Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]([CH2:15][CH:16]([O:37]C(=O)C)[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)[C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:1]([N:4]([CH2:15][CH:16]([OH:37])[CH2:17][N:18]1[CH2:19][CH2:20][N:21]([CH:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:22][CH2:23]1)[C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(CN1CCN(C(c2ccccc2)c2ccccc2)CC1)CN(C(C)=O)c1cccc2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(=O)N(CC(O)CN1CCN(C(c2ccccc2)c2ccccc2)CC1)c1cccc2ncccc12
Reaction time: 8 h
Yield: 98.6 %

Procedure:
In a mixed solvent of 10 ml of methanol and 5 ml of water were dissolved 0.55 g of 5-[N-acetyl-(2-acetoxy-3-(4-diphenylmethylpiperazine-1-yl)propylamino)]quinoline and 0.5 g of potassium carbonate, and the liquid was allowed to stand at room temperature overnight. The liquid was extracted with methylene chloride, and the extract was then dried with anhydrous magnesium sulfate and was concentrated to obtain 0.5 g of the desired compound.
Reaction SMILES: [C:1]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)(=[O:4])[CH2:2][CH3:3].[Br:10]Br.[Br-].CCO>C(Cl)(Cl)(Cl)Cl.C(=S)=S>[Br:10][CH:2]([CH3:3])[C:1]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)=[O:4]
Reactant: CCC(=O)c1cccs1
Reactant: BrBr
Agent: [Br-]
Solvent: CCO
Solvent: S=C=S
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)C(=O)c1cccs1
Temperature: 25 °C

Procedure:
An ice cold solution of 2-propionylthiophene (1.40 g) in carbon tetrachloride (25 ml) was treated with a solution of bromine (0.54 ml) in carbon tetrachloride (20 ml) over 5 mins. The resulting solution was then stirred at room temperature. After 1.5 h the mixture was evaporated to an amber oil (2.17 g). A portion of the oil (600 mg) was subjected to preparative thin-layer chromatography on silica developing with chloroform-petrol (b.p. 60°-80° C.) (1:4) (4 runs) and gave an amber oil, the title bromide (410 mg), λmax (EtOH) 272.5 nm (ε7,910), 294 nm (ε8,340), νmax (CS2) 1658, 713 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15](Cl)=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([NH:29][C:15]([C:9]1[C:10]2[N:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[N:4][C:5]=2[CH:6]=[C:7]([N+:19]([O-:21])=[O:20])[C:8]=1[CH3:18])=[O:16])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC
Product: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)NCc3ccccc3)c2nc1OC
Reaction time: 24 h

Procedure:
Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 250 mg (0.80 mmol) and benzylamine 90 μL (0.84 mmol). Reaction was continued for 24 hours, and the crude product was eluted through a flash column (7:3 hexanes:ethyl acetate), 260 mg (84%), mp 171-173° C.; 1H NMR (CCl3): δ 8.32 (s, 1H), 7.32 (m, 5H), 6.12 (br s, 1H), 4.68 (d, 2H, J=5.6 Hz), 4.06 (s, 3H), 3.92 (s, 3H), 2.56 (s, 3H); MS (APCI): m/z 383 (M+1).
Reaction SMILES: [CH:1]1([S:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:16].[OH:17]OS([O-])=O.[K+]>CC(C)=O>[CH:1]1([S:7]([C:8]2[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=2)(=[O:17])=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O
Reactant: N#Cc1ccc(SC2CCCCC2)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(S(=O)(=O)C2CCCCC2)cc1
Temperature: 0 °C
Yield: 94 %

Procedure:
Dissolve 4-cyclohexylthio-benzonitrile (1.17 g, 5.4 mmol) in acetone (10 mL) and add water until the sulfide starts to come out of solution. Then add a drop of acetone to rehomogenize the solution. Cool the mixture to 0° C. and then add oxone (4.2 g, 6.73 mmol) in one portion while stirring vigorously at 0° C. for h. Concentrate in vacuo, take up the residue in DCM and filter the suspension through a frit. Concentrate in vacuo to obtain the desired intermediate (1.27 g, 94%) as a white solid.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27]1>>[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[N:6]2[C:21]([C:20]2[CH:24]=[CH:25][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[O:22])=[CH:27]1
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: c1ccc2[nH]ccc2c1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)N2c3ccccc3-c3ccccc3C2c2c[nH]c3ccccc23)cc1

