Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@:3]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:34])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1.[O:41]1[C:45](=[O:46])[CH2:44][CH2:43][C:42]1=[O:47].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:42]([CH2:43][CH2:44][C:45]([NH:1][CH2:2][C@:3]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:34])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1)=[O:46])([OH:47])=[O:41]
Reactant: C=C(C)[C@@H]1CC[C@]2(CN)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(CNC(=O)CCC(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 18 h
Yield: 21 %

Procedure:
To a solution of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aminomethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (20 mg, 0.037 mmol) in DCM (2 ml) was added dihydrofuran-2,5-dione (11.04 mg, 0.110 mmol) followed by DMAP (4.49 mg, 0.037 mmol) and DIPEA (6.42 μl, 0.037 mmol). The mixture was stirred at rt for 18 h. The solvent was removed in vacuo and the resulting residue was purified by prep. HPLC. The product was isolated as a white solid (5 mg, 21.1%). LCMS: m/e 644.5 (MH+), 2.80 min (method 3). 1H NMR (400 MHz, MeOD) δ ppm 7.94 (d, J=8.5 Hz, 2H), 7.16-7.34 (m, 2H), 5.32 (dd, J=6.4, 1.6 Hz, 1H), 4.74 (d, J=2.0 Hz, 1H), 4.62 (s, 1H), 3.54 (d, J=13.6 Hz, 1H), 3.04 (d, J=13.8 Hz, 1H), 2.57-2.71 (m, 2H), 2.44-2.57 (m, 2H), 2.17 (dd, J=17.2, 6.4 Hz, 1H), 2.09 (dd, J=13.1, 1.8 Hz, 1H), 1.85 (dd, J=12.2, 3.4 Hz, 2H), 1.65-1.82 (m, 8H), 1.61 (br. s., 2H), 1.53 (d, J=10.5 Hz, 3H), 1.48 (d, J=2.0 Hz, 1H), 1.35-1.45 (m, 3H), 1.24-1.35 (m, 3H), 1.16-1.24 (m, 4H), 1.02-1.16 (m, 8H), 0.99 (s, 3H), 0.95 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([NH:15][C:16]2[C:25]([CH3:26])=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][N:20]([C@H:28]([CH3:31])[CH2:29]O)[C:21]3=[O:27])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C(Cl)Cl.C1(C)C=CC=CC=1.C1C=CC(OP(OC2C=CC=CC=2)([N:51]=[N+:52]=[N-:53])=O)=CC=1.N12CCCN=C1CCCCC2>>[N:51]([CH2:29][C@H:28]([N:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][CH:24]=[C:25]([CH3:26])[C:16]=2[NH:15][C:13](=[O:14])[CH2:12][C:4]2[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:9])[F:10])=[C:2]([F:1])[CH:3]=2)[C:21]1=[O:27])[CH3:31])=[N+:52]=[N-:53]
Reactant: Cc1ccc2c(=O)n([C@H](C)CO)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc2c(=O)n([C@H](C)CN=[N+]=[N-])ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 104 %

