Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7]2=[N:10][O:11][C:12]([CH3:13])=[C:6]2[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:4]1)[CH3:2]>[Pd].C(O)C>[C:12]([C:6]1[C:5]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:4][N:3]([CH2:1][CH3:2])[C:8](=[O:9])[C:7]=1[NH2:10])(=[O:11])[CH3:13]
Reactant: CCn1nc(-c2ccccc2)c2c(C)onc2c1=O
Agent: [Pd]
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(N)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
A mixture of 6-ethyl-3-methyl-4-phenylisoxazolo[3,4-d]pyridazin-7(6H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) (2.0 g, 7.83 mmol) and 10% palladium on charcoal (400 mg) in ethanol (400 ml) was shaken under hydrogen at room temperature and 2 bar for 3 h. The catalyst was filtered off and the solvent was removed under reduced pressure to yield the title compound (1.97 g, 98% yield).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].[NH:6]1[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[CH2:7]1>>[CH2:2]([N:6]1[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[CH2:7]1)[CH2:3][CH2:4][CH3:5]
Reactant: O=C1CCCNC1
Reactant: CCCCI
Product: CCCCN1CCCC(=O)C1

Procedure:
In a manner similar to Preparation 1, react 1-iodobutane with 3-piperidinone to obtain the title compound.
Reaction SMILES: C([S:4][CH2:5][C:6]1[N:7]=[C:8]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[O:9][C:10]=1[CH3:11])(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:11][C:10]1[O:9][C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)=[N:7][C:6]=1[CH2:5][SH:4]
Reactant: COC(=O)c1ccc(-c2nc(CSC(C)=O)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(-c2nc(CS)c(C)o2)cc1
Yield: 102.7 %

Procedure:
A mixture of methyl 4-[4-[(acetylsulfanyl)methyl]-5-methyl-1,3-oxazol-2-yl]benzoate (4.29 g, 14.05 mmol, 1.00 equiv) and potassium carbonate (4.85 g, 34.84 mmol, 3.00 equiv) in methanol (50 mL) was stirred at 35° C. under an inert atmosphere of nitrogen for 30 min Water (100 mL) was then added and the resulting solution was extracted with 3×150 mL of dichloromethane. The combined organic layers was washed with 2×300 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to yield 3.8 g of crude methyl 4-[5-methyl-4-(sulfanylmethyl)-1,3-oxazol-2-yl]benzoate as a white solid. LC-MS: (ES, m/z): 305 [M+CH3CN+H]+, 264 [M+H]+, 230.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:16]([C:17](=[O:30])[NH:18][C@H:19]([CH2:28][OH:29])[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:15]2[CH2:31][C@H:12]1[CH2:13][CH2:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[C@H:16]([C:17](=[O:30])[NH:18][C@H:19]([CH:28]=[O:29])[CH2:20][C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[C@@H:15]2[CH2:31][C@H:12]1[CH2:13][CH2:14]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](CO)NC(=O)[C@@H]1[C@H]2CC[C@H](C2)N1C(=O)OCc1ccccc1
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@@H](C=O)NC(=O)[C@@H]1[C@H]2CC[C@H](C2)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
A solution of (1R,3S,4S)-3((S)-2-tert-Butoxycarbonyl-1-hydroxymethyl-ethylcarbamoyl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid benzyl ester (1.1 g) in DCM (10 ml) was cooled to 0° C. under nitrogen. 2,2,6,6-tetramethylpiperidinyloxy (TEMPO, 4 mg) was then added followed by trichloroisocyanuric acid (621 mg) portionwise over 30 minutes. The mixture was stirred at ambient temperature for 1 hour, then filtered through celite. The filtrate was washed with water, 1M sodium thiosulfate solution and brine. Drying over magnesium sulfate and concentration under reduced pressure gave the sub-title compound as a colorless oil (698 mg, 64%); 1H NMR (400 MHz, d-6 DMSO) δ 1.16-1.89 (16H, m), 2.30-2.80 (2H, m), 3.68-3.81 (1H, m), 4.19 (1H, brm), 4.39 (1H, m), 4.91-5.16 (2H, m), 7.21-7.43 (5H, m), 8.45 (0.4H, d), 8.60 (0.6, d), 9.19 (0.6H, S), 9.37 (0.4H, s).
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH2:21][N:22]([C@H:30]([CH3:40])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][OH:39])[CH:33]=2)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]>ClCCl.[O-2].[Mn+4].[O-2]>[C:1]([O:5][C:6]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:41][Si:42]([C:45]([CH3:46])([CH3:48])[CH3:47])([CH3:44])[CH3:43])[CH2:21][N:22]([C@H:30]([CH3:40])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]=[O:39])[CH:33]=2)[C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](Cc1cccc(CO)c1)N(C[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OC(=O)OC(C)(C)C)c2[nH]c(=O)ccc12)C(=O)OC(C)(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: C[C@H](Cc1cccc(C=O)c1)N(C[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OC(=O)OC(C)(C)C)c2[nH]c(=O)ccc12)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
tert-Butyl (R)-2-(8-(tert-butoxycarbonyloxy)-2-oxo-1,2-dihydroquinolin-5-yl)-2-(tert-butyldimethylsilyloxy)ethyl((R)-1-(3-(hydroxymethyl)phenyl)propan-2-yl)carbamate (Example 276, step g) (0.609 g) was dissolved in dichloromethane (30 mL), treated with manganese (IV) oxide (0.791 g) and the resulting suspension stirred at room temperature over a weekend. More manganese (IV) oxide (0.801 g) was added and the suspension was stirred for a further 4 hours. The mixture was filtered through diatomaceous earth, washing the residue well with DCM, and the combined filtrate and washings were concentrated in vacuo to afford the subtitled compound. Yield 0.521 g. Material used immediately in the next step.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:12](O)(=O)[CH3:13].N1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O>C1C=CC=CC=1>[CH2:10]([O:9][C:1](=[O:8])[C:2](=[CH:17][C:18]1[CH:13]=[CH:12][CH:21]=[CH:20][CH:19]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: C1CCNCC1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)O
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1ccccc1)C(=O)OCC

