Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5](OC)[C:4]=1[C:15]1[O:16][CH2:17][C:18]([CH3:21])([CH3:20])[N:19]=1)[CH3:2].[CH3:22][Mg]Br>O1CCCC1.C(OCC)C>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([CH3:22])[C:4]=1[C:15]1[O:16][CH2:17][C:18]([CH3:21])([CH3:20])[N:19]=1)[CH3:2]
Reactant: C[Mg]Br
Reactant: CCc1cc(C(F)(F)F)cc(OC)c1C1=NC(C)(C)CO1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1cc(C(F)(F)F)cc(C)c1C1=NC(C)(C)CO1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 50.4 %

Procedure:
To a 0° C. solution of 100 mg (0.332 mmol) 2-(2-ethyl-6-methoxy-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole (obtained by reaction of 2-(2,6-dimethoxy-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole with ethylmagnesium bromide) in 0.6 ml tetrahydrofuran, was added drop-wise 0.332 ml (0.996 mmol) of a 3M methylmagnesium bromide solution in diethyl ether maintaining the temperature below 5° C. The mixture was allowed to warm to room temperature and stirred for 3.5 hours and then heated in a 70° C. oil bath for 4 days. The mixture was cooled in an ice bath and quenched dropwise with 3 ml saturated ammonium chloride solution. Ethyl acetate was added. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude orange oil (286 mg) was purified with flash column chromatography on silica eluting with a gradient formed from n-heptane and ethyl acetate (0 to 10%) to provide 50 mg (yield: 50.4%) of the title compound as a light yellow oil. MS (m/e): 286.2 (M+H+).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NOCCc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NOCCc1ccccn1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.20 g, 0.72 mmol) in dry DCM (20 mL) were added 2-[2-(aminooxy)ethyl]pyridine 125 (0.12 g, 0.86 mmol, J. Med. Chem. 1997, 40(15), 2363-2373), 1-hydroxybenzotriazole (0.14 g, 1.10 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.20 g, 1.10 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight, and then concentrated under vacuum. The residue was purified by column chromatography to give (2S,5R)-6-(benzyloxy)-7-oxo-N-[2-(pyridin-2-yl)ethoxy]-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 126 (0.26 g, 91%) as a clear thick oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][CH2:11][CH2:12][CH2:13]Cl)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH:15][C:16]1([C:22]2[CH:23]=[N:24][C:25]3[C:30]([CH:31]=2)=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][CH2:11][CH2:12][CH2:13][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:23]=[N:24][C:25]5[C:30]([CH:31]=4)=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:17][CH2:18]3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: OC1(c2cnc3ccccc3c2)CCNCC1
Reactant: ClCCCOc1ccc2[nH]ccc2c1
Product: OC1(c2cnc3ccccc3c2)CCN(CCCOc2ccc3[nH]ccc3c2)CC1
Yield: 45.6 %

Procedure:
Beginning with 0.275 gm (1.3 mMol) 3-chloropropyl indol-5-yl ether and 0.300 gm (1.3 mMol) 4-hydroxy-4-(quinolin-3-yl)piperidine, 0.238 gm (45%) of the title compound were recovered as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4]Cl)[CH3:2].[OH:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.C(N(CC)CC)C>C1COCC1>[CH2:1]([O:3][CH2:4][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOCCl
