Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:23][CH:22]=3)[C:11]=2[CH2:12]P(OCC)(OCC)=O)=[O:6])[CH2:3][CH2:2]1.[H-].[Na+].[C:34]([N:53]1[CH:57]=[CH:56][N:55]=[C:54]1[CH:58]=O)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>C1COCC1>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:26]=3)[C:11]=2/[CH:12]=[CH:58]/[C:54]2[N:53]([C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:57]=[CH:56][N:55]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: O=Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CP(=O)(OCC)OCC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2/C=C/c2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a suspension of N-cyclopropyl-5-(diethylphosphonomethyl)-1-{4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxamide (500 mg) obtained in Example 321b) in THF (20 ml) was added sodium hydride (50% oil dispersion, 80 mg) at 0° C., and the mixture was stirred at room temperature for 1 hr. A solution of 1-trityl-1H-imidazole-2-carbaldehyde (367 mg) in THF (5 ml) was added to the obtained reaction mixture, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure to give a crude product of the title compound as a pale-yellow solid (670 mg).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:15](=[O:16])[CH2:14][CH2:13][C:12]3=[O:17])[CH2:7][CH2:6]2)[O:4]CC1.Cl>C(#N)C>[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15](=[O:16])[CH2:14][CH2:13][C:12]2=[O:17])[CH2:7][CH2:6]1
Reactant: O=C1CCC(=O)N1C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC#N
Product: O=C1CCC(N2C(=O)CCC2=O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(1,4-dioxaspiro[4.5]decan-8-yl)pyrrolidine-2,5-dione (60 mg, 0.25 mmol) from above step A, was dissolved in acetonitrile, treated with 6N HCl, and stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, treated with saturated NaHCO3 to pH 6. The solvents were removed under vacuum and the residue treated with saturated NaCl (2 mL) and extracted with 4:1 EtOAc/iPrOH (x4). The organic fractions were combined, filtered and evaporated to give the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=2[C:12]([O:14]C)=[O:13])[CH2:3]1.[Cl:21][C:22]1[CH:23]=[C:24]([C:28]2[O:29][C:30]([CH3:35])=[C:31]([CH2:33]I)[N:32]=2)[CH:25]=[CH:26][CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([C:28]2[O:29][C:30]([CH3:35])=[C:31]([CH2:33][O:1][CH:2]3[CH2:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][C:10]4[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:11]=4[C:12]([OH:14])=[O:13])[CH2:3]3)[N:32]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1c(C)cccc1COC1CCCC(O)C1
Reactant: Cc1oc(-c2cccc(Cl)c2)nc1CI
Product: Cc1cccc(COC2CCCC(OCc3nc(-c4cccc(Cl)c4)oc3C)C2)c1C(=O)O

