Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of (tert-butoxy)-N-[2-(4-nitrophenyl)ethyl]-carboxamide (570 mg, 2.15 mmol, Step A), iron powder (602 mg, 10.75 mmol) and NH4Cl (82 mg, 1.5 mmol) in EtOH (6 mL) and H2O (6 ml) was stirred for 4 h at 80° C. Filtration and concentration gave the crude compound, which was used in next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]([CH3:22])([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)[CH3:5].[OH-].[K+]>O1CCOCC1>[CH3:22][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][N:13]=2)[CH2:10][CH2:11]1)([CH3:5])[C:3]([OH:23])=[O:2]
Reactant: COC(=O)C(C)(C)N1CCN(c2ccc(C(F)(F)F)cn2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C(=O)O)N1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A solution of 2-methyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-propionic acid methyl ester (1.05 g, 3.17 mmoles) from Example 14B in dioxane (10 mL) was treated with 5N potassium hydroxide (10 mL) and stirred for 4 hours at 60° C. The dioxane was removed under reduced pressure, the residue was neutralized with 1N HCl to pH=7 and extracted three times with 4:1 THF:DCM. The combined organic extracts were dried (MgSO4), filtered and the filtrate concentrated under reduced pressure to provide the title compound as a white solid.
Reaction SMILES: [N:1]1[C:2]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][NH:15][C:14](=[O:18])[CH:13]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Br[C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31][CH2:30][C:25]=3[N:26]([CH3:29])[C:27]=2[CH:28]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.[Cu]I>[N:1]1[C:2]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]([C:20]3[CH:21]=[CH:22][C:23]4[C:24]5[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31][CH2:30][C:25]=5[N:26]([CH3:29])[C:27]=4[CH:28]=3)[C:14](=[O:18])[CH:13]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=c1cc(OCc2cn3ccccc3n2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(OCc5cn6ccccc6n5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Temperature: 135 °C
Reaction time: 8 h
Yield: 26.2 %

Procedure:
A suspension of 4-(imidazo[1,2-a]pyridin-2-ylmethoxy)pyridin-2(1H)-one (231 mg, 0.960 mmol), tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (421 mg, 1.15 mmol), CuI (219 mg, 1.15 mmol), 8-hydroxyquinoline (84 mg, 0.576 mmol) and Cs2CO3 (345 mg, 1.06 mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min. The suspension was put under Ar and heated at 135° C. with stirring overnight. The suspension was cooled, 40:9:1 CH2Cl2/MeOH/NH4OH (50 mL) was added, and the resulting suspension was stirred at 25° C. for 30 min. The suspension was passed through a plug of silica gel, and the filtrate was washed with brine and 10% CuSO4 solution. The solution was dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(4:0.9:0.1 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100) gave the title compound (132 mg, 26%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J=6.9 Hz, 1H), 7.70 (br s, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.33-7.18 (m, 3H), 7.02 (d, J=7.5 Hz, 1H), 6.82 (dd, J=6.9, 6.9 Hz, 1H), 6.17 (d, J=2.1 Hz, 1H), 6.08 (dd, J=7.5, 2.1 Hz, 1H), 5.25 (s, 2H), 3.84 (br s, 2H), 3.63 (s, 3H), 2.84-2.79 (m, 2H), 1.72-1.60 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.N1C=CC=CC=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>ClCCl>[CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][N:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1)[S:28]([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)(=[O:30])=[O:29]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(CNCc1ccc(F)cc1)OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(CN(Cc1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 25 °C
Yield: 66.6 %