Procedure:
[6-(1H-Indol-3-yl)-6H-phenanthridin-5-yl]-(4-methoxy-phenyl)-methanone was prepared from phenanthridine, 4-methoxybenzoyl chloride, and indole according to GP 2. Yield, 67%. 1H-NMR (DMSO-d6): δ=3.72 (s, 3H), 6.20 (dd, J=2.5 Hz, J=0.8 Hz, 1H), 6.39 (d, br., J=8 Hz, 1H), 6.81 (d, J=9.0 Hz, 2H), 6.81-6.88 (m, 1H), 6.98-7.08 (m, 2H), 7.12 (ddd, J=J=7.5 Hz, J=1.2 Hz, 1H), 7.15-7.26 (m, 2H), 7.18 (d, J=9.0 Hz, 2H), 7.42 (ddd, J=J=7.4 Hz, J=1.2 Hz, 1H), 7.53 (“t”, J≈7 Hz, 2H), 7.90 (“d”, J≈7 Hz, 1H), 7.95 (dd, J=7.9 Hz, J=1.3 Hz, 1H), 8.09 (“d”, J≈8 Hz, 1H), 10.68 (s, 1H); (+)-ESI-MS: m/z=431 [M+H]+, 314 [M-indole+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:16])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](C(O)=O)=[C:5]2[O:14][CH3:15].[H-].[Na+].[CH3:19][C@@H:20]1[CH2:22][O:21]1>C1(OC2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[F:1][C:2]1[C:3]([CH3:16])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:19][C@H:20]([OH:21])[CH3:22])[CH:6]=[C:5]2[O:14][CH3:15]
Reactant: C[C@@H]1CO1
Reactant: COc1c(C(=O)O)[nH]c2ccc(F)c(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cn(C[C@@H](C)O)c2ccc(F)c(C)c12
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A suspension of 1.98 g of 5-fluoro-3-methoxy-4-methylindole-2-carboxylic acid in 16 ml of diphenyl ether was stirred at 260° for 0.5 hour and, after cooling to 0°, diluted with 44 ml of tetrahydrofuran. 0.33 g of sodium hydride dispersion was added and the mixture was stirred for one hour. Subsequently, 1 ml of (R)-methyloxirane was added and the reaction mixture was stirred at room temperature for 90 hours. The mixture was extracted with diethyl ether, water and saturated sodium chloride solution and the organic phase was dried over sodium surfate. The solvent was removed and the residue was chromatographed over 120 g of silica gel with toluene and toluene-ethyl acetate (9:1). 1.69 g (80%) of (R)-1-(5-fluoro-3-methoxy-4-methylindol-1-yl)-propan-2-ol were obtained as a pale brown oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=1.[Si:13]([O:20][C:21]([C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1)([CH3:23])[CH3:22])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C1COCC1.C([O-])([O-])=O.[Na+].[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:13]([O:20][C:21]([C:24]1[N:25]=[CH:26][C:27]([C:2]2[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=2)=[CH:28][CH:29]=1)([CH3:23])[CH3:22])([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:15])[CH3:14]
Reactant: NC(=O)c1cc(Br)sc1[N+](=O)[O-]
Reactant: CC(C)(O[Si](C)(C)C(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O[Si](C)(C)C(C)(C)C)c1ccc(-c2cc(C(N)=O)c([N+](=O)[O-])s2)cn1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
5-Bromo-2-nitrothiophene-3-carboxamide (602 mg, 2.40 mmol), 2-(1-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (905 mg, 2.40 mmol), and Pd(PPh3)4 (139 mg, 0.12 mmol) were combined in a vial and evacuated/backfilled with nitrogen. THF (5.6 mL) and 2 N Na2CO3 (2.4 mL) were added, and the reaction was stirred at 90° C. overnight. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Flash chromatography of the crude residue (10-100% EtOAc/hexanes) afforded the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].BrC[CH2:11][CH2:12][O:13][CH3:14].[C:15](#N)C>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:11][CH:12]([O:13][CH3:14])[CH3:15]
Reactant: Oc1ccccc1Br
Reactant: CC#N
Reactant: COCCCBr
Product: COC(C)COc1ccccc1Br
Yield: 101 %