Reactant: O=Cc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of chloromethyl ethyl ether (5.65 g, 0.06 mol) in 20 ml of THF at 0° C. is added to a mixture of 4-hydroxybenzaldehyde (5 g, 0.041 mol) and 12 ml of triethylamine in 30 ml of THF and the mixture is stirred at ambient temperature for 2 hrs. The triethylamine hydrochloride is filtered off and the solvent is evaporated under reduced pressure to give the 4-ethoxymethoxybenzaldehyde in the form of an oil (6.63 g, 90%).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[C:21]([F:22])=[CH:20][C:19]([O:23][CH3:24])=[CH:18][C:17]=2[F:25])=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.O[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[C:29]([CH3:40])[C:28]=1[CH3:41]>>[F:25][C:17]1[CH:18]=[C:19]([O:23][CH3:24])[CH:20]=[C:21]([F:22])[C:16]=1[C:8]1[C:7]([CH2:6][O:5][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:29]([CH3:40])[C:28]=2[CH3:41])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: COc1cc(F)c(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)c(F)c1
Product: COc1cc(F)c(-c2nsc(C(F)(F)F)c2COc2ccc(CCC(=O)O)c(C)c2C)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (5-(trifluoromethyl)-3-(2,6-difluoro-4-methoxyphenyl) isothiazol-4-yl)methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 6.93 (d, J=8.4 Hz, 1H), 6.52-6.59 (m, 3H), 5.02 (s, 2H), 3.85 (s, 3H), 2.94 (t, J=7.2 Hz, 2H), 2.60 (t, J=7.5 Hz, 2H), 2.20 (s, 3H), 1.97 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C23H20F5NO4S, 502.1 (M+H). found 502.1.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[F:7][C:8]1[CH:9]=[C:10]([CH2:15][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C@H:17]2[CH2:19][O:18]2)[CH:11]=[C:12]([F:14])[CH:13]=1>>[C:23]([O:22][C:21](=[O:27])[NH:20][C@@H:16]([CH2:15][C:10]1[CH:9]=[C:8]([F:7])[CH:13]=[C:12]([F:14])[CH:11]=1)[C@H:17]([OH:18])[CH2:19][N:1]=[N+:2]=[N-:3])([CH3:24])([CH3:25])[CH3:26]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CN=[N+]=[N-]
Temperature: 77.5 °C
Reaction time: 16 h

Procedure:
Sodium azide (0.22 g, 4 mmole) and ammonium chloride (2 eq) are added to tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiranyl]ethylcarbamate (V, EXAMPLE 3, 0.6 g, 2 mmole). The reaction is heated to 75-80 degrees C. and stirred for 16 hours. The reaction is monitored by TLC to insure completion. The solvent is removed under reduced pressure. The concentrate is partitioned between ethyl acetate and water, the phases are separated and the organic phase is washed with bicarbonate and saline, dried over anhydrous sodium sulfate and concentrated to give the title compound, TLC (ethyl acetate/hexane) Rf=0.45; MS (MH+)=343.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[C:33]1([N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)N)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:33]3[C:34]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:4][CH:3]=1
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(I)cc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(I)cc4)n(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-iodophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 682.1 (M+H)+.
Reaction SMILES: ClC1C=CC(N2[C:17]3[C:12](=[C:13]([CH3:21])[C:14]([OH:20])=[C:15]([CH3:19])[C:16]=3C)[CH2:11]C3(CCC3)C2)=CC=1.[N+:25]([O-:28])(O)=[O:26]>C(O)(=O)C>[CH3:21][C:13]1[C:12]([CH3:11])=[C:17]([N+:25]([O-:28])=[O:26])[CH:16]=[C:15]([CH3:19])[C:14]=1[OH:20]
Reactant: O=[N+]([O-])O
Reactant: Cc1c(C)c2c(c(C)c1O)CC1(CCC1)CN2c1ccc(Cl)cc1
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])c(C)c(C)c1O
Reaction time: 0.5 h

Procedure:
2,3,6-trimethyl phenol 1 (19.1 g) was dissolved in acetic acid (190 mL). This solution was added to an acetic acid solution of HNO3 (150 mL, 1M) at room temperature in 4.5 hours. After another 0.5 hour, the mixture was evaporated, and the residue was taken up by EtOAc (350 mL). This solution was washed with water (150 mL×2), and brine (150 mL), dried and evaporated. Elution on a silica column (Hexane: EtOAc, 5:1-5:2), gave 2,3,6-trimethyl-4-nitrophenol (7.56 g), as a yellow solid. 1H-NMR, (300 MHz, CDCl3) δ=7.61 6, (br s, 1H), 2.432 (s, 3H), 2.275 (s, 3H), 2.242 (s, 3H) ppm.
