH2:15]
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2c1c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione (10.7 g), allyl bromide (5.2 ml), anhydrous potassium carbonate (10.3 g), and N,N-dimethylformamide (75 ml) was stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate and water, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered through a small amount of silica gel. The silica gel was washed with ethyl acetate, and the eluate was concentrated under reduced pressure. Recrystallization of the residue from ethyl acetate (50 ml) and hexane (100 ml) gave 10.57 g of the title compound.
Reaction SMILES: [C:1]1([CH3:52])[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH2:11][CH2:12][CH2:13][N:14]([S:42]([C:45]2[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=2)(=[O:44])=[O:43])[CH2:15][CH2:16][N:17]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH2:18][CH2:19][CH2:20][NH:21][S:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Na+]>CN(C=O)C>[C:28]1([CH3:31])[CH:29]=[CH:30][C:25]([S:22]([N:21]2[CH2:20][CH2:19][CH2:18][N:17]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[CH2:16][CH2:15][N:14]([S:42]([C:45]3[CH:46]=[CH:47][C:48]([CH3:51])=[CH:49][CH:50]=3)(=[O:44])=[O:43])[CH2:13][CH2:12][CH2:11][N:10]([S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:52])=[CH:2][CH:3]=3)(=[O:8])=[O:9])[CH2:19][CH2:18][N:17]([S:32]([C:35]3[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=3)(=[O:34])=[O:33])[CH2:16][CH2:15]2)(=[O:24])=[O:23])=[CH:26][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)NCCCN(CCN(CCCNS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a stirred solution of 1,5,8,12-tetra(p-toluenesulfonyl)-1,5,8,12-tetraazadodecane prepared as in Example 11A (36.9 g, 0.0467 mole) in anhydrous DMF (470 ml) was added sodium hydride (2.80 g-80% in mineral oil, 0.0933 mole) in portions under a dry nitrogen blanket. The resulting mixture was stirred for 30 minutes under. a dry argon atmosphere. The solution was then heated to 100° C. and a solution of 3-(p-toluenesulfonyl)-3-azapentane-1,5-di-p-toluenesulfonate prepared as in Example 11B (26.5 g, 0.0467 mole) in anhydrous DMF (230 mole) was added dropwise over a 3 h period, maintaining the temperature at 100° C. After stirring the solution an additional 1 h at 100° C., the mixture was concentrated in vacuo to a volume of 400 ml. H2O (1.5 l) was slowly added at room temperature to crystallize the product. The resulting pale yellow solid was filtered, washed thoroughly with H2O and dried in vacuo. The crude product was purified by recrystallization from CH2Cl2 -hexane to give 26.3 g (55% yield) of the product as a white crystalline solid: mp 235.5°-6.5° C. (dec.); 1H NMR (CDCl3) δ 2.09 (quint, J=6.6 Hz, 4H), 2.44 (s, 6H), 2.45 (s, 6H), 2.46 (s, 3H), 3.04 (t, J=7.5 Hz, 4H), 3.13 (t, J=7.1 Hz, 4H), 3.23 (m, 8H), 3.45 (m, 4H), 7.33 (m, 10H), 7.72 (m, 10H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[NH:4][N:3]=1.[O:17]1[CH2:21][CH2:20][C:19](B2OC(C)(C)C(C)(C)O2)=[CH:18]1>>[O:17]1[CH2:21][CH2:20][C:19]([C:2]2[C:10]3[C:5](=[CH:6][N:7]=[C:8]([C:11]4[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=4)[CH:9]=3)[NH:4][N:3]=2)=[CH:18]1
Reactant: Ic1n[nH]c2cnc(-c3cccnc3)cc12
Reactant: CC1(C)OB(C2=COCC2)OC1(C)C
Product: C1=C(c2n[nH]c3cnc(-c4cccnc4)cc23)CCO1
Yield: 40 %

Procedure:
Following the procedures Example 281, 3-iodo-5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridine from Example 4 and 2-(4,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were reacted to give 284 as a white solid (0.1 g, 40%). 1H NMR (400 MHz, DMSO): δ 9.42 (s, 1H), 9.09 (s, 1H), 8.56-8.57 (m, 2H), 8.51 (s, 1H), 7.86 (s, 1H), 7.47-7.49 (m, 1H), 4.46-4.50 (m, 2H), 3.12-3.14 (m, 2H). ESI MS m/z=265 (M+1)
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[C:9]([OH:20])=[C:10]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:11]([O:13][CH3:14])=[O:12].C(N(CC)CC)C>ClCCl>[CH3:6][O:7][C:8]1[C:9]([O:20][S:2]([CH3:1])(=[O:4])=[O:3])=[C:10]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(OC)c(OC)c1O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)c(OC)c1OS(C)(=O)=O
Temperature: 25 °C

