Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#N)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].[CH3:16]I.C[N:19]([CH3:22])C=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([CH3:12])([CH3:16])[C:22]#[N:19])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CN(C)C=O
Reactant: COc1ccc(CC#N)cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(C(C)(C)C#N)cc1OC

Procedure:
A conventional alkylation reaction was carried out using a dimethylformamide solution (10 ml) of 1.77 g of 2-(3,4-dimethoxyphenyl)acetonitrile, 1.00 g of sodium hydride and 4.26 g of methyl iodide to give 1.78 g of 2-(3,4-dimethoxyphenyl)-2-methylpropionitrile. A conventional catalytic hydrogenation reaction was carried out using an ethanolic solution (30 ml) of 1.75 g of 2-(3,4-dimethoxyphenyl)-2-methylpropionitrile, 3.0 ml of an aqueous 28% ammonia solution and 4.3 g of Raney nickel to give 1.59 g of 2-(3,4-dimethoxyphenyl)-2-methylpropylamine. Then, a conventional cyclization reaction was carried out using a formic acid solution (8 ml) of 1.58 g of 2-(3,4-dimethoxyphenyl)-2-methylpropylamine and 0.252 g of paraformaldehyde to give 1.34 g of 6,7-dimethoxy-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline as a pale yellow oily substance. A conventional alkylation reaction was carried out using a solution (10 ml) of 1.77 g of 2-(3,4-dimethoxyphenyl)acetonitrile in dimethylformamide, 1.00 g of sodium hydride and 4.26 g of methyl iodide to give 1.78 g of 2-(3,4-dimethoxyphenyl)-2-methylpropionitrile.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:3]=1[C:4]([O:6][CH2:7][CH2:8][O:9][CH3:10])=[O:5].S(Cl)([Cl:19])(=O)=O.CC(N=NC(C#N)(C)C)(C#N)C>O>[Cl:19][CH2:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:3]=1[C:4]([O:6][CH2:7][CH2:8][O:9][CH3:10])=[O:5]
Reactant: COCCOC(=O)c1c(C)cccc1C
Reactant: O=S(=O)(Cl)Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Product: COCCOC(=O)c1c(C)cccc1CCl

Procedure:
10.4 g of 2-methoxyethyl 2,6-dimethylbenzoate are admixed at room temperature with 5.4 g of sulfuryl chloride and 40 mg of AIBN. The mixture is stirred at 60–90° C. for 1–2 h. Afterwards, the mixture is admixed with 20 ml of water, the phases are separated and the organic phase is dried over magnesium sulfate. The product is distilled under high vacuum (0.02 mbar, 95–103° C.). Yield: 6.4 g (66% of theory; 91.8 area %).
Reaction SMILES: [C:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][N:7]=1)([O:3][CH2:4][CH3:5])=[O:2].S(Cl)([Cl:17])=O>>[C:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:17])=[O:11])=[CH:8][N:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1ccc(C(=O)O)cn1
Reactant: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(C(=O)Cl)cn1

Procedure:
The starting material is prepared as follows: The suspension of 10 g of 6-carbethoxynicotinic acid in 40 ml of thionyl chloride is refluxed for 2 hours and evaporated. The residue is suspended in toluene and the mixture again taken to dryness. Another such cycle is repeated to yield the pure 6-carbethoxynicotinoyl chloride. It is dissolved in 150 ml of acetone and the solution cooled in an ice bath to 10°. 4.2 g of sodium azide, dissolved in 20 ml of water, are added dropwise to the acetone solution, whereupon a solid separates after several minutes. The mixture is stirred for 2 hours in the ice bath, then 150 ml of ice water are added and the solid is collected and washed with ice water, to yield the 6-carbethoxynicotinoyl azide.