Procedure:
A solution of (R)-2-(3-fluoro-4-(trifluoromethyl)phenyl)-N-(2-(1-hydroxypropan-2-yl)-6-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)acetamide (0.5 g, 0.001 mol) in methylene chloride (20 mL, 0.3 mol) and toluene (10 mL, 0.09 mol) was cooled to 0° C. and treated with diphenylphosphonic azide (600 mg, 0.002 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.3 g, 0.002 mol) under nitrogen. The mixture was stirred at 0° C. for 2 h then allowed to warm to room temperature and was stirred overnight. The mixture was concentrated and the residue was treated with water (50 mL) and ethyl acetate (100 mL). The organic layer was separated, washed with brine, dried and evaporated. The residue was purified via flash chromatography to afford the desired product as a clear oil (0.48 g, yield 90%).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([OH:14])=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:25]=[CH:26][CH:27]=1)[C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20].C(N(CC)CC)C>C(Cl)Cl.C(O)C>[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([NH:15][C:16]1[CH:27]=[CH:26][CH:25]=[C:18]([CH:17]=1)[C:19]([O:21][CH:22]([CH3:23])[CH3:24])=[O:20])=[O:14]
Reactant: CC(C)OC(=O)c1cccc(N)c1
Reactant: CC1=C(C(=O)O)SCCO1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CC1=C(C(=O)Nc2cccc(C(=O)OC(C)C)c2)SCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
Thionyl chloride (3.5 g, 0.029 mole) was added to a stirred mixture of 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxylic acid (4.7 g, 0.029 mole) and methylene chloride (100 ml). The mixture was warmed to 30°-35° C. for 4 hours, then evaporated under reduced pressure. The residue, crude 5,6-dihydro-2-methyl-1,4-oxathiin-3-carbonyl chloride, was dissolved in methylene chloride (100 ml), and the ice-chilled solution treated dropwise with a solution of 1-methylethyl 3-aminobenzoate (5,.2 g, 0.029 mole) and triethylamine (2.9 g, 0.029 mole) in methylene chloride (50 ml). The reaction mixture was stirred overnight at room temperature and then worked up by washing in sequence with water, dilute hydrochloric acid, water, 2% sodium hydroxide and water. Evaporation of the solvent left an oil, which solidified. After recrystallization from ethanol (30 ml) the product (4.0 g, 42% yield) melted at 92°-94° C. Analysis: Calc.: C 59.79, H 5.96, N 4.36, Found: C 59.46, H 6.21, N 4.51
Reaction SMILES: [CH:1]1([C:4]2[C:13]([CH:14]=O)=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.P(=O)([O-])O[C:25](CC)(CC)[C:26]#[N:27].[Cl-].[OH-].[Na+]>C(CP(=O)(OCC)OCC)#N.C1(C)C=CC=CC=1.O>[CH:1]1([C:4]2[C:13]([CH:14]=[CH:25][C:26]#[N:27])=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Reactant: CCC(C#N)(CC)O[PH](=O)[O-]
Agent: CCOP(=O)(CC#N)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC=Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
In a 100 mL-volume glass flask equipped with a stirrer, a thermometer and a dropping funnel were placed under argon atmosphere 4.98 g (17.1 mmol) of 2-cyclo-propyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde, 3.10 mL (18.8 mmol) of diethylcyanomethyl phosphonate (purity 98%), 0.15 mL (0.33 mmol) of tricaprilmethylammonium chloride (Aliquat 336, available from Aldrich Corp.), and 35 mL of toluene. To the content kept at 25-35° C. (liquid temperature) was slowly added 10.1 g (50.5 mmol) of aqueous sodium hydroxide solution (20 wt. %), and the mixture was reacted for 3 hours at the same temperature. Subsequently, 0.14 mL (0.85 mmol) of diethyl (cyanomethyl)-phosphonate (purity 98%) was added, and the mixture was reacted for 66 hours at the same temperature. After the reaction was complete, 5 mL of water was added to the reaction mixture, and the mixture was stirred for 30 minutes. To the mixture was added 50 mL of toluene, and the organic portion is taken out. The organic portion was washed with 10 mL of an aqueous sodium hydroxide solution (10 wt. %), and to the washed portion was added 10 mL of saturated aqueous sodium chloride solution. The aqueous mixture was neutralized by addition of 5.6 mL of hydrochloric acid (1 mol/L)., and the organic portion was taken out. The organic portion was placed in a 200 mL-volume glass flask equipped with a stirrer. To the organic portion was added 1.60 g of anhydrous sodium sulfate, and the mixture was stirred for one hour at room temperature. To the mixture were further added 0.14 g of active carbon (powder, available from Wako Junyaku Co., Ltd.) and 0.62 g of silica gel (Wakogel C-200, available from Wako Junyaku Co., Ltd.). The mixture was then stirred for 1.75 hours at room temperature, and filtered. through a celite. The celite was washed with 50 mL of toluene. The reaction liquid was concentrated under reduced pressure to precipitate a crystalline product. The crystalline product was heated to melt, and after addition of 30 mL of hexane, heated under reflux for 30 minutes. Thereafter, the liquid was chilled to 5° C., and stirred for 2 hours to precipitate a crystalline product. The crystalline product was collected by filtration, washed with 30 mL of hexane, and dried at 55° C. under reduced pressure, to obtain 4.81 g (yield 90%) of 3-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]prop-2-enenitrile as a white crystalline product.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:13][N:12]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[O:23])[N:11]=2)=[CH:6][CH:5]=1.C(=O)(O)[O-].[Na+]>COCCOC.[Ti](Cl)(Cl)(Cl)Cl>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH:14]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[CH2:13][N:12]([C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:27][CH:26]=3)=[O:23])[NH:11]2)=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)N1CC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)=N1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: COCCOC
Product: O=C(Nc1ccc(C(F)(F)F)cc1)N1CC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 24.3 %