Procedure:
2-Bromophenol (861 mg, 4.97 mmol) and 1-bromo-3-methoxypropane (1000 mg, 6.53 mmol) in acetonitrile (10 ml) was treated as for preparation 62 to afford crude title compound as a colourless liquid (1.23 g, 101%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12](=O)([O-])[O-].[K+].[K+].C(O)C.[NH2:21][CH:22]([C:25]([OH:27])=[O:26])[CH2:23][OH:24]>O>[CH3:12][O:26][C:25](=[O:27])[CH:22]([CH2:23][OH:24])[NH:21][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: O=C([O-])[O-]
Reactant: NC(CO)C(=O)O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COC(=O)C(CO)Nc1ccccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
To 15.66 g of 1-fluoro-2-nitrobenzene (VII), 16.87 g of potassium carbonate, 100 ml of 95% ethanol, and 40 ml of water are added 11.66 g of DL-serine. The reaction is stirred at 90° overnight and then cooled. The solvents are removed under vacuum and the residue is azeotroped with toluene to remove residual water. The resulting solid is washed with ether and toluene to remove unreacted 1-fluoro-2-nitrobenzene. The solid is then stirred for 18 hr at 20°-25° in 80 ml of DMF with 15.34 g of potassium carbonate and 24 ml of iodomethane. Excess iodomethane and DMF are then removed under vacuum and the residue is partitioned between a mixture of methylene chloride, chloroform and water. The organic layers are dried over sodium sulfate and concentrated. Ethyl ether and hexane are added to the residue and the solid is collected and dried to give the title compound, mp 138°-140°; NMR (CDCl3) 2.15, 3.83, 4.10, 4.41, 6.73-6.81, 7.46, 8.22, 8.60 δ.
Reaction SMILES: [CH:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17](=[O:18])[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:22][CH:21]=3)[C:15]([CH2:34][CH2:35][CH3:36])=[N:14][C:13]=2[CH3:37])=[CH:8][CH:7]=1)([CH2:3][CH3:4])[CH3:2].Cl.[NH2:39]O.[C:41](=[O:44])([O-])[OH:42].[Na+]>CS(C)=O.C(OCC)(=O)C>[CH:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[C:17](=[O:18])[N:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]4[NH:39][C:41](=[O:44])[O:42][N:33]=4)=[CH:22][CH:21]=3)[C:15]([CH2:34][CH2:35][CH3:36])=[N:14][C:13]=2[CH3:37])=[CH:10][CH:11]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: O=C([O-])O
Reactant: NO
Reactant: CCCc1nc(C)c(-c2ccc(OC(C)CC)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(C)c(-c2ccc(OC(C)CC)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
4′-{[5-(4-sec-Butoxyphenyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.5 g) was dissolved in dimethyl sulfoxide (5 mL), and hydroxylamine hydrochloride (0.79 g) and sodium hydrogen carbonate (1.2 g) were added. The mixture was stirred overnight at 90° C. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The residue was dissolved in tetrahydrofuran (5 mL), and N,N′-carbonyldiimidazole (0.28 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.26 mL) were added. After stirring for 30 min, the reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.45 g, 81%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH:10]([CH2:15][CH2:16][CH2:17][Br:18])[C:11](OC)=[O:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)C>[Br:18][CH2:17][CH2:16][CH2:15][CH:10]1[C:11](=[O:12])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8]1
Reactant: COC(=O)C(Br)CCCBr
Reactant: Nc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: O=C1Nc2ccccc2OC1CCCBr
Yield: 20.3 %