Reaction SMILES: [CH2:1]([C:3]1[CH:57]=[CH:56][C:6]([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C@@H:17]4[O:46][C@H:45]([CH2:47][O:48]CC5C=CC=CC=5)[C@@H:36]([O:37]CC5C=CC=CC=5)[C@H:27]([O:28]CC5C=CC=CC=5)[C@H:18]4[O:19]CC4C=CC=CC=4)[CH:15]=3)[NH:10][CH:9]=2)=[CH:5][CH:4]=1)[CH3:2].[OH-].[Na+]>C1COCC1.O>[CH2:1]([C:3]1[CH:57]=[CH:56][C:6]([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C@@H:17]4[O:46][C@H:45]([CH2:47][OH:48])[C@@H:36]([OH:37])[C@H:27]([OH:28])[C@H:18]4[OH:19])[CH:15]=3)[NH:10][CH:9]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Cc2c[nH]c3ccc([C@@H]4O[C@H](COCc5ccccc5)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)cc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(Cc2c[nH]c3ccc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)cc23)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
3-(4-Ethylbenzyl)-5-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1H-indole: Part E (0.68 g, 0.78 mmol) was dissolved in THF (15 mL) and 25% aqueous sodium hydroxide (5 mL) and the resulting solution was brought to reflux for 3 h. After cooling to room temperature, the mixture was diluted with water (30 mL), and extracted with ethyl acetate. The organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by chromatography on silica gel eluting with ethyl acetate/hexane (1:3) to provide the title compound (0.5 g, 85%) as white solid. G. 3-(4-Ethylbenzyl)-5-(β-D-glucopyranosyl)-1H-indole: A solution of Part F (0.30 g, 0.4 mmol) in ethanol (10 mL) and ethyl acetate (20 mL) was hydrogenated over 10% Pearlman's catalyst (0.30 g) under 14 psi of H2 for 40 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The crude product was purified by chromatography on silica gel eluting with methanol/chloroform (10:100) to provide the titled compound (0.04 g, 25%) as a white solid. 1HNMR (300 MHz, CD3OD) δ 7.51 (s, 1H), 7.32 (d, J=8.52 Hz, 1H), 7.19–7.15 (m, 3H), 7.06 (d, J=7.87 Hz, 2H), 6.95 (s, 1H), 4.18–4.15 (m, 1H), 4.04 (s, 2H), 3.87 (d, J=12.2 Hz, 1H), 3.71–3.65 (m, 1H), 3.53–3.48 (m, 2H), 3.45–3.41 (m, 2H), 2.58 (q, J=7.58 Hz, 2H), 1.19 (t, J=7.65 Hz, 3H). MS: m/z (M+Na) 420.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:14])[F:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1([CH2:27][O:28][CH3:29])[CH2:26][O:25][CH2:24]1>C(#N)C>[Br:1][C:2]1[C:7]([O:8][CH2:22][C:23]2([CH2:27][O:28][CH3:29])[CH2:26][O:25][CH2:24]2)=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:13])[F:14])=[CH:4][CH:3]=1
Reactant: COc1c(OC(F)F)ccc(Br)c1O
Reactant: COCC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCC1(COc2c(Br)ccc(OC(F)F)c2OC)COC1
Temperature: 80 °C
Yield: 70.2 %

Procedure:
To a stirring solution of 6-bromo-3-(difluoromethoxy)-2-methoxyphenol (200 mg, 0.743 mmol) in acetonitrile (10 mL) was added potassium carbonate (307 mg, 2.228 mmol) and 3-(bromomethyl)-3-(methoxymethyl)oxetane (288 mg, 1.48 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure to afford 200 mg of 3-((6-Bromo-3-(difluoromethoxy)-2-methoxyphenoxy)methyl)-3-(methoxymethyl)oxetane as a solid.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([NH:23][S:25]([CH3:24])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