Reaction SMILES: CS(O[CH:6]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C.O>[N:29]([CH:6]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[CH2:7][N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2)=[N+:30]=[N-:31]
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2ccncc2)CCN(C)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(N=[N+]=[N-])c2ccncc2)CCN(C)C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To a solution of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethyl methanesulfonate (900 mg, 2.18 mmol) in DMF (10 mL) was added sodium azide (212.5 mg, 3.2 mmol) and the reaction mixture was stirred at 100° C. for 1 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 5-(2-azido-2-(pyridin-4-yl)ethyl)-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (650 mg). The resulting racemate was purified and resolved by chiral preparative HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.8 (d, 2H), 8.0 (d, 2H), 7.31 (d, 1H), 7.3 (s, 1H), 7.04 (d, 1H), 5.45 (m, 1H), 4.7 (d, 1H), 4.59 (t, 1H), 4.4 (m, 2H), 3.9 (d, 1H), 3.6 (m, 1H), 3.4 (m, 1H), 3.2 (m, 1H), 3.1 (s, 3H), 2.4 (s, 3H).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][C:21]([O:28][CH:29]([CH3:31])[CH3:30])=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)[O:15][N:14]=2)=[C:9]2[C:5]=1[C:6]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[CH:7][NH:8]2.Cl>C1COCC1.O>[F:3][C:4]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][C:21]([O:28][CH:29]([CH3:30])[CH3:31])=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)[O:15][N:14]=2)=[C:9]2[C:5]=1[C:6]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:7][NH:8]2
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4cnc(OC(C)C)c(C(F)(F)F)c4)n3)ccc(F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ncc(-c2nc(-c3ccc(F)c4c(CCC(=O)O)c[nH]c34)no2)cc1C(F)(F)F
Temperature: 90 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
Sodium hydroxide (30 mg) was added to a solution of ethyl 3-(4-fluoro-7-{5-[6-[(1-methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (D49) (161 mg) in THF (3 mL) and water (3 mL). The reaction mixture was stirred at 90° C. for 1 hour. Then 0.5 M HCl was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-(4-fluoro-7-{5-[6-[(1-methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoic acid (E24) (93 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.38 (6H, d), 2.62 (2H, t), 3.05 (2H, t), 5.54 (1H, m), 6.98 (1H, dd), 7.26 (1H, d), 7.92 (1H, dd), 8.74 (1H, d), 9.32 (1H, d), 11.12 (1H, s), 12.14 (1H, br s). δF (DMSO-d6, 376 MHz): −118.6, −62.8. MS (ES): C22H18F4N4O4 requires 478; found 479.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:12])[CH3:11])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(C(C)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
To a stirred solution of 4-Acetyl-benzoic acid methyl ester (5.0 g, 28.06 mmol) in MeOH (25 mL) at 0° C., was added sodium borohydride (NaBH4) (2.12 g, 56.12 mmol), the reaction mixture was stirred at rt for 3 h. The solvent was removed under reduced pressure, was diluted with H2O, the reaction mixture was extracted with ethyl acetate (150 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product was dried under vacuum for 3 h to afford 4-(1-hydroxy-ethyl)-benzoic acid methyl ester (4.9 g, 99%): 1H NMR (300 MHz, CDCl3): δ 8.0 (d, J=7.8 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 5.20 (q, J=6.9 Hz, 1H), 3.91 (s, 3H), 2.02 (d, J=7.2, Hz, 3H). TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (1:2); R1=0.5.
Reaction SMILES: [N:1]1[C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][OH:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:33][C:34]1([Cl:50])[CH:36]([C:37]2[CH:42]=[CH:41][C:40](O)=[CH:39][CH:38]=2)[CH:35]1[CH2:44][C:45]([O:47]CC)=[O:46].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(O)(C(F)(F)F)=O>C1COCC1>[Cl:33][C:34]1([Cl:50])[CH:36]([C:37]2[CH:42]=[CH:41][C:40]([O:13][CH2:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[CH2:6][CH2:7][CH2:8][NH:9][C:10]=4[N:1]=3)=[CH:39][CH:38]=2)[CH:35]1[CH2:44][C:45]([OH:47])=[O:46]
Reactant: CCOC(=O)CC1C(c2ccc(O)cc2)C1(Cl)Cl
