Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:24])[N:5]2[C:10]3[CH:11]=[CH:12][N:13](S(C4C=CC(C)=CC=4)(=O)=O)[C:9]=3[N:8]=[CH:7][C:6]=12.C([O:27][C:28]([CH2:30][N:31]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32]1)=[O:29])C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][C:4]1[N:5]2[C:10]3[CH:11]=[CH:12][NH:13][C:9]=3[N:8]=[CH:7][C:6]2=[C:2]([C:34]2[CH:33]=[N:32][N:31]([CH2:30][C:28]([OH:29])=[O:27])[CH:35]=2)[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2c(Br)nc(C)n23)cc1
Reactant: CCOC(=O)Cn1cc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(-c2cnn(CC(=O)O)c2)c2cnc3[nH]ccc3n12
Temperature: 85 °C
Reaction time: 0.17 h

Procedure:
3-Bromo-1-methyl-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine (0.356 g, 0.878 mmol) (Preparation #AB.1), 1-(ethoxycarbonylmethyl)-1H-pyrazole-4-boronic acid, pinacol ester (0.295 g, 1.05 mmol), and Cs2CO3 (0.1716 g, 2.20 mmol) were combined in 1,4-dioxane (7.0 mL) and water (1.8 mL). The mixture was degassed by bubbling N2 directly into the mixture. After about 10 min, PdCl2(PPh3)2 (0.043 g, 0.061 mmol) was added and degassing continued for about 5 more min. The mixture was heated at about 85° C. for about 16 h. Aqueous NaOH (1 N, 3 mL) was added and heating continued for about 2 h. The mixture was allowed to cool to rt and aqueous HCl (1 N, 10 mL) was added. The mixture was concentrated in vacuo to give 2-(4-(1-methyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)-1H-pyrazol-1-yl)acetic acid: LCMS (Table 2, Method b) Rt=1.37 min.; MS m/z: 297 (M+H)+
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:11][C@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C:27]([C@@H:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][OH:38])[CH2:29][C@:13]12[CH3:14])=[C:26]1[C:21](=[CH:22][C:23](=[O:39])[CH2:24][CH2:25]1)[CH2:20][CH2:19]3)(=[O:10])[CH3:9].O.[Cl-].[NH4+]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.CO>[C:8]([O:11][C@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C:27]([C@@H:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][C:1](=[O:3])[CH3:2])[CH2:29][C@:13]12[CH3:14])=[C:26]1[C:21](=[CH:22][C:23](=[O:39])[CH2:24][CH2:25]1)[CH2:20][CH2:19]3)(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](CCCCCCCCO)C[C@]12C
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: CO
Solvent: O
Product: CC(=O)OCCCCCCCC[C@H]1C[C@]2(C)[C@@H](OC(C)=O)CC[C@H]2[C@@H]2CCC3=CC(=O)CCC3=C12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.6 cm3 of acetic anhydride and 95 mg of 4-(dimethylamino) pyridine are added to a solution of 1.4 g of 17beta-(acetyloxy) 11beta-(8-hydroxy octyl)-estra-4,9-dien-3-one (obtained by a similar process to Stage D of the preparation of Example 50 of the European Patent Application EP 384 842) in 10 cm3 of pyridine. The solution is agitated for one hour at ambient temperature, 5 cm3 of water and 5 cm3 of methanol are added, followed by agitation for ten minutes at 0°/+5° C., the whole is poured into a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate, washed with a saturated solution of sodium chloride, dried and evaporated to dryness under reduced pressure after having entrained the pyridine with toluene. 1.61 g of crude product is obtained which is chromatographed on silica, eluant: ethyl acetate-cyclohexane 3-7. In this way 1.28 g of desired product is collected.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH:11]2[C:6]3([CH2:15][CH:3]1[CH2:4][CH2:5]3)[C:7]([CH3:14])([CH3:13])[CH2:8][CH2:9][C:10]2=O.[C:17](O)(=O)C.[CH:21]([NH2:23])=[NH:22]>C(O)CCC>[CH3:13][C:7]1([CH3:14])[C:6]23[CH2:15][CH:3]([C:2]([CH3:16])([CH3:1])[CH:11]2[C:10]2[N:23]=[CH:21][N:22]=[CH:17][C:9]=2[CH2:8]1)[CH2:4][CH2:5]3
Reactant: N=CN
Reactant: CC1(C)C2CCC3(C2)C1C(=O)CCC3(C)C
Reactant: CC(=O)O
Solvent: CCCCO
Product: CC1(C)C2CCC3(C2)C1c1ncncc1CC3(C)C
Temperature: 120 °C
Yield: 83.9 %

Procedure:
A 5 L reaction vessel was charged with 1,3,4,6,7,8a-hexahydro-1,1,5,5-tetramethyl-2H-2,4a-methanonaphthalene-8(5H)-one (440 g, 2.0 mol) (commercially available at IFF), formamidine acetate (1040 g, 10.0 mol) and butanol (2 L). The reaction mixture was heated to 120° C. for 10 hours and then cooled to 25° C. The reaction mixture was washed twice with brine (1 L) and purified by vacuum distillation to afford crude product 6,6,10,10-tetramethyl-5,7,8,9,10,10a-hexahydro-6H-6a,9-methanobenzo[H]quinazoline (430 g) having a boiling point of 159° C. at a pressure of 1.0 mmHg Further recrystallization from ethanol afforded 6,6,10,10-tetramethyl-5,7,8,9,10,10a-hexahydro-6H-6a,9-methanobenzo[H]quinazoline (95% purity) (125 g) with a melting point of 44-45° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([C:12](O)=[O:13])[O:11][C:6]=2[CH:5]=[C:4]([CH3:15])[CH:3]=1.B.S(C)C.CO>O1CCCC1>[CH3:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([CH2:12][OH:13])[O:11][C:6]=2[CH:5]=[C:4]([CH3:15])[CH:3]=1
Reactant: Cc1cc(C)c2c(c1)OC(C(=O)O)CC2
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: Cc1cc(C)c2c(c1)OC(CO)CC2
Yield: 96 %