Dissolve 3-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine (400 mg, 1.34 mmol) in anhydrous pyridine (10 mL) and add methanesulfonyl chloride (616 mg, 416□L, 5.38 mmol). Stir overnight at room temperature, then concentrate. Take residue up in ethyl acetate and 1N HCl and separate the layers. Extract aqueous layer with ethyl acetate, combine organics, and dry (MgSO4). Concentrate to a brown oil. Purify via silica gel chromatography (2:3 ethyl acetate:hexanes) to yield 350 mg (70%) of yellow foam, mp 66.3° C. 1H NMR (CDCl3) δ 2.71 (s, 3H), 2.75-3.56 (br m, 4H), 6.09 (s, 1H), 6.64-7.43 (m, 13H); MS (ES) 398 (M+23), 374 (M−H). HPLC shows 96% purity.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH3:26])[S:20]([CH2:23][CH2:24][NH2:25])(=[O:22])=[O:21])[CH2:15][CH2:14]1)([CH3:12])[CH3:11]>>[ClH:1].[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH3:26])[S:20]([CH2:23][CH2:24][NH:25][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:9])(=[O:21])=[O:22])[CH2:15][CH2:14]1)([CH3:12])[CH3:11]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: CC(C)N1CCC(N(C)S(=O)(=O)CCN)CC1
Product: CC(C)N1CCC(N(C)S(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1
Product: Cl

Procedure:
5-Chloro-thiophene-2-carboxylic acid {2-[(1-isopropyl-piperidin-4-yl)-methyl-sulfamoyl]-ethyl}-amide was prepared by an analogous procedure as described for example 1 iii) starting from 318 mg (2 equiv.) 5-chloro-thiophene-2-carboxylic acid and 258 mg (0.98 mmol) crude 2-amino-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-methyl-amide. Final purification was achieved by preparative RP-HPLC (CH3CN/H2O gradient+0.1% TFA). After lyophilisation and transformation into its hydrochloride the title compound was obtained as a colorless, amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.S(=O)(=O)(O)O.[CH3:22]O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH3:22])=[O:15])[C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1
Reactant: CC1Oc2c(cc(Cl)cc2C(=O)O)NC1=O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Cl)cc2c1OC(C)C(=O)N2
Reaction time: 40 h

Procedure:
A mixture of 10 g of 6-chloro-3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid, 150 ml of methanol and 5 ml of concentrated sulfuric acid is refluxed under heating with stirring for 40 hours, and then cooled. The precipitated crystals are collected by filtration, washed with methanol and dried to give 9.5 g of methyl 6-chloro-3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylate, melting at 186°-189° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=2)[N:6]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=2)[C@H:5]([CH2:24][CH3:25])[C:4]1=[O:26])[CH3:2].C([C@H]1N(C(=O)C2C=CC(O)=CC=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=2)[N:6]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C@H:5]([CH2:24][CH3:25])[C:4]1=[O:26])[CH3:2]
Reactant: CC[C@@H]1C(=O)N(CC)c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Agent: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(O)cc1
Product: CC[C@@H]1C(=O)N(CC)c2ccc(F)cc2N1C(=O)c1ccc(O)cc1
Yield: 83 %

Procedure:
(3R)-1,3-Diethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one was treated according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-hydroxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3R)-1,3-diethyl-6-fluoro-4-(4-hydroxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (83%). [α]D25=−300° (c=0.010 G/ML, CHCl3); MS (ESI) m/z 343 ([M+H]+); MS (ESI) m/z 341 ([M−H]−); HRMS: calcd for C19H19FN2O3, 342.1380; found (ESI_FT), 343.14482.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[O:45][C:30]3=[CH:31][N:32]=[C:33]([C:35]4[CH:40]=[CH:39][C:38]([C:41]([NH2:43])=O)=[CH:37][C:36]=4[F:44])[CH:34]=[C:29]3[CH:28]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH2:23][CH:24]([C:27]2[O:45][C:30]3=[CH:31][N:32]=[C:33]([C:35]4[CH:40]=[CH:39][C:38]([C:41]#[N:43])=[CH:37][C:36]=4[F:44])[CH:34]=[C:29]3[CH:28]=2)[CH2:25][CH2:26]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(C(N)=O)cc4F)ncc3o2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(C#N)cc4F)ncc3o2)CC1