Procedure:
One mole of a correspondingly substituted benzaldehyde is heated on a water trap with 160 g. (1 mole) of diethyl malonate, 30 ml. of glacial acetic acid, and 3 ml. of piperidine in 1 liter of benzene until 1 mole of water has been split off. The benzenic solution is worked up as usual.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][C:9]([OH:17])([CH2:10]3)[CH2:8]1)[CH2:14]2)[C:4]([OH:6])=[O:5].[OH-].[Na+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>O>[CH2:24]([O:23][C:21]([NH:2][C@@H:3]([C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][C:9]([OH:17])([CH2:10]3)[CH2:8]1)[CH2:14]2)[C:4]([OH:6])=[O:5])=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N[C@H](C(=O)O)C12CC3CC(CC(O)(C3)C1)C2
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(N[C@H](C(=O)O)C12CC3CC(CC(O)(C3)C1)C2)OCc1ccccc1
Reaction time: 4 h
Yield: 115.3 %

Procedure:
The (2S)-2-amino-2-(3-hydroxyadamantan-1-yl)acetic acid hydrochloride (20 g) was dissolved in 100 ml water at 25-30° C. The pH of the solution was adjusted to 8.5-9.5 with aqueous sodium hydroxide solution at 5° C. To the mixture benzyl chloroformate (10.7 g) was added and set aside for 4 h at 25-30° C. The reaction mass was washed with MTBE (25 ml) and the pH of the aqueous phase adjusted to 2-3 with dilute hydrochloric acid. Aqueous phase was extracted with ethyl acetate, the organic phase dried and evaporated to yield 26 g (95%) of the title product. M.P 55-58° C., H1NMR (300 MHz, CDCl3): 1.39-1.58 (m, 12H), 2.04-2.07 (s, 2H), 3.86-3.89 (dd, 1H), 4.98 (s, 2H), 5.11 (s, 1H), 7.0 (d, 1H), 7.16-7.27 (m, 5H).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[NH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[S:33][CH:32]=[CH:31][CH:30]=2)[CH2:24][CH2:23]1>[OH-].[Na+]>[C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9]([NH:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[S:33][CH:32]=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)=[O:11])=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: NN1CCN(Cc2cccs2)CC1
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)NN1CCN(Cc2cccs2)CC1
Reaction time: 6 h
Yield: 63.9 %