Procedure:
20 g of (2,2-dimethoxy-ethyl)-(4-fluoro-benzyl)-amine (crude 1) were dissolved in 120 ml of dichloromethane. 20 mL of pyridine were added. At 0° C. a solution of 23.8 g p-toluenesulfonic acid chloride in dichloromethane was added dropwise. The reaction was allowed to warm to room temperature and stirring was continued until conversion was completed. For workup, the reaction mixture was washed twice with 2M hydrochloric acid, twice with sodium bicarbonate solution and once with brine. The organic layer was dried over magnesium sulfate, evaporated to dryness and the obtained crude product was purified by silica gel chromatography to yield 22.95 g of compound 2 as an orange oil. Rt=1.71 min (Method C). Detected mass: 336.1 (M-OMe−).
Reaction SMILES: [C:1]([C@H:5]1[C:33](=[O:34])[N:32]2[CH2:35][C@@H:29]([CH2:30][C@H:31]2[C:36]([O:38]C)=[O:37])[O:28][C:17]2=[N:18][C:19]3[CH:20]=[C:21]([O:26][CH3:27])[CH:22]=[CH:23][C:24]=3[N:25]=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:40][C@H:9]2[O:8][C:7](=[O:41])[NH:6]1)([CH3:4])([CH3:3])[CH3:2].O.C1COCC1.O[Li].O.Cl>CCOC(C)=O>[C:1]([C@H:5]1[C:33](=[O:34])[N:32]2[CH2:35][C@@H:29]([CH2:30][C@H:31]2[C:36]([OH:38])=[O:37])[O:28][C:17]2=[N:18][C:19]3[CH:20]=[C:21]([O:26][CH3:27])[CH:22]=[CH:23][C:24]=3[N:25]=[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[CH2:40][C@H:9]2[O:8][C:7](=[O:41])[NH:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1nc3ccc(OC)cc3nc1O2
Agent: Cl
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2nc3c(nc2c1)O[C@@H]1C[C@@H](C(=O)O)N(C1)C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCC3
Temperature: 20 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A solution (0.1 M) of methyl (1aR,5S,8S,10R,22aR)-5-tert-butyl-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoxaline-8-carboxylate in a 1:1 mixture of H2O/THF was treated with LiOH.H2O (3 eq). The resulting mixture was stirred at 20° C. for 18 h, acidified with aqueous HCl (0.2 M) and diluted with EtOAc. The organic phase was separated, washed with aqueous HCl (0.2 M) and brine then dried. Removal of the volatiles afforded the title compound (98%) as a solid. MS (ES+) m/z 555 (M+H)+
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[C:2]([O:4]C)=O.C[O-].[Na+].CO.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[CH:17][CH:16]=1.Cl>C(OCC)C.C(OCC)(=O)C>[CH3:8][O:7][C:1](=[O:6])[C:2](=[O:4])[CH2:22][C:21]([C:18]1[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=1)=[O:23]
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C(=O)CC(=O)c1ccc(Cl)cc1
Yield: 11.8 %

Procedure:
Dimethyl oxalate (23.6 g, 200 mmol) was placed in a 500 mL three-necked round bottom flask, and dissolved in diethyl ether (200 mL). To the stirred solution was added 25% sodium methoxide in methanol (48 mL, 210 mmol) via an addition funnel over a 2 minute period. Next, 4′-chloroacetophenone (25.91 g, 200 mmol) was dissolved in diethyl ether (50 mL), and added to the reaction dropwise over 3-minutes. After stirring overnight (18 hours), 1N HCl (400 mL) and ethyl acetate (750 mL) were added. The organic layer was collected, washed with brine (350 mL), dried over MgSO4, filtered, and concentrated in vacuo to give 5.7 g of a yellow solid. The solid was recrystallized from ethyl acetate and iso-octane to give 23 g (48%) of the dione: mp 108.5-110.5° C.
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]=[CH:7][CH:3]([CH2:4]2)[CH2:2]1.[CH2:8]=[CH:9][CH:10]=[CH2:11]>CC1C=CC(O)=CC=1>[CH:3]12[CH2:4][CH:5]([CH:1]3[C:2]1=[CH:11][CH2:10][CH2:9][CH2:8]3)[CH2:6][CH2:7]2
Reactant: C1=CC2CCC1C2
Reactant: C=CC=C
Agent: Cc1ccc(O)cc1
Product: C1=C2C3CCC(C3)C2CCC1
Temperature: 200 °C
Yield: 145.8 %