Procedure:
Using methyl 2-(3-hydroxycyclohexyloxymethyl)-6-methylbenzoate and 2-(3-chlorophenyl)4-iodomethyl-5-methyloxazole as starting materials in the procedure of Example XXXI, gave the product 57 of molecular weight 469.97 (C26H28CINO5), MS(ESI): 470.43 (M+H+).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH:17]3OCC[O:18]3)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.O.C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCOCC1>[CH3:1][O:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH:17]=[O:18])[CH2:11][CH2:10]2)[CH2:7][CH2:8]1
Reactant: CO[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: CO[C@H]1CC[C@H]([C@H]2CC[C@H](CCC=O)CC2)CC1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
6.2 g of 2-[2-[trans-4-(trans-4-methoxycyclohexyl)cyclohexyl]ethyl]-1,3-dioxolane were treated with 100 ml of water, 50 ml of glacial acetic acid and 20 ml of dioxan while gassing with nitrogen. The mixture was stirred at 100° C. (bath temperature) for 1.5 hours, then neutralized with dilute sodium hydrogen carbonate solution and extracted three times with diethyl ether. The combined ether phases were washed once with water and twice with dilute sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered and evaporated. Recrystallization of the crude aldehyde obtained (4.34 g) from 150 ml of petroleum ether at -20° C. gave 2.8 g of 3-[trans-4-(trans-4-methoxycyclohexyl)cyclohexyl]propionaldehyde in a purity of 96%; m.p. 36° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:19][CH2:18][C:11]2([NH:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([NH:15][C:14](=[O:16])[N:13]([CH2:26][C:25]3[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)[C:12]2=[O:17])[CH2:18][CH2:19]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)NC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)NC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To 1 g (3.7 mmol) of 2,4-dioxo-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester were added successively 554 μL (4.08 mmol) of 4-methoxybenzyl chloride, 565 mg (4.08 mmol) of potassium carbonate and 37 mL of anhydrous DMF. The reaction mixture was stirred overnight at room temperature. Then 250 mL of water were added and a white precipitated solid was collected by filtration. This crude material was back washed with diethyl ether and dried under reduced pressure yielding 1.15 g (79%) of 3-(4-methoxybenzyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][C@@:9]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:14][C:13](=[O:15])[N:12]([C@H:16]([C:18]3[CH:23]=[CH:22][C:21](B4OC(C)(C)C(C)(C)O4)=[CH:20][CH:19]=3)[CH3:17])[CH2:11][CH2:10]2)=[N:4][N:3]=1.I[C:40]1[CH:45]=[CH:44][N:43]([CH3:46])[C:42](=[O:47])[CH:41]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][C@@:9]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:14][C:13](=[O:15])[N:12]([C@H:16]([C:18]3[CH:19]=[CH:20][C:21]([C:40]4[CH:45]=[CH:44][N:43]([CH3:46])[C:42](=[O:47])[CH:41]=4)=[CH:22][CH:23]=3)[CH3:17])[CH2:11][CH2:10]2)=[N:4][N:3]=1
Reactant: Cn1ccc(I)cc1=O
Reactant: Cc1nnc(CC[C@]2(c3ccccc3)CCN([C@@H](C)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)C(=O)O2)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1nnc(CC[C@]2(c3ccccc3)CCN([C@@H](C)c3ccc(-c4ccn(C)c(=O)c4)cc3)C(=O)O2)o1
Yield: 41.8 %

Procedure:
To a solution of (R)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-6-phenyl-3-((S) -1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (60 mg, 0.12 mmol) and 4-iodo-1-methylpyridin-2(1H)-one (33 mg, 0.14 mmol) in dry 1,4-dioxane (15 mL) were added Cs2CO3 (2M, 1 mL) and Pd(PPh3)Cl2 (7.7 mg, 0.01 mmol). The mixture was heated at reflux for 2 h under N2 atmosphere, the solid was filtered off, and the mixture was diluted with water (30 mL) and EtOAc (30 mL). The combined organic layers was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by prep TLC to afford (R)-6-(2-(5-methyl -1,3,4-oxadiazol-2-yl)ethyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (25 mg, yield: 41.8%). LC-MS Method 2 tR=0.984 min, m/z=499.1; 1H NMR (CDCl3): (51.48-1.50 (m, 3H), 2.16-2.20 (m, 1H), 2.23-2.26 (m, 1H), 2.27-2.32 (m, 2H), 2.39 (s, 3H), 2.40-2.47 (m, 1H), 2.49-2.54 (m, 1H), 2.87-2.90 (m, 1H), 2.98-3.01 (m, 1H), 3.58 (s, 3H), 5.62-5.64 (m, 1H), 6.45-6.48 (m, 1H), 6.87 (s, 1H), 6.92-6.94 (d, 2H), 7.20-7.24 (m, 4H), 7.25-7.35 (m, 4H).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)=O)(C)(C)C.Cl[C:19]1[C:20]([C:30]#[N:31])=[N:21][CH:22]=[C:23](/[CH:25]=[CH:26]/[CH2:27][O:28][CH3:29])[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CO>[CH3:29][O:28][CH2:27]/[CH:26]=[CH:25]/[C:23]1[CH:22]=[N:21][C:20]2[C:19]([CH:24]=1)=[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]1=[N:8][C:30]=2[NH2:31]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
Reactant: COC/C=C/c1cnc(C#N)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CO
Product: COC/C=C/c1cnc2c(N)nc3ccccc3c2c1
Temperature: 25 °C

