Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][P:2]1(=[O:8])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:10]1[CH:11]=[CH:12][C:13]([N+:18]([O-:20])=[O:19])=[C:14]([O:16][CH3:17])[CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:17][O:16][C:14]1[CH:15]=[C:10]([N:5]2[CH2:6][CH2:7][P:2](=[O:8])([CH3:1])[CH2:3][CH2:4]2)[CH:11]=[CH:12][C:13]=1[N+:18]([O-:20])=[O:19]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CP1(=O)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N2CCP(C)(=O)CC2)ccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
A mixture of 4-methyl-[1,4]azaphosphinane-4-oxide (133 mg, 1.00 mmol), 5-fluoro-2-nitroanisole (340 mg, 2.00 mmol), K2CO3 (345 mg, 2.50 mmol), and DMF (5 mL) was heated to 50° C. After 2 h, the reaction mixture was concentrated and purified by silica gel chromatography (0-5% 7N ammonia in methanol:dichloromethane) to afford 1-(3-methoxy-4-nitrophenyl)-4-methyl-1,4-azaphosphinane 4-oxide as a bright yellow solid (272 mg, 96% yield).
Reaction SMILES: [BH4-].[Na+].[OH-].[Na+].O.[CH3:6][CH2:7][C:8](=[O:14])[CH2:9][C:10](=[O:13])[CH2:11][CH3:12]>CO>[CH3:6][CH2:7][CH:8]([OH:14])[CH2:9][CH:10]([OH:13])[CH2:11][CH3:12]
Reactant: CCC(=O)CC(=O)CC
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(O)CC(O)CC
Yield: 90 %

Procedure:
To the mixture of 2.5 g sodium borohydride, 0.05 g sodium hydroxide, and 25 ml water, was added dropwise the solution of 14.2 g 3,5-heptandione in 30 ml methanol at 0-10° C. Upon completion, the solvent was removed by reduced pressure distillation, and the residue was continuously extracted with 40 ml ethyl acetate for 15 hours. The solvent was removed to give 3,5-heptandiol as a white solid with the yield 90%, m.p. 60-65° C. IR spectrum had a strong absorption peak at 3400 cm−1, but had no absorption peak at about 1700 cm−1.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:30]1[CH:31]=[C:32]([NH:37][S:38]([N:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)(=[O:40])=[O:39])[C:33]([Cl:36])=[N:34][CH:35]=1.O>C1COCC1>[Cl:36][C:33]1[N:34]=[CH:35][C:30]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)=[CH:31][C:32]=1[NH:37][S:38]([N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)(=[O:40])=[O:39]
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: O=S(=O)(Nc1cc(Br)cnc1Cl)N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)N4CCCCC4)c3)cc2s1
Reaction time: 0.17 h
Yield: 12.8 %

Procedure:
To a microwave vial equipped with a stirbar and charged with N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.16 g, 0.51 mmol), cesium carbonate (0.41 g, 1.3 mmol), Pd Cl2 (dppf)-DCM (0.062 g, 0.076 mmol), N-(5-bromo-2-chloropyridin-3-yl)piperidine-1-sulfonamide (0.150 g, 0.42 mmol) in THF (3 ml) was added water (0.5 ml). The vial was capped and placed into CEM Microwave for 10 minutes at 100° C., while 100 watts of energy was supplied via Powermax® (Simultaneous heating while cooling technology). The progress of the reaction was monitored by LC/MS, which showed desired material in the mixture. The organic layer was extracted from the microwave vial by pipet and then diluted the organic with acetonitrile (15 ml) and TFA (0.1 ml). The crude was purified by reverse-phase HPLC. The fractions with desired product were combined and concentrated. The crude was recrystallized from 5:1 EtOAc/Methanol and Hexanes to give N-(6-(6-chloro-5-(piperidine-1-sulfonamido)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (0.025 g, 13% yield) as a tan crystalline solid. MS (ESI pos. ion) m/z: 466 (MH+). Calc'd exact mass for C19H20ClN5O3S2: 465. 1H NMR (400 MHz, DMSO-d6): 1.39 (s, 2H), 1.47 (s, 3H), 1.65 (s, 4H), 2.14 (s, 3H), 2.93 (s, 3H), 7.51 (s, 1H), 7.69 (s, 11H), 7.74 (s, 1H), 7.90 (s, 1H), 8.02 (s, 1H).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]([NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)=[C:5]2[C:9]([N:10]=1)=[N:8][CH:7]=[N:6]2.[N+:23]([C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29])([O-:25])=[O:24]>>[N+:23]([C:26]1[CH:27]=[C:28]([NH:29][C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][NH:8]3)=[C:4]([NH:11][C:12]3[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=3)[N:3]=2)[CH:30]=[CH:31][CH:32]=1)([O-:25])=[O:24]
Reactant: CCOC(=O)c1ccc(Nc2[nH]c(Cl)nc3ncnc2-3)cc1
Reactant: Nc1cccc([N+](=O)[O-])c1
Product: CCOC(=O)c1ccc(Nc2nc(Nc3cccc([N+](=O)[O-])c3)nc3[nH]cnc23)cc1
Yield: 54.1 %

