Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[CH3:14][Mg]Br.[NH4+].[Cl-]>C1COCC1>[F:1][C:2]([F:12])([F:13])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]([OH:9])[CH3:14])=[CH:6][CH:5]=1
Reactant: C[Mg]Br
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A cooled (0° C.) solution of 4-(trifluoromethoxy)benzaldehyde (3.000 g; 15.78 mmol) in anh. THF (50 ml) was treated dropwise with a solution of methylmagnesium bromide (3 M in Et2O; 6.30 ml; 18.90 mmol), and the resulting mixture was stirred at rt, under nitrogen, for 4 h. The resulting reaction mixture was cooled to 0° C., and aq. sat. NH4Cl (30 ml) was added dropwise. The separated aq. layer was further extracted with AcOEt (3×20 ml), and the mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=40/1) afforded 1-(4-(trifluoromethoxy)phenyl)ethanol as a colorless oil. LC-MS (conditions D): tR=0.88 min.; no ionisation.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:19][C:20]([SH:23])(Cl)Cl>C(Cl)(Cl)Cl>[C:3]1([CH3:2])[CH:11]=[CH:10][C:6]([C:7]2[N:9]=[C:20]([Cl:19])[S:23][N:8]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(C(=N)N)cc1
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2nsc(Cl)n2)cc1
Temperature: 5 °C
Yield: 44 %

Procedure:
To a mixture of p-methylbenzamidine hydrochloride (5.1 g, 30.0 mmol) in CHCl3 (100 ml) is added triethyl amine (15.12 g, 20.9 ml, 150.0 mmol) and cooled to 5° C. in an ice-water bath. To the mixture is slowly added perchloromethyl mercaptan (95%, 6.16 g, 31.5 mmol) in CHCl3(10 ml) over 1 hour. The yellow solution is allowed to warm up to room temperature. After 2 hours the mixture is washed with water (100 ml×2) and brine (100 ml). The organic layer is dried over MgSO4 and the solvent is removed under reduced pressure to yield a brown oil. The oil is purified on a bed of silica gel, eluting with 1:1 CHCl3:hexanes to yield 3-(p-tolyl)-5-chloro-1,2,4-thiadiazole as a yellow solid (2.78 g, 44%). 1H NMR (CDCl3): δ 2.41 (s, 3H), 7.30(d, 2H), 8.13 (d, 2H).
Reaction SMILES: CN(C)CCO.[Li]CCCC.[CH:12]1([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2[O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH2:14][CH2:13]1.[C:26](=[O:28])=[O:27]>CCCCCC.C(OCC)C>[CH:12]1([C:15]2[C:20]([O:21][CH2:22][CH:23]3[CH2:24][CH2:25]3)=[CH:19][C:18]([C:26]([OH:28])=[O:27])=[N:17][CH:16]=2)[CH2:14][CH2:13]1
Reactant: c1cc(OCC2CC2)c(C2CC2)cn1
Reactant: O=C=O
Agent: CN(C)CCO
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(O)c1cc(OCC2CC2)c(C2CC2)cn1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 28.6 %

Procedure:
To a solution of N,N-Dimethylethanolamine (CAN 108-01-0, 2.372 g, 3.08 mL, 30.6 mmol) in hexane cooled at −15° C. under an argon atmosphere was slowly added BuLi 1.6M in Hexane (38.2 mL, 61.1 mmol). The reaction was stirred at −15° C. during 20 minutes and was then cooled down to −78° C. before addition of 3-cyclopropyl-4-cyclopropylmethoxypyridine (Example 42b, 2.314 g, 12.2 mmol). The reaction was stirred 1 hour at −78° C. followed by addition of carbon dioxide (2.09 g, 47.6 mmol) (pellets from a dry ice dispenser) into the mixture. A white precipitate formed and the reaction was slowly warmed up to −20° C. The reaction was quenched with water, stirred 5 minutes and the volatiles were removed in vacuo. The residue was suspended into ethylacetate and extracted with 19 mL of a 2.0M aqueous solution hydrochloric acid. The organic phase was collected, dried over sodium sulfate and evaporated down to dryness to give an yellow oil. The former oil was dissolved in diethylether which gave a white precipitate. The suspension was stored at 0° C. for 1 hour and the solution was separated from the white solid. The white solid was dried under high vacuum to give the titled compound (815 mg, 66%). MS (ESI, m/z): 234.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][CH:26]=2)=[CH:15][C:14](C(N2CCOCC2)=O)=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.NCCC1C2C(=CC=C([C:56]3[C:57]([CH3:65])([CH3:64])[C:58](=[O:63])[N:59]([CH2:61][CH3:62])[N:60]=3)C=2)NC=1C1C=C(C)C=C(C)C=1.[NH4+].[OH-]>C(Cl)Cl.CO>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])=[CH:29][CH:30]=2)=[CH:15][C:14]([C:56]2[C:57]([CH3:65])([CH3:64])[C:58](=[O:63])[N:59]([CH2:61][CH3:62])[N:60]=2)=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CCN1N=C(c2ccc3[nH]c(-c4cc(C)cc(C)c4)c(CCN)c3c2)C(C)(C)C1=O
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)N4CCOCC4)cc3c2CCNCCCCc2ccc(NS(C)(=O)=O)cc2)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCN1N=C(c2ccc3[nH]c(-c4cc(C)cc(C)c4)c(CCNCCCCc4ccc(NS(C)(=O)=O)cc4)c3c2)C(C)(C)C1=O
Yield: 55 %

