Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])[CH:23]=[CH2:24].C(N(CC)CC)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.II.CC(O)=O>CC([O-])=O.CC([O-])=O.[Pd+2].O.CCOC(C)=O.CC#N>[C:16]1(=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:5]2[CH:6]=[CH:7][C:2](/[CH:24]=[CH:23]/[C:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:3][CH:4]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Oc1ccc(C(=C2CCCCC2)c2ccc(Br)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC(=O)O
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCC2)c2ccc(O)cc2)cc1
Temperature: 75 °C
Yield: 75.9 %

Procedure:
To a round-bottomed flask were added 4-[(4-bromophenyl)(cyclohexylidene)methyl]phenol (6) (0.465 g, 1.35 mmol), tert-butyl acrylate (0.58 mL, 0.508 g, 3.96 mmol, 2.9 eq), Pd(OAc)2 (0.03 g, 0.134 mmol, 0.1 eq), triethylamine (0.54 mL, 0.39 g, 3.87 mmol, 2.9 eq), P(o-tolyl)3 (0.08 g, 0.26 mmol, 0.19 eq), and CH3CN (6 mL). The reaction mixture was heated overnight at 75° C. with stirring under a nitrogen atmosphere. Thin layer chromatography indicated the reaction was not complete. To the reaction mixture were added P(o-tolyl)3 (0.087 g, 0.29 mmol, 0.21 eq), tert-butyl acrylate (0.58 mL, 0.51 g, 3.96 mmol, 2.9 eq), paladium II acetate (0.033 g, 0.147 mmol), triethylamine (0.54 mL, 0.39 g, 3.87 mmol), and CH3CN (2 mL). The reaction mixture was heated at 75° C. with stirring under a nitrogen atmosphere for three days. The reaction mixture was allowed to cool to room temperature and transferred to a separatory funnel with the aid of EtOAc and H2O. The layers were separated and the organic phase was washed with brine. The organic solution was dried over MgSO4, filtered, and the filtrate was concentrated to give the crude product as an oil. The crude product was purified by flash chromatography on silica gel with hexanes:EtOAc (100:0 to 50:50) to give 0.40 g (76%) of compound 7 as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 1.45 (s, 9 H), 1.52 (m, 6 H), 2.14 (m, 4 H), 6.43 (d, J=15.9 Hz, 1 H), 6.66 (d, J=8.5 Hz, 2 H), 6.84 (d, J=8.4 Hz, 2 H), 7.05 (d, J=8.1 Hz, 2 H), 7.48 (d, J=15.9 Hz, 1 H), 7.57 (d, J=8.1 Hz, 2 H), 9.31 (s, 1 H). The sample was silated prior to EI analysis. HRMS (EI) Calcd for C29H38O3Si: 462.2590 (M+). Found: 462.2592.
Reaction SMILES: C([C@H](CCCCCC)C(O)=O)CC.[C:14]1([CH:20]([NH2:22])[CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[C:14]1([C@H:20]([NH2:22])[CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(N)c1ccccc1
Agent: CCCCCC[C@@H](CCC)C(=O)O
Solvent: CC#N
Product: C[C@@H](N)c1ccccc1
Yield: 88.2 %