Procedure:
A 400 ml autoclave was charged with bicyclo[2,2,1]-2-heptene (152 g, Aldrich), 4-methylphenol (1 g, Aldrich), and butadiene (110 g). The mixture was heated at 200° C. for 10 hours. The reaction mixtures from four identical reactions were combined and distilled at atmosphere to give starting bicyclo[2,2,1]-2-heptene (307 g). Further distillation at reduced pressure afforded octahydro-1,4-methanonaphthalene (349 g with 97–98% purity, bp 47° C./0.05 Torr, yield 73%, based on consumed bicyclo[2,2,1]-2-heptene) and about 120 g of product with lower purity (bp 47° C./2 Torr to 58° C./0.16 Torr).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]#[CH:18])[CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:6])[CH2:2][CH3:3].[OH-].[K+]>CO.O.C(Cl)(Cl)Cl>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]#[CH:18])[CH:16]=1)[C:10]([OH:12])=[O:11])=[O:6])[CH2:20][CH3:21]
Reactant: C#Cc1cc(C(=O)OC)cc(C(=O)N(CCC)CCC)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C#Cc1cc(C(=O)O)cc(C(=O)N(CCC)CCC)c1
Reaction time: 4 h

Procedure:
To a stirred mixture of the protected methyl 3-[(dipropylamino)carbonyl]-5-ethynylbenzoate (XXXII, Step 1, 185.3 mg, 0.49 mmol) in methanol (2.5 mL) is added a mixture of potassium hydroxide (2.9 mL of a 1 M mixture in water, 2.9 mmol). The reaction mixture is stirred for 4 hours diluted with chloroform (40 mL), the phases are separated and the organic phase is concentrated under reduced pressure to give 3-[(dipropylamino)carbonyl]-5-ethynylbenzoic acid, NMR (300 MHz, CDCl3): δ 8.22, 8.05, 7.71, 3.48, 3.17, 3.16, 1.71, 1.55, 1.00 and 0.78.
Reaction SMILES: Br[C:2]([Br:13])([Br:12])[CH2:3][CH:4]1[C:7]([CH3:9])([CH3:8])[CH:6](Br)[C:5]1=[O:11].[OH-].[Na+].[O:16]1CCOCC1>O>[Br:13][C:2]([Br:12])=[CH:3][C@H:4]1[C:7]([CH3:8])([CH3:9])[C@H:6]1[C:5]([OH:11])=[O:16]
Reactant: CC1(C)C(Br)C(=O)C1CC(Br)(Br)Br
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)[C@H](C=C(Br)Br)[C@@H]1C(=O)O
Temperature: 80 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
700 mg (1.56 mmols) of 2-(2',2',2'-tribromoethyl)-3,3-dimethyl-4-bromocyclobutanone are stirred with a solution of 190 mg of NaOH in 5 ml of water, to which 0.5 ml of dioxane has been added, for 2 hours at room temperature. The mixture is then stirred for 1 hour at 80° C. The clear solution is worked up to the acid in the customary way. 410 mg (88% of theory) of cis-2-(2',2'-dibromovinyl)-3,3-dimethylcyclopropanecarboxylic acid are obtained.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[C-:19]#[N:20].[Na+]>O>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][C:19]#[N:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: ClCc1cccc(Oc2ccccc2)c1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCc1cccc(Oc2ccccc2)c1
Yield: 91 %