Procedure:
Reductive amination of 4-[4-(methanesulfonamido)phenyl] butyraldehyde (EXAMPLE 4) with 5-[3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-ethyl-4,4-dimethyl-2,4-dihydropyrazol-3-one was carried out according to the method of Example 6.2, Step F, except that 90:10 CH2Cl2-MeOH was used to develop the preparative TLC plates, while 90:10:1 CH2Cl2-MeOH-concd. NH4OH was used to extract the product. This gave a 55% yield of very pale golden-yellow glass; homogeneous by TLC in 92.5:7.5 CH2Cl2-MeOH. 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (ESI): m/e=628.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][NH:32]C(=O)OC(C)(C)C)[CH2:27][CH2:26]1.Cl.O1CCOCC1>CS(C)=O>[NH2:32][CH2:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([NH:24][C:5]2[CH:4]=[C:3]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[N:10]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:26][CH2:27]1
Reactant: Fc1cccc(COc2cccc(-c3cc(F)ncc3Cl)n2)c1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](N)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: NC[C@H]1CC[C@H](Nc2cc(-c3cccc(OCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Temperature: 102.5 °C
Reaction time: 40 h

Procedure:
To 5′-chloro-2′-fluoro-6-(3-fluorobenzyloxy)-2,4′-bipyridine (30 mg, 0.090 mmol) was added DMSO (0.8 ml), TEA (0.025 ml, 0.180 mmol), and tert-butyl (trans-4-aminocyclohexyl)methylcarbamate (41.2 mg, 0.180 mmol). The reaction mixture was flushed with argon and stirred at 100-105° C. for 40 hr. Formation of the intermediate product tert-butyl(trans-4-(5′-chloro-6-(3-fluorobenzyloxy)-2,4′-bipyridin-2′-yl-amino)cyclohexyl)methylcarbamate was indicated by LCMS. (LCMS (m/z): 541.4 (MH+), retention time=1.05 min.). The solvent DMSO was removed under reduce pressure. The Boc group was removed from the intermediate by adding 4M HCl in Dioxane (1.5 ml, 6.00 mmol), followed with stirring at ambient temperature for 90 minutes. The solvent was removed under reduced pressure. The crude product was dissolved in 1.0 ml of DMSO with 0.075 ml of water, filtered and purified by prep LC. After lyphilization, 28.3 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 441.3 (MH+), retention time=0.76 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.12-1.29 (m, 2H) 1.29-1.47 (m, 2H) 1.60-1.76 (m, J=14.76, 7.51, 3.66, 3.66 Hz, 1H) 1.92 (d, J=12.60 Hz, 2H) 2.16 (d, J=10.55 Hz, 2H) 2.84 (d, J=6.74 Hz, 2H) 3.58-3.71 (m, 1H) 5.43 (s, 2H) 6.92-6.99 (m, 2H) 6.99-7.08 (m, 1H) 7.18 (d, J=9.67 Hz, 1H) 7.25 (d, J=7.62 Hz, 1H) 7.30-7.42 (m, 2H) 7.83 (t, J=7.77 Hz, 1H) 8.01 (s, 1H)
Reaction SMILES: [C:1]([N:5]=[C:6]=[S:7])([CH3:4])([CH3:3])[CH3:2].[CH:8]1(N)[CH2:12][CH2:11][CH2:10][CH2:9]1.CC[N:16](C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[C:1]([N:5]([CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[C:6]([NH2:16])=[S:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N=C=S
Reactant: NC1CCCC1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)N(C(N)=S)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of t-butyl isothiocyanate (5.0 mL; 39.41 mmol) in CH2Cl2 (200 mL) was added cyclopentylamine (4.67 mL; 47.29 mmol) followed by DIEA and the reaction mixture was stirred at RT for 2 h. The mixture was diluted with EtOAc, washed with 10% citric acid (2×), saturated NaHCO3 (2×), H2O (2×) and brine (1×). The organic layer was dried over anhydrous MgSO4, filtered and evaporated to dryness to obtain the t-butyl-cyclopentylthiourea as a white solid (3.70 g; 47% yield).
Reaction SMILES: [CH2:1](Cl)/[CH:2]=[CH:3]/[CH2:4]Cl.[C:7]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C1C=CC=CC=1.[OH-].[K+]>O>[CH:2]([CH:3]1[CH2:4][C:8]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:7]([O:15][CH2:16][CH3:17])=[O:14])=[CH2:1]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClC/C=C/CCl
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: C=CC1CC1(C(=O)OCC)C(=O)OCC
Temperature: 60 °C
Yield: 65.7 %