Procedure:
The procedure is carried out as in stage 2 of Example 1, using 238 mg of the product obtained in stage 1 of Example 1 and 520 mg of 3-nitroaniline in place of trans-1,4diaminocyclohexane. 170 mg of the expected product are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:17][C@H:18]2[CH2:38][CH2:37][C:20]3([O:24][C@H:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C@@H:22]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:21]3)[CH2:19]2)[C:13](=[O:16])[CH:14]=[CH2:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[O:39]1[CH2:43][CH2:42][O:41][CH:40]1[C:44]1[CH:45]=[CH:46][C:47]([CH:50]=[O:51])=[N:48][CH:49]=1.C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:17][C@H:18]2[CH2:38][CH2:37][C:20]3([O:21][C@H:22]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@@H:23]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[O:24]3)[CH2:19]2)[C:13](=[O:16])[CH2:14][CH2:15][C:50]([C:47]2[CH:46]=[CH:45][C:44]([CH:40]3[O:41][CH2:42][CH2:43][O:39]3)=[CH:49][N:48]=2)=[O:51])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: O=Cc1ccc(C2OCCO2)cn1
Reactant: C=CC(=O)C(C[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)C(=O)CCC(=O)c2ccc(C3OCCO3)cn2)cc1Cl
Temperature: 25 °C
Yield: 33.4 %

Procedure:
To a solution of 4-[3-chloro-4-(methylsulfonyl)phenyl]-5-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]pent-1-en-3-one (624 mg) in ethanol (5 mL) were added 5-(1,3-dioxolan-2-yl)pyridine-2-carbaldehyde (244 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (33.7 mg) and triethylamine (68 μL), and the mixture was stirred with heating under reflux for 1 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (276 mg, yield 33%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: [NH2:1][C:2]1[C:14]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[CH:13][C:5]2[N:6]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[S:8][C:4]=2[CH:3]=1.[C:22](=O)(O)[O-:23].[Na+].C(Cl)(Cl)=S.[OH-].[Na+]>C(Cl)(Cl)Cl.O>[C:9]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([N:1]=[C:22]=[O:23])[C:14]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)=[CH:13][C:5]=2[N:6]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CN1CCN(c2cc3nc(C(C)(C)C)sc3cc2N)CC1
Reactant: O=C([O-])O
Agent: S=C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN1CCN(c2cc3nc(C(C)(C)C)sc3cc2N=C=O)CC1
Reaction time: 4 h

Procedure:
To a stirred mixture of 75 g of 6-amino-2-tert-butyl-5-(4-methylpiperazin-1-yl)benzothiazole and 29 g of sodium bicarbonate in 1100 ml of chloroform at 0° is added 41 g of thiophosgene and the mixture stirred at 10° for 4 hours. After filtering off the solid, the solution is evaporated to get an yellow solid which is dissolved in water and the pH of the solution is brought to 7 by the addition of dilute sodium hydroxide. The solid separated is extracted with hexane and filtered through 150 g of neutral alumina to give 2-tert-butyl-6-isocyanato-5-[4-methyl-piperazin-1-yl]benzothiazole melting at 124°-126°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:28]2[C:19](=[C:20]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][CH2:22][O:21]3)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH:15]([CH3:14])[C:28]4[C:19](=[C:20]5[C:25](=[CH:26][CH:27]=4)[O:24][CH2:23][CH2:22][O:21]5)[CH2:18][CH2:17]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2c1ccc1c2OCCO1
Product: CC1c2ccc3c(c2CCN1C(=O)c1cc2ncc(Br)cn2n1)OCCO3