Procedure:
Using the crystal comprising (2R)-2-propyloctanoic acid and R)-(+)-1-phenylethylamine (6.8 g) produced in the second recrystallization and acetonitrile (102 mL), the same operation as in the second recrystallization was made to give the crystal comprising (2R)-2-propyloctanoic acid and (R)-(+)-1-phenylethylamine (6.0 g, 98.9% e.e.; yield 88%).
Reaction SMILES: [CH3:1][C:2]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3]1.[H-].[Na+].[Cl:10][C:11]1[C:16]2[C:17](=[O:35])[N:18]3[CH2:34][CH2:33][CH2:32][C@H:19]3[C:20]3[N:21]([CH:22]=[N:23][C:24]=3[C:25](N3C=CN=C3)=[O:26])[C:15]=2[CH:14]=[CH:13][CH:12]=1.O>CN(C)C=O>[Cl:10][C:11]1[C:16]2[C:17](=[O:35])[N:18]3[CH2:34][CH2:33][CH2:32][CH:19]3[C:20]3[N:21]([CH:22]=[N:23][C:24]=3[C:25]([O:7][C:2]3([CH3:1])[CH2:6][CH2:5][CH2:4][CH2:3]3)=[O:26])[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Reactant: CC1(O)CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(OC(=O)c2ncn3c2C2CCCN2C(=O)c2c(Cl)cccc2-3)CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.2 g (12 mmol) of 1-methyl-cyclopentanol in 25 ml of dry dimethylformamide is treated with 0.5 g (10.3 mmol) of sodium hydride (55% oil dispersion) and to the resulting solution there are added portionwise at -20° 3.79 g (10.3 mmol) of (S)-1-[(8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl)carbonyl]imidazole. The mixture is stirred at room temperature for 1 hour, poured into about 250 ml of water, the precipitated material is filtered off under suction, washed with water and dried. There is obtained 1-methyl-cyclopentyl 8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 190°-191°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].I[C:21]1[CH:37]=[CH:36][C:24]([O:25][C:26]2[N:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[N:27]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([O:25][C:26]2[N:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[N:27]=2)=[CH:36][CH:37]=1
Reactant: COc1cc(OC)nc(Oc2ccc(I)cc2)n1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Product: COC(=O)C(C/C=C/c1ccc(Oc2nc(OC)cc(OC)n2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 56.8 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (30 mg) was reacted with 2-(4-iodophenoxy)-4,6-dimethoxypyrimidine (40 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(4,6-dimethoxypyrimidin-2-yloxy)phenyl]pent-4-enoic acid methyl ester (30 mg). Column chromatography (silica gel, eluent: hexane/ethyl acetate=2/1) was used for purification.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C@@H:10]([NH2:11])[C:4]2=[N:3][CH:2]=1.[Cl:16][C:17]1[CH:31]=[CH:30][C:20]([C:21]([NH:23][C:24]2([C:27](O)=[O:28])[CH2:26][CH2:25]2)=[O:22])=[CH:19][CH:18]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>ClCCl.C(N(CC)CC)C>[Cl:16][C:17]1[CH:31]=[CH:30][C:20]([C:21]([NH:23][C:24]2([C:27](=[O:28])[NH:11][C@@H:10]3[CH2:9][CH2:8][C:7]4[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=4[N:5]4[CH:1]=[CH:2][N:3]=[C:4]34)[CH2:25][CH2:26]2)=[O:22])=[CH:19][CH:18]=1
Reactant: N[C@@H]1CCc2ccccc2-n2ccnc21
Reactant: O=C(NC1(C(=O)O)CC1)c1ccc(Cl)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1(C(=O)N[C@@H]2CCc3ccccc3-n3ccnc32)CC1)c1ccc(Cl)cc1
Temperature: -20 °C
Yield: 93.58 %

Procedure:
Concentrate the ethanolic solution of (4R)-5,6-Dihydro-4H-imidazo[1,2-a][1]benzazepin-4-amine to dryness prior to use in the coupling reaction. Dissolve 15.0 g (4R)-5,6-Dihydro-4H-imidazo[1,2-a][1]benzazepin-4-amine and 18.03 g 1-[(4-Chlorobenzoyl)amino]cyclopropanecarboxylic acid in 120 ml of dichloromethane and 32 ml triethylamine. After cooling to −20° C., add 53.0 ml (1.2 eq.) of T3P within 40 minutes maintaining a temperature of −19° C. Allow the reaction to warm to room temperature over night. Test by HPLC for complete consumption of starting materials. After aqueous quench (75 ml of water) at 0 to 6° C. and further dilution with dichloromethane (precipitating solids dissolved after adding additional 180 ml of dichloromethane), separate the phases. Wash the organic layer two times with 75 ml of water and then back-extract the combined aqueous layers once with 75 ml of dichloromethane. Concentrate the organic extract phases (420 ml) removing 290 ml of solvents (beginning precipitation of solids). Add 240 ml of isopropyl acetate and then remove a further 250 ml of solvents. Warm the resulting thick suspension to 70° C., add 30 ml of n-heptane and slowly cool the suspension to room temperature over night. Filter the suspension via glass filter nutsch and wash the filter cake with n-heptane. After drying with a rotavap, results in a pale brown solid, 29.65 g (93.58% yield, HPLC (achiral). LC-MS (mass spectrometry) (m/z): 421.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([O:19]C)=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:24])[C:6]=2[CH:25]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].N1C=CC=CC=1.[Li+].[OH-]>C(Cl)Cl>[C:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=3)[C:17]([OH:19])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:24])[C:6]=2[CH:25]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(N)cc3c2C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2sc(S(=O)(=O)Nc3cccc(C(=O)O)c3)c(C)c2c1
Reaction time: 4 h
Yield: 56 %