Procedure:
To illustrate yet another variation of the present process a reaction vessel fitted with a suitable stirrer, Dean-Stark trap, and condenser was charged with 866 g (6.9 mol) trans 1,4-dichlorobutene-2, 640 g (4.0 mol) diethyl malonate, 1.2 g (0.08 mol percent based on malonate) tricaprylylmethylammonium chloride and 1.8 liters benzene. The reactor and its contents were heated to 60° C. with stirring and incremental additions of flaked solid (85%) potassium hydroxide made over a 4.75-hour period while azeotropically removing water of reaction. A total of 528 grams solid KOH were charged. After 5.5 hours the theoretical amount of water was removed and the reaction mixture was cooled, filtered to remove potassium salts and the benzene solution concentrated. The crude brown oil, upon distillation at reduced pressure, yielded the desired diethyl 2-vinylcyclopropane-1,1-dicarboxylate (65.7% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[N:12]1C=CC=CC=1.C(OC(=O)N[CH:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:39]3[O:38][CH:37]=[CH:36][C:35]=3[CH:34]=[C:33]([NH2:40])[CH:32]=2)[CH2:27][CH2:26]1)(C)(C)C>C(Cl)Cl>[ClH:1].[NH2:12][CH:29]1[CH2:30][CH2:25][CH2:26][CH2:27][N:28]1[C:31]1[C:39]2[O:38][CH:37]=[CH:36][C:35]=2[CH:34]=[C:33]([NH:40][S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])(=[O:10])=[O:9])[CH:32]=1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(N)cc3ccoc23)CC1
Solvent: ClCCl
Product: Cl
Product: NC1CCCCN1c1cc(NS(=O)(=O)c2ccccc2Cl)cc2ccoc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
2-Chlorobenzenesulfonyl chloride (76.0 mg, 0.36 mmol) and pyridine (219 mL) were added to tert-butyl[1-(5-amino-1-benzofuran-7-yl)piperidin-4-yl]carbamate (100.0 mg, 0.30 mmol; Intermediate 49) in DCM (1 mL). The mixture was shaken at room temperature for 1 h, solvent was removed in vacuo and the residue was purified by preparative HPLC using acetonitrile-water gradients containing 0.1% trifluoroacetic acid. N-deprotection and conversion into the hydrochloride salt was performed by treatment with 2 M HCl in ether. This furnished to 60.6 mg (50%) of the title product. HPLC 100%, RT: 1.702 (System A; 10-97% MeCN over 3 min). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.69-1.72 (m, 2H) 2.01-2.02 (m, 2H) 2.76 (t, J=11.62 Hz, 2H) 3.21 (s, 1H) 3.68 (d, J=12.56 Hz, 2H) 6.58 (s, 1H) 6.82 (d, J=2.20 Hz, 1H) 6.88 (s, 1H) 7.47 (t, J=7.54 Hz, 1H) 7.62-7.63 (m, 2H) 7.87 (d, J=1.88 Hz, 1H) 7.99 (d, J=7.54 Hz, 1H) 8.23 (s, 3H) 10.33 (s, 1H). LC-MS 406 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[C:4]([CH3:14])=[N:3]1>C(O)C.[Pd]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[C:4]([CH3:14])=[N:3]1
Reactant: Cc1nn(C)c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CCO
Product: Cc1nn(C)c2ccc(N)cc12
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
To a solution of 307a (crude, 2.5 mmol) in ethanol (95%, 30 mL) was added NH2NH2 water (1.25 g, 25.0 mmol), Pd/C (100 mg) under nitrogen protection. The mixture was stirred at 50° C. for 1.5 h. It was then cooled to room temperature and filtered through a pad of CELITE®. The filtrate was concentrated under reduced pressure and the residue was recrystallized from anhydrous ethanol (5 mL) to afford 307b as white solid (340 mg, 84% over two steps). MS-ESI: [M+H] 162.3
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[Br:7][C:8]1[C:9]([Cl:15])=[N+:10]([O-])[CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C>C(#N)C>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:5]#[N:6])=[N:10][C:9]=1[Cl:15]
Reactant: [O-][n+]1cccc(Br)c1Cl
Reactant: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ccc(Br)c(Cl)n1
Temperature: 50 °C

Procedure:
Trimethylsilyl cyanide (19 mL, 0.15 mol) was added to a stirred solution of 3-bromo-2-chloropyridine 1-oxide (C27) (31.6 g, 0.152 mol) and triethylamine (63.4 mL, 0.46 mol) in acetonitrile (400 mL). The reaction mixture was heated to 50° C. for 2 hours. It was then cooled to room temperature and additional trimethylsilyl cyanide (19 mL, 0.15 mol) was added. After the reaction mixture was heated at 50° C. for 1.5 hours, a final portion of trimethylsilyl cyanide (28.5 mL, 0.23 mol) was added and the reaction was heated at reflux for 3 days. After dilution with dichloromethane (2 L), the reaction was washed with saturated aqueous sodium bicarbonate solution (800 mL), then with water (1 L), dried over magnesium sulfate and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 20% to 25% ethyl acetate in heptane) afforded the title compound as a yellow solid. Yield: 14.92 g, 68.6 mmol, 45%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br.Br[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)=[O:29]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH2:27][C:28](=[O:29])[C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[O:17])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: O=C(CBr)c1ccncc1
Agent: Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: O=C(Cc1ccc(OCc2ccccc2)cc1)OCC(=O)c1ccncc1
Reaction time: 1 h
Yield: 49.8 %

Procedure:
To a 10° C. stirred solution of 2-(4-(benzyloxy)phenyl)acetic acid (5.0 g, 0.02 mol) in MeOH (50 mL) was added a solution of potassium tert-butoxide (2.43 g, 0.02 mol) in MeOH (50 mL) under an inert atmosphere. The reaction mixture was stirred for 1 h, concentrated in vacuo and the residue was dissolved in DMF (30 mL). Potassium tert-butoxide (3.6 g, 0.03 mmol) was then added followed by 2-bromo-1-(pyridin-4-yl)ethanone hydrobromide (10.3 g, 0.05 mol), and the reaction mixture at RT. The reaction mixture was then stirred for an additional 16 h at RT, quenched with water, stirred for an additional 10 min and the precipitated solid was filtered. The crude solid was dissolved in EtOAc (200 mL) and washed with water, dried over Na2SO4, filtered and concentrated in vacuo to afford 2-oxo-2-(pyridin-4-yl)ethyl 2-(4-(benzyloxy)phenyl)acetate (3.6 g, 48%) as a solid.
Reaction SMILES: [Br-:1].[CH:2]1([C:8]([OH:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]([O:11]CC2CCC[N+]2(C(C2C=CON=2)C(=O)N)C)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Br-].O[CH2:37][C@H:38]1[CH2:42][CH2:41][CH2:40][N+:39]1([CH2:44][C:45](=[O:52])[NH:46][C:47]1[CH:51]=[CH:50][O:49][N:48]=1)[CH3:43].[Br-].OC1CC[N+](CC(=O)NC2C=CON=2)(C)CC1>>[Br-:1].[CH:2]1([C:8]([OH:34])([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:9]([O:11][CH:42]2[CH2:37][CH2:38][N+:39]([CH2:44][C:45](=[O:52])[NH:46][C:47]3[CH:51]=[CH:50][O:49][N:48]=3)([CH3:43])[CH2:40][CH2:41]2)=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: C[N+]1(CC(=O)Nc2ccon2)CCC[C@@H]1CO
Reactant: C[N+]1(C(C(N)=O)c2ccon2)CCCC1COC(=O)C(O)(c1ccccc1)C1CCCCC1
Agent: C[N+]1(CC(=O)Nc2ccon2)CCC(O)CC1
Agent: [Br-]
Product: C[N+]1(CC(=O)Nc2ccon2)CCC(OC(=O)C(O)(c2ccccc2)C2CCCCC2)CC1

