Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14](F)=[CH:13][C:12]=2F)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:13][C:12]=2[N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2F)CC1
Product: CC(=O)N1CCC(C(=O)c2ccc(N3CCCCC3)cc2N2CCCCC2)CC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture consisting of 2.67 g of 1-acetyl-4-(2,4-difluorobenzoyl)piperidine and 5.0 ml of piperidine was stirred at 100° C. for 24 hours and the reaction mixture was then worked up in the same manner as Example 2 to give 3.3 g of the title compound as oil.
Reaction SMILES: [Br:1][C:2]1[C:3](=O)[NH:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.O=P(Cl)(Cl)[Cl:12]>CN(C=O)C>[Br:1][C:2]1[C:3]([Cl:12])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cc(Cl)cc1Br
Solvent: CN(C)C=O
Product: Clc1cnc(Cl)c(Br)c1
Temperature: 70 °C
Reaction time: 72 h
Yield: 89 %

Procedure:
To a solution of 3-bromo-5-chloropyridin-2-one (84.3 g, 0.404 tool) in DMF (100 mL) was added POCl3 (56.5 mL, 0.61 tool) via dropping funnel over 3 hours at room temperature. The resulting black solution was then heated to 70° C. and allowed to stir for 3 days. After cooling to room temperature, the solution was poured into 1L of ice/water, filtered, and the solid dried in a vacuum oven to provide 81.76 g (89%) of the desired 3-bromo-2, 5-dichloropyridine as an off-white solid, m.p. 39°-41° C.: IR(CHCl3) 3867, 3663, 2989, 2734, 1812, 1606, 1547, 1400, 1366, 1230, 1155, 1129, 1074, 1027, 894, 658, 563cm ; HNMR (300 MHz, CDCl3)δ 8.0 (d, 1H, J=2.2Hz) , 8.35 (d, 1H, J=2.2Hz); 13C NMR (CDCl3)δ 120.43, 130.74, 141.46, 146.64, 148.99; exact mass calculated for C5H2NBrCl2 =224.8748; high resolution mass spec. 224.8764.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:6]([OH:15])=[C:7]([CH:11]=[CH:12][C:13]=2[OH:14])[C:8]([NH2:10])=[O:9])[CH2:3][CH2:2]1.I[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:34]=[CH:33][C:24]2[CH2:25][CH2:26][CH:27]([C:29]([O:31][CH3:32])=[O:30])[O:28][C:23]=2[C:22]=1[CH2:35][CH2:36][CH3:37]>>[NH2:10][C:8]([C:7]1[CH:11]=[CH:12][C:13]([O:14][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:34]=[CH:33][C:24]3[CH:25]=[CH:26][CH:27]([C:29]([O:31][CH3:32])=[O:30])[O:28][C:23]=3[C:22]=2[CH2:35][CH2:36][CH3:37])=[C:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[C:6]=1[OH:15])=[O:9]
Reactant: CCCc1c(OCCCI)ccc2c1OC(C(=O)OC)CC2
Reactant: NC(=O)c1ccc(O)c(CC2CC2)c1O
Product: CCCc1c(OCCCOc2ccc(C(N)=O)c(O)c2CC2CC2)ccc2c1OC(C(=O)OC)C=C2

Procedure:
The compound of Example 66 and the compound of Example 23 are reacted together under the conditions described in Example 24. The crude product is purified by chromatography on silica gel using ethyl acetate/hexane (4:6) as eluant to afford the product.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=O.[C:11]1([C@@H:17]([NH2:19])[CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1>[C:11]1([C:17](=[N:19][C@H:2]([C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=2)[CH3:1])[CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: C[C@H](N)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: CC(=N[C@@H](C)c1ccc(Cl)cc1)c1ccccc1
Yield: 99 %