Procedure:
4-Acetylamino-5-chloro-2-methoxybenzoic acid (3.67 g, 0.015 mole) was treated with thionyl chloride (30 ml) at 50° for 1/2 hour. The mixture was evaporated in vacuo and the residue azeotroped twice with anhydrous toluene (100 ml), redissolved in hot anhydrous toluene (150 ml) and filtered. Triethylamine (2 ml) was added to the filtrate followed by N-amino-N'-2-thenylpiperazine (2.70 g, 0.0137 mole) and the reaction left for 6 hours at room temperature. The mixture was basified with 10% sodium hydroxide (10 ml) and the toluene layer separated, dried over K2CO3 and evaporated in vacuo to yield 4-acetylamino-5-chloro-2-methoxy-N-[1-(2-thenyl)-4-piperazinyl]-benzamide (3.7 g, 64%) as colourless microcrystals, m.p. 178°-181° C. (ex EtOAc-light petroleum 40°-60°).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([N:15]([C:31](=[O:33])[CH3:32])[CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[C:10]2[CH:34]=[CH:35][C:36]([Cl:38])=[CH:37][C:9]1=2)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[F:30][C:27]([F:28])([F:29])[C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=1)[CH2:16][N:15]([CH:11]1[CH2:12][CH2:13][CH2:14][NH:8][C:9]2[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:10]1=2)[C:31](=[O:33])[CH3:32]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCNc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a solution of 5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-8-chloro-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (7.9 g, 14.0 mmol) in dichloromethane (100 mL) add a solution of trifluoroacetic acid (50 mL) in dichloromethane (50 mL). After stirring at room temperature for 1 h, neutralize the reaction with concentrated sodium bicarbonate. Separate the organic phase and wash with water (100 mL) and brine (100 μL). Dry the organics over sodium sulfate, filter, and remove solvent under vacuum. Crystallize the compound from dichloromethane/hexane. This provides the title compound (5.3 g, 81%) as a colorless solid: MS (ES+): 465 (M+H).
Reaction SMILES: [Mg].[CH3:2]I.[I:4][CH:5]=[CH:6][C:7](=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl-].[NH4+]>CCOCC>[OH:13][C:7]([CH3:2])([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:6]=[CH:5][I:4]
Reactant: CCCCCC(=O)C=CI
Reactant: CI
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCCCC(C)(O)C=CI
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a Grignard solution prepared from 1.05 g (0.41 moles) of magnesium and 6.2 g (0.435 moles) of methyl iodide in 30 ml of dry ether under argon is added dropwise 10 g of 1-iodo-1-octen-3-one (Example 183) in 45 ml of ether. The resulting solution is stirred at ambient temperature for one hour. After the addition of 75 ml of saturated ammonium chloride the ether layer is separated and the aqueous layer is separated and the aqueous layer is extracted several times with ether. The combined ether extracts are washed successively with ammonium chloride and water, dried and taken to dryness to give 9.24 g of product as an oil; λ max 2.89, 3.23, 6.24 and 10.5.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])=[CH:4][CH:3]=1.Cl[S:20]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>N1C=CC=CC=1.CCOCC>[CH3:34][O:33][C:31](=[O:32])[CH2:30][CH2:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[O:7])=[CH:17][CH:18]=2)(=[O:21])=[O:22])=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc(N)cc1
Reactant: COC(=O)CCc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: COC(=O)CCc1ccc(S(=O)(=O)Nc2ccc(C(=O)NNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of tert-butyl 2-(4-aminobenzoyl)hydrazinecarboxylate (200 mg, 0.80 mmol) in anhydrous pyridine (4 mL) was added dropwise methyl 3-(4-chlorosulfonylphenyl)propionate (251 mg, 0.96 mmol) at rt. After 60 min, aminomethyl resin (Polymers Laboratories PL-AMS, 1.96 mmol/g, 200 mg) was added and the resulting mixture was stirred for 1 hr at rt. After filtration and rinsing the resin, water (100 mL) was added into the filtrate. Extraction with EtOAc (100 mL), washing with HCl (1N, 60 mL) and an aqueous saturated solution of NaHCO3 (50 mL), drying over MgSO4 and evaporation under vacuo gave a yellow oil. The residue was taken up in Et2O and a white solid precipitated out. Filtration and washing with Et2O gave the title compound (214 mg) was obtained as a white solid (56%) in 99.3% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[CH2:11][C@@H:12]([OH:29])[CH2:13][O:14][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH3:16].N1C=CN=C1.[C:39]([Si:43](Cl)([CH3:45])[CH3:44])([CH3:42])([CH3:41])[CH3:40].C(OCC)(=O)C>CN(C)C=O>[Si:43]([O:29][C@H:12]([CH2:11][N:7]1[CH2:8][CH2:9][CH2:10][C@H:6]1[CH2:5][C:4]1[CH:30]=[CH:31][C:32]([CH3:33])=[C:2]([F:1])[CH:3]=1)[CH2:13][O:14][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH3:16])([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:45])[CH3:44]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)CCc1ccccc1[C@@H](C)OC[C@H](O)CN1CCC[C@H]1Cc1ccc(C)c(F)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccccc1[C@@H](C)OC[C@@H](CN1CCC[C@H]1Cc1ccc(C)c(F)c1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 91 %