Procedure:
This compound is prepared by an analogous method to (1R/S,2R)-2-((R/S)-(2-Cyclohexyl-2-hydroxy-2-phenyl-acetoxymethyl)-1-(isoxazol-3-yl carbamoylmethyl)-1-methyl-pyrrolidinium bromide (Example 1) by replacing (1R/S,2R)-2-hydroxymethyl-1-(isoxazol-3-ylcarbamoyl-methyl)-1-methyl-pyrrolidinium bromide (Intermediate B) with 4-hydroxy-1-(isoxazol-3-ylcarbamoylmethyl)-1-methyl-piperidinium bromide (Intermediate I).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:42][O:43][C:44]1[C:45]2[N:58]=[C:57]([NH2:59])[S:56][C:46]=2[C:47]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[N:48][CH:49]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:59][C:57]1[S:56][C:46]2[C:47]([N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)=[N:48][CH:49]=[C:44]([O:43][CH3:42])[C:45]=2[N:58]=1)=[O:7]
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reaction time: 16 h
Yield: 61.6 %

Procedure:
To a stirred solution of 455 mg (2.25 mmol) 2-bromo-isonicotinic acid in 8 ml THF were added 914 mg (2.40 mmol) HATU and 0.50 ml (4.51 mmol) N-methylmorpholine and stirring continued at 50° C. for 16 h. 200 mg (0.75 mmol) 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine was then added and stirring continued at 60° C. for 4 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (methanol/dichloromethane) afforded 208 mg (62%) 2-bromo-N-(7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-isonicotinamide as a yellow crystalline solid. ES-MS m/e (%): 452 (M{81Br}+H+, 95), 450 (M{79Br}+H+, 100).
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:23]2[CH:22]=[C:21]([CH3:24])[N:20]=[C:19]([NH2:25])[C:18]=2[N:17]=[C:16]1[CH2:26][O:27][CH2:28][CH3:29].C(N(CC)CC)C>C(Cl)(Cl)Cl>[NH2:25][C:19]1[C:18]2[N:17]=[C:16]([CH2:26][O:27][CH2:28][CH3:29])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[C:23]=2[CH:22]=[C:21]([CH3:24])[N:20]=1
Reactant: CCOCc1nc2c(N)nc(C)cc2n1CCCCN
Reactant: O=C(Cl)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc(C)cc2n1CCCCNC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
4-Morpholinecarbonyl chloride (202 μL, 1.73 mmol) was added to a solution of 1-(4-aminobutyl)-2-ethoxymethyl-6-methyl-1H-imidazo[4,5-c]pyridin-4-amine (0.435, 1.57 mmol) in a mixture of triethylamine (280 μL, 2.04 mmol) and chloroform (8 mL). The reaction mixture was stirred at ambient temperature for 4 hours then it was diluted with chloroform (20 mL) and washed with saturated sodium bicarbonate (10 mL). The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography (30 g of silica gel eluting with 1 L of 2% methanol in chloroform containing 0.5% triethylamine. The resulting glassy solid was triturated with acetonitrile to provide 0.417 g of N-{4-[4-amino-2-(ethoxymethyl)-6-methyl-1H-imidazo[4,5-c]pyridin-1-yl]butyl}morpholine-4-carboxamide as an off white powder, m.p. 156.5-159.5° C. Analysis: C19H30N6O3.0.20 HCl: %C, 57.37; %H, 7.65; %Cl, 1.78; %N, 21.13; Found: %C, 57.19; %H, 7.56; %Cl, 1.84; %N, 21.14. 1H NMR (300 MHz, CDCl3) δ6.51 (s, 1 H), 5.46 (bs, 2 H), 4.71 (s, 2 H), 4.45 (bs, 1 H), 4.17 (t, J=7.5 Hz, 2 H), 3.68 (t, J=4.9 Hz, 4 H), 3.57 (quartet, J=7.1 Hz, 2 H), 3.32 (m, 6 H), ), 2.49 (s, 3 H), 1.86 (quintet, J=7.5 Hz, 2 H), 1.58 (quintet, J=7.3 Hz, 2 H), 1.22 (t, J=7.2 Hz, 3 H); MS(CI) m/e 391 (M+H)
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)[C:2]([CH3:5])([CH3:4])[CH3:3].[N+:16]([O-])([OH:18])=[O:17].O>C(OC(=O)C)(=O)C>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=1)[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(=O)Nc1ccc(CC(C)(C)C)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(CC(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 96.7 %