Reactant: OCCc1ccc2c(n1)NCCC2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=C(O)CC1C(c2ccc(OCCc3ccc4c(n3)NCCC4)cc2)C1(Cl)Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.5 %

Procedure:
To a solution of 2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-1-ethanol (0.16 g, 0.9 mmol) and Polymer bound PPh3(0.3 g, 0.9 mmol) in dry THF (6 mL) was added ethyl [2,2-dichloro-3-(4-hydroxyphenyl)cyclopropyl]acetate (0.18 g, 0.6 mmol) followed by diisopropyl azodicarboxylate (0.2 mL, 1 mmol). The reaction mixture was stirred at room temperature. After 18 hours, the reaction mixture was filtered through Celite to remove the polymer and washed with excess THF. Filtrate was concentrated. The concentrated residue in 50% acetonitrile in water (4 mL) was added LiOH (01 g). The reaction mixture was stirred 3 hours at room temperature. Reaction mixture was acidified by adding TFA and purified by reverse phase HPLC to afford 0.12 g (36%) of desired product. 1H NMR (CD3OD) δ 7.64 (d, 1H, J=8 Hz), 7.26 (d, 2H, J=8.4 Hz), 6.93 (d, 2H, J=8.8 Hz), 6.77 (d, 1H, J=7.6 Hz), 4.32 (t, 2H, J=6 Hz), 3.53 (t, 2H, J=5.6 Hz), 3.19 (t, 2H, J=6 Hz), 2.87-2.59 (m, 5 H), 2.32-2.26 (m, 1H), 2.01-1.95 (m, 2 H). HRMS calcd for C21H22N2O3 (M+H): 421.1080. found 421.1069.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13]3[N:12]([CH2:14][CH2:15][NH:16][C:17](=O)[CH3:18])[CH:11]=[CH:10][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:20]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)C>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13]3[N:12]4[CH2:14][CH2:15][N:16]=[C:17]([CH3:18])[C:11]4=[CH:10][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:20]=1
Reactant: CC(=O)NCCn1ccc2c1-c1ccc(Cl)cc1CC2
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: CC1=NCCn2c1cc1c2-c2ccc(Cl)cc2CC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
N-[2-(7-Chloro-4,5-dihydro-1H-benzo[g]indol-1-yl)ethyl]acetamide (2.8 g) was treated with 20 ml of phosphorus oxychloride under argon and the mixture was stirred at 100° C. for 30 minutes. The cooled mixture was added to 1500 g of ice-water and treated with 100 ml of 2N sodium hydroxide solution and 150 ml of 28% sodium hydroxide solution. The mixture was extracted once with 300 ml of methylene chloride and twice with 100 ml of methylene chloride each time, the organic phases were combined, dried with MgSO4 and freed from solvent. The residue (2.6 g) was dissolved in a 20-fold amount of hot ethanol and treated while hot with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There were obtained 3.3 g (88%) of 3-chloro-5,6,10,11-tetrahydro-8-methylbenzo[g]pyrazino[1,2-a]indole fumarate (1:1); m.pt. 195°-196° C. (dec.).
Reaction SMILES: C(N(CC)CC)C.Cl.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](Cl)=[O:16].[NH2:18][C:19]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])=[CH:32][CH:31]=2)=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:39]([S:36]([C:33]1[CH:32]=[CH:31][C:30]([O:29][C:26]2[CH:27]=[CH:28][C:19]([NH:18][C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=3)=[O:16])=[C:20]([CH:25]=2)[C:21]([O:23][CH3:24])=[O:22])=[CH:35][CH:34]=1)(=[O:38])=[O:37])[CH3:40]
Reactant: O=C(Cl)c1ccccn1
Reactant: CCS(=O)(=O)c1ccc(Oc2ccc(N)c(C(=O)OC)c2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)c1ccc(Oc2ccc(NC(=O)c3ccccn3)c(C(=O)OC)c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54.6 %

Procedure:
With cooling with ice, 4.4 ml of triethylamine and 2.8 g of picolinic acid chloride hydrochloride were added to a chloroform (30 ml) solution of 2.65 g of methyl 2-amino-5-[4-(ethylsulfonyl)phenoxy]benzoate, and stirred at room temperature for 90 minutes. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, extracted with chloroform, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=2/1 to 1/1) to obtain 1.9 g of the entitled compound as a creamy white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:14][NH:15][CH2:16][CH3:17])([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]=O>C(O)=O>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:14][N:15]([CH2:16][CH3:17])[CH3:18])([OH:13])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: CCNCC1(O)CCN(Cc2ccccc2)C1
Solvent: O=CO