Procedure:
At first, zinc chloride (0.16 g, 1.1 mmol) was added to a toluene solution (100 ml) containing 16.6 g (107 mmol) of 4-chloroacetophenone (1b) as a ketone and 14.3 g (118 mmol) of (S)-1-phenylethylamine ((S)-2a) as an optically active primary amine. Then, the same steps as those of Example 1-7a were conducted, thereby obtaining 27.3 g of (S)-N-(1-phenylethylidene)-1-(4-chlorophenyl)-ethylamine ((S)-3ba, purity: 95%, yield: 94%).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+]([O-])=O)[CH:13]=1)([O-:11])=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:14]2[CH:13]=[C:12]([N+:9]([O-:11])=[O:10])[CH:17]=[CH:16][CH:15]=2)=[CH:1][CH:2]=1
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Reactant: Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cc1ccc(Oc2cccc([N+](=O)[O-])c2)cc1
Temperature: 100 °C
Yield: 65.8 %

Procedure:
EX-41A) To a solution of p-cresol (5.76 g, 0.053 mol) and 1,3-dinitrobenzene (8.97 g, 0.053 mol) in 100 mL of dimethylsulfoxide was added cesium carbonate (43.4 g, 0.133 mol). The reaction mixture was heated at 100° C. for 18 h, then cooled to room temperature, quenched with water, and extracted with diethyl ether. The organic layers were combined, washed with 0.1 N HCl and water, dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1:4 ethyl acetate in hexane to afford 8.0 g (66%) of the desired 3-(4-methylphenoxy)nitrobenzene product as a yellow oil. 1H NMR (CDCl3) δ 7.83 (s, 1H), 7.64 (t, 1H), 7.32 (d, 1H), 7.18 (d, 1H), 7.09 (d, 2H), 6.8 (d, 2H), 2.20 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[O:19]=[C:20]1[C:25]2=[CH:26][NH:27][C:28]([CH:29]=O)=[C:24]2[CH2:23][CH2:22][O:21]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[C:16]3[C:12]([C:13](=[CH:29][C:28]4[NH:27][CH:26]=[C:25]5[C:20](=[O:19])[O:21][CH2:22][CH2:23][C:24]=45)[C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]cc3c2CCOC3=O)c1

Procedure:
6-(3-Methoxy-phenyl)-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: CC([O-])(C)C.[K+].[CH2:7]([O:9]C=O)[CH3:8].[CH3:12][CH:13]([CH3:19])[CH2:14][CH2:15][C:16](=[O:18])C>C1COCC1.CC(=O)OCC>[OH:18][CH:16]=[C:15]([CH2:14][CH:13]([CH3:19])[CH3:12])[C:7](=[O:9])[CH3:8]
Reactant: CC(=O)CCC(C)C
Reactant: CCOC=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)C(=CO)CC(C)C
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 65.6 %

Procedure:
To a solution of KOtBu (50 g, 446 mmol) in THF (400 mL) is added during 30 min ethylformate (92 g, 1.25 mol). Strong gas evolution occurs. The mixture is cooled during the addition with a water bath at 10° C. After complete addition, the mixture is stirred until the gas evolution ceases (15 min). The mixture is cooled with ice at 0° C. and a mixture of 5-methyl-2-hexanone (34.25 g, 300 mmol) and ethylformate (41 g, 0.55 mol) is added slowly during 30 min. The mixture is stirred for 15 h, diluted with EA (500 mL) and washed with 1 N aq. HCl (100 mL), 1 M aq. NaH2PO4 solution (100 mL) and brine (100 mL). The organic extract is dried (MgSO4), filtered and evaporated to give crude 4-hydroxy-3-isobutyl-but-3-en-2-one (28 g) which is used without further purification; LC-MS: tR=0.80 min, [M+1]=143.39.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH2:15][C:16]4[S:17][CH:18]=[CH:19][C:20]=4[C:13]=3[NH:12][N:11]=2)=[CH:6][CH:5]=1.[CH3:21][Si:22]([CH2:25][CH2:26][O:27][CH2:28]Cl)([CH3:24])[CH3:23]>C1COCC1>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]3[CH2:15][C:16]4[S:17][CH:18]=[CH:19][C:20]=4[C:13]=3[N:12]([CH2:28][O:27][CH2:26][CH2:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[N:11]=2)=[CH:6][CH:5]=1
Reactant: Brc1ccc(-c2n[nH]c3c2Cc2sccc2-3)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)cc2)c2c1-c1ccsc1C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
At 0° C., NaH (60 percent, 0.48 g, 12 mmol) was added to a THF solution (15 mL) containing 6-(4-Bromo-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (3.1 g, 9.7 mmol). Then SEM-Cl (90% pure, 2.4 mL, 12 mmol) was added to the reaction mixture and the resulting mixture was stirred at 0° C. for 30 min, warmed up to 80° C. and stirred for 2 hr. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and washed with saturated aqueous NH4Cl, dried over MgSO4(s), and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to give 6-(4-Bromo-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (3.0 g, 6.7 mmol) as brown solid in 69% yield.
Reaction SMILES: [CH3:1][C:2]1[S:10][C:9]2[CH:8]([OH:11])[CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](F)[CH:16]=[CH:17][C:18]=1[Cl:19]>>[Cl:12][C:13]1[CH:14]=[C:15]([O:11][CH:8]2[CH2:7][NH:6][CH2:5][C:4]3[CH:3]=[C:2]([CH3:1])[S:10][C:9]2=3)[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: Cc1cc2c(s1)C(O)CNC2
Reactant: Fc1ccc(Cl)c(Cl)c1
Product: Cc1cc2c(s1)C(Oc1ccc(Cl)c(Cl)c1)CNC2