Procedure:
A solution of methyl 3-{2-[(1R)-1-({(2R)-3-[(2S)-2-(3-fluoro-4-methylbenzyl)pyrrolidin-1-yl]-2-hydroxypropyl}oxy)ethyl]phenyl}propanoate (596 mg, 1.30 mmol) which had been obtained in Example 2 (2a), in N,N-dimethyl formamide was added with imidazole (221 mg, 3.25 mmol) and tert-butyl(chloro)dimethylsilane (294 mg, 1.95 mmol), and stirred at room temperature. After stirring for 24 hours, the reaction solution was added with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=85/15) to give the title compound as a pale yellow oily substance (676 mg, yield 91%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25]O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][O:9][C:8](=[O:10])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: O=C(O)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCOC(=O)Cc2ccccc2)CC1
Reaction time: 8 h
Yield: 96.7 %

Procedure:
To a mixture of phenylacetic acid (327 mg, 2.40 mmol, 1.2 equiv.) and 1-(tert-butoxycarbonyl)-4-(2-hydroxyethyl)piperidine (459 mg, 2.00 mmol) in CH2Cl2 (10 mL) were added DCC (495 mg, 2.40 mmol, 1.2 equiv.) and DMAP (12.2 mg, 100 μmol, 0.1 equiv.). The reaction mixture was allowed to stand overnight. After filtration, the liquid phase was washed with brine and dried over Na2SO4. After the solvent was removed, the residue was purified by CC (SiO2, hexane/EtOAc 4:1). The ester (672 mg, 97%) was obtained as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.31 (m, 5H), 4.14 (t, 2H, J=6.8 Hz), 4.03 (d, 2H, J=13.2 Hz), 3.61 (s, 2H), 2.60 (dt, 2H, J=2.0, 12.8 Hz), 1.56 (m, 5H), 1.45 (s, 9H), 1.06 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([NH2:18])=[O:17])=[C:11]3[NH:10][CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](=[O:21])=O.[H-].[Na+].[C:24](N1C=CN=C1)(N1C=CN=C1)=[S:25]>O1CCCC1.CC(C)=O>[CH3:19][O:21][C:5]1[CH:6]=[C:1]([C:7]2[N:12]3[C:11]4[N:10]([C:24](=[S:25])[NH:18][C:16](=[O:17])[C:15]=4[CH:14]=[N:13]3)[CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: O=C=O
Reactant: NC(=O)c1cnn2c1NCC=C2c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(C2=CCn3c(=S)[nH]c(=O)c4cnn2c43)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4,5-dihydro-7-(3-methyoxyphenyl)pyrazolo1,5-a]pyrimidine-3-carboxamide (prepared as described in Example 3) in dry tetrahydrofuran is stirred and cooled at -78° C. (dry-ice, acetone), under nitrogen and two equivalents of sodium hydride (60% dispersion in mineral oil) is added. The mixture is stirred at 78° C. for 30 minutes, then 1,1'-thiocarbonyldiimidazole is added in one portion. The temperature is kept at -78° C. for 2 hours, then the mixture is allowed to warm slowly to room temperature while stirring is continued for 48 hours. The reaction mixture is quenched with water and neutralized to pH 6-7 with 5% aqueous hydrochloric acid. A crystalline solid forms which is collected by filtration, triturated with ether, filtered and dried to give 4,5-dihydro-8-(3-methoxyphenyl)-5-thioxo-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[O:13])[C:7](=O)[CH2:8][CH3:9].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[O:13][C:7]=1[CH2:8][CH3:9]
Reactant: CCC(=O)C(CCCCCl)NC(=O)c1ccc(C)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1oc(-c2ccc(C)cc2)nc1CCCCCl
Yield: 90.1 %

Procedure:
To 150 ml of toluene, 6.5 g of 8-chloro-4-(p-toluoylamino)-3-octanone was dissolved, and 4.1 ml of phosphorus oxychloride was added and heated to reflux for 1.5 hours. The reaction solution was cooled, poured into ice-cold water and extracted with ethyl acetate. The extract was washed with an aqueous solution of saturated sodium hydrogen carbonate and brine sequentially, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=8:1) to provide 5.5 g of the objective compound as yellowish crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH3:21])[CH2:10][C:11]1[C:19]2[O:18][CH:17]=[CH:16][C:15]=2[CH:14]=[C:13]([F:20])[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN(C)[CH:29]=[O:30]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([CH3:21])[CH2:10][C:11]1[C:19]2[O:18][C:17]([CH:29]=[O:30])=[CH:16][C:15]=2[CH:14]=[C:13]([F:20])[CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(Cc1cc(F)cc2ccoc12)NC(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(Cc1cc(F)cc2cc(C=O)oc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.6 %

