Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:15]=3)[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[CH:30]1([CH:33]=O)[CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.Cl>ClCCCl>[CH2:16]([N:14]1[CH:15]=[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[NH:1][CH2:33][CH:30]2[CH2:32][CH2:31]2)[N:12]=[N:13]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(-c3cn(Cc4ccccc4)nn3)ccc21
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: c1ccc(Cn2cc(-c3ccc4[nH]nc(NCC5CC5)c4c3)nn2)cc1
Reaction time: 16 h

Procedure:
A mixture of Example 64A (100 mg, 0.256 mmol), cyclopropanecarbaldehyde (0.057 mL, 0.76 mmol), sodium triacetoxyborohydride (163 mg, 0.76 mmol) and acetic acid (0.044 mL, 0.76 mmol) in 1,2-dichloroethane (5 mL) was stirred at ambient temperature for about 2.5 hours. Hydrochloric acid (4 N in dioxane, 4 mL) was added and the reaction mixture was stirred for about 16 hours. The precipitate was collected by filtration, rinsing with ether (10 mL). The solid was dissolved in dichloromethane (10 mL) and treated with trifluoroacetic acid (0.1 mL) and the reaction mixture was stirred at room temperature for about 2 hours. The reaction mixture was neutralized by the addition of 15% aqueous sodium hydroxide solution (about 15 mL) and the organic layer was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by reverse-phase HPLC using acetonitrile/water (0.05 M ammonium acetate) gradient elution method to afford the title compound as the acetate salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.43 (s, 1H), 8.41 (s, 1H), 8.28 (s, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.32-7.45 (m, 5H), 7.26 (d, J=8.6 Hz, 1H), 6.08 (t, J=5.7 Hz, 1H), 5.64 (s, 2H), 3.12 (t, J=6.2 Hz, 2H), 1.04-1.22 (m, 1H), 0.35-0.53 (m, 2H), 0.17-0.32 (m, 2H). MS (ESI+) m/z 345 (M+H)+.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]3[N:36]([CH3:37])[N:35]=[CH:34][CH:33]=3)[N:26]=2)=[CH:21][CH2:20]1)[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)(C(C)(C)C)(C)C.C(OCC)(=[O:40])C>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C@H:10]([N:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]4[N:36]([CH3:37])[N:35]=[CH:34][CH:33]=4)[N:26]=3)=[CH:21][C:20]2=[O:40])[CH2:9][OH:8])=[CH:12][C:13]=1[F:18]
Reactant: Cn1nccc1Nc1nccc(C2=CCN([C@H](CO[Si](C)(C)C(C)(C)C)c3ccc(Cl)c(F)c3)C=C2)n1
Reactant: CCOC(C)=O
Product: Cn1nccc1Nc1nccc(-c2ccn([C@H](CO)c3ccc(Cl)c(F)c3)c(=O)c2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.6 %