Procedure:
The same method as in Example 1 was conducted using 2-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 30) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [F:1][S:2]([C:5]1[CH:6]=[C:7]([CH:29]=[CH:30][CH:31]=1)[C:8]([C:10]1[S:14][C:13]([NH:15]C(OCC(Cl)(Cl)Cl)=O)=[C:12]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:11]=1)=[O:9])(=[O:4])=[O:3]>[Zn].C(O)(C)C>[NH2:15][C:13]1[S:14][C:10]([C:8](=[O:9])[C:7]2[CH:29]=[CH:30][CH:31]=[C:5]([S:2]([F:1])(=[O:3])=[O:4])[CH:6]=2)=[CH:11][C:12]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)c1cc(C(=O)c2cccc(S(=O)(=O)F)c2)sc1NC(=O)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CC(C)O
Product: CCOC(=O)c1cc(C(=O)c2cccc(S(=O)(=O)F)c2)sc1N
Yield: 56 %

Procedure:
A solution of 175 g (0.33 mole) of ethyl 5-(m-fluorosulfonylbenzoyl)-2-(2,2,2-trichloroethoxycarbonylamino)-3-thenoate and 4200 ml of isopropyl alcohol was treated with 175 g of zinc dust at 75° to 77° C. over a 6-minute period. The mixture was held at gentle reflux for 50 minutes before a sudden onset of reaction, characterized by vigorous boiling of the solvent, was noticed. Heating was removed until the reaction subsided. Reflux was continued until all the urethane was consumed, as indicated by thin-layer chromatography in 30 percent acetone:70 percent hexane. The mixture was filtered hot through Celite (diatomaceous earth) and the filtrate was evaporated slowly in an evaporating dish until about one liter of solvent had been removed. The solid was collected by filtration to yield 66 g (56 percent) of yellow solid, melting point 170° to 172° C. A second crop was obtained by further evaporation (melting point 153° to 168° C.), and this was recrystallized from isopropyl alcohol to yield 14.5 g (12 percent) of yellow solid, melting point 168° to 170° C.
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([NH:9][C:10](=[O:16])[C@@H:11]([NH2:15])[CH2:12][CH2:13][CH3:14])=[N:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:17][C:18]([CH:20]1[CH2:22][CH2:21]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH:1]([C:4]1[S:8][C:7]([NH:9][C:10](=[O:16])[C@@H:11]([NH:15][CH:18]([CH:20]2[CH2:22][CH2:21]2)[CH3:17])[CH2:12][CH2:13][CH3:14])=[N:6][CH:5]=1)([CH3:2])[CH3:3]
Reactant: CCC[C@H](N)C(=O)Nc1ncc(C(C)C)s1
Reactant: CC(=O)C1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC[C@H](NC(C)C1CC1)C(=O)Nc1ncc(C(C)C)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(S)-amino-pentanoic acid (5-isopropyl-thiazol-2-yl)-amide (150 mg, 0.54 mmol) and cyclopropyl methyl ketone(45 mg, 0.54 mmol)in 10 mL of methylene chloride and 5 drops of acetic acid was treated with sodium triacetoxyborohydride (172 mg, 0.8 mmol) and stirred at room temperature overnight. The mixture was quenched with dilute ammonium hydroxide and extracted with methylene chloride. The organic layer was separated and concentrated to dryness. The residue was purified by HPLC to give 2-(S)-(1-cyclopropyl-ethylamino)-pentanoic acid (5-isopropyl-thiazol-2-yl)-amide as a colorless oil, LC-MS RT=1.4 min, M+1=310.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.Br[CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[H-].[Na+]>CN(C=O)C.CC(=O)OCC>[CH:15]1([CH2:14][O:1][C:2]2[CH:3]=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: BrCC1CCCCC1
Reactant: COc1cc(O)cc(C(C)=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(OCC2CCCCC2)cc(C(C)=O)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 56.2 %