Procedure:
A solution of 0.50 gm (1.7 mMol) N-tert-butoxycarbonyl 1-(5-fluorobenzofur-7-yl)-2-aminopropane in 75 mL tetrahydrofuran was cooled to −78° C. under a nitrogen atmosphere. To this solution were then added 2.4 mL (3.81 mMoL) n-butyllithium (1.6 M in hexane) dropwise, resulting in an orange solution. After 5 minutes 0.66 mL (8.52 mMol) dimethylformamide were added dropwise. After stirring 18 hours at room temperature the reaction mixture was quenched by addition of 20 mL saturated aqueous ammonium chloride. The reaction mixture was partitioned between 300 mL ethyl acetate and 300 mL water. The phases were separated and the aqueous phase was extracted twice with 200 mL ethyl acetate. The organic phases were combined and washed sequentially with two 200 mL portions of water and one 200 mL portion of saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexane containing 20% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.38 gm (69%) of the desired compound as a yellow solid.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][C@H:6]([F:8])[CH2:5][N:4]1[C:9]([C@@H:11]([NH:30]C(=O)OC(C)(C)C)[C:12]([CH3:29])([S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)[CH3:13])=[O:10])#[N:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+].C(Cl)[Cl:51]>>[ClH:51].[NH2:30][C@@H:11]([C:12]([CH3:29])([S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=1)[CH3:13])[C:9]([N:4]1[CH2:5][C@@H:6]([F:8])[CH2:7][C@H:3]1[C:1]#[N:2])=[O:10]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1C[C@@H](F)C[C@H]1C#N)C(C)(C)SCc1cccc(Oc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(SCc1cccc(Oc2ccccc2)c1)[C@H](N)C(=O)N1C[C@@H](F)C[C@H]1C#N
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a CH2Cl2 solution (45 mL) containing tert-butyl (1R)-1-{[(2S,4S)-2-cyano-4-fluoropyrrolidin-1-yl]carbonyl}-2-methyl-2-[(3-phenoxybenzyl)thio]propylcarbamate (500 mg, 0.0010 mol) was added TFA (5 mL). The reaction mixture was allowed to stir at RT for a period of 16.0 hours followed by neutralization with sat. NaHCO3. The organics were separated, dried over MgSO4 and concentrated to dryness to afford a crude solid. The resulting solid was purified using silica gel chromatography (99% CH2Cl2/1% MeOH with 2.0 M NH3). The pure solid was dissolved into an acetone/ether mixture (1/1) and precipitated using 2.0 N HCl in ether. The resulting solid was filtered in vacuo and washed with ether. After drying under high vacuum the reaction yielded a total of 132 mg of the title compound.
Reaction SMILES: C(OC([NH:8][CH:9]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:19][CH2:20][N:15]([CH2:16][CH2:17]2)[CH2:14]1)=[O:11])=O)(C)(C)C.[ClH:28]>C1COCC1>[ClH:27].[ClH:28].[NH2:8][CH:9]([C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:17][CH2:16][N:15]([CH2:20][CH2:19]2)[CH2:14]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Product: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 201.2 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)acetate (C47) (250 mg, 0.63 mmol) in THF (5 ml), was added 37% hydrogen chloride (1.0 ml, 12.2 mmol). The reaction was stirred at RT for 15 hours. The solvent was evaporated to obtain (R)-quinuclidin-3-yl 2-amino-2-(4-chlorophenyl)acetate dihydrochloride (233 mg; quantitative yield).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH:14]1(B(O)O)[CH2:16][CH2:15]1>>[CH:14]1([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH2:16][CH2:15]1
Reactant: OB(O)C1CC1
Reactant: O=Cc1ccc(Cl)c(C(F)(F)F)c1
Product: O=Cc1ccc(C2CC2)c(C(F)(F)F)c1
Yield: 87.6 %

Procedure:
With 4-chloro-3-(trifluoromethyl)benzaldehyde (1.00 g) and cyclopropylboronic acid (1.24 g) being used as starting materials, the same technique as in Reference Example 6-3 was applied to give the titled compound as a pale yellow oil (900 mg).