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-Methyl-2,3,5,6,7,8-hexahydro-1,4-dioxa-7-aza-phenanthrene to provide the title compound in moderate yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[CH2:12]([N:14](CC)CC)[CH3:13].C(Cl)(=O)C.C(=O)([O-])[O-].[NH4+].[NH4+]>CN(C)C1C=CN=CC=1.CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:8])[NH:14][C:12]([CH3:13])=[N:11]2)=[CH:9][CH:10]=1
Reactant: Nc1cc(Br)ccc1C(=O)O
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)Cl
Solvent: CN(C)C=O
Product: Cc1nc2cc(Br)ccc2c(=O)[nH]1
Temperature: 90 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 0.81 g 4-bromoanthranilic acid (J. Org. Chem. 1997, 62, 1240-1256), 39 mg 4-(dimethylamino)pyridine and 2.09 ml triethylamine in dry dimethylformamide is added dropwise 0.69 ml acetylchloride at 3° C. for 20 min. in an ice-water bath under argon. The reaction mixture is then heated at 90° C. for 3 h. and 1.08 g ammonium carbonate is added portionwise over 10 min., and the mixture is stirred at the same temperature for 1 h. After cooling, the mixture is poured onto 20 ml water and the precipitate is filtered, washed with water and dried in vacuo to give 0.46 g (51%) of crude 7-Bromo-2-methyl-3H-quinazolin-4-one as a light-brown solid. Mp. >191° C. (dec.). MS (EI): peaks at m/e: 240(M+, 100%), 223 (14%), 197(18%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[CH2:23][CH2:24][C:25](=O)[CH3:26]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:25]([CH3:26])[CH2:24][CH2:23][C:17]2[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=2[Cl:15])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: CC(=O)CCc1c(F)cccc1Cl
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1c(F)cccc1Cl

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 4-(2-chloro-6-fluoro-phenyl)-butan-2-one.
Reaction SMILES: N1C=NN=N1.C(N(C(C)C)[P:10]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(C)C.[OH:24][CH2:25][CH2:26][NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[OH:38]O>C1COCC1>[C:17]([O:16][P:10]([O:24][CH2:25][CH2:26][NH:27][C:28](=[O:37])[O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:38])([CH3:18])([CH3:19])[CH3:20]
Reactant: OO
Reactant: CC(C)N(C(C)C)P(OC(C)(C)C)OC(C)(C)C
Reactant: O=C(NCCO)OCc1ccccc1
Agent: c1nnn[nH]1
Solvent: C1CCOC1
Product: CC(C)(C)OP(=O)(OCCNC(=O)OCc1ccccc1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.1 %

Procedure:
Tetrazole (3 wt % solution in CH3CN, 32 mL, 11.0 mmol) and di-tert-butyl N,N-diisopropylphosphoramidite (95%, 2.73 mL, 8.2 mmol) were added to a solution of benzyl N-2-hydroxyethylcarbamate (224) (1.07 g, 5.48 mmol) in THF (20 mL) and the mixture was stirred at room temperature for 16 h. The mixture was cooled to 0° C. and H2O2 (70% aqueous, 1.0 mL, 24 mmol) was added. After 15 min. the cooling bath was removed and the mixture was stirred for a further 6 h, then aqueous Na2SO3 (10%, 50 mL) was added with water bath cooling. After 25 min the organic solvents were removed under reduced pressure and the aqueous residue was extracted with EtOAc (×2). The combined extracts were washed with brine, dried, and evaporated. The residue was purified by chromatography, eluting with EtOAc/petroleum ether (1:1) to give benzyl 2-{[di(tert-butoxy)phosphoryl]oxy}ethylcarbamate (225) (1.36 g, 64%) as a colourless oil: 1H NMR [CDCl3] δ 7.37-7.28 (m, 5H), 5.43 (br 9, 1H), 5.11 (s, 2H), 4.07-4.00 (m, 2), 3.46 (q, J=5.1 Hz, 2H), 1.47 (s, 18H). HRMS (FAB) calcd. for C18H31NO6P (M+) m/z 388.1889, found 388.1889.
Reaction SMILES: [CH2:1](CC(=O)C)C(C)=O.C(=O)C1C=CC=CC=1.[C:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)[CH3:18]>>[CH3:18][C:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH2:1]
Reactant: CC(=O)CCC(C)=O
Reactant: CC(=O)c1ccccc1
Solvent: O=Cc1ccccc1
Product: C=C(C)c1ccccc1