Procedure:
24 g of 2-aminophenol, 55 g of methyl 2,5-dibromovalerate and 30 g of potassium carbonate were heated to reflux for 5 hours in 250 ml of acetone. For work-up, the reaction mixture was diluted with 250 ml of diethyl ether, washed with 200 ml of water and acidified to pH=1 using 12N hydrochloric acid solution. The organic phase was separated, washed twice with 100 ml of water each time, dried and evaporated. The residue was crystallized from methanol. 11 g of 2-(3-bromopropyl)-2H-1,4-benzoxazin-3(4H)one were obtained.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:14]([CH2:15][S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1[S:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24])=[O:7])(C)(C)C.C(OCC1CCCCN(S(C2C=CC(OC)=CC=2)(=O)=O)C1C(O)=O)(=O)C>>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([S:23]([N:9]2[CH2:10][CH:11]=[CH:12][CH2:13][CH:14]([CH2:15][S:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:8]2[C:6]([OH:7])=[O:5])(=[O:25])=[O:24])=[CH:31][CH:30]=1
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(CSc3ccccc3)C2C(=O)OC(C)(C)C)cc1
Agent: COc1ccc(S(=O)(=O)N2CCCCC(COC(C)=O)C2C(=O)O)cc1
Product: COc1ccc(S(=O)(=O)N2CC=CCC(CSc3ccccc3)C2C(=O)O)cc1

Procedure:
1-(4-Methoxy-benzenesulfonyl)-3-phenylsulfanylmethyl-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid was synthesized from 1-(4-Methoxy-benzenesulfonyl)-3-phenylsulfanylmethyl-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid tert-butyl ester in the same manner as the procedures used for the preparation of 3-Acetoxymethyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid: MS (M-H)- =432.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1.FC(F)(F)C(O)=O.C[O-].[Na+]>ClCCl.CO>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)cc1[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(N2CCNCC2)c(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
To a stirred solution of 1,1-dimethylethyl 4-[2-methyl-5-(methyloxy)-4-nitrophenyl]-1-piperazinecarboxylate (4.8 g, 13.67 mmol) in 80 mL of dichloromethane was added trifluoroacetic acid (˜5.5 mL). The mixture stirred at room temperature for 24 hours. The solvent was rotovaped down. The crude product was taken up in 50 mL of methanol and neutralized with 0.5 N sodium methoxide. 12 g of Silica gel was added and the solvent was rotovaped down. The crude product was purified by flash chromatography to give 1-[2-methyl-5-(methyloxy)-4-nitrophenyl]piperazine (3.43 g, 13.53 mmol, 98%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (s, 1 H), 6.69 (s, 1 H), 3.88 (s, 3 H), 3.08-3.18 (m, 8 H), 2.15-2.21 (m, 3 H).
Reaction SMILES: [CH3:1][C:2]1[C:15](=[O:16])[CH:14]=[C:13]2[C:4](=[N:5][C:6]3[C:11]([S:12]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.C(N(CC)CC)C.[CH2:24]([SH:28])[CH2:25][CH2:26][CH3:27].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClC(Cl)C>[CH2:24]([S:28][C:14]1[C:15](=[O:16])[C:2]([CH3:1])=[CH:3][C:4]2[C:13]=1[S:12][C:11]1[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=1)[N:5]=2)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCS
Reactant: Cc1cc2nc3ccccc3sc-2cc1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCSc1c2sc3ccccc3nc-2cc(C)c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2-methyl-phenothiazin-3-one (0.23 g) in 12 ml dichloroethane was added triethylamine (0.8 ml) and n-butanethiol (0.7 ml). The mixture was stirred at room temperature for 72 hours. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (0.22 g) was added. The mixture was stirred at room temperature for 2 hours. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue was chromatographed on neutral alumina (Act III) eluting with 15% EtOAc/hexane to give the title compound (120 mg), m.p. 97° C.
Reaction SMILES: C([N:4]([C@@H:17]([CH3:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:5]([CH:14]=[CH:15][CH3:16])[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])C=C.C[C@H](N[C@H](C1C=CC=CC=1)CC(OC(C)(C)C)=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:24][C@H:17]([NH:4][C@@H:5]([CH:14]=[CH:15][CH3:16])[CH2:6][C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C=CCN([C@@H](C=CC)CC(=O)OC(C)(C)C)[C@@H](C)c1ccccc1
Agent: C[C@H](N[C@@H](CC(=O)OC(C)(C)C)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC=C[C@@H](CC(=O)OC(C)(C)C)N[C@@H](C)c1ccccc1