Procedure:
1-(3-Hydroxy-5-methoxyphenyl)ethanone (O3.033; 1.5 g) and bromomethylcyclohexane (1.76 g) were dissolved in DMF (20 ml), and sodium hydride (260 mg) was added. After stirring at 50° C. for 24 h, the DMF was drawn off. The residue was taken up in EA, washed with water, dried, filtered and concentrated. The residue was purified using silica gel (40 g cartridge, n-heptane/EA 0-50% within 30 min). 1.33 g of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][C:18]3[CH:19]=[N:20][NH:21][CH:22]=3)[C:6](=[O:23])[N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:35][C:36]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:37]=1[CH2:38]Br.N1CCOCC1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][C:18]3[CH:22]=[N:21][N:20]([CH2:38][C:37]4[C:40]([F:44])=[CH:41][CH:42]=[CH:43][C:36]=4[Cl:35])[CH:19]=3)[C:6](=[O:23])[N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:4]=2[N:3]=1
Reactant: Fc1cccc(Cl)c1CBr
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCc1cn[nH]c1)c(=O)n2CCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: CCCCCn1c(=O)n(CCCc2cnn(Cc3c(F)cccc3Cl)c2)c(=O)c2[nH]c(Cl)nc21
Temperature: 45 °C
Yield: 74.9 %

Procedure:
8-Chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione (61 mg, 0.15 mmol) in dry DMF (2 ml) was stirred with sodium carbonate (64 mg, 0.6 mmol) and 2-chloro-6-fluorobenzyl bromide (134 mg, 0.6 mmol) and heated at 45° C. for 18 h under nitrogen. After cooling to rt the mixture was degassed by evacuating and readmitting nitrogen, and stirred with tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.303 mmol) and morpholine (0.13 ml) for 5.5 h. The mixture was partitioned between EtOAc and 2M HCl, the organic phase separated and evaporated and the residue purified by aminopropyl SPE (5 g, washing with THF-MeOH (1:1) then neat MeOH and finally eluting with DCM-MeOH (1:1) containing 5% AcOH) to give the title compound (57 mg) as a solid.
Reaction SMILES: [O:1]1[CH2:6][C:5](=[O:7])[NH:4][C:3]2[N:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C.C(OC(=O)C)(=O)C>[N+:12]([C:9]1[CH:10]=[CH:11][C:2]2[O:1][CH2:6][C:5](=[O:7])[NH:4][C:3]=2[N:8]=1)([O-:14])=[O:13]
Reactant: O=C1COc2cccnc2N1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1COc2ccc([N+](=O)[O-])nc2N1
Reaction time: 8 h

Procedure:
2H-Pyrido[3,2-b]-1,4-oxazin-3(4H)-one (2.5 g) was dissolved in acetic acid (6 mL) and acetic anhydride (30 mL). Fuming nitric acid (3 mL) was added dropwise to the reaction solution in ice-bath. The reaction solution was stirred in ice-bath overnight. Solution was poured into crashed ice. The light yellow precipitation was collected by filtration, washed with water and dried to give a mixture of nitrated products (regio-isomers). The mixture was crystallized from dichloromethane to give 6-nitro-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (1 g) as a light yellow solid.
Reaction SMILES: N12CCN(CC1)CC2.[CH2:9]([N:11]([CH2:28]C)[C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:25][CH:24]([OH:26])[CH2:23][C:22]2=[O:27])(=[O:20])=[O:19])=[CH:14][CH:13]=1)C.[C:30](Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl.C(OCC)(=O)C>[CH3:28][N:11]([CH3:9])[C:12]1[CH:13]=[CH:14][C:15]([S:18]([N:21]2[CH2:25][CH:24]([O:26][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23][C:22]2=[O:27])(=[O:19])=[O:20])=[CH:16][CH:17]=1
Reactant: CCN(CC)c1ccc(S(=O)(=O)N2CC(O)CC2=O)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)c1ccc(S(=O)(=O)N2CC(OC(=O)C(C)(C)C)CC2=O)cc1
Reaction time: 16 h