Procedure:
Polar substances contained in the recovered main fraction were quantified by gas chromatography (GC-14A, Shimadzu Corp.). The amount of polar substances was taken to be the total amount of acetonylacetone, 3-methyl-2-cyclopetenone, benzaldehyde and acetophenone. The polar substance removal rate was determined based on the following formula 1. Removal rate (%)=Amount of reduction in polar substances (ppm)/Content of polar substances before purification (ppm)×100
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[S:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31]>>[CH3:1][N:2]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[C:29]2[S:25][C:26](=[O:31])[NH:27][C:28]2=[O:30])=[CH:19][CH:18]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: O=C1CSC(=O)N1
Reactant: CN(CCCCOc1ccc(C=O)cc1)c1nc2ccccc2o1
Product: CN(CCCCOc1ccc(C=C2SC(=O)NC2=O)cc1)c1nc2ccccc2o1

Procedure:
The title compound (m.p. 168° C.) was prepared from 4-[4-(N-methyl-N-(2-benzoxazolyl)amino)butoxy]benzal dehyde (3.5 g) and 2,4-thiazolidinedione (1.4 g) by a similar procedure to that described in Example 4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:17][C:16]3[C:11](=[N:12][CH:13]=[N:14][CH:15]=3)[N:10]=2)=[C:5]([O:18][CH2:19][CH2:20][S:21][CH3:22])[CH:4]=1.OO.C(=O)([O-])[O-:26].[K+].[K+]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:17][C:16]3[C:11](=[N:12][CH:13]=[N:14][CH:15]=3)[N:10]=2)=[C:5]([O:18][CH2:19][CH2:20][S:21]([CH3:22])=[O:26])[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(-c2nc3ncncc3[nH]2)c(OCCSC)c1
Agent: OO
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2nc3ncncc3[nH]2)c(OCCS(C)=O)c1
Reaction time: 3.5 h

Procedure:
One gram of 8-[4-methoxy-2-(2-methylmercapto-ethoxy)phenyl]purine was dissolved in 10 ml of glacial acetic acid and mixed with 0.5 ml of 30% hydrogen peroxide. After standing for 3.5 hours at room temperature, the reaction mixture was diluted with water and made alkaline by means of potassium carbonate. The precipitate was recrystallized from isopropanol/ethanol in a volume ratio of 1:1.
Reaction SMILES: [C:1]([C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:10][C@H:9]2[N:19]([CH3:20])[C@@H:6]1[CH2:7][CH2:8]2)(=O)[CH2:2][CH3:3].C[NH:22][OH:23].Cl.[C:25](=O)(O)[O-].[K+]>CO>[CH3:25][O:23][N:22]=[C:1]([CH:5]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:10][CH:9]2[N:19]([CH3:20])[CH:6]1[CH2:7][CH2:8]2)[CH2:2][CH3:3]
Reactant: CCC(=O)[C@H]1[C@@H](c2ccc(F)cc2)C[C@@H]2CC[C@H]1N2C
Reactant: CNO
Reactant: O=C([O-])O
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CCC(=NOC)C1C(c2ccc(F)cc2)CC2CCC1N2C

Procedure:
The ketone, 2β-(1-Propanoyl)-3β-(4-fluorophenyl)tropane, is dissolved in an appropriate organic solvent such as methanol and then at room temperature the desired alkyl-hydroxyl-amine, such as methyl-hydroxyl-amine, is added in excess (1.01 to 10 equivalents but preferably 5 equivalents). This amine is added as its hydrochloride or as a free base. If a salt is used such as a hydrochloride then an equivalent amount of mild base should be added, such as potassium bicarbonate or other equivalent salt in order to neutralize the amine hydrochloride. If necessary the solution is boiled until reaction occurs, typically 15 minutes to 24 hours is needed. The desired oxime, 1-[3-(4-Fluoro-phenyl)-8-methyl-8-aza-bicyclo[3.2.1]oct-2-yl]-propan-1-one O-methyl-oxime is isolated as an E, Z-mixture and if so desired separated by flash silica gel chromatography to provide either the pure E or pure Z-compound. The pH of the reaction solution is most preferably about 4 but may range from 1-12. See, for example, Morgan et al. J. Am. Chem. Soc. 1994, 116(8),3251-3260.
Reaction SMILES: CC([O-])(C)C.[K+].C1COCC1.[OH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH2:25][C:26]([NH2:28])=[O:27])=[CH:17]1.C[O:30][C:31](=O)[C:32]([C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:42]=1[N:41]([CH3:43])[CH:40]=[CH:39]2)=O.Cl>CN(C=O)C.CCOC(C)=O>[OH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25]2[C:26](=[O:27])[NH:28][C:31](=[O:30])[C:32]=2[C:34]2[CH:35]=[CH:36][CH:37]=[C:38]3[C:42]=2[N:41]([CH3:43])[CH:40]=[CH:39]3)=[CH:17]1
Reactant: NC(=O)Cc1cn(CCCO)c2ccccc12
Reactant: COC(=O)C(=O)c1cccc2ccn(C)c12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ccc2cccc(C3=C(c4cn(CCCO)c5ccccc45)C(=O)NC3=O)c21
Temperature: 25 °C
Reaction time: 14 h
Yield: 66.1 %