Procedure:
The title compound (32) was prepared from compound (12) of Example 4 using the above-described procedure. [α]D21 -45.1 (c 1.69, CHCl3); νmax (CHCl3)/cm-1 1728 s (C=O); δH (300 MHz; CDCl3) 7.32-7.18 (5H, m, Ph), 5.55 (1H, dq, J=15.2 and 6.4, CH3CH=CH), 5.26 (ddq, J=15.2, 8.0 and 1.6, CH3CH=CH), 3.84 (1H, q, J=6.5, PhCHCH3), 3.45 (1H, m, NCHCH2), 2.41, 2.35 (2H, ABX system, JAB =14.5, JAX =6.6, JBX =6.5, CH2CO), 1.65 (3H, dd, J=6.4 and 1.6, CH3C=C), 1.45 (9H, s, (CH3)3C), 1.33 (3H, d, J=6.5, PhCHCH3); δC (50 MHz; CDCl3) 171.53 (C=O), 146.51 (Ph:Cipso), 133.07 (CH3C=C), 128.53, 126.82 (Ph:Cortho, Cmeta), 126.96 (Ph:Cpara), 80.28 (C(CH3)3), 55.14, 54.57 (CHN), 41.78 (CH2CO), 28.03 (C(CH3)3), 23.12 (NCHCH3), 17.83 (CH3C=C); m/z (CI) 290 (MH+, 100%), 234 (30), 174 (45), 105 (35); (Found: C, 74.61; H, 9.63; N, 4.62. C18H27NO2 requires C, 74.70; H, 9.40; N, 4.84%).
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[C:28]12([CH2:38][O:39][C:40]3[C:48]([CH:49]4[CH2:52][CH2:51][CH2:50]4)=[CH:47][C:43]([C:44]([OH:46])=O)=[C:42]([F:53])[CH:41]=3)[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2.CS(N)(=O)=O.[N:59]1([S:63]([NH2:66])(=[O:65])=[O:64])[CH2:62][CH2:61][CH2:60]1>>[C:28]12([CH2:38][O:39][C:40]3[C:48]([CH:49]4[CH2:50][CH2:51][CH2:52]4)=[CH:47][C:43]([C:44]([NH:66][S:63]([N:59]4[CH2:62][CH2:61][CH2:60]4)(=[O:65])=[O:64])=[O:46])=[C:42]([F:53])[CH:41]=3)[CH2:29][CH:30]3[CH2:36][CH:34]([CH2:33][CH:32]([CH2:31]3)[CH2:37]1)[CH2:35]2
Reactant: NS(=O)(=O)N1CCC1
Reactant: O=C(O)c1cc(C2CCC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CCC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(adamantan-1-ylmethoxy)-5-cyclobutyl-2-fluorobenzoic acid and to replace methanesulfonamide with azetidine-1-sulfonamide, the title compound was obtained as a colorless solid (0.043 g, 13%): 1H NMR (300 MHz, CDCl3) δ 8.66 (d, J=16.5 Hz, 1H), 7.88 (d, J=9.3 Hz, 1H), 6.54 (d, J=14.6 Hz, 1H), 4.24 (t, J=7.7 Hz, 4H), 3.69-3.58 (m, 1H), 3.49 (s, 2H), 2.39-1.99 (m, 10H), 1.87-1.64 (m, 13H); MS (ES−) m/z 475.2 (M−1).
Reaction SMILES: [Br:1][CH2:2][C:3]([CH2:8][Br:9])([CH2:6]O)[CH2:4][OH:5].[C:10](=[O:13])(O)[O-].[K+].S(OC)(O[CH3:19])(=O)=O.C(=O)(O)[O-].[Na+]>>[Br:1][CH2:2][C:3]([CH2:6][O:13][CH3:10])([CH2:4][O:5][CH3:19])[CH2:8][Br:9]
Reactant: O=C([O-])O
Reactant: COS(=O)(=O)OC
Reactant: OCC(CO)(CBr)CBr
Agent: [K+]
Agent: [Na+]
Product: COCC(CBr)(CBr)COC
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 22.6 %