Procedure:
Crude (S)-1-(2-((tert-butyldimethylsilyl)oxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H-one (48 mg) was dissolved in ethyl acetate (4 mL) and treated dropwise slowly (over 2 minutes) with an ethyl acetate solution (1.0 mL, which had been saturated with HCl gas). The reaction stirred at room temperature for 15 minutes, after which time LCMS indicated complete consumption of the starting material. The reaction mixture was concentrated to an oily residue and purified by prep RP HPLC to yield (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (20.8 mg, 54.6% yield) as a lyophilized powder. 1H NMR (400 MHz, (CD3)2SO) δ 9.58 (s, 1H), 8.60 (d, J=5.1 Hz, 1H), 7.91 (t, J=9.0 Hz, 1H), 7.58 (t, J=8.1 Hz, 1H), 7.52-7.41 (m, 2H), 7.37 (d, J=1.8 Hz, 1H), 7.14 (dd, J=10.7, 5.1 Hz 2H), 6.86 (dd, J=7.3, 1.8 Hz, 1H), 6.27 (d, J=1.7 Hz, 1H), 5.97 (dd, J=7.7, 5.7 Hz, 1H), 5.31 (t, J=5.2 Hz, 1H), 4.15 (m, 1H), 4.10-3.95 (m, 1H), 3.69 (s, 3H); LCMS m/z 441 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14]OS(C)(=O)=O)=[CH:7][CH:6]=1)([OH:3])=[O:2].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C>[C:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][N:20]=[N+:21]=[N-:22])=[CH:7][CH:6]=1)([OH:3])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCCCc1ccc(CC(=O)O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCc1ccc(CC(=O)O)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Compound 6 (6 g, 0.02 mol) was dissolved in 80 ml of dry DMF then sodium azide (1.8 g, 0.027 mol) was added. The suspension was stirred at 80° C. (oil bath) for 3 h. The solvent was then removed at reduced pressure and the residual oil was treated with CH2Cl2 (100 mL).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][SH:10])=[CH:7][CH:6]=1.[C:13]([O:17][C:18]([N:20]1[CH2:24][C@@H:23](OS(C)(=O)=O)[CH2:22][C@H:21]1[C:30](=[O:34])[NH:31][CH2:32][CH3:33])=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[Na+]>CN(C)C=O>[C:13]([O:17][C:18]([N:20]1[CH2:24][C@@H:23]([S:10][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)[CH2:22][C@H:21]1[C:30](=[O:34])[NH:31][CH2:32][CH3:33])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1ccc(CS)cc1
Reactant: CCNC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
3.57 g of sodium hydride (as a 55% w/w suspension in mineral oil) was added, whilst ice-cooling, to a solution of 11.31 ml of 4-methoxybenzyl mercaptan dissolved in 150 ml of dry dimethylformamide and the mixture was stirred at 0° to 5° C. for 30 minutes. A solution of 26.00 g of (2S, 4S)-1-t-butoxycarbonyl-2-ethylcarbamoyl-4-methanesulfonyloxypyrrolidine in 100 ml of dry dimethylformamide was then added to the resulting mixture, and the whole was stirred at room temperature for 2 hours. At the end of this time, the reaction mixture was poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel using a 1:1 by volume mixture of hexane and ethyl acetate as an eluent, to afford 17.00 g of the title compound as colorless crystals, melting at 92°-94° C.
Reaction SMILES: Cl.[F:2][C:3]([F:14])([C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[CH2:4][NH:5][CH3:6].C(N(CC)CC)C.[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29].O>C(Cl)Cl>[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][S:28]([N:5]([CH2:4][C:3]([F:14])([F:2])[C:7]([F:12])([F:13])[C:8]([F:9])([F:10])[F:11])[CH3:6])(=[O:30])=[O:29]
Reactant: CNCC(F)(F)C(F)(F)C(F)(F)F
Reactant: O=S(=O)(Cl)CCCCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CN(CC(F)(F)C(F)(F)C(F)(F)F)S(=O)(=O)CCCCCCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.5 %

Procedure:
500 mg of N-(2,2,3,3,4,4,4-heptafluorobutyl)-N-methylamine hydrochloride (obtained according to European Patent No. 384,842 Example 75) and then, at 0° to 5° C., 0.55 ml of triethylamine were added to a solution of 200 mg of 5-chloropentane sulfonyl chloride in 5 ml of methylene chloride, and the mixture was stirred at ambient temperature for 2 hours. Water was added and extraction was carried out with methylene chloride. The extracts were washed with water, then with a saturated aqueous solution of sodium chloride, dried and evaporated to dryness under reduced pressure to obtain 378 mg of the expected product.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11]Br)=[CH:6][CH:5]=1.[F:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH:21]([CH:24]2[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]2)[CH2:20][CH2:19]1.Cl>CCOCC>[F:15][CH2:16][CH2:17][CH:18]1[CH2:19][CH2:20][CH:21]([CH:24]2[CH2:29][CH2:28][C:27]([CH2:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=3)=[CH:26][CH2:25]2)[CH2:22][CH2:23]1
Reactant: FC(F)(F)Oc1ccc(CCBr)cc1
Reactant: O=C1CCC(C2CCC(CCF)CC2)CC1
Agent: Cl
Solvent: CCOCC
Product: FCCC1CCC(C2CC=C(CCc3ccc(OC(F)(F)F)cc3)CC2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 46.4 %