Procedure:
A 1.0 M solution of KOtBu in THF (9.2 mL, 9.2 mmol) was added to a solution of 2-[1-(3-hydroxypropyl)-1H-indol-3-yl]-acetamide (616 mg, 2.65 mmol) and (1-methyl-1H-indol-7-yl) -oxo-acetic acid methyl ester (566 mg, 2.61 mmol) in DMF (40 mL). The initially light yellow solution turned red-orange and was stirred 14 h at rt. 1N HCl was added and the mixture poured into EtOAc. The EtOAc layer was separated and washed with water (3×), saturated aq NaHCO3 (2×) and brine (3×), dried (MgSO4), filtered and concentrated onto SiO2. Flash chromatography (1:1 EtOAc:CH2Cl2) afforded a red solid that was dried at 70° C. for 72 h giving the title compound (689 mg, 66%) as a bright red solid. 1H NMR (400 MHz, DMSO-d6) 11.12 (s, 1H), 8.05 (s, 1H), 7.61 (d, J=8 Hz, 1H), 7.43 (d, J=8 Hz, 1H), 7.25 (d, J=3 Hz, 1H), 6.92–7.04 (m, 2H), 6.87 (d, J=8 Hz, 1H), 6.44–6.50 (m, 2H), 6.21 (d, J=8 Hz, 1H), 4.64 (m, 1H), 4.27 (t, J=7 Hz, 2H), 3.68 (s, 3H), 3.30–3.40 (m, 2H), 1.80–1.90 (m, 2H). 13C NMR (75.5 MHz, DMSO-d6) 173.43, 172.37, 136.15, 134.62, 134.26, 131.54, 129.58, 129.19, 128.57, 125.20, 124.11, 122.07, 121.53, 121.03, 120.12, 118.56, 115.18, 110.34, 104.28, 100.73, 57.54, 42.94, 34.68, 32.54. IR (CHCl3, cm−1) 3436, 1721. MS (electrospray, m/z) 400 (M++1), 398 (M−−1). Anal. Calcd. for C24H21N3O3: C, 72.17; H, 5.30; N, 10.52. Found: C, 71.87; H, 5.29; N, 10.45.
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[O:18][CH:17]2[C@:13]([CH3:21])([O:14][C:15]([CH3:20])(C)[O:16]2)[CH2:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][C:23]([O:25]C(C)=O)=[O:24].N1C=CC=CC=1.[CH2-]C(C)=O>C(O)(=O)C.C(OCC)(=O)C.CN(C1C=CN=CC=1)C>[C:1]([O:9][CH2:10][C@@H:11]1[CH2:12][C@:13]([O:25][C:23](=[O:24])[CH3:22])([CH3:21])[CH:17]([O:16][C:15](=[O:14])[CH3:20])[O:18]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)OC2O[C@H](COC(=O)c3ccccc3)C[C@@]2(C)O1
Agent: CN(C)c1ccncc1
Agent: [CH2-]C(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CC(=O)OC1O[C@H](COC(=O)c2ccccc2)C[C@@]1(C)OC(C)=O
Temperature: 70 °C
Yield: 75.5 %