Reaction time: 0.5 h

Procedure:
Trifluoroacetic anhydride (26 μL) is added to a solution of 4-[5-(2-fluoro-4-aminocarbonyl-phenyl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (40 mg) and triethylamine (51 μL) in dichloromethane (3 mL) at room temperature. The solution is stirred at room temperature for 2 h before another portion of trifluoroacetic anhydride (26 μL) and triethylamine (51 μL) is added. The solution is stirred for 0.5 h and then aqueous NaHCO3 solution is added. The resulting mixture is extracted with dichloromethane and the combined extracts are washed with brine, dried (Na2SO4), and concentrated. The residue is triturated with ether and then with methanol to give the title compound. LC (method 3): tR=1.52 min; Mass spectrum (ESI+): m/z=422 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[NH:35]1[CH2:39][CH2:38][CH2:37][CH:36]1[CH2:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([O:50][CH3:51])=[O:49])=[CH:44][N:43]=1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:35]2[CH2:39][CH2:38][CH2:37][CH:36]2[CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]([O:50][CH3:51])=[O:49])=[CH:44][N:43]=2)=[O:23])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Reactant: COC(=O)c1ccc(OCC2CCCN2)nc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A mixture of pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate (351.7 mg, 0.732 mmol), methyl 2-[(2-pyrrolidinyl)methoxy]pyridine-5-carboxylate (173.0 mg, 0.732 mmol), Et3N (122.4 μl, 0.878 mmol) in DMF (5.2 mL) was stirred for 1 hr at room temp. The mixture was diluted with EtOAc, washed with brine, and dried over Na2SO4. The solvent was removed under a reduced pressure and the residue was chromatographed on silica-gel with n-hexane:EtOAc (1:5, v/v) as eluent to afford methyl 2-[[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxy]pyridine-5-carboxylate (338.4 mg, 87%) as an oil. To a stirred solution of this compound in THF (5.6 mL) and H2O (1.4 mL) was added LiOH (45.7 mg, 1.91 mmol), and the reaction mixture was stirred at room temp overnight. The mixture was diluted with CHCl3, and treated with sat. NH4Cl, washed with brine, dried over Na2SO4. The solvent was removed under a reduced pressure, and the obtained crude solid was recrystallized from n-hexane-Et2O—CHCl3—MeOH to afford 193.8 mg (59%) 40 as a white crystalline powder. mp 125-128; IR (KBr) 1716, 1600, 1533, 1255 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ1.67-2.03 (m, 4H), 2.50 (s, 3H), 3.33-3.42 (m, 1H), 3.52 (m, 2H), 3.58 (d, J=4.4 Hz, 1H), 3.83 (s, 3H), 4.27-4.31 (m, 2H), 4.42-4.47 (m, 1H), 6.73 (d, J=7.8 Hz, 1H), 6.87-6.95 (m, 3H), 7.11-7.17 (m, 2H), 7.79 (d, J=8.3 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 8.14 (dd, J=2.0, 8.8 Hz, 1H), 8.46 (s, 1H), 8.56 (s, 1), 8.69 (d, J=2.0 Hz, 1H), 13.06 (br s, 1H); MS (FAB) m/z 519 (M++1); Anal. Calcd. for C28H30N4O6.1/2H2O: C, 63.75; H, 5.92; N, 10.62. Found: C, 63.61; H, 5.94; N, 10.27.