Procedure:
To a solution of 218 g. m-phenoxy-benzyl chloride in 850 ml. of 96% ethyl alcohol a solution of 57.8 g. of sodium cyanide in 100 ml. of water is added at once. The reaction mixture is boiled under stirring until the starting material cannot be detected anymore by thin layer chromatography. When the reaction is completed the reaction mixture is poured into 1 liter of water and the separating oil is extracted with 3×500 ml. of benzene. The combined benzene solutions are washed with 1 liter of water and dried above sodium sulphate. Sodium sulphate is filtered off and benzene is distilled off. 190 g. (91%) of m-phenoxy-benzyl cyanide are obtained (purity more than 90%, determined by gas chromatography). Boiling point 138° C./0.2 mmHg.
Reaction SMILES: C([NH:11][C:12]([CH3:33])([C:14]([NH:16][CH2:17][CH:18]1[O:32][C:21]2=[C:22]3[C:27](=[C:28]([CH3:30])[CH:29]=[C:20]2[CH2:19]1)[NH:26][C:25](=[O:31])[CH:24]=[CH:23]3)=[O:15])[CH3:13])(OCC1C=CC=CC=1)=O.[H][H]>CN(C)C=O.CO.[Pd]>[CH3:30][C:28]1[CH:29]=[C:20]2[CH2:19][CH:18]([CH2:17][NH:16][C:14](=[O:15])[C:12]([CH3:13])([CH3:33])[NH2:11])[O:32][C:21]2=[C:22]2[C:27]=1[NH:26][C:25](=[O:31])[CH:24]=[CH:23]2
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)C(C)(C)NC(=O)OCc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)C(C)(C)N)C2
Yield: 95.5 %

Procedure:
2-(N-Carbobenzyloxy-α-methylalanyl]aminomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (2.46 g, 5.48 mmol) was dissolved in dimethylformamide (190 ml). To the obtained solution, 10% palladium-on-carbon (2.46 g) was added, followed by stirring at room temperature for 3 hours in the atmosphere of hydrogen. The reaction mixture was filtered, and the filtrate was condensed. The resultant residue was dissolved in methanol (70 ml). To the obtained solution, 1.37 N-HCl--methanol (4.39 ml) was added at room temperature, followed by condensing under reduced pressure. The resultant residue was submitted to a recrystallizing procedure using methanol to obtain 1.65 g of the title compound as pale yellow powdery crystals (85.6%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:10](Cl)(Cl)=[O:11].[OH-].[Na+].Cl>C1(C)C=CC=CC=1>[Cl:8][C:6]1[CH:7]=[C:2]2[NH:1][C:10](=[O:11])[S:9][C:3]2=[N:4][CH:5]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1cc(Cl)cnc1S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cc(Cl)cnc2s1
Temperature: 50 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
3-Amino-5-chloro-2-mercaptopyridine (18.8 g) was added to an ice-cooled solution of phosgene (30 g) in toluene (350 ml). 10% Aqueous solution of sodium hydroxide (300 ml) was added dropwise to the stirred mixtured for a period of 1 hour below 20° C. The final mixture was stirred for 1.5 hous at ambient temperature and then stirred for an additional 1 hour at 50° C. After cooling, the aqueous layer was adjusted to pH 4.0 with 4N hydrochloric acid. The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide to give white powder of 6-chloro-2-oxo-1,2-dihydrothiazolo[5,4-b]pyridine (15.08 g).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH:13]=[C:12]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[NH:26])[NH2:25])=[CH:20][CH:19]=2)=[O:15])[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:34]([O:36][CH3:37])=[O:35]>O.O1CCCC1>[NH2:26]/[C:24](=[N:25]\[C:34](=[O:35])[O:36][CH3:37])/[C:21]1[CH:20]=[CH:19][C:18]([CH2:17][NH:16][C:14]([C:12]2[CH:11]=[N:10][N:9]([CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:13]=2)=[O:15])=[CH:23][CH:22]=1
Reactant: N=C(N)c1ccc(CNC(=O)c2cnn(Cc3ccccc3)c2)cc1
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)/N=C(\N)c1ccc(CNC(=O)c2cnn(Cc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
57 mg of 1-benzyl-N-[(4-carbamimidoylphenyl)methyl]pyrazole-4-carboxamide hydrochloride and 59 mg of potassium carbonate were dissolved in 0.72 ml of water and 3.6 ml of tetrahydrofuran. The mixture was stirred at room temperature, and 0.012 ml of methyl chloroformate (Sigma-Aldrich) added. Stirring is continued for 1 h, following which the organic layer is removed, and dried in vacuo to obtain the synthetic target. The mass of the compound was verified using LC/MS/MS.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]([NH:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:22]([F:25])([F:24])[F:23])[CH:9]=2)[N:4]=1)#[N:2].C1C[O:29]CC1>CCO>[C:1]([C:3]1[CH:12]=[C:11]([NH:13][CH2:14][C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:22]([F:25])([F:24])[F:23])[CH:9]=2)[N:4]=1)(=[O:29])[NH2:2]
Reactant: CC(C)(C)OC(=O)CNc1cc(C#N)nc2ccc(C(F)(F)F)cc12
Reactant: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)CNc1cc(C(N)=O)nc2ccc(C(F)(F)F)cc12
Temperature: 75 °C
Reaction time: 3 h