Procedure:
A mixture of 3.8 g of ((5S,6aR)-2,2,6a-trimethyl-dihydro-5H-furo[3,2-d][1,3]dioxol-5-yl)methyl benzoate (from step 9) in 25 mL of 70% acetic acid was heated to 70° C. for 48 h. The reaction mixture was diluted with ethyl acetate and washed with water and saturated NaHCO3. The organic layers were dried over anhydrous Na2SO4, filtered and concentrated. Crude diol obtained was aceylated using Ac2O (0.03373 mol, 3.18 mL) and 20 mL of anhydrous pyridine with catalytic amount of DMAP (5 mol %). The progress of the reaction was monitored by TLC. Pyridine was removed under vacuum and the residue was diluted with ethyl acetate and was washed with 1N HCl and saturated NaHCO3. The organic layers were dried over anhydrous Na2SO4, filtered and concentrated. Purified by column chromatography to give 3.3 g of the title compound (88% yield) and 0.55 g of starting material acetonide was recovered.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[Li][C:13]([CH3:16])([CH3:15])[CH3:14].[Br:17][C:18]1[CH:31]=[CH:30][C:29]2[C:28](=[O:32])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:33])[C:20]=2[CH:19]=1>C1COCC1.CCCCC>[Br:17][C:18]1[CH:31]=[CH:30][C:29]2[C:28]([C:2]3[CH:11]=[CH:10][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH:3]=3)([OH:32])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([C:5]3[CH:4]=[CH:9][C:16]4[C:13](=[CH:15][CH:3]=[CH:2][CH:11]=4)[CH:14]=3)([OH:33])[C:20]=2[CH:19]=1
Reactant: Brc1ccc2ccccc2c1
Reactant: O=C1c2ccccc2C(=O)c2cc(Br)ccc21
Reactant: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: OC1(c2ccc3ccccc3c2)c2ccccc2C(O)(c2ccc3ccccc3c2)c2cc(Br)ccc21
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of 2-bromonaphthalene (6.49 g, 31.3 mmol) in dry THF (50 ml) was added dropwise t-BuLi (18.4 ml of a 1.7 M solution in pentane) at −78° C. under nitrogen. After the mixture had been stirred for 30 min, 2-bromoanthraquinone (3.00 g, 10.4 mmol) was added at −78° C. The cooling bath was removed and the mixture was stirred for 2 hours at room temperature. The mixture was quenched with saturated aqueous ammonium chloride solution (50 ml) and extracted with ethyl ether (3×50 ml). The combined organic extracts were dried over MgSO4 and concentrated under vacuum. The crude product was slurried in petroleum ether, filtered off with suction, and washed with petroleum ether. After drying, the 2-bromo-9,10-di-naphthalene-2-yl-9,10-dihydro-anthracene-9,10-diol (5.30 g, 93%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.Cl[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[O:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O.[Cl:43]C(Cl)C>>[Cl:43][C:19]1[CH:18]=[CH:17][C:16]([C:21]2[O:27][C:24]([CH2:25][NH:1][C:2]3[CH:3]=[CH:4][C:5]([C@@H:8]4[CH2:10][C@H:9]4[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=3)=[CH:23][CH:22]=2)=[CH:15][CH:20]=1
Reactant: O=Cc1ccc(-c2ccccc2Cl)o1
Reactant: Nc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Reactant: CC(Cl)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(NCc2ccc(-c3ccc(Cl)cc3)o2)cc1
Reaction time: 48 h
Yield: 60 %

Procedure:
To a mixture of (of racemic-(trans)-2-(4-aminophenyl)cyclopropanecarboxylic acid (I-1) (0.057 g, 0.322 mmol) in dichloroethane (2.5 mL) was added 5-(2-chlorophenyl)furfural (0.059 g, 0.285 mmol). The mixture was stirred for 2 days followed by addition of sodium triacetoxyborohydride (0.097 g, 0.458 mmol). The mixture was stirred for 7 h at RT. Water was added (10 mL), and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2×10 mL). The combined organics were dried with MgSO4 and concentrated. The crude material was purified by chromatography (EtOAc/hexanes) to give the title compound as a yellow solid (0.06 g, 60%). 1H NMR (400 MHz, DMSO-d6): δ 12.13 (s, 1H), 7.64 (d, J=8.6 Hz, 2H), 7.43 (d, J=8.6 Hz, 2H), 6.87 (d, J=3.3 Hz, 1H), 6.85 (d, J=8.4 Hz, 2H), 6.57 (d, J=8.4 Hz, 2H), 6.36 (d, J=3.3 Hz, 1H), 6.03 (t, J=6.0 Hz, 1H), 4.25 (d, J=6.0 Hz, 2H), 2.19 (m, 1H), 1.58 (m, 1H), 1.28 (m, 1H), 1.17 (m, 1H). ES-MS m/z 366.13 (MH−).