Procedure:
To a solution of 0.473 g (0.0025 mol) of titanium tetrachloride in 10 mL of 1,2-dimethoxyethane was added 0.189 g (0.0048 mol) of sodium borohydride all at once at 0° C. The green solution was stirred at 0° C. for 5 minutes and 0.500 g (0.0012 mol) of 3,4-bis(4-chlorophenyl)-4,5-dihydro-N-[4-(trifluoromethyl)phenyl]-1H-pyrazole-1-carboxamide dissolved in 5 mL of 1,2-dimethoxyethane was added dropwise over 5 minutes. The cooling bath was removed and the dark brown solution was stirred at room temperature for 3 hours. The crude reaction mixture was poured into 100 mL of saturated sodium bicarbonate solution and extracted with ethyl acetate (3×50 mL). The ethyl acetate was washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure to afford a yellow solid. The crude reaction product was chromatographed on silica gel with ethyl acetate/hexanes (40%:60%) as eluent and afforded 0.140 g of the title compound as a white solid; mp 242°-243° C.
Reaction SMILES: [O-]I(=O)(=O)=O.[Na+].[CH3:7][O:8][C:9]([C:11]1[N:12]([CH3:40])[N:13]=[C:14]([O:16][CH2:17][C:18]2[C:19]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[N:20][O:21][C:22]=2[C@@H:23]([OH:32])[C@H](O)C2C=CC=CC=2)[CH:15]=1)=[O:10]>C1COCC1.O>[CH3:7][O:8][C:9]([C:11]1[N:12]([CH3:40])[N:13]=[C:14]([O:16][CH2:17][C:18]2[C:19]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[N:20][O:21][C:22]=2[CH:23]=[O:32])[CH:15]=1)=[O:10]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2[C@@H](O)[C@H](O)c2ccccc2)nn1C
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C=O)nn1C
Temperature: 0 °C
Yield: 88.6 %

Procedure:
Sodium (meta)periodate (3.67 g, 17.2 mmol) was added at 0° C. to a mixture of 5-[5-((1S,2R)-1,2-dihydroxy-2-phenyl-ethyl)-3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (5.35 g, 11.4 mmol) in THF (29.6 ml) and water (6.1 ml) and the resulting mixture stirred at 0° C. over night. The reaction mixture was extracted with water and ethyl acetate, and the organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica, heptane:ethyl acetate=1:0 to 4:1) afforded the title compound (3.63 g, 88%) as a white solid. MS: m/e=418.1 [M+OAc]−.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[S:11][C:12]4[C:17]([N:18]=3)=[CH:16][CH:15]=[C:14]([C:19]3([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:21][CH2:20]3)[N:13]=4)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:28]([O:30][C:31](=[O:34])[CH:32]=[CH2:33])[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[C:22]1([C:19]2([C:14]3[N:13]=[C:12]4[S:11][C:10]([C:6]5[CH:5]=[C:4]6[C:9](=[CH:8][CH:7]=5)[N:1]([CH2:33][CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:34])[CH:2]=[CH:3]6)=[N:18][C:17]4=[CH:16][CH:15]=3)[CH2:20][CH2:21]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C=CC(=O)OCC
Reactant: c1ccc(C2(c3ccc4nc(-c5ccc6[nH]ccc6c5)sc4n3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)CCn1ccc2cc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)ccc21
Reaction time: 3 h

Procedure:
To 2-(1H-indol-5-yl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (90 mg, 0.245 mmol) was added acetonitrile (2.4 mL), ethylacrylate (80 μl, 735 μmol), and cesium carbonate (160 mg, 0.490 mmol) before it was stirred at ambient temp. for 3 h; the reaction mixture was quenched with 2 N HCl, concentrated, and was diluted with 75 mL of EtOAc, added to a separatory funnel, partitioned with water, washed 1 time with 50 mL of water, separated, dried over sodium sulfate, and concentrated via rotovap to give ethyl 3-(5-(5-(1-phenylcyclopropyl)[1,3]thiazolo[5,4-b]pyridin-2-yl)-1H-indol-1-yl)propanoate.
Reaction SMILES: C([NH:8][C:9]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][S:11](=[O:14])(=[O:13])[CH2:10]1)C1C=CC=CC=1>CCO.[Pd]>[NH2:8][C:9]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][S:11](=[O:14])(=[O:13])[CH2:10]1
Reactant: CCOC(=O)CC1(NCc2ccccc2)CS(=O)(=O)C1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1(N)CS(=O)(=O)C1
Temperature: 50 °C
Reaction time: 16 h
Yield: 100.5 %