Procedure:
0.41 g of 1,4-diazabicyclo [2.2.2]octane (DABCO) is added at 3° C. to a solution of 1 g of [1-(4-diethylamino-benzenesulphonyl)-4-hydroxy-pyrrolidin-2-one] in 20 cm3 of methylene chloride, and then 0.43 g of pivaloyl chloride in solution in 3 cm3 of methylene chloride is added slowly, and the whole mixture is left at ambient temperature for 16 hours. Another equivalent of pivaloyl chloride and DABCO is added, the mixture is left at ambient temperature for 4 hours, brought to dryness, the residue is taken up in ethyl acetate, washed with water (at a pH of about 6), followed by filtering and bringing to dryness under reduced pressure, and the residue is chromatographed on silica (eluant: ethyl acetate - hexane 4-1). 0.6 g of expected crude product and 0.3 g of product containing a double bond in position 3,4 of the pyrrolidinone are obtained. The crude product is added to a previous preparation in order to obtain, after recrystallization from an ethyl acetate - hexane mixture (3-50), 0.86 g of the desired product. M.p.=117-118° C.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([NH2:19])=O)=[C:4]2[CH2:3]1.O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]#[N:19])=[C:4]2[CH2:3]1
Reactant: CN1Cc2c(C(N)=O)ncn2-c2ccccc2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CN1Cc2c(C#N)ncn2-c2ccccc2C1=O

Procedure:
0.5 g of 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide is heated to reflux while stirring for 40 hours together with 0.5 g of Sicapent in 150 ml of toluene. The mixture is treated with a 0.5 g portion of Sicapent after 16 hours, 19 hours and 24 hours. The mixture is subsequently cooled and treated with water. The mixture is adjusted to pH 9 with 28 percent sodium hydroxide. After separation of the organic phase, the alkaline-aqueous phase is extracted twice with 250 ml of ethyl acetate each time. The organic extracts are washed twice with saturated sodium chloride solution, dried and evaporated. After recrystallisation of the residue from methylene chloride/hexane, there is recovered a portion of unreacted starting material. The mother liquor is evaporated and chromatographed on 100 g of silica gel while eluting with ethyl acetate and alcohol. After recrystallisation of the thus-obtained substance from acetone, there is obtained 5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]benzodiazepine-3-carbonitrile of melting point 184°-185° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]1[NH:13][CH2:14][CH2:15][C:6]21[CH3:16].Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C@H:7]1[N:13]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14][CH2:15][C@@:6]21[CH3:16]
Reactant: COc1ccc2c(c1)C1(C)CCNC1N2C
Reactant: BrCCc1ccccc1
Product: COc1ccc2c(c1)[C@]1(C)CCN(CCc3ccccc3)[C@@H]1N2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred mixture, under nitrogen, of 8.73 g of 1,2,3,3a,8,8a-hexahydro-5-methoxy-3a,8-dimethylpyrrolo[2,3-b]-indole, 9.25 g of 2-(bromoethyl)benzene and 8.29 g of milled, anhydrous potassium carbonate in 75 ml of degassed, dry dimethylformamide is heated at 70°-75° for 8 hours and thereafter stirred at room temperature overnight. The reaction mixture is decanted into 1.5 liters of water and the product is extracted into ethyl acetate (2×250 ml). The combined organic extracts are washed twice with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue is subjected to flash chromatography over silica gel using methanol/ethyl acetate mixtures as eluent. The fractions containing the product are combined and concentrated to afford pure (3aS-cis)-1,2,3,3a,8,8a-hexahydro-5-methoxy-1-(2phenylethyl) -3a,8-dimethylpyrrolo[2,3-b]indole.
Reaction SMILES: C[O:2][C:3](=[O:20])/[C:4](/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:5]/[OH:6].CO.[OH-].[Na+].Cl>O>[OH:6]/[N:5]=[C:4](\[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)/[C:3]([OH:20])=[O:2]
Reactant: COC(=O)/C(=N/O)c1ccccc1Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)/C(=N/O)c1ccccc1Oc1ccccc1
Yield: 72.9 %