Procedure:
A solution of tert-butyl 2-((2-cyano-6-(trifluoromethyl)quinolin-4-yl)amino)acetate (329 mg, 0.94 mmol) from above step A, in EtOH (3 mL) water (600 uL) and THF (5 mL) was added hydrido(dimethylphosphinous acid-kp)[hydrogen bis(dimethylphosphinito-kp)]platinum(ii) (80 mg, 0.18 mmol) and stirred at 75° C. for 3 h. The mixture was filtered to remove the white solid that had formed and the filtrate was evaporated under vacuum. The residue was purified by silica column chromatography to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:19]=[C:13]3[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][N:12]3[N:11]=2)=[CH:5][C:4]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([N:26]3[C:38](=[O:39])[C:37]4[S:36][C:35]5[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=5[C:29]=4[CH:28]=[N:27]3)[C:21]=2[CH:40]=[O:41])=[CH:3]1.[BH4-].[Na+]>CO>[OH:41][CH2:40][C:21]1[C:22]([N:26]2[C:38](=[O:39])[C:37]3[S:36][C:35]4[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=4[C:29]=3[CH:28]=[N:27]2)=[N:23][CH:24]=[CH:25][C:20]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:19]=[C:13]3[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][N:12]3[N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: CN1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6c7c(sc6c5=O)CCCC7)c4C=O)cn(C)c3=O)cc2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6c7c(sc6c5=O)CCCC7)c4CO)cn(C)c3=O)cc2C1
Temperature: 30 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
A mixture of 181a (300 mg, 0.50 mmol) and NaBH4 (60 mg, 1.5 mmol) in methanol (20 mL) was stirred at 30° C. for 1 h. The mixture was quenched with water and concentrated under reduced pressure. The residue was extracted with ethyl acetate (3×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 181 (100 mg, 35%). MS-ESI: [M+H]+ 571.2. 1H NMR (500 MHz, CHCl3) δ 8.64 (d, J=5.0 Hz, 1H), 8.30 (s, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.53 (d, J=5.0 Hz, 1H), 7.43 (s, 1H), 5.70 (s, 1H), 4.45-4.43 (m, 2H), 4.32 (bs, 1H), 4.11-4.09 (m, 2H), 3.71 (s, 3H), 3.63 (s, 2H), 2.99-2.97 (m, 2H), 2.93-2.91 (m, 2H), 2.88-2.86 (m, 2H), 2.50 (s, 3H), 2.00-1.98 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19](=[O:29])[NH:20][CH:21]2[CH:26]3[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]3)[CH2:22]2)[C:5]2[N:6]=[C:7]([NH:9]C(=O)OC(C)(C)C)[O:8][C:4]=2[CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:23]12[CH2:22][C@@H:21]([NH:20][C:19]([C:17]3[CH:18]=[C:2]([Cl:1])[CH:3]=[C:4]4[O:8][C:7]([NH2:9])=[N:6][C:5]=34)=[O:29])[CH:26]([CH2:27][CH2:28]1)[CH2:25][CH2:24]2
Reactant: CC(C)(C)OC(=O)Nc1nc2c(C(=O)NC3CN4CCC3CC4)cc(Cl)cc2o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc2c(C(=O)N[C@@H]3CN4CCC3CC4)cc(Cl)cc2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.5 %