Procedure:
A solution of methyl 3-{[(5-amino-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoate (7 mg, 0.019 mmol) in CH2Cl2 (200 uL), acetic anhydride (5 mg, 0.022 mmol) and pyridine (11 uL) was stirred at room temperature over night. The mixture was concentrated and dissolved in THF/water (1 mL) and LiOH (1 mg, 0.024 mmol) was added. The diacetylated intermediate was hydrolyzed at room temperature for 4 h. The crude product was purified by preparative HPLC (ACE C8, 5 μm, 21×50 mm, flow 25 ml/min, 50 mM NH4OAc in water/MeCN) to give 4.3 mg (56%) of the title compound. MS (ESI+) calcd for C18H16N2O5S2 404.050063, found 404.050323.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[NH:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[N:13]=[CH:12][CH:11]=1)(=O)C.[ClH:25]>CO>[ClH:25].[F:24][C:21]([F:22])([F:23])[C:17]1[CH:16]=[C:15]([N:14]2[C:10]([NH:9][C:5]3[NH:6][CH2:7][CH2:8][N:4]=3)=[CH:11][CH:12]=[N:13]2)[CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)N1CCN=C1Nc1ccnn1-c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CO
Product: FC(F)(F)c1cccc(-n2nccc2NC2=NCCN2)c1

Procedure:
1-Acetyl-2-[1-(3-Trifluoromethylphenyl)-5-pyrazolyl] amino-2-imidazoline (14.5 g.) was treated with HCl in methanol as described in Example II to give 10.69 g. product as the HCl salt, mp 151°-153°.
Reaction SMILES: [H-].[Na+].C(OC(=O)[CH2:7][CH2:8][N:9]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:10][CH:11]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)[C:12](OCC)=[O:13])C.O>C1(C)C=CC=CC=1.C(O)C>[CH2:25]([N:9]1[CH2:8][CH2:7][C:12](=[O:13])[CH:11]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH2:10]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)CCN(Cc1ccccc1)CC(C(=O)OCC)c1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a solution of sodium hydride (60% in oil, 4.85 g) in toluene (109 mL) was added a solution of the compound (34.6 g) obtained in step 3 in ethanol (25.1 mL), and the mixture was stirred at 75° C. for 2 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. A solution of the obtained residue (30.3 g) in concentrated hydrochloric acid (100 mL) and acetic acid (34 mL) was stirred at 140° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was made basic with aqueous sodium hydroxide solution. The resultant product was extracted with ethyl acetate, and the organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10→50% ethyl acetate/hexane) to give 1-benzyl-3-(3,4-dichlorophenyl)-4-piperidinone (18.2 g, 73%) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@@H:14]([C:16]#[N:17])[CH2:15][C@@:9]1([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:10]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:32]=[N+:33]=[N-:34].[Na+].Cl.C(N(CC)CC)C.CN(C)C=O>O>[CH2:1]([N:8]1[C@@H:13]2[C@@H:14]([C:16]3[NH:34][N:33]=[N:32][N:17]=3)[CH2:15][C@@:9]1([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C@H:10]([O:18][Si:19]([C:22]([CH3:24])([CH3:25])[CH3:23])([CH3:21])[CH3:20])[CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H]2[C@@H](C#N)C[C@]1(c1ccccc1)N2Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H]2[C@@H](c3nnn[nH]3)C[C@]1(c1ccccc1)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 99.4 %

Procedure:
A mixture of (1R*,2R*,5S*,6S*)-8-benzyl-2-(tert-butyldimethylsilyloxy)-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octane (Description 42; 43 g), sodium azide (27 g), triethylamine hydrochloride (55 g) and N,N-dimethylformamide (150 ml) was stirred at +130° C. for 7 hours. The reaction mixture was cooled to room temperature, treated with water (500 ml) and extracted into ethyl acetate (4×200 ml). The combined organic extracts were washed with water (3×200 ml) and brine. The combined water layers were extracted again with ethyl acetate (2×200 ml). The organic phase was washed with small amount of water (50 ml). The combined organic extracts were dried (Na2SO4) and concentrated to give crude (1R*,2R*,5S*,6S*)-8-benzyl-2-(tert-butyldimethylsilyloxy)-1-phenyl-6-(tetrazol-5-yl]-8-azabicyclo[3.2.1]octane (47 g), which was mixed with potassium carbonate (25 g) and acetonitrile (220 ml), warmed up to +70° C. and finally treated with 2-methoxyethoxymethyl chloride (20 ml). The reaction mixture was stirred for 15 minutes, cooled to room temperature, then treated with water (500 ml) and extracted into ethyl acetate (3×200 ml). The combined organic extracts were dried (Na2SO4) and concentrated to give a 1:1.5 mixture of isomers A and B, respectively. Regioisomers were separated by chromatography on silica gel (iso-hexane:diethyl ether).
Reaction SMILES: Cl.NO.C([N:6](CC)CC)C.[C:11]1([C:17]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:18]2[CH:22]=[C:21]([CH:23]3[CH2:25][CH:24]3[CH:26]=O)[N:20]=[CH:19]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(=O)OC(=O)C2=CC=CC=C12>C(#N)C>[C:11]1([C:17]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:18]2[CH:22]=[C:21]([C@@H:23]3[CH2:25][C@H:24]3[C:26]#[N:6])[N:20]=[CH:19]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(CC)CC
Reactant: O=CC1CC1c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Agent: NO
Agent: O=C1OC(=O)c2ccccc21
Solvent: CC#N
Product: N#C[C@@H]1C[C@H]1c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 2 h
Yield: 58.1 %