Procedure:
To a solution of ethyl 2-[3-(benzylamino)-1,1-dioxo-thietan-3-yl]acetate (example 160b, 0.5 g, 1.68 mmol) in EtOH (12.5 ml) under an argon atmosphere was added palladium on charcoal 10% (w/w 10%) (50.0 mg, 470 μmol). The reaction flask was put under a pressure of 2.5 bar H2 and the reaction mixture was then stirred at 50° C. for 16 hours. Palladium catalyst was removed by filtration over a pad of Celite and the filter cake was washed with ethanol twice. The filtrate was evaporated down to dryness to yield the title compound (350 mg, 100%) as a crude product which was used without any purification. MS (ESI, m/z): 208.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:5]=[C:4]([NH:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[N:5]=[C:4]([NH:23][CH2:24][C:25]([CH3:26])([CH3:28])[CH3:27])[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(NCC(C)(C)C)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(NCC(C)(C)C)nc1-c1ccc(C)cc1
Yield: 87.2 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-methyl-2-(neopentylamino)-6-p-tolylpyrimidin-5-yl)pentanoate (0.057 g; 0.149 mmol), sodium hydroxide 10N (0.10 mL; 1.00 mmol) in methanol (1 mL) at 60° C. for 18 h. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water and extracted with diethyl ether. The pH of the aqueous layer was adjusted between 2 and 3 by addition of a solution of hydrochloric acid 6N until a precipitate was formed. The suspension was extracted twice with ethyl acetate and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 0.048 g (87%) of the title compound.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1)[CH2:2][CH3:3].Cl.[NH2:19][OH:20]>>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14](=[N:19][OH:20])[CH2:13][CH2:12]1)[CH2:2][CH3:3]
Reactant: NO
Reactant: CCCOCCCCCCN1CCC(=O)CC1
Agent: Cl
Product: CCCOCCCCCCN1CCC(=NO)CC1

Procedure:
1-(6-Propoxyhexyl)-4-piperidone oxime is prepared from 1-(6-propoxyhexyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:11]([O:13][CH:14]([Cl:16])[CH3:15])=[O:12]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:3]([N:2]([CH3:1])[C:11](=[O:12])[O:13][CH:14]([Cl:16])[CH3:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNCc1ccccc1
Reactant: CC(Cl)OC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(Cl)OC(=O)N(C)Cc1ccccc1
Yield: 54.9 %

Procedure:
To a vigorously stirred suspension of N-methylbenzylamine (0.260 mL, 2 mmol) in EtOAc (3 mL) and 3 mL of saturated NaHCO3 solution was added 1-chloroethyl chloroformate (0.160 mL, 2 mmol). Effervescence was observed. Once gas production had ceased, the reaction mixture was diluted with hexanes (10 mL). The aqueous phase was removed and the organic phase was washed with brine (5 mL), dried and concentrated to give the crude product as an oil (˜0.250 g). The compound was used in the subsequent step without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[NH:17][CH:16]2[C:34](O)=[O:35])[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:42][C@@H:41]([CH2:43][CH2:44][NH2:45])[CH2:40][O:39]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:42][C@H:41]([CH2:40][OH:39])[CH2:43][CH2:44][NH:45][C:34]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=2)[C:19]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)([C:20]#[N:21])[CH:18]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[NH:17]1)=[O:35]
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: CCC(CC)C1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)C1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Yield: 96.4 %

Procedure:
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 43c (0.55 g, 1 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.2 g, 1.3 mmol), HATU (0.4 g, 1.1 mmol) and iPr2NEt (0.2 g, 1.5 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(1-ethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.5 g, 96%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:21])=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[C:7](=[O:14])[N:6]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:5]2=[O:20].CO.[H][H]>[Pd].C(O)(=O)C>[NH2:1][C:2]1[C:3]([CH3:21])=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[C:7](=[O:14])[N:6]([CH2:15][CH2:16][N:17]([CH3:18])[CH3:19])[C:5]2=[O:20]
Reactant: [H][H]
Reactant: Cc1c(N)c([N+](=O)[O-])cc2c1C(=O)N(CCN(C)C)C2=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(N)c(N)cc2c1C(=O)N(CCN(C)C)C2=O