Product: CCN(C)CC1(O)CCN(Cc2ccccc2)C1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
21.8 g (93 mmol) 1-benzyl-3-ethylaminomethyl-3-hydroxy-pyrrolidine (according to example Ca) are dissolved in a mixture of 9.5 g formic acid and 8.5 g 37% proof aqueous formaldehyde solution. The mixture is stirred at 80° C. for 4 hours. The solvents are removed in vacuo, the residue is taken up in water, and the pH is adjusted alkaline with potassium carbonate. The reaction mixture is then extracted with chloroforme, and the organic phase is dried with potassium carbonate. After filtration the organic solvent is removed in vacuo and the residue is destilled.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].F[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1>CN(C)C=O>[C:10]1(=[O:11])[N:6]([CH2:5][CH2:4][O:3][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)[C:7](=[O:16])[C:8]2=[CH:15][CH:14]=[CH:13][CH:12]=[C:9]12
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% dispersion in oil, 2 g) was added portionwise to a solution of N-(2-hydroxyethyl)phthalimide (9.6 g) in dry dimethylformamide (70 ml) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour prior to the addition of 4-fluorobenzaldehyde (6.2 g, 5.3 ml), and the mixture then heated at 80° C. for 15 hours. The solvent was evaporated and the residue dissolved in water (100 ml) and extracted with ethyl acetate (2×100 ml). The combined ethyl acetate layers were washed with water (2×100 ml), brine (100 ml), dried (MgSO4) and evaporated to yield an oil. The oil was triturated with hexane, and the residue chromatographed on silica gel with 1.5% methanol in dichloromethane to afford the title compound mp 138° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:19])[C:16]#[C:17][CH3:18])[CH:6]=[CH:7][C:8]=1[N:9]=[CH:10][N:11](C)C)#[N:2].[Br:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)N>C(O)(=O)C>[Br:20][C:21]1[CH:27]=[C:26]([NH:2][C:1]2[C:3]3[C:8](=[CH:7][CH:6]=[C:5]([NH:14][C:15](=[O:19])[C:16]#[C:17][CH3:18])[CH:4]=3)[N:9]=[CH:10][N:11]=2)[CH:25]=[CH:23][CH:22]=1
Reactant: CC#CC(=O)Nc1ccc(N=CN(C)C)c(C#N)c1
Reactant: Nc1cccc(Br)c1
Solvent: CC(=O)O
Product: CC#CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reaction time: 0.25 h

Procedure:
A solution of 3.0 g (11.8 mmol) of N-[3-cyano-4-[[(dimethylamino)methylene]amino]phenyl]-2-butynamide and 2.23 g (12.98 mmol) of 3-bromo aniline in 18 mL of acetic acid was refluxed gently with stirring under nitrogen for 1 hr 15 min. The mixture was cooled in an ice bath and a solid mass formed. The solid was collected by filtration and washed with ether-acetonitrile 1:1 to give a yellow solid which was recrystallized from ethanol giving 2.51 g of N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide: mass spectrum (m/e): 381, 383.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][O:10]COC.C([Li])CCC.[B:19](OC(C)C)(OC(C)C)[O:20]C(C)C.Cl>C1COCC1.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[B:19]([OH:20])[O:10][CH2:9][C:3]=2[CH:4]=1
Reactant: COCOCc1cc(F)ccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OB1OCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60.4 %

Procedure:
To a solution of 5b (73.2 g, 293 mmol) in dry THF (400 mL) was added n-butyllithium (1.6 M in hexanes; 200 mL) over 45 min at −78° C. under nitrogen atmosphere. Anion precipitated. After 5 min, (i-PrO)3B (76.0 mL, 330 mmol) was added over 10 min, and the mixture was allowed to warm to room temperature over 1.5 h. Water and 6 N HCl (55 mL) were added, and the solvent was removed under reduced pressure to about a half volume. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. To a solution of the residue in tetrahydrofuran (360 mL) was added 6 N HCl (90 mL), and the mixture was stirred at 30° C. overnight. The solvent was removed under reduced pressure to about a half volume. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the residue was treated with i-Pr2O/hexane to give 19b (26.9 g, 60%) as a white powder: mp 118-120° C.; 1H NMR (300 MHz, DMSO-d6) δ (ppm) 4.95 (s, 2H), 7.15 (m, 1H), 7.24 (dd, J=9.7, 1.8 Hz, 1H), 7.74 (dd, J=8.2, 6.2 Hz, 1H), 9.22 (s, 1H); ESI-MS m/z 151 (M−H)−; HPLC purity 97.8%; Anal (C7H6BFO2) C, H.