Procedure:
A Grignard reagent prepared from the above 2-(4-trifluoromethoxyphenyl)bromoethane (7.0 g, 30.3 mmol) and dried Mg (0.74 g, 30.4 mmol) in an ether solvent (40 ml) was cooled down to 0° C., followed by dropwise adding thereto a 30 ml ether solution of 4-(4-(2-fluoroethyl)cyclohexyl)cyclohexanone (2.2 g, 9.7 mmol) prepared at the third step, stirring the mixture at 0° C. for 3 hours, adding 6N HCl to the reaction solution, extracting the resulting product with toluene, washing the extraction solution successively with a saturated aqueous solution of sodium bicarbonate and water, drying over magnesium sulfate, distilling off the solvent, adding toluene (100 ml) and Amberlist (500 mg) to the resulting yellow oily substance, refluxing the mixture for 4 hours, while removing water formed by the reaction by means of Dean-Stark, filtering off Amberlist, distilling off the solvent, purifying the residue according to column chromatography treatment using toluene as a developing solvent, on silica gel, to isolate 4-(4-(2-fluoroethyl)cyclohexyl)-1-(2-(4-trifluoromethoxyphenyl)ethyl)-1-cyclohexene (1.8 g, 4.5 mmol), hydrogenating this product (1.2 g, 3.0 mmol) in the presence of 5% Pd/C catalyst (0.12 g) in ethanol solution, filtering off the catalyst, distilling off the solvent under reduced pressure, and recrystallizing the residue, to isolate only trans-form of colorless 1-(2-(4-(4-(2-fluoroethyl)-cyclohexyl)cyclohexyl)ethyl-4-trifluoromethoxybenzene (0.37 g, 0.90 mmol) exhibiting smectic phase. The yield of this product from 4-(4-(2-fluoroethyl)chclohexyl)cyclohexanone was 9.3%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]([NH:15]CC2C=CC=CC=2)[C:12]([N+:23]([O-])=O)=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]>[Pd].C1COCC1.CO>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]([NH2:15])[C:12]([NH2:23])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COCCOc1cc(NCc2ccccc2)c([N+](=O)[O-])cc1C(=O)O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COCCOc1cc(N)c(N)cc1C(=O)O

Procedure:
Prepared analogously to example 655d by hydrogenation of the product obtained from (685a) using palladium on charcoal in THF and methanol.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:11]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:26]OCC1C=CC=CC=1>>[CH2:1]([O:8][CH2:9][N:10]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C:12](=[CH2:26])[C:11]1=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCOCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCN(COCc2ccccc2)C(=O)C1
Product: C=C1C(=O)N(COCc2ccccc2)CCCN1C(=O)OC(C)(C)C

Procedure:
The title was prepared from tert-butyl 4-[(benzyloxy)methyl]hexahydro-3-oxo-1H-1,4-diazepine-1-carboxylate and benzyl chloromethyl ether essentially following the procedure described in Example 3, Step 1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C[C:28]([N:30](C)C)=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Zn]>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=[C:2]([C:28]#[N:30])[CH:3]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3ccnc23)cc1
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ccc(CN(c2ccccc2)c2cc(C#N)nn3ccnc23)cc1
Temperature: 150 °C
Yield: 98 %