Procedure:
A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and (E)-3-chloro-5-(3-methoxyprop-1-enyl)picolinonitrile (from step 1) (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (2.0 eq.) in toluene/ethanol (2:1, 0.03 M) was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction content was diluted with methanol. The insoluble solids were filtered off, and the filtrate was concentrated en vacuo to obtain a crude residue. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give (E)-2-(3-methoxyprop-1-enyl)benzo[f][1,7]naphthyridin-5-amine as a yellow solid. 1H NMR (dmso-d6): δ 9.24 (d, 1H), 9.18 (d, 1H), 8.54 (d, 1H), 7.52-7.58 (m, 2H), 7.31 (m, 1H), 7.11 (bs, 2H), 6.86-7.00 (m, 2H), 4.18 (d, 2H), 3.36 (s, 3H). LRMS [M+H]=266.2.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[OH:19].[N:20]#[C:21]Br>O1CCCC1.C(OCC)(=O)C>[NH2:20][C:21]1[O:19][C:3]2[CH:4]=[C:5]([O:6][C:7]3[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=3)[C:10]([O:12][CH3:13])=[O:11])[CH:17]=[CH:18][C:2]=2[N:1]=1
Reactant: COC(=O)c1cccc(Oc2ccc(N)c(O)c2)c1
Reactant: N#CBr
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(Oc2ccc3nc(N)oc3c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.7 %

Procedure:
To a solution of methyl 3-(4-amino-3-hydroxyphenoxy)benzoate (13.1 g, 50.5 mmol) in tetrahydrofuran (200 mL) was added cyanogen bromide (9.76 g, 92.1 mmol), and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added cyanogen bromide (1.78 g, 16.8 g), and the mixture was further stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate (300 mL), washed with saturated aqueous sodium hydrogencarbonate solution (150 mL×2) and saturated brine (150 mL), successively, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (13.6 g, yield (total of 4 steps) 95%) as brown crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1([C:12](OC)=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C(OCC)C>[CH3:1][O:2][CH2:3][CH2:4][C:5]1([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COCCC1(C(=O)OC)CCCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COCCC1(CO)CCCCCC1
Temperature: 0 °C

Procedure:
A solution of EXAMPLE 134B (2.25 g) in diethyl ether (10 mL) was added dropwise to a suspension of LiAlH4 (0.40 g) in diethyl ether (20 mL). Once the addition was finished, the mixture was refluxed for 90 minutes, and cooled to 0° C. Aqueous NaOH (2N, 50 mL) was added slowly. The mixture was then extracted with ethyl acetate (300 mL) and the organic layer was washed with brine and dried over Na2SO4. Filtration and concentration provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:23]([N:10]1[C:11]2[C@:12]3([CH3:22])[C:19]([CH3:21])([CH3:20])[C@@H:15]([CH2:14][CH2:13]3)[C:16]=2[C:17](=[O:18])[N:9]1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Cl:1])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3Cl)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC1(C)[C@H]2CC[C@]1(C)c1c2c(=O)n(-c2ccc(F)cc2Cl)n1Cc1ccccc1
Temperature: 80 °C
Yield: 47.6 %

Procedure:
A mixture of (4R,7S)-2-(2-chloro-4-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 43; 150 mg, 0.47 mmol), tetrabutylammonium iodide (174 mg, 0.47 mmol) and benzyl bromide (223 μL, 1.9 mmol) in dimethylformamide (3 mL) was heated at 80° C. overnight and then stirred at room temperature over the weekend. The solvent was evaporated and dichloromethane (50 mL) was added. The solution was washed with water (2×20 mL), saturated aqueous sodium thiosulfate (20 mL), and brine (20 mL), dried (magnesium sulfate), filtered, concentrated, purified by chromatography, eluting with 60-70% ethyl acetate/petroleum ether, and dried under high vacuum overnight to give (4R,7S)-1-benzyl-2-(2-chloro-4-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (92 mg, 38%) as a light tan solid. APCI(+)-MS (M+H) 411.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:26])[C:16]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:17][N:18]=3)[S:13][C:6]=12.[Cl-].[NH4+].C(O)C>[Fe].O>[F:1][C:2]1[CH:30]=[C:29]([CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:26])[C:16]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:17][N:18]=3)[S:13][C:6]=12)[NH2:31]
Reactant: Cn1c(CN2CCOCC2)cnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cn1c(CN2CCOCC2)cnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Temperature: 90 °C
Yield: 82.5 %