Procedure:
To a solution of hydroxylamine hydrochloride (816 mg, 12 mmol) in anhydrous acetonitrile (35 mL), were added triethylamine (1.6 ml, 12 mmol), and 2-[1-(triphenylmethyl)imidazol-4-yl]cyclopropanecarbaldehyde (4.0 g, 11 mmol) The resulting mixture was stirred for about 2 hours followed by the addition of phthalic anhydride (1.6 g, 11 mmol) under nitrogen. Then the reaction mixture was heated under reflux for 8 hours, concentrated under reduced pressure, diluted with 5% aqueous ammonia (30 mL), and extracted with ethyl acetate (3×40 ml). The organic layer was dried with MgSO4, and then evaporated under reduced pressure. The resulting residue was purified on a silica gel column using ethyl acetate/hexane (v/v:1/6) as the eluting solvent to give the title compound as a pale yellow solid (2.4 g, 64% yield).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]1[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=1[O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:14]([O:13][C:12]1[CH:20]=[CH:21][CH:22]=[CH:23][C:11]=1[O:10][CH3:9])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)COc1ccccc1OC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)Oc1ccccc1OC
Reaction time: 7 h
Yield: 105.9 %

Procedure:
A solution of N-bromosuccinimide (13.35 g), azoisobutyronitrile (200 mg) and ethyl 2-(2-methoxyphenoxy)acetate (15.1 g) in anhydrous carbon tetrachloride (ex. calcium hydride) (100 ml) was irradiated with a 120 W sunlamp under reflux and a nitrogen atmosphere for 7 hours. The resulting suspension was allowed to stand at room temperature for 72 hours and was then filtered to remove the suspended solids, which were washed with toluene (40 ml). The combined filtrates were evaporated under vacuum leaving a brown liquid (22 g) Rf 0.75 (dichloromethane).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:13]O>>[NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 62 %

Procedure:
To a mixture of 2-amino-4-chlorobenzoic acid (150 g, 0.88 mol) in MeOH (2.6 L) was added conc. HCl (0.5 L, 16.5 mol) and the reaction mixture was allowed to stir at reflux. After 12 h, the reaction mixture was allowed to cool to rt and was concentrated. Water (0.5 L) was added to the residue and the solution basified with 10% aqueous NaOH. The resulting precipitate was filtered to give methyl 2-amino-4-chlorobenzoate (101 g, 62%).
Reaction SMILES: [N:1]1[CH:6]=CC=C[CH:2]=1.Cl.C([C:11]1[N:15]2[CH2:16][CH2:17][CH2:18][N:19]=[C:14]2SC=1C(Cl)=O)CC.C(SC1C=CC(N)=CC=1)CCCCCC>CN(C)C=O>[CH3:11][NH:15][C:16]1[CH:2]=[N:1][CH:6]=[C:18]([NH:19][CH3:14])[CH:17]=1
Reactant: c1ccncc1
Reactant: CCCC1=C(C(=O)Cl)SC2=NCCCN21
Agent: CCCCCCCSc1ccc(N)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CNc1cncc(NC)c1