Procedure:
To a 20 ml microwave vial was added 6-chloro-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine (0.66 g, 1.8 mmol) from Example XXXI, step (1a), zinc cyanide (0.13 g, 1.1 mmol), Pd2(dba)3 (0.033 g, 0.036 mmol), 1,1′-bis(diphenylphosphino)-ferrocene [dppf] (0.040 g, 0.07 mmol), zinc dust (0.012 g, 0.18 mmol) and DMA (11.0 ml, 0.17 M). The reaction mixture was sealed and pump/purged 3× with nitrogen then heated in a microwave for 20 minutes at 150° C. Upon cooling, the suspension was diluted with ethyl acetate (50 ml) and filtered through a plug of celite. To the resulting solution was added 10% LiCl solution and the layers separated. The organic layer was washed two additional times with 10% LiCl solution, then brine (1×), dried over Na2SO4, filtered and concentrated in vacuo. This residue was purified on silica gel (ISCO—80 gram) using a 30-100% ethyl acetate/heptane gradient over 20 minutes. To provide 8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazine-6-carbonitrile (0.63 g, 98%). m/z=(357, M+1).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:13]([CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C@@H:12]([OH:23])[CH2:11][C@H:10]1[OH:24].[C:26]1([C:37]2CCCCCCCCCC=2)[CH2:36]CCCCCCCNN=1.C(I)CC>CC(C)=O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:13]([CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH:26]([CH3:37])[CH3:36])=[O:21])[C@@H:12]([OH:23])[CH2:11][C@H:10]1[OH:24]
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Reactant: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CCCI
Solvent: CC(C)=O
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC(C)C)[C@@H](O)C[C@H]1O
Reaction time: 8 h

Procedure:
20 mg (0,056 mmol) of 11 epi PGF2alpha (Cayman Chemicals, U.S.) were dissolved in acetone at room temperature. To this solution were added 54.5 mg (0.336 mmol) of diazabicycloundecene (DBu) and 76.15 mg (0.448 mmol) of propyl iodide, whereupon the mixture was left to stand at room temperature for 8 hours. The solvent was removed in vacuo, the residue then being dissolved in 50 ml of ethyl acetate, washed with 20 ml of water, 20 ml of 3% citric acid and 5% sodium hydrogen carbonate; thereafter the organic phase was dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by means of column chromatography on silica gel, with ethyl acetate-acetone (1:1) as the eluent. The yield of the product was about 76%, and its purity was tested by means of thin layer chromatography and NMR.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][CH2:9][N:10]([CH2:22][CH3:23])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O>[H][H].[Pd]>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][N:10]([CH2:22][CH3:23])[CH2:9][CH2:8][C:7]2[CH:24]=[CH:25][C:4]([NH2:1])=[CH:5][CH:6]=2)=[CH:18][CH:17]=1
Reactant: [H][H]
Reactant: CCN(CCc1ccc([N+](=O)[O-])cc1)CCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Product: CCN(CCc1ccc(N)cc1)CCc1ccc(N)cc1