Procedure:
To 2,2-bis(bromomethyl)propane-1,3-diol (100 g) was added potassium bicarbonate (80 g) and dimethyl sulphate (170 g). The mixture was stirred and heated to 100° C. After about 30 minutes at this temperature the reaction became very vigorous (Care!). After a further 2 hours heating and stirring the mixture had become very viscous. The mixture was cooled, made slightly basic by the addition of sodium bicarbonate, and then extracted with chloroform (4×200 cm3). The chloroform extracts were combined and the solvent removed under reduced pressure to give the crude product. Repeated distillation under reduced pressure gave the pure product (25 g) as a colourless liquid (b.p. 65°-70° C. at 0.1 mmHg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@H:12]([CH3:14])[N:11]([C:15]2[O:16][C:17]3[C:18](=[C:20]([C:24](O)=[O:25])[CH:21]=[CH:22][CH:23]=3)[N:19]=2)[C@@H:10]([CH3:27])[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[NH2:31][C@H:32]1[CH:37]2[CH2:38][CH2:39][N:34]([CH2:35][CH2:36]2)[CH2:33]1>>[N:34]12[CH2:33][C@@H:32]([NH:31][C:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:17]4[O:16][C:15]([N:11]5[C@@H:12]([CH3:14])[CH2:13][N:8]([CH2:1][C:2]6[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=6)[C:9](=[O:28])[C@@H:10]5[CH3:27])=[N:19][C:18]=34)=[O:25])[CH:37]([CH2:38][CH2:39]1)[CH2:36][CH2:35]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: C[C@H]1CN(Cc2ccccc2)C(=O)[C@H](C)N1c1nc2c(C(=O)O)cccc2o1
Agent: Cl
Product: C[C@H]1CN(Cc2ccccc2)C(=O)[C@H](C)N1c1nc2c(C(=O)N[C@@H]3CN4CCC3CC4)cccc2o1

Procedure:
Following the general procedure GP-C2, a mixture of 2-((2S,6S)-4-benzyl-2,6-dimethyl-3-oxopiperazine-1-yl)benzoxazole-4-carboxylic acid and (S)-(−)-3-aminoquinuclidine dihydrochloride were coupled to provide (S)—N-(quinuclidine-8-yl) 2-((2S,6S)-4-benzyl-2,6-dimethyl-3-oxopiperazine-1-yl)benzoxazole-4-carboxamide which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].C(N(CC)CC)C.Cl[C:16](=[N:23]O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Na+].[Cl-]>C(O)C.C(OCC)(=O)C>[CH3:5][C:4]1[O:6][N:23]=[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:3]=1[C:2](=[O:7])[CH3:1]
Reactant: CC(=O)CC(C)=O
Reactant: ON=C(Cl)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)c1c(-c2ccccc2)noc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of pentane-2,4-dione (13.23 g, 0.132 mol) and triethylamine (13.35 g, 0.132 mol) in ethanol was added α-chlorobenzaldehyde oxime (13.70 g, 0.088 mol) at room temperature. The reaction mixture was stirred overnight at room temperature. To the reaction was added ethyl acetate and saturated aqueous NaCl. The organic phase was washed with saturated aqueous NaCl (twice) and dried with MgSO4, and the organic solvent was removed under reduced pressure to provide 17.7 g of the title compound. The yield was 100%.