Procedure:
In the mixture of 50 ml of pyridine and 5 ml of dimethylformamide was suspended 1.07 g of 3-propyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carbonylchloride hydrochloride (described in Example 13). To the suspension were added 850 mg of 4-n-heptylthioaniline obtained in Reference Example 6, and 56 mg of 3,5-dimethylaminopyridine, followed by stirring at 70° C. for 12 hours. The reaction mixture was concentrated and to the concentrate was added saturated sodium hydrogencarbonate aqueous solution. The mixture was extracted with chloroform. The extract was washed with saturated sodium chloride aqueous solution, dried over anhydrous potassium carbonate and treated with active carbon. The solvent was removed under reduced pressure. The residue was dissolved in ethanol. To the mixture was added saturated hydrogenchloride diethylether solution, followed by stirring at room temperature. The solvent was removed under reduced pressure. The residue was precipitated from ethanol-diethylether to collect by filtration. The precipitated powder was recrystallized from methanoldiethylether to yield 992 mg of the titled compound.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[N:18]([CH3:25])[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:15]=3[C:14]3[C:26](=[O:29])[NH:27][CH2:28][C:13]=3[C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)#[N:2].[C:30](O)(=[O:32])C>CO>[C:1]([CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[N:18]([CH3:25])[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:15]=3[C:14]3[C:26](=[O:29])[NH:27][CH:28]([O:32][CH3:30])[C:13]=3[C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)#[N:2]
Reactant: CC(=O)O
Reactant: Cn1c2ccccc2c2c3c(c4c5ccccc5n(CCC#N)c4c21)CNC3=O
Solvent: CO
Product: COC1NC(=O)c2c1c1c3ccccc3n(CCC#N)c1c1c2c2ccccc2n1C

Procedure:
356 mg (0.94 mmole) 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo[2,3a]pyrrolo[3,4-c]carbazole (Example 2) are stirred for 16 hours at 20° C. in 50 mL glacial acetic acid and 1 mL methanol. The further preparation is carried out in Example 4 and the crude product is chromatographed on silica gel with dichloromethane/methanol 199:1 (v/v). The fraction with an Rf of 0.25 in toluene/ethyl acetate 4:1 (v/v) is isolated. 12-(2-Cyanoethyl)-6,7,12,13-tetrahydro-7-methoxy-13-methyl-5-oxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole is obtained in the form of beige crystals which decompose above about 200° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12])[C:5](=[O:8])[CH2:6][Cl:7])[C:2]#[CH:3].C1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([N:4]([CH2:9][CH:10]1[O:11][CH2:12][CH2:14][O:13]1)[C:5](=[O:8])[CH2:6][Cl:7])[C:2]#[CH:3]
Reactant: C#CCN(CC(OC)OC)C(=O)CCl
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C#CCN(CC1OCCO1)C(=O)CCl

Procedure:
N-Propargyl-N-(2,2-dimethoxyethyl)-α-chloroacetamide (8.5 grams), ethandiol-1,2 (2.16 ml) and trace amounts of toluenesulfonic acid were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux until no more ethanol was given off. After this time sodium carbonate (1 gram) was added to the mixture with stirring and the resulting mixture was distilled to yield the desired product N-propargyl-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide having a boiling point of 160° to 165° C. at 1 mm of Hg pressure.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][C:12]([CH3:18])([CH2:15][NH:16][NH2:17])[C:13]#[N:14].C(N(CC)CC)C>O1CCOCC1>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[N:16]([CH2:15][C:12]([CH3:18])([CH3:11])[C:13]#[N:14])[NH2:17]
Reactant: Clc1nc2ccccc2o1
Reactant: CC(C)(C#N)CNN
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C#N)CN(N)c1nc2ccccc2o1
Reaction time: 8 h

Procedure:
A solution of 2,2-dimethyl-2-cyanoacetaldehyde (9.4 g.) in ethanol (100 ml.) is added dropwise to a solution of hydrazine hydrate (40 g.) in ethanol (400 ml.), heated under reflux over a period of 3 hours. The solvent and excess of reagent are removed in vacuo to give 2,2-dimethyl-2-cyanoacetaldehyde hydrazone. This is dissolved in ethanol (100 ml.) and treated at room temperature with sodium borohydride (3.7 g.). The reaction mixture is stirred for two hours, acidified with acetic acid to pH 5, diluted with water and extracted with methylene chloride. The organic phase is dried and concentrated in vacuo to give 2,2-dimethyl-3-hydrazinopropanenitrile. A solution of 2-chlorobenzoxazole (15.3 g.) in dioxane (150 ml.) is added dropwise at 0° C. to a solution of 2,2-dimethyl-3-hydrazinopropanenitrile (11.3 g.) and triethylamine (10.1 g.) in dioxane (400 ml.). Stirring is continued overnight at room temperature. The precipitate is filtered and the filtrate concentrated in vacuo. The residue is washed with water and crystallized to give 3-[1-(2-benzoxazolyl) hydrazino)-2,2-dimethylpropanenitrile.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH2:21][CH3:22])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:24][OH:25].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH2:21][CH3:22])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:24]\[OH:25])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCCC(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCC(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 5-[3-(4-bromo-phenyl)-hexanoyl]-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound as a colorless solid, MS (ESI+): m/z=377.1 [M+H]+.