Procedure:
N,N-Bis-(4-nitrophenethyl)ethylamine (0.45 g) was reduced using H2 /Pd/C in a similar fashion to Example 23(B) to provide the title compound, yield 0.32 g.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:35])[C:5]2[S:10][C:9](=[O:11])[N:8]([CH2:12][O:13][CH:14]([CH2:25][O:26]C(=O)C3C=CC=CC=3)[CH2:15][O:16]C(=O)C3C=CC=CC=3)[C:6]=2[N:7]=1.C[O-].[Na+]>CO>[NH2:1][C:2]1[NH:3][C:4](=[O:35])[C:5]2[S:10][C:9](=[O:11])[N:8]([CH2:12][O:13][CH:14]([CH2:15][OH:16])[CH2:25][OH:26])[C:6]=2[N:7]=1
Reactant: Nc1nc2c(sc(=O)n2COC(COC(=O)c2ccccc2)COC(=O)c2ccccc2)c(=O)[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1nc2c(sc(=O)n2COC(CO)CO)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5-Amino-3-(1,3-dibenzoyloxy-2-propoxymethyl)thiazolo[4,5-d]pyrimidine-2,7(3H, 6H)-dione (0.4 g, 0.798 mmol), sodium methoxide (0.2 g) and MeOH (100 mL) was stirred at ambient temperature for 18 h. Amberlite IR-120(H+) (1 g, washed with H2O, then MeOH) was added and the mixture was stirred until neutral. The resin was removed by filtration and the MeOH solution was evaporated. The residue was extracted with Et2O (2×50 mL) and then crystallized from H2O . The crystalline product was dried in vacuum at 90° C. for 2 days; 0.115 g (0.399 mmol, 50%), mp 256-258° C. Ir (KBr): ν3370, 3210 and 3170 (NH, NH2, OH), and 1650 broad(C=O, C=N) cm-1. Uv, λmax (nm) (ε×10-3): pH 1, 302 (9.62), 248 (9.16), 216 (27.6); MeOH, 302 (9.08), 248 (8.43), 216 (25.0); pH 11, 292 (7.37), 246 (8.04). 1H nmr (DMSO-d6): δ3.28-3.34 (m, 2H, CH2), 3.41-3.46 (m, 2H, CH2), 3.66 (t, 1H, CH), 4.53 (t, 2H, 2 OH), 5.24 (s, 2H, NCH2), 6.91 (br s, 2H, NH2), and 11.13 (br s, 1H, NH). Anal. Calc'd for C9H12N4O5S (288.28): C, 37.50; H, 4.08; N, 19.43. Found: C, 37.43; H, 4.08; N, 19.23.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[C:23]1[CH:24]=[N:25][N:26](C(OC(C)(C)C)=O)[CH:27]=1.[N:35]1([C:40]2[CH:41]=[N:42][CH:43]=[C:44](B3OC(C)(C)C(C)(C)O3)[CH:45]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CN(C=O)C>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([C:23]4[CH:27]=[N:26][NH:25][CH:24]=4)=[C:2]([C:44]4[CH:43]=[N:42][CH:41]=[C:40]([N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)[CH:45]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(-c3cnn(C(=O)OC(C)(C)C)c3)sc2n1
Reactant: CC1(C)OB(c2cncc(N3CCCC3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cncc(N4CCCC4)c3)c(-c3cn[nH]c3)sc2n1
Temperature: 120 °C
Yield: 64.7 %

Procedure:
A mixture of 1,1-dimethylethyl 4-(3-bromo-4-{[(3-chlorophenyl)sulfonyl]amino}-6-methylthieno[2,3-b]pyridin-2-yl)-1H-pyrazole-1-carboxylate (Description 75) (100 mg, 0.171 mmol), 3-(1-Pyrrolidinyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Description 79) (181 mg, 0.66 mmol), potassium carbonate (71.0 mg, 0.514 mmol), tetrakis(triphenylphosphine)palladium(0) (19.79 mg, 0.017 mmol) and bis(triphenylphosphine)palladium(II) chloride (12.02 mg, 0.017 mmol) were weighed into a microwave vial. 1,4-Dioxane (2 mL), DMF (1 mL) and water (0.5 mL) were added and the mixture heated in a microwave at 120° C. for 15 min. At this point, all three mixtures were combined and concentrated. The residue was passed through an SCX cartridge, eluting with MeOH (75 mL) and then 2M NH3 in MeOH (150 mL). The basic methanolic solution was concentrated and purified by normal phase chromatography, eluting with 0-10% MeOH in DCM and then further purified by MDAP (acidic conditions), to give the title compound (61 mg). LCMS (A) m/z: 551 [M+1]+, Rt 0.79 min (acidic).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][OH:6])[CH2:3][CH2:2]1.CN(C=O)C.[H-].[Na+].[Br:14][C:15]1[CH:16]=[CH:17][C:18](F)=[N:19][CH:20]=1>CC(=O)OCC.O>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:6][CH2:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[N:19][CH:20]=1
Reactant: OCCC1CC1
Reactant: Fc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Brc1ccc(OCCC2CC2)nc1
Reaction time: 4 h