Procedure:
Methanesulfonyl chloride (634 Π, 0.008 mol) was added dropwise to an ice-cooled solution of methyl 3,4-dimethoxy-2-hydroxybenzoate (1.58 g, 0.0075 mol) and triethylamine (1.27 ml, 0.009 mol) in dichloromethane (30 ml) and the reaction then allowed to warm to room temperature, with stirring. The reaction mixture was washed with water (2×25 ml) and the organic layer dried (MgSO4), filtered and evaporated under reduced pressure. The crude product was purified on silica gel eluting with a solvent gradient of diethyl ether:hexane (60:40 to 100:0, v/v) to give the subtitle compound as a colourless oil that crystallised on standing (1.94 g, 90%). MS m/z 308 (MNH4)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[O:25][CH2:24][CH:23]=[CH:22][C:17]4=3)[NH:12][C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[O:28]([CH2:35][CH2:36][CH2:37][CH2:38]Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:21][CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[O:25][CH2:24][CH:23]=[CH:22][C:17]4=3)[N:12]([CH2:38][CH2:37][CH2:36][CH2:35][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=Cc2c(ccc3[nH]c4c(c23)CCN(Cc2ccccc2)CC4)OC1
Reactant: BrCCCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C1=Cc2c(ccc3c2c2c(n3CCCCOc3ccccc3)CCN(Cc3ccccc3)CC2)OC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 28.7 %

Procedure:
To a solution containing the compound of Example 3 (0.08 g., 0.24 mmol) in N,N-dimethylformamide (5.00 mL) was added sodium hydride (0.011 g., 60% in oil, 0.29 mmol) at 0° C. The mixture was stirred at room temperature for 20 minutes, then cooled to 0° C. 4-Phenoxybutyl bromide (0.072 g., 0.32 mmol) was added to the mixture, the resulting mixture was stirred at room temperature for 16 hours. Water and ethyl acetate then were added to the mixture, and the organic and aqueous phases were separated. The aqueous layer then was extracted with ethyl acetate (2×). The combined ethyl acetate solution was dried (MgSO4) and filtered. The filtrate was concentrated in vacuo. The residue was subjected to preparative thin layer chromatography (silica gel, 50% EtOAc/hexane) to yield the alkylated compound (0.033 g, 29%) as a light yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.42, 7.13, 7.03, 6.95, 6.87, 6.71, 5.81, 4.69-4.67, 4.09, 3.93, 3.75, 3.17-3.14, 2.97-2.94, 1.87-1.76; MS (ESI+) m/z 479 (M++1).
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH2:20]([S:27](Cl)(=[O:29])=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][S:27]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:29])=[O:28])=[CH:10][CH:11]=1
Reactant: NCc1ccc(OC(F)F)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(Cc1ccccc1)NCc1ccc(OC(F)F)cc1
Reaction time: 3 h
Yield: 92.2 %

Procedure:
4-(Difluoromethoxy)benzyl amine (1.73 g, 9.97 mmol) was dissolved in THF (10 mL). It was cooled in an ice-bath. Under nitrogen atmosphere, triethylamine (1.46 mL, 10.46 mmol) was added and then benzylsulfonyl chloride (1.9 g, 9.97 mmol) in THF (10 mL) was dropped in. The cooling bath was removed after the addition. The mixture was stirred for 3 h and then evaporated to dryness. DCM (50 mL) was added to the residue. It was then washed with 1% HCl (15 mL), water (50 mL×3) and brine, dried (MgSO4) and evaporated to give the title compound (3.01 g. 92%) as a solid; 1H NMR (400 MHz, CDCl3): δ 7.32-7.40 (m, 5H), 7.26 (d, 2H), 7.09 (d, 2H), 6.49 (t, 1H), 4.36 (bt, 1H), 4.24 (s, 2H), 4.10 (d, 2H); Mass Spectrum: M−H+ 326.