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:28][NH2:29]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([NH:28][NH2:29])=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(C(=O)NN)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(tert-butoxycarbonyl) azetidine-3-carboxylic acid (5 g, 24.8 mmol) was suspended in dichloromethane (15 mL) and 1,1′-carbonyldiimidazole (4.56 g, 28.1 mmol) was added in portions. The resulting mixture was stirred at rt for 30 minutes and then added dropwise to a solution of hydrazine hydrate (1.94 mL, 39.9 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was stirred for 30 min at rt. The reaction mixture was washed with saturated aqueous Na2CO3 solution (2×), brine, dried (Na2SO4) and concentrated under vacuum to give a white crystalline solid, which was triturated with diethyl ether overnight, filtered and air-dried for 5 h to give a white solid.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([O:11][C:12](=[O:26])[NH:13][CH2:14][C:15]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH:18]3O)[CH2:16]1)[CH2:22]2)([CH3:10])([CH3:9])[CH3:8].CC1C=CC(S([CH2:37][N+:38]#[C-])(=O)=O)=CC=1.CCO>COCCOC>[C:7]([O:11][C:12](=[O:26])[NH:13][CH2:14][C:15]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH:18]3[C:37]#[N:38])[CH2:16]1)[CH2:22]2)([CH3:10])([CH3:9])[CH3:8]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)NCC12CC3CC(C1)C(O)C(C3)C2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC12CC3CC(C1)C(C#N)C(C3)C2
Temperature: 25 °C
Yield: 65.3 %

Procedure:
Solid t-BuOK (240 mg, 2.15 mmol) was added as 6 portions to a solution of ketone 1B (300 mg, 1.07 mmol) and TosMIC (273 mg, 1.40 mmol) in a mixture of DME (5.0 mL) and absolute EtOH (1 mL) while keeping the temperature between 5 and 10° C. The reaction mixture was allowed to warm to rt and was maintained for 30 min. The reaction mixture was then heated at 35-40° C. for 30 min and was then allowed to cool to rt. The precipitate (TosK) was removed by filtration and the filter cake was washed with DME. The combined organic layers were concentrated and the residue was purified by column chromatography (0/100 to 10/90 MeOH/EtOAc) to provide nitrile 17A (203 mg, 70%) as a mixture of equatorial and axial isomers. Data: LC/MS (ESR) m/z=291 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:26]([O:28]C(C)(C)C)=[O:27])=[C:10]([NH:13][C:14]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)=[O:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:26]([OH:28])=[O:27])=[C:10]([NH:13][C:14]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)=[O:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:13][C:14]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)=[O:15])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1c(-c2ccc(Br)cc2)csc1NC(=O)N1CCc2ccccc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccc(Br)cc2)cs1)N1CCc2ccccc2C1
Product: O=C(O)c1c(-c2ccc(Br)cc2)csc1NC(=O)N1CCc2ccccc2C1
Yield: 16.3 %
Yield: 55.5 %

Procedure:
A solution of tert-butyl 4-(4-bromophenyl)-2-(2-1,2,3,4-tetrahydroisoquinolylcarbonylamino)thiophene-3-carboxylate (70) (46.3 mg) in TFA/DCM (1:1, 3 ml) was stirred at r.t. for 40 min. After evaporated to dryness, the residue was dissolved in DMF and then subjected to reverse phase prep HPLC purification. 22.9 mg 4-(4-bromophenyl)-2-(2-1,2,3,4-tetrahydroisoquinolylcarbonylamino)thiophene-3-carboxylic acid (71A) (yield: 55.5%) and 6.1 mg N-[4-(4-bromophenyl)(2-thienyl)]-2-1,2,3,4-tetrahydroisoquinolylcarboxamide (71B) (yield: 16.3%) were isolated as white solids respectively.
Reaction SMILES: [CH2:1](O)C.[CH3:4][CH2:5][C@@:6]1([OH:29])[C:11](=[O:12])[O:10][CH2:9][C:8]2[C:13]([N:15]3[C:27](=[CH:28][C:7]1=2)[C:26]1[N:25]=[C:24]2[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]2)=[CH:18][C:17]=1[CH2:16]3)=[O:14].S(=O)(=O)(O)O.OO>O>[CH3:4][CH2:5][C@@:6]1([OH:29])[C:11](=[O:12])[O:10][CH2:9][C:8]2[C:13]([N:15]3[C:27](=[CH:28][C:7]1=2)[C:26]1[C:17](=[C:18]([CH3:1])[C:19]2[C:24]([N:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:16]3)=[O:14]
Reactant: CCO
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Agent: O=S(=O)(O)O
Agent: OO
Solvent: O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Ferrous sulfate heptahydrate (4.17 g, 15 m-mol) and ethanol (3 ml, 60 m-mol) were dissolved in water (30 ml). Camptothecin (700 mg, 2 m-mol) was suspended in the solution and dissolved therein by adding concentrated sulfuric acid (15 ml) in small portions to the suspension. To the mixture was added dropwise under ice-cooling and agitation a 30% aqueous solution of hydrogen peroxide (1.63 ml, 16 m-mol). After addition of the hydrogen peroxide, the mixture was stirred for 6 hours at room temperature. To the reaction mixture was added ferrous sulfate heptahydrate (2.0 g, 7.2 m-mol) and then was added dropwise under ice-cooling and agitation a 30% aqueous solution of hydrogen peroxide (1 ml, 9.8 m-mol). The agitation was continued for 15 hours at room temperature. To complete the reaction, additional ferrous sulfate heptahydrate (4.2 g, 15 m-mol) and a 30% aqueous solution of hydrogen peroxide (1.5 ml, 14.7 m-mol) were added to the reaction mixture and the whole was stirred for 8 hours at room temperature. The reaction mixture was diluted with ice water (2.5 liters) and extracted with chloroform (3 liters). The chloroform layer was dried with anhydrous magnesium sulfate, filtered and evaporated until dryness under reduced pressure. The residue was purified by way of column chromatography (chloroform) through silica gel (10 g) followed by recrystallization from n-hexane-chloroform whereby 127 mg (17.5%) of the objective compound were obtained as yellow needle crystals. M.P. 280°-281° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([CH:17]([OH:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:13]=[CH:12][C:11]=2[C:10]([CH3:26])([CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:29]I.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([CH:17]([O:24][CH3:29])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:13]=[CH:12][C:11]=2[C:10]([CH3:26])([CH3:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(C(O)c3ccccc3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(c1ccccc1)c1cc2c(cn1)C(C)(C)CN2C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a solution of 6-(hydroxy-phenyl-methyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (0.15 g, 0.42 mmol) in THF (5 mL) was added sodium hydride (60%, 0.02 g, 0.50 mmol) and the mixture was stirred for 1 h. Methyl iodide (52 μL, 0.84 mmol) was added and the reaction mixture was stirred for 18 h at ambient temperature. Water (10 mL) was added and the product was extracted with EtOAc (2×10 mL). The combined organic phase was dried (MgSO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-70% EtOAc in 40-60 petroleum ether) gave the title compound (0.11 g, 70%) as an oil. MS: [M+H]+=369.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Cl-].[Cl-].[Cl-].[Al+3].[F:15][C:16]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:18]([C:17]3[CH:21]=[CH:22][CH:23]=[C:24]([O:25][CH3:26])[C:16]=3[F:15])=[O:19])=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: COc1cccc(C(=O)Cl)c1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1cccc(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5-bromo-1H-pyrrolo[2,3-b]pyridine (67, 2.00 g, 0.0102 mol) in methylene chloride (120 mL), under an atmosphere of nitrogen, was added aluminum trichloride (8.20 g, 0.0615 mol). The reaction was stirred at room temperature for 60 minutes, then 2-fluoro-3-methoxy-benzoyl chloride (34, 2.12 g, 0.0112 mol, prepared from the corresponding carboxylic acid using the protocol of Example 1, Scheme 13, Step 4), dissolved in methylene chloride (20.0 mL), was added. After 2 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel chromatography, eluting with 25% ethyl acetate in hexane to provide P-0265 (approx 2.6 g, 73%). MS (ESI) [M−H+]+=347, 349.