Procedure:
A mixture of 2-cyclopropyl-ethanol (4.1 g) and DMF (15 mL) under argon was treated with NaH (60% in oil, 0.45 g). After 4 hours 5-bromo-2-fluoro-pyridine (3.0 g) was added at 0° C. After 4 hours at room temperature, the mixture was distributed between water and EA. The organic phase was washed twice (water), dried (Na2SO4) and concentrated. The residue was purified by chromatography (SiO2; EA/heptane 1:4) to provide the subtitle compound. MS ESI+: m/z=242 [M+H]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:32]=[CH:31][C:12]2[CH2:13][CH:14]([CH2:16][CH2:17][C:18]3[CH:30]=[CH:29][C:21]([O:22][CH2:23][C:24](OCC)=[O:25])=[CH:20][CH:19]=3)[O:15][C:11]=2[CH:10]=1>CCOCC>[CH3:7][O:8][C:9]1[CH:32]=[CH:31][C:12]2[CH2:13][CH:14]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH2:24][OH:25])=[CH:29][CH:30]=3)[O:15][C:11]=2[CH:10]=1
Reactant: CCOC(=O)COc1ccc(CCC2Cc3ccc(OC)cc3O2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1ccc2c(c1)OC(CCc1ccc(OCCO)cc1)C2
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To the stirred slurry of LiAlH4 (0.01 g, 0.026 mmol) in anhydrous Et2O (5 ml) the solution of the product of Step C (0.04 g, 0.11 mmol) in anhydrous Et2O (2 ml) was added drop wise and stirring was continued for 0.5 h at room temperature. The reaction mixture was quenched with EtOAc: H2O: MeOH mixture (7 ml: 3 ml: 1 ml), diluted to 20 ml with EtOAc and filtered through Celite. The filtrate was evaporated under reduced pressure and dried in vacuo to give the title compound (0.032 g, 94%), as colourless solid. 1H-NMR (CDCl3) 7.13 (d, 2H, J=8.54 Hz); 6.99 (d, 1H, J=8.56 Hz); 6.84 (d, 2H, J=8.58 Hz); 6.38-6.34 (m, 2H); 4.79-4.74 (m, 1H); 4.65 (t, 2H, J=4.14 Hz); 3.96-3.90 (m, 2H); 3.75 (s, 3H); 3.22-3.14 (m, 1H); 2.82-2.68 (m, 2H); 2.11-1.91 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:11])=[O:7].C1CCNCC1.[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Cl)=[CH:34][CH:33]=1.C1(N=C=O)C=CC=CC=1>CC#N>[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][N:17]2[CH2:18][CH2:19][CH:14]([CH2:13][NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:20]=[CH:21][CH:22]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:4]=3)[CH2:15][CH2:16]2)=[CH:34][CH:33]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCNCC1
Solvent: CC#N
Solvent: C1CCNCC1
Solvent: O=C=Nc1ccccc1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of 4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (30 mg, 0.087 mmol) in CH3CN (1.0 mL) and (piperidinomethyl)polystyrene (80 mg, 2.7 mmol base/g resin) were added to a solution of 4-chlorobenzyl chloride (11.7 mg, 0.073 mmol) in CH3CN (1.0 mL). The reaction mixture was stirred at 60° C. for 2 h. Phenyl isocyanate (10.4 mg, 0.087 mmol) was added to the cooled reaction mixture and the mixture was stirred at 25° C. for 1 h. The reaction mixture was loaded onto Varian™ SCX column and washed with CH3OH (20 mL). Product was eluted off using 2 N NH3 in CH3OH (6 mL) and concentrated to afford 1-(4-chlorobenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine as a colorless oil used without purification. Iodomethane (28 mg, 0.20 mmol) was added to a solution of 1-(4-chlorobenzyl)-4-8 {N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine in CH3CN (2.0 mL) and the reaction mixture was stirred at 70° C. for 4 h. The solvent was removed under reduced pressure to afford 1-(4-chlorobenzyl)-1-methyl-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidinium iodide as a pale yellow oil (31.7 mg, 71%): The purity was determined by RPLC/MS (99%); ESI/MS m/e 482.1 (M+, C24H28ClF3N3O2).