Procedure:
A mixture of nitro compound 296 (907 mg, 1.932 mmol), iron powder (917 mg, 16.42 mmol) and ammonium chloride (89 mg, 1.661 mmol) in a solvent system ethanol (24.0 mL) and water (12.0 mL) was heated to 90° C. for 1 hr. The reaction mixture was filtered while hot and concentrated. The residue was purified by Biotage (MeOH.DCM, 0-20%, SNAP 25 g cartridge) to give title compound 297 (700 mg, 1.593 mmol, 82% yield) as a white solid. MS: 440 (MH+).
Reaction SMILES: [CH:1]1(Br)[CH2:3][CH2:2]1.[Mg].II.[F:8][C:9]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19](F)[C:10]=1[C:11]([NH:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])=O>O1CCCC1>[CH:1]1([C:19]2[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=[C:9]([F:8])[C:10]=2[C:11]2[O:16][CH2:15][C:14]([CH3:18])([CH3:17])[N:13]=2)[CH2:3][CH2:2]1
Reactant: COc1cc(F)c(C(=O)NC(C)(C)CO)c(F)c1
Reactant: BrC1CC1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cc(F)c(C2=NC(C)(C)CO2)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of cyclopropyl bromide (12.1 g, 100 mmol) in anhydrous tetrahydrofuran (100 mL) was added magnesium turnings (2.4 g, 100 mmol) followed by a crystal of iodine, at room temperature. After a few minutes the reaction initiated and came to reflux without any additional heating. When the reflux was complete the reaction was cooled to room temperature and stirred for 2 hours. A solution of the fluoro compound from preparation 2 (9.64 g, 40 mmol) in tetrahydrofuran (50 mL) was cooled in an ice-bath to 0° C., and the grignard solution (50 mL) was added dropwise over 15 minutes, the cooling bath was removed and reaction warmed to room temperature and stirred for 1 hour. Further grignard solution (20 mL) was added and stirred for 1 hour. Further grignard solution (10 mL) was added and stirred for 1 hour. The reaction mixture was then quenched with 1M citric acid (30 mL), as some solid remained undissolved 2M hydrochloric acid (30 mL) was added. The resultant mixture was partitioned between ethyl acetate (400 mL) and water (200 mL), basified with concentrated ammonia solution and the organic layer separated, washed with water (150 mL), brine (150 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluting with hexane:isopropyl alcohol 85:15) to give the title compound as a clear oil (10.32 g, 98%).
Reaction SMILES: N#N.[CH3:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[O:13][CH3:14].N1C(C)=CC(C)=CC=1C.[Cl:24][C:25]([Cl:30])([Cl:29])[C:26](Cl)=[O:27]>C(#N)C>[CH3:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[C:26](=[O:27])[C:25]([Cl:30])([Cl:29])[Cl:24])=[CH:10][CH:9]=[CH:8][C:7]=2[O:13][CH3:14]
Reactant: COc1cccc2cc(C)[nH]c12
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: N#N
Solvent: Cc1cc(C)nc(C)c1
Solvent: CC#N
Product: COc1cccc2c(C(=O)C(Cl)(Cl)Cl)c(C)[nH]c12
Yield: 100.5 %

Procedure:
To a 2 L round-bottomed flask equipped with a magnetic stirrer and a N2 bubbler were added 2-methyl-7-methoxyindole (12 g, 74 mmol), acetonitrile (125 mL) and collidine (15 mL, 113 mmol). The mixture was stirred to give a solution and was cooled with an ice water bath. Trichloroacetyl chloride (14 mL, 112 mmol) was added. The cooling bath was removed and the reaction mixture stirred at RT for 3 h. 1N HCl (500 mL) was then added over 10 minutes. The resulting slurry was stirred at RT for 30 minutes and filtered. The cake was washed with DI water (3×50 mL) and suction dried for 17 h to give 2-methyl-3-trichloroacetyl-7-methoxyindole (22.8 g, 96% yield). 1H NMR (CDCl3) δ2.79 (s, 3H), 3.96 (s, 3H), 6.71 (d, J=7.9 Hz, 1H), 7.19 (dd, J=7.9, 8.4 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 8.92 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][O:18][CH2:19][CH3:20].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:16][CH2:17][O:18][CH2:19][CH3:20]
Reactant: Oc1ccccc1Br
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCOc1ccccc1Br
Temperature: 70 °C
Reaction time: 4 h