Procedure:
To E-α-hydroxyimino-2-phenoxyphenylacetic acid methyl ester (9.99 g, 0.0368 mole) were added methanol (36.8 ml), sodium hydroxide (3.23 g, 0.081 mole) and water (36.8 ml) and the mixture was heated under reflux for one hour. After heating, conc. hydrochloric acid (1 ml) was added to the mixture under ice cooling and the precipitated crystals were filtered off and recrystallized (methanol/ethyl acetate/n-hexane) to obtain E-α-hydroxyimino-2-phenoxyphenylacetic acid (6.90 g, yield: 72.9%) as colorless crystals (decomposition: 180° C.).
Reaction SMILES: [OH-].[K+].[I:3][C:4]1[CH:5]=[C:6]([CH:9]=[O:10])[NH:7][CH:8]=1.Br[CH2:12][CH2:13][OH:14].C(O)(=O)C>O1CCOCC1>[OH:14][CH2:13][CH2:12][N:7]1[CH:8]=[C:4]([I:3])[CH:5]=[C:6]1[CH:9]=[O:10]
Reactant: OCCBr
Reactant: O=Cc1cc(I)c[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=Cc1cc(I)cn1CCO
Temperature: 60 °C
Yield: 50 %

Procedure:
Potassium hydroxide (3.1 g, 54.3 mmol) was added to a stirred solution of 4-iodo-1H-pyrrole-2-carbaldehyde (4.0 g, 18.1 mmol) in dioxane (20 mL). 2-Bromo-ethanol (2.56 mL, 36.2 mmol) was added to the reaction mixture and heated at 60° C. for 16 h. The reaction mixture was cooled to room temperature and the pH was adjusted to ˜6 by the addition of acetic acid. The reaction mixture was then concentrated in vacuo to give a residue which was partitioned between water and ethyl acetate. The organic phase was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue which was purified by column chromatography over silica gel (100-200 mesh) using 10% ethyl acetate in petroleum ether as eluent to afford 1-(2-hydroxyethyl)-4-iodo-pyrrole-2-carbaldehyde (2.4 g, 50%) as a colourless solid.
Reaction SMILES: C([C:3]1([C:19]([O-:21])=[O:20])[O:7][C:6]2=[C:8]([O:16]C)[CH:9]=[CH:10][C:11](C)([C:12]([O-:14])=[O:13])[C:5]2=[C:4]1[CH3:18])C.CN(C)P(=O)(N(C)C)N(C)C.O.[C:34]1(C)C=CC=C[CH:35]=1>>[CH2:34]([O:21][C:19]([C:3]1[O:7][C:6]2[C:8]([OH:16])=[CH:9][CH:10]=[C:11]([C:12]([OH:14])=[O:13])[C:5]=2[C:4]=1[CH3:18])=[O:20])[CH3:35]
Reactant: Cc1ccccc1
Reactant: CCC1(C(=O)[O-])OC2=C(OC)C=CC(C)(C(=O)[O-])C2=C1C
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1oc2c(O)ccc(C(=O)O)c2c1C
Temperature: 25 °C

Procedure:
The solution of 2-ethyl-4-methyl-7-methoxy-3-methylbenzo[b]furan-2,4-dicarboxylate (from step 5 of example 1) (13.0 g), sodium p-thiocresolate (20.26 g, 1.5 equiv.) and hexamethylphosphoric acid triamide (24.80 g, 1.5 equiv.) was heated in dry toluene at reflux temperature under nitrogen for 2-6 h. The reaction mixture was cooled to room temperature, water was added and aqueous layer was washed with dichloromethane. Aqueous layer was acidified at 10-15° C. with concentrated hydrochloric acid. The precipitated product was filtered and dried.