Procedure:
To a solution of tert-butyl 6-chloro-4-(quinuclidine-8-yl-carbamoyl)benzoxazole-2-yl-carbamate (71 mg, 0.17 mmol) in CH2Cl2 (1 mL) was added TFA (1 mL). The reaction mixture stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the crude material was treated with concentrated ammonium hydroxide to adjust the pH to 7. The mixture was concentrated under reduced pressure and the crude material was purified by preparative TLC (90:9:1 CH2Cl2/CH3OH/concentrated NH4OH) to afford (S)—N-(quinuclidine-8-yl)-2-amino-6-chlorobenzoxazole-4-carboxamide (21 mg, 38%) as a white solid, which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[OH:22])=[O:14])[CH:4]=1)=O.[Cl-].[C:24]([C:26]1([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][NH2+:29][CH2:28][CH2:27]1)#[N:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(N(CC)CC)C>ClC(Cl)C>[C:24]([C:26]1([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][N:29]([CH2:1][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]=[C:5]([C:13]([NH:15][C@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]3[OH:22])=[O:14])[CH:4]=2)[CH2:28][CH2:27]1)#[N:25]
Reactant: O=Cc1cc(C(=O)N[C@H]2CCCC[C@@H]2O)nc2ccccc12
Reactant: N#CC1(c2ccncc2)CC[NH2+]CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: N#CC1(c2ccncc2)CCN(Cc2cc(C(=O)N[C@H]3CCCC[C@@H]3O)nc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-formyl-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide (0.035 g, 0.117 mmol) in 0.50 mL dichloroethane was added 4-cyano-4-(pyridin-4-yl)piperidinium chloride (0.032 g, 0.141 mmol), sodium triacetoxyborohydride (0.037 g, 0.176 mmol), and triethylamine (0.016 mL, 0.117 mmol). The reaction mixture was stirred at room temperature overnight and concentrated. The resultant residue was subjected to purification via reverse phase HPLC. The isolated material was then purified via preparative TLC (7% MeOH/CH2Cl2) to afford the titled compound that gave a mass ion (ES+) of 470.2551 for M+H+.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1[CH:14]=[C:13]([CH:15](O)[CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:11][C:10]=1[O:26][CH3:27]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:8][C:9]1[CH:14]=[C:13]([CH:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[CH:12]=[CH:11][C:10]=1[O:26][CH3:27]
Reactant: COc1ccc(C(O)CCCc2ccccc2)cc1C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccc(C2CCCc3ccccc32)cc1C
Reaction time: 0.08 h
Yield: 52.7 %

Procedure:
A 1M solution of titanium tetrachloride in toluene (74.1 mL, 74.1 mmol) was added dropwise to a solution of 2-methyl-4-(1-hydroxy-4-phenyl-1-butyl) anisole (5.0 g, 18.5 mmol) in methylene chloride. The mixture was stirred at room temperature for 3h, then the reaction was quenched by pouring into excess aqueous saturated sodium bicarbonate. After stirring for 5 min the mixture was extracted with ether, and the organic phase was dried over magnesium sulfate, concentrated, and purified by chromatography over silica gel eluted with hexanes to afford 2.46 g of 2-methyl-4-(1-tetralinyl) anisole as a clear oil.
Reaction SMILES: [Na].[NH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]([O:11][CH2:12]C)=[O:10])[CH:4]=1>CO>[NH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]=1
Reactant: CCOC(=O)c1cc(N)n(C)n1
Agent: [Na]
Solvent: CO
Product: COC(=O)c1cc(N)n(C)n1
Yield: 74.8 %

Procedure:
To a solution of 48 mg (2.1 mmol) of sodium in 40 ml of methanol is added 2.0 mg (11.8 mmol) of 5-amino-3-ethoxycarbonyl-1-methylpyrazole, and the mixture is refluxed over night, and distilled under reduced pressure. To the resulting residue are added a small amount of water and sodium chloride, and the mixture is extracted 6 times with chloroform. The extract is dried with magnesium sulfate, chromatographed on a column of silica gel and eluted with ethyl acetate to give 1.37 g (74.1% yield) of the objective compound.