Procedure:
In DMF (120 ml) was dissolved 2-bromophenol (12 g). To the mixture was added potassium carbonate (12.5 g) and then was added 2-bromoethylethyl ether (9.1 ml), and the mixture was stirred at 70° C. for 4 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=12/1) to give 1-bromo-2-(2-ethoxyethoxy)benzene (14.8 g).
Reaction SMILES: [Mg].II.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([Mg]Br)[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27]>C1COCC1>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:22]([C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[C:19]([N+:26]([O-:28])=[O:27])[CH:20]=2)[OH:23])[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: COc1cc(OC)cc([Mg]Br)c1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(O)c2ccc(OC)c([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Grignard reagent was prepared in an oven-dried three necked flask outfitted with a reflux condenser, dropping funnel, and magnetic stirrer. Approximately ¼ of a solution of 3,5-bromoveratrole (10 g, 46.1 mmol) in anhydrous THF (60 mL) was added to a mixture of magnesium turnings (1.12 g, 46.1 mmol) in THF (10 mL) with a small piece of iodine. As soon as the solution became colorless (heating sometimes necessary), the remaining 3,5-bromoveratrole solution was added dropwise to the reaction mixture under mild reflux, over 30 min. The resulting mixture was refluxed for 3 h then cooled to room temperature for 30 min. The (3,5-dimethoxy-phenyl) magnesium bromide was then added slowly to a stirred solution of 4-methoxy-3-nitro-benzaldehyde (6.95 g, 38.4 mmol) in THF (60 mL) at 0° C. After complete addition, the reaction mixture was stirred at cold for 10 min and then at room temperature for 2 h. The solution was cooled to 0° C. and quenched with saturated NH4Cl solution (90 mL). The aqueous layer was extracted with ether (3×90 mL). The combined organic layers were washed with water (2×120 mL), brine (120 mL) and dried (MgSO4). Removal of solvent gave the crude (3,5-dimethoxy-phenyl)-(4-methoxy-3-nitro-phenyl)-methanol, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.[C:14](OC(=O)C)(=[O:16])C>C(O)=O>[CH:14]([N:10]1[CH2:11][CH:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([CH2:13]2)[CH2:9]1)=[O:16]
Reactant: Clc1ccc(C23CNCC2C3)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CN1CC2CC2(c2ccc(Cl)cc2)C1

Procedure:
A solution of 1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane in formic acid is added at 0°-5° C. to aceticformic anhydride prepared from 2 volumes of acetic anhydride and one volume of formic acid. The mixture is warmed to 40°-50° C. and poured onto ice to give 3-formyl-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane as the product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1)[CH3:2].[N:15]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][NH2:15])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cccc(N)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CCc1cccc(NN)c1
Reaction time: 1 h

Procedure:
To a solution of 3-(3-aminophenyl)propionic acid ethyl ester (14 g, 72.5 mmol) in conc. HCl (200 mL) was added aqueous (10 mL) NaNO2 (5 g, 72.5 mmol) at 0° C. and the resulting mixture was stirred for 1 h. A solution of SnCl2.2H2O (33 g, 145 mmol) in conc. HCl (150 mL) was then added at 0° C. The reaction solution was stirred for an additional 2 h at RT. The precipitate was filtered and washed with EtOH and ether to yield 3-(3-hydrazinophenyl)propionic acid ethyl ester as a white solid, which was used for the next reaction without further purification. MS (ESI): m/z: 209 (M+H+).
Reaction SMILES: [OH:1][C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:7][CH2:6][N:5]([C@H:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]([O:11][C@H](C2C=CC=CC=2)C)=[O:10])[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>ClCCl>[OH:1][C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:3][CH2:4][N:5]([C@H:8]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:9]([OH:11])=[O:10])[CH2:6][CH2:7]1
Reactant: C[C@H](OC(=O)[C@@H](c1ccccc1)N1CCC(O)(c2ccccc2)CC1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)[C@@H](c1ccccc1)N1CCC(O)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a solution of (S)-1-phenylethyl (R)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-2-phenylacetate (0.350 g, 0.84 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) and the mixture was stirred at room temperature for 2 hours. The volatiles were subsequently removed in vacuo and the residue was purified by reverse-phase preparative HPLC (Primesphere C-18, 20×100 mm; CH3CN—H2O-0.1% TFA) to give the title compound (as TFA salt) as a white solid (0.230 g, 88%). LCMS: Anal. Calcd. for C19H21NO3: 311. found: 312 (M+H)+.