Procedure:
To a solution of 5-amino-2-(2-(dimethylamino)ethyl)-4-methyl-6-nitroisoindoline-1,3-dione (0.40 g, 1.37 mmol) in the mixture of methanol (8 mL) and acetic acid (0.4 mL) was added Pd/C (20 mg), and the resulting reaction mixture was hydrogenated for 2-3 h at 20-25 psi of hydrogen at rt. The reaction mixture was filtered through a pad of Celite and washed with methanol. The combined solvents were concentrated under vacuum to dryness. The crude product was used for the next step reaction without further purification. Mass (ESI, positive) m/z 263.0 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].Cl[C:15]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=1.C([O-])([O-])=O.[K+].[K+].C(N(CC)CC)C>C1COCC1>[C:10]([O:9][C:7](=[O:8])[CH2:6][CH:2]1[CH2:3][CH2:4][CH2:5][N:1]1[C:15]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)CC1CCCN1
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(N2CCCC2CC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
Tert-butyl 2-(pyrrolidin-2-yl)acetate (1.00 g, 5.40 mmol) was added to a solution of methyl 6-chloro-5-nitronicotinate (1.169 g, 5.40 mmol) in THF (Volume: 10 ml). The reaction mixture was stirred at rt for 1 h and K2CO3 (0.760 g, 5.50 mmol) was added. The reaction mixture was stirred for 2 h and triethylamine (0.379 ml, 2.70 mmol) was added. The mixture was stirred for 1 h, filtered and concentrated in vacuo. Flash column chromatography on silica gel (120 g SiO2, hexanes:ethyl acetate 9:1) afforded methyl 6-(2-(2-tert-butoxy-2-oxoethyl)pyrrolidin-1-yl)-5-nitronicotinate (1.79 g, 4.90 mmol, 91% yield) as a yellow oil. [M+H] calc'd for C17H23N3O6, 365. found, 365.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[NH:6][N:5]=1)([CH3:3])[CH3:2].[CH2:12](O)[CH3:13].C(Cl)(=O)C>C1C=CC=CC=1>[CH:1]([C:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CCO
Reactant: CC(C)c1cc(C(=O)O)[nH]n1
Solvent: CC(=O)Cl
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(C(C)C)n[nH]1

Procedure:
To a clean round bottom flask equipped with a stir bar, Dean-Stark trap, and reflux condenser was added 3-isopropyl-1H-pyrazole-5-carboxylic acid (1 gram, 6.49 mmol, purchased from Fisher Scientific). 30 mL of ethanol (95%, purchased from Fisher Scientific) was added followed by 30 mL of benzene. 43 μL of acetyl chloride was then added and the solution refluxed over the three days. The solvent was then removed using a Buchi rotoevaporator. The residue was then taken up in ethyl acetate and washed with NaHCO3 (saturated). It was then dried with sodium sulfate, filtered and concentrated. Purification using a Teledyne ISCO silica chromatography (hexanes/ethyl acetate gradient) afforded the desired ester. Yield, 85% 1H-NMR δ 6.7 (s, 1H), 5.1 (bs, NH), 4.41 (q, 2H), 3.13 (septet, 1H), 1.38 (t, 3H), 1.33 (d, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]#[N:27])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.N.[H][H]>[Ni].CO>[NH2:27][CH2:26][CH2:25][N:22]1[CH2:23][CH2:24][CH:19]([NH:18][C:10]2[N:9]([CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=2)[CH2:20][CH2:21]1
Reactant: [H][H]
Reactant: N#CCN1CCC(Nc2nc3cccnc3n2Cc2ccc(F)cc2)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCN1CCC(Nc2nc3cccnc3n2Cc2ccc(F)cc2)CC1
Yield: 68 %

Procedure:
A mixture of 15 parts of 4-[[3-[(4-fluorophenyl)methyl]-3H-imidazo [4,5-b]pyridin-2-yl]amino]-1-piperidineacetonitrile and 400 15 parts of methanol saturated with ammonia was hydrogenated at normal pressure and at room temperature with 3 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from a mixture of acetonitrile and 2,2'-oxybis-propane, yielding 10 parts (68%) of N-[1-(2-aminoethyl)-4-piperidinyl]-3-[(4-fluorophenyl)methyl]-3H-imidazo[4,5-b]pyridin-2-amine; mp. 174.5° C. (50). In a similar manner there were also prepared: