Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6](/[C:9](=N/OC)/[CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2].C(O)(=O)C(C)=[O:31]>Cl>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:31])[CH2:10][O:11][C:12]2[CH:25]=[CH:24][C:15]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(/C(COc2ccc(CC3SC(=O)NC3=O)cc2)=N/OC)nc1
Reactant: CC(=O)C(=O)O
Agent: Cl
Product: CCc1ccc(C(=O)COc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Reaction time: 2 h

Procedure:
A stirring solution of 5-(4-{[(2Z)-2-(5-ethylpyridin-2-yl)-2-(methoxyimino)ethyl]oxy}benzyl)-1,3-thiazolidine-2,4-dione (81 mg, 0.20 mmol; Supplier=Kalexsyn; Lot=1003-TTP-194) in 6M HCl (2 ml) and pyruvic acid (0.5 ml) was heated at 75° C. After 2 h at 75° C. HPLC showed reaction was complete. Neutralized with sat'd NaHCO3 and extracted with EtOAc. Extract dried (Na2SO4), filtered and evaporated in vacuo to give 45 mg (60%) pale yellow oil. 1H-NMR (DMSO-d6): δ12.02 (brs, 1H), 8.64 (s, 1H), 7.91 (m, 1H), 7.14 (d, J=8.5 Hz, 2H), 6.88 (d, J=8.5 Hz, 2H), 5.66 (s, 2H), 4.87 (dd, J=9.2, 4.3 Hz, 1H), 3.31 (m, 1H), 3.05 (dd, J=14.1, 9.1 Hz, 1H), 2.74 (q, J=7.7 Hz, 2H), 1.23 (t, J=7.7 Hz, 3H). HPLC (3.860 min., 100area % @ 210 and 254 nm. MS (ESI−) for C19H18N2O4S m/z 371.3 (M+H)+; m/z 369.4 (M−H)−
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C@H:42]2[CH2:47][CH2:46][C@H:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([C@H:42]4[CH2:43][CH2:44][C@H:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:46][CH2:47]4)=[C:35]4[C:39]=3[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH3:29])[CH:15]=1)([O:22][CH2:23][CH3:24])=[O:25])[CH3:21]
Reactant: CCOC(=O)[C@H]1CC[C@H](c2ccc(N)c3c2CN(C)C3=O)CC1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOC(=O)[C@H]1CC[C@H](c2ccc(Nc3nc(Nc4ccc(CP(=O)(OCC)OCC)cc4OC)ncc3C(F)(F)F)c3c2CN(C)C3=O)CC1

Procedure:
This compound was prepared in a manner analogous to Example 87 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and ethyl trans-4-(7-amino-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexanecarboxylate. 1H NMR (400 MHz, MeOD) δ ppm 8.51 (d, J=8.84 Hz, 1H), 8.36 (s, 1H), 7.89 (d, J=8.08 Hz, 1H), 7.40 (d, J=8.84 Hz, 1H), 7.08 (t, J=2.02 Hz, 1H), 6.97 (dt, 1H), 4.53 (s, 2H), 4.06-4.20 (m, 6H), 3.92 (s, 3H), 3.35-3.36 (m, 1H), 3.29-3.31 (m, 1H), 3.20 (s, 3H), 2.44-2.68 (m, 2H), 2.14 (d, J=10.61 Hz, 2H), 1.91-1.98 (m, 2H), 1.57-1.77 (m, 4H), 1.30 (q, 9H). MS (ES+): m/z=734.84 [MH+]. HPLC: tR=1.74 min (UPLC TOF, polar—3 min).
Reaction SMILES: Cl.O=[C:3]1[NH:22]C2=NC=C(C3C=CC(C(=N)OCC)=CC=3)N=C2[N:4]1CCN1CCCCC1.[O:31]=[C:32]1[NH:48][C:35]2=[N:36][CH:37]=[C:38]([C:40]3[CH:47]=[CH:46][C:43]([C:44]#[N:45])=[CH:42][CH:41]=3)[N:39]=[C:34]2[N:33]1[CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1.Cl>C(O)C>[N:4]1[N:45]=[C:44]([C:43]2[CH:42]=[CH:41][C:40]([C:38]3[N:39]=[C:34]4[N:33]([CH2:49][CH2:50][N:51]5[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56]5)[C:32](=[O:31])[NH:48][C:35]4=[N:36][CH:37]=3)=[CH:47][CH:46]=2)[NH:22][CH:3]=1
Reactant: CCOC(=N)c1ccc(-c2cnc3[nH]c(=O)n(CCN4CCCCC4)c3n2)cc1
Reactant: N#Cc1ccc(-c2cnc3[nH]c(=O)n(CCN4CCCCC4)c3n2)cc1
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c2ncc(-c3ccc(-c4nnc[nH]4)cc3)nc2n1CCN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
Ethyl 4-(2-oxo-3-(2-(piperidin-1-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzimidate hydrochloride. 4-(2-Oxo-3-(2-(piperidin-1-yl)ethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)benzonitrile (0.5 g., 1.43 mmol) was placed in anhydrous ethanol (5 mL) and cooled on an ice bath. The mixture was charged with hydrogen chloride gas for 15 min, capped and allowed to stir overnight while warming to rt. The solvent was removed and the residue treated with ether, filtered and dried under high vacuum to yield the title compound (0.4 g., 64.6% yield). MS (ESI) m/z 395.6[M+1]+
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][C:16](NC)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33].C(CN)O.CN1CCOCC1>>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][CH2:16][OH:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33]
Reactant: CNC(=O)CNC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Solvent: NCCO
Solvent: CN1CCOCC1
Product: Cc1ccc(C(=O)NCCO)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Yield: 63 %

Procedure:
The title compound was prepared by a procedure similar to the one described for 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methyl-N-{1-[(methylamino)carbonyl]methyl}benzamide using ethanolamine (0.16 mL 2.5 mmol) as the amine and without the addition of a second equivalent of N-methylmorpholine. After reverse phase HPLC purification, the organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (551.7 mg, 63%) as white solid. 1H-NMR (CD3OD, 400 MHz) δ 8.32 (s, 1H), 7.92 (dd, 1H, J=2 Hz), 7.77 (d, 1H, J=2 Hz), 7.62 (m, 1H), 7.53 (d, 1H, J=8 Hz), 7.01 (m, 2H), 5.60 (q, 2H, J=12.4 Hz), 3.68 (t, 2H), 3.48 (t, 2H), 2.19 (s, 3H) ; ES-HRMS m/z 494.0518 (M+H C21H19BrF2N3O4 requires 494.0522).
Reaction SMILES: [In].[C:2]([S:6]([NH2:8])=[O:7])([CH3:5])([CH3:4])[CH3:3].[F:9][C:10]1[CH:11]=[CH:12][C:13]([O:18][CH:19]2[CH2:23][CH2:22][O:21][CH2:20]2)=[C:14]([CH:17]=1)[CH:15]=O.Br[CH2:25][CH:26]=[CH2:27]>C1COCC1.O>[F:9][C:10]1[CH:11]=[CH:12][C:13]([O:18][CH:19]2[CH2:23][CH2:22][O:21][CH2:20]2)=[C:14]([C@H:15]([NH:8][S@:6]([C:2]([CH3:5])([CH3:4])[CH3:3])=[O:7])[CH2:27][CH:26]=[CH2:25])[CH:17]=1
Reactant: C=CCBr
Reactant: CC(C)(C)S(N)=O
Reactant: O=Cc1cc(F)ccc1OC1CCOC1
Agent: [In]
Solvent: C1CCOC1
Solvent: O
Product: C=CC[C@@H](N[S@@](=O)C(C)(C)C)c1cc(F)ccc1OC1CCOC1
Temperature: 0 °C

Procedure:
A mixture of Indium powder (27 g, 235 mmol), S-tert-butyl sulfinamide (26.3 g, 216 mmol), 5-fluoro-2-((tetrahydrofuran-3-yl)oxy)benzaldehyde (38.0 g, 181 mmol) and Ti(OEt)4 (61.8 g, 271 mmol) in THF (380 mL) was refluxed for 2 h. Reaction mass was cooled to 0° C. and added 3-bromoprop-1-ene (28.4 g, 235 mmol) slowly for a period of 30 min. Reaction mass was heated to reflux for 16 h, cooled to room temperature and diluted with water (1.0 L), the hazy solution was filtered through celite bed and the solids were washed with ethyl acetate (1.0 L). The filtrate was extracted with ethyl acetate (600 ml). The combined organic phases were washed with water and brine which was dried over Na2SO4 and concentrated to get the desired product as viscous liquid. This was purified over 60-120 mesh silica using 50-60% ethyl acetate and hexane as an eluent to get the pure product (30 g, yield: 47%). MS (ESI): m/z 356.45 (M+H)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:3]=1.[Br:18][CH2:19][CH2:20]O.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:20][CH2:19][Br:18])=[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:3]=1
Reactant: OCCBr
Reactant: Oc1ccc(Br)cc1-c1cc2ccccc2[nH]1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrCCOc1ccc(Br)cc1-c1cc2ccccc2[nH]1
Reaction time: 1 h
Yield: 100.2 %

Procedure:
To a mixture of 4-bromo-2-(1H-indol-2-yl)phenol (1.44 g, 5 mmol) and 2-bromoethanol (1.12 g, 9 mmol) in 20 mL of THF was added DBAD (2.07 g, 9 mmol) followed by triphenylphosphine (2.36 g, 9 mmol) in portions at room temperature with stirring. After 1 hour, the reaction was concentrated to near dryness, and purified using flash column chromatography (hexane/EtOAc 30:1) to provide the crude product of 2-(5-bromo-2-(2-bromoethoxy)phenyl)-1H-indole (1.98 g, 100%). MS (M+H)+: 394/396/398.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:32][CH2:33][CH2:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[Cl:32][CH2:33][CH2:34][S:35]([N:22]1[CH2:23][CH2:24][CH:19]([C:10]2[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[NH:12][CH:11]=2)[CH2:20][CH2:21]1)(=[O:37])=[O:36]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Reactant: O=S(=O)(Cl)CCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)CCCl)CC3)c[nH]c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.2 %

Procedure:
To a solution of 5-phenyl-3-(4-piperidinyl)-1H-indole-7-carboxamide (65 mg, 0.2 mmol) in CH2Cl2 (5 mL) at 0° C., triethylamine (0.11 mL, 0.8 mmol) and 2-chloroethanesulfonyl chloride (0.042 mL, 0.4 mmol) were added. After stirring at 0° C. for 30 min. the reaction mixture was partitioned between CH2Cl2 and water. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic phase was dried over magnesium sulfate and the solvent removed under reduced pressure. The resulting residue was purified by filtration through an SPE Cartridge (Aminopropyl NH2, 500 mg/6 mL) to give the desired product (26 mg, 32%).
Reaction SMILES: [O:1]1[CH:5]([CH2:6][OH:7])[CH2:4][C:3]2[CH:8]=[CH:9][C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=3[C:2]1=2.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1.O>[CH3:26][C:16]1[CH:21]=[CH:20][C:19]([S:22]([O:7][CH2:6][CH:5]2[O:1][C:2]3[C:15]4[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=4[CH:9]=[CH:8][C:3]=3[CH2:4]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: OCC1Cc2ccc3c(c2O1)CCCC3
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2Cc3ccc4c(c3O2)CCCC4)cc1
Temperature: 40 °C
Reaction time: 12 h
Yield: 85.2 %

Procedure:
To a solution of (±)-2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-2-ylmethanol (1.37 g, 6.71 mmol) in dichloromethane (50 mL) was added p-toluenesulfonyl chloride (2.56 g, 13.41 mmol), 4-(dimethylamino)pyridine (0.164 g, 1.34 mmol), and triethylamine (1.70 g, 16.77 mmol) and the reaction mixture was allowed to stir at 40° C. for 12 h. The reaction mixture was diluted with water (250 mL) and the aqueous layer extracted with dichloromethane (2×150 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried (magnesium sulfate), and the solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:5) gave 2.05 g (85%) of (±)-2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan-2-ylmethyl 4-methylbenzenesulfonate as a colorless oil. Rf=0.5 (silica, ethyl acetate:hexanes 1:4); Anal. calcd. for C20H22O4S: C, 67.01; H, 6.19. Found: C, 66.50; H, 6.27.
Reaction SMILES: [Na].[CH2:2]([C@@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([O:14]CC)=[O:13])[CH2:8][CH2:7]1)[CH2:3][CH2:4][CH3:5].O>C(O)C>[CH2:2]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCC[C@H]1CC[C@@H](C(=O)OCC)CC1
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCCC[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 20 °C

Procedure:
Sodium (7.5 g, 0.33 mol) was dissolved in anhydrous ethanol (200 ml) and ethyl cis-4-n-butylcyclohexanecarboxylate (13) was added. The reaction mixture was heated at reflux for 16 hr and was then cooled to 20° C. Water (38 ml) was added and the mixture was re-heated to reflux for a further 24 hr. The resulting mixture was evaporated to a small volume and the residue was dissolved in water (115 ml). The solution was acidified using concentrated hydrochloric acid and the product was then extracted into dichloromethane (4×50 ml). The combined dichloromethane extracts were evaporated to give predominantly trans-4-n-butylcyclohexanecarboxylic acid (11, 45.6 g).
Reaction SMILES: [N+](C1C=CC(C(OO)=O)=CC=1)([O-])=[O:2].[CH3:14][S:15][C:16]1[S:17][CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.O>[CH3:14][S:15]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])=[O:2]
Reactant: O=C(OO)c1ccc([N+](=O)[O-])cc1
Reactant: CSc1sccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CS(=O)c1sccc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 2 h

Procedure:
There was added 0.95 g of p-nitroperbenzoic acid to a solution of 0.88 g of 2-methylthio-3-nitrothiophene in 15 ml of chloroform at a temperature from 0° to 10° C. After stirring for 2 hours at 5° C., a solution of 2 g of sodium bicarbonate in approximately 50 ml of water was added; the reaction mixture was then stirred for 15 minutes. The chloroform layer was separated, washed with water, and filtered. After distilling the solvent, the desired product was obtained in a yield of 0.95 g; melting-point 155° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:12][O-:13].[Na+]>CN(C=O)C>[CH3:12][O:13][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: C[O-]
Reactant: Brc1cnc2ccccc2c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cnc2ccccc2c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 6.2 %

Procedure:
A solution of 3-bromoquinoline (22.54 g, 108 mmol) in anhydrous DMF (110 mL) was treated with sodium methoxide (11.70 g, 217 mmol) and stirred at 80° C. for 16 hours. The reaction mixture was then concentrated and the residue taken up in ethyl acetate (300 mL) and water (60 mL). The organic phase was separated, washed with brine (2×60 mL), dried (MgSO4), filtered, concentrated and purified by column chromatography on silica gel (ethyl acetate/hexane; 1:3) to give 3-methoxyquinoline (1.06 g, 6%). 1H NMR (CDCl3) δ 3.95 (s, 3H), 7.38 (d, 1H, J=1.5 Hz), 7.54 (m, 2H), 7.72 (d, 1H, J=7.5 Hz), 8.04 (d, 1H, J=7.5 Hz), 8.67 (d, 1H, J=1.5 Hz).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][NH:17][C:14]2=[CH:15][N:16]=1)[CH3:2].[H-].[Na+].Cl[CH2:23][C:24]1[CH:29]=[C:28]([CH:30](C)C)[CH:27]=[CH:26][C:25]=1[CH3:33].O>CN(C=O)C.CCOC(C)=O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][N:17]([CH2:23][C:24]3[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=3[CH3:33])[C:14]2=[CH:15][N:16]=1)[CH3:2]
Reactant: Cc1ccc(C(C)C)cc1CCl
Reactant: CCc1cccc(CC)c1-c1cc2cc[nH]c2cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1-c1cc2ccn(Cc3cc(C)ccc3C)c2cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(2,6-diethyl-phenyl)-1H-pyrrolo[2,3-c]pyridine (15 mg, 0.06 mmol) in DMF (0.5 mL) is added NaH (95%, 4 mg). The reaction mixture is stirred at room temperature for 30 minutes, and 2-chloromethyl-4-isopropyl-1-methyl-benzene (33 mg, 0.18 mmol) is then added. The mixture is heated at 60° C. for three hours and cooled. To the mixture, water (2 mL) and EtOAc (2 mL) are added. The organic layer is separated, washed with water once and concentrated under reduced pressure. The residue is purified by PTLC (Hexane/EtOAc 4:1) to give the titled compound. 1H NMR: (CDCl3) 8.81 (s, 1H), 7.47 (s, 1H), 7.28 (t, 1H), 7.13-7.19 (m, 5H), 6.77 (s, 1H), 6.52 (d, 1H), 5.39 (s, 2H), 2.80 (m, 1H), 2.27-2.40 (m, 7H), 1.14 (d, 2H), 1.01 (t, 6).
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[C:8]([CH2:17][O:18][C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)=[N:9][CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1.C(N(CC)CC)C.[Cl:33][C:34]1[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][C:35]=1[C:36](Cl)=[O:37]>O>[Cl:6][C:7]1[C:8]([CH2:17][O:18][C:19]2[CH:25]=[CH:24][C:22]([NH:23][C:36](=[O:37])[C:35]3[CH:39]=[C:40]([N+:43]([O-:45])=[O:44])[CH:41]=[CH:42][C:34]=3[Cl:33])=[CH:21][CH:20]=2)=[N:9][CH:10]=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:12]=1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: Nc1ccc(OCc2ncc(C(F)(F)F)cc2Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(OCc2ncc(C(F)(F)F)cc2Cl)cc1)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
To 5 mL of a tetrahydrofuran solution comprising 300 mg of 4-(3-chloro-5-trifluoromethyl-2-pyridylmethyloxy)aniline and 120 mg of triethylamine, 5 mL of a tetrahydrofuran solution comprising 220 mg of 2-chloro-5-nitrobenzoylchloride was dropwise added, followed by stirring for about 30 minutes, and then water was added thereto, and the precipitated crystals were collected by filtration. The collected crystals were washed with water and then dried to obtain 380 mg of N-(4-(3-chloro-5-trifluoromethyl-2-pyridylmethyloxy)phenyl)-2-chloro-5-nitrobenzamide (Compound No. 135) having a melting point of from 193 to 195° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C:9]2=[O:14])=[C:4]([Cl:15])[CH:3]=1.Cl[C:17](OC1C=CC([N+]([O-])=O)=CC=1)=[O:18].N1C=CC=CC=1.[N:35]1([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38][CH2:37][NH:36]1.C(N(C(C)C)C(C)C)C>ClCCl>[Cl:15][C:4]1[CH:3]=[C:2]([NH:1][C:17]([N:36]2[CH2:37][CH2:38][CH2:39][N:35]2[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[O:18])[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][C:9]1=[O:14]
Reactant: CC(C)(C)OC(=O)N1CCCN1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(N2CCOCC2=O)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCN1C(=O)Nc1ccc(N2CCOCC2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
340 mg (1.5 mmol) of 4-(4-amino-2-chlorophenyl)morpholin-3-one are dissolved in 10 ml of dichloromethane (DCM), 302 mg (1.5 mmol) of 4-nitrophenyl chloroformate and 121 μl (1.5 mmol) of pyridine are subsequently added successively, and the mixture is stirred at RT for 1 h. 300.0 mg (0.7 mmol) of tert-butyl pyrazolidine-1-carboxylate and 0.765 mg (4.5 mmol) of N-ethyldiisopropylamine are added to this reaction mixture. After stirring at RT for 20 h, the mixture is subjected to conventional work-up, giving 420 mg (57.3%) of step 1; MS (FAB) m/e=425/427 (M+H)+.
Reaction SMILES: C([N:6]1[CH2:23][CH2:22][N:9]2[C:10]3[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=3[CH2:12][N:13]3[CH:17]=[CH:16][CH:15]=[C:14]3[CH:8]2[CH2:7]1)(OCC)=[O:2].[CH2:24]([OH:26])[CH3:25].[OH-].[K+].[C:29]([O:32]CC)(=[O:31])[CH3:30]>>[C:29]([OH:32])(=[O:31])/[CH:30]=[CH:25]\[C:24]([OH:2])=[O:26].[CH2:7]1[CH:8]2[C:14]3[N:13]([CH:17]=[CH:16][CH:15]=3)[CH2:12][C:11]3[CH:18]=[CH:19][CH:20]=[CH:21][C:10]=3[N:9]2[CH2:22][CH2:23][NH:6]1
Reactant: CCO
Reactant: CCOC(=O)N1CCN2c3ccccc3Cn3cccc3C2C1
Reactant: CCOC(C)=O
Agent: [K+]
Agent: [OH-]
Product: O=C(O)/C=C\C(=O)O
Product: c1ccc2c(c1)Cn1cccc1C1CNCCN21

Procedure:
The mixture of 930 mg of 2-carbethoxy-1,3,4,14b-tetrahydro-10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]-benzodiazepine, 40 ml of ethanol and 20 ml of 20% aqueous potassium hydroxide is refluxed for 2 days. After cooling, it is diluted with ethyl acetate, washed with water, dried and evaporated. The residue is taken up in diethyl ether and the solution combined with 0.55 g of maleic acid in the minimum amount of acetone. The precipitate formed is collected and washed with diethyl ether, to yield the 1,3,4,14b-tetrahydro-2H,10H-pyrazino[1,2-a]pyrrolo[2,1-c][1,4]-benzodiazepine maleate melting at 173°-175°.
Reaction SMILES: [O:1]1[C:5]2[CH:6]([NH2:10])[CH2:7][CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1.[CH3:11][CH2:12][O:13]C(C)=O.O(C(C)C)C(C)C.[NH4+].[OH-]>C(Cl)Cl.CO>[O:1]1[C:5]2[C@H:6]([NH:10][C:12](=[O:13])[CH3:11])[CH2:7][CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1
Reactant: NC1CCCc2ccoc21
Reactant: CCOC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: CC(=O)N[C@@H]1CCCc2ccoc21
Reaction time: 17 h

Procedure:
Following the general procedure, 4,5,6,7-tetrahydrobenzofuran-7-ylamine (150 mg, 1.09 mmol), CALB (45 mg), EtOAc (0.43 mL) and iPr2O (4.0 mL) were stirred for 17 hours. The conversion determined from 1H NMR by integration of the peaks at 5.09 ppm (CHNHAc) and 3.95 ppm (CHNH2) was 55%. Flash chromatography of the material on silica gel using 1:20 MeOH:CH2Cl2 followed by 1:1:4 NH4OH:MeOH:CH2Cl2 furnished (R)-N-(4,5,6,7-tetrahydrobenzofuran-7-yl)acetamide ((104 mg, 53%) in 79% ee (chiral GC method: 120° C. for 15 min, ramp rate of 2° C./min to 160° C., hold 20 min at 160° C., (S)-(−)-enantiomerrt=43.6 min, (R)-(+)-enantiomerrt=45.8 min); [α]D=+58° (c 1.04, CHCl3); 1H NMR (CDCl3, 300 MHz) δ 1.65-1.86 (m, 3H), 1.90-1.2.04 (m, 1H), 1.94 (s, 3H), 2.30-2.50 (m, 2H), 5.09 (br s, 1H), 6.16 (s, 1H), 7.24 (s, 1H); 13C NMR (CDCl3) δ 20.6, 22.4, 23.6, 31.0, 43.6, 110.7, 120.9, 142.2, 148.8, 170.1; MS m/z: 180 (M+H+). The unreacted (S)-4,5,6,7-tetrahydrobenzofuran-7-ylamine (was isolated in 39% yield (59 mg) and 94% ee (chiral GC, (S)-enantiomerrt=12.6 min, (R)-enantiomerrt=13.5 min); [α]D=−18° (c 0.59, CHCl3); 1H NMR (CDCl3, 300 MHz): δ 1.50-1.75 (m, 4H), 1.76-1.90 (m, 1H), 2.01-2.20 (m, 1H), 2.30-2.50 (m, 2H), 3.94 (t, 1H, J=5.7 Hz), 6.17 (d, 1H, J=1.5 Hz), 7.26 (d, 1H, J=1.5 Hz); 13C NMR (CDCl3): δ 21.1, 22.6, 34.0, 45.5, 110.5, 117.9, 141.3, 153.6; MS m/z: 160 (M+Na+).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[S:21][C:20]3[CH:22]=[CH:23][C:24]([C:26](O)=[O:27])=[CH:25][C:19]=3[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].C(Cl)CCl.Cl.C[O:39][C:40](=[O:43])[CH2:41][NH2:42]>CN(C1C=CN=CC=1)C>[CH3:32][C:2]([CH3:1])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[S:21][C:20]3[CH:22]=[CH:23][C:24]([C:26]([NH:42][CH2:41][C:40]([OH:39])=[O:43])=[O:27])=[CH:25][C:19]=3[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29]
Reactant: COC(=O)CN
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(C(=O)O)ccc2s1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(C(=O)NCC(=O)O)ccc2s1
Yield: 70.4 %

Procedure:
2-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-5-carboxylic acid (310 mg, 0.686 mmol), DMAP (167 mg, 1.37 mmol), EDC (197 mg, 1.03 mmol), and glycine methyl ester hydrochloride (172 mg, 1.37 mmol) are reacted and hydrolyzed in a sequence analogous to Example 5 to afford the title compound (246 mg, 70%).