Procedure:
To a suspension of N-(4-neopentylphenyl)acetamide (Preparation 98, 2.54 g, 12.4 mmol) in acetic anhydride (20 mL) cooled in an ice bath was added a solution of nitric acid (0.78 mL, 18 mmol) in acetic anhydride (5 mL) dropwise. The solution was allowed to warm to room temperature for 18 hours. The yellow solution was added to water and extracted with dichloromethane (3×). The organic layers were dried over anhydrous magnesium sulphate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with a 0-50% ethyl acetate/hexanes gradient to provide the title compound (3.0 g, 97%) as a yellow oil.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:5]=2[N:6]=1.[OH-].[K+].C(O)(=O)C.IC[C:20]#[N:21]>O.C(O)C>[NH2:6][C:5]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:4]=1[S:3][CH2:2][C:20]#[N:21]
Reactant: N#CCI
Reactant: Nc1nc2cc(F)ccc2s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: N#CCSc1ccc(F)cc1N
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
A suspension of 2-amino-5-fluoro-benzothiazole (3.45 g) was stirred for 7 h at 165-170 ° C. under nitrogen in a solution of potassium hydroxide (6.9 g) in water (13.5 ml). The resulting mixture was cooled on an ice bath to 10° C., supplemented with water (5 ml) and then a solution of acetic acid (3.5 ml) in water (4 ml). The mixture was diluted with 96% ethanol (20 ml) and subsequently a solution of iodoacetonitrile (3.42 g) in 96% ethanol (5 ml) was added. After stirring for 15 min the mixture was adjusted to pH ˜7 by adding acetic acid and approx. half of the solvent was removed in vacuo. The residue was diluted with water (100 ml) and extracted with ethyl acetate (50+3×25 ml). The combined extracts were dried over sodium sulfate, filtered and evaporated to give the title compound as a practically pure yellow oil. Yield 3.60 g (96%); 1H-NMR (DMSO-d6), δ (ppm): 7.32-7.43 (dd, 1H, Ar—H), 6.49-6.60 (dd, 1H, Ar—H), 6.29-6.43 (ddd, 1H, Ar—H), 5.88 (br, 2H, NH2), 3.82 (s, 2H, CH2).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@@:4]([NH:27]C(=O)OC(C)(C)C)([CH2:7][C:8]#[C:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=3)[CH:13]=[CH:12][N:11]=2)[C:3]1=[O:35].OS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C>[NH2:27][C@@:4]1([CH2:7][C:8]#[C:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=3)[CH:13]=[CH:12][N:11]=2)[CH2:5][CH2:6][N:2]([CH3:1])[C:3]1=[O:35]
Reactant: CN1CC[C@](CC#Cc2cc(-c3cccc(OC(F)(F)F)c3)ccn2)(NC(=O)OC(C)(C)C)C1=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN1CC[C@@](N)(CC#Cc2cc(-c3cccc(OC(F)(F)F)c3)ccn2)C1=O
Reaction time: 0.75 h
Yield: 97.1 %

Procedure:
A solution of tert-butyl N-[(3S)-1-methyl-2-oxo-3-[3-[4-[3-(trifluoromethoxy)phenyl]-2-pyridyl]prop-2-ynyl]pyrrolidin-3-yl]carbamate (8.91 g, 18.19 mmol) (which may be prepared as described in Description 106) in 1,4-dioxane (70 mL) was cooled in an ice bath and treated dropwise with conc. H2SO4 (7.4 mL, 93.22 mmol). The mixture was allowed to reach room temperature and after 45 mins, the mixture was again cooled in an ice bath and treated cautiously with satd. aq. Na2CO3 solution (˜150 ml). The mixture was diluted with ethyl acetate (200 ml) and the product was extracted into ethyl acetate (2×150 ml). The combined organic extracts were dried (Na2SO4) and concentrated to give the title compound (D107) as an orange oil (6.88 g, 97%) consistent spectroscopically with that prepared by Method A.