Procedure:
To a stirred mixture of 109 parts of 3,4-dihydro-5,7-dimethyl-2H-1-benzopyran-2-carboxylic acid in 135 parts of tetrahydrofuran were added, during a period of 20 minutes, 292 parts of a solution of borane, compound with thiobismethane, in tetrahydrofuran 2M (foaming). The whole was stirred and refluxed for 2 hours. The mixture was decomposed by the addition of 24 parts of methanol. After stirring for 10 minutes at reflux temperature, the solvent was distilled off. Water was added to the residue. Concentrate hydrochloric acid was added and the product was extracted with 1,1'-oxybisethane. The organic layer was washed with water and sodium chloride, dried, filtered and evaporated, yielding 97.5 parts (96%) of 3,4-dihydro-5,7-dimethyl-2H-1-benzopyran-2-methanol as an oily residue (intermediate 16).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][N:21]=[CH:22][CH:23]=3)[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[C:34]([CH3:41])=[C:35]([OH:40])[C:36]([CH3:39])=[CH:37][CH:38]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][N:21]=[CH:22][CH:23]=3)[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[O:40][C:35]2[C:36]([CH3:39])=[CH:37][CH:38]=[C:33]([F:32])[C:34]=2[CH3:41])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(F)c(C)c1O
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2c(Cl)n(-c3ccccc3)c3cnccc23)CC1
Product: Cc1ccc(F)c(C)c1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccncc2n1-c1ccccc1

Procedure:
The title compound was prepared analogously as described in example 1, step 6, from the compound of example 16, step 5, (100 mg, 227 μmol) and 3-fluoro-2,6-dimethylphenol.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6]/[CH:7]=[C:8]1\[CH2:9][C@@H:10]2[C@H:14]([CH2:15]\1)[C@@H:13](/[CH:16]=[CH:17]/[C@@H:18]([OH:25])[CH:19]([CH3:24])[CH2:20][C:21]#[C:22][CH3:23])[C@H:12]([OH:26])[CH2:11]2)(O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.[Cl-].[NH4+]>CN(C)C=O>[O:42]1[CH2:43][CH2:44][N:39]([CH2:1][CH2:4][CH2:5][CH2:6]/[CH:7]=[C:8]2\[CH2:9][C@@H:10]3[C@H:14]([CH2:15]\2)[C@@H:13](/[CH:16]=[CH:17]/[C@@H:18]([OH:25])[CH:19]([CH3:24])[CH2:20][C:21]#[C:22][CH3:23])[C@H:12]([OH:26])[CH2:11]3)[CH2:40][CH2:41]1
Reactant: CC#CCC(C)[C@H](O)/C=C/[C@@H]1[C@H]2C/C(=C/CCCC(=O)O)C[C@H]2C[C@H]1O
Reactant: C1COCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC#CCC(C)[C@H](O)/C=C/[C@@H]1[C@H]2C/C(=C/CCCCN3CCOCC3)C[C@H]2C[C@H]1O
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 30.4 %

Procedure:
20 mg of (1S,2R,3R,5S)-7-[(E)-4-carboxybutylidene]-2-[(3S,1E)-3-hydroxy-4-methyl-6-octyne-1-enyl]-3-hydroxybicyclo[3.3.0]octane was taken and dissolved in 2 mL of dimethylformamide. After addition of 20 mg of 1,1′-carbonyldiimidazole, it was stirred at 50° C. for 1.5 hours. It was then cooled to ambient temperature, and 100 mg of morpholine was added. After stirring at 50° C. for 2 hours, an aqueous solution saturated with ammonium chloride was added and extraction was performed with ethyl acetate. The organic layer was washed with a saturated saline solution, and dried with anhydrous sodium sulfate. After filtration and concentration, 3 mL of tetrahydrofurane was added. While stirring, 100 mg of lithium aluminium hydride was added, and stirring continued at 50° C. for 3 hours. While stirring at ambient temperature, 200 μL of an aqueous solution saturated with sodium sulfate was added, then 1 g of anhydrous sodium sulfate was added, and stirred for 16 hours. A filtration was performed over celite, and after washing the residue with ethyl acetate, the filtrate was concentrated and subjected to a silicagel column chromatography, to obtain 7 mg of the compound presented in the title (40% yield).
Reaction SMILES: [N:1]1([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:6][CH2:5]C(C(OCC)=O)[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:32]([O:35][C:36]([CH3:40])([CH3:39])[CH:37]=[O:38])(=[O:34])[CH3:33].[O:41]1CC[CH2:43][CH2:42]1>>[C:42]([O:38][CH:37]1[C:33]2([CH2:3][CH2:2][N:1]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])[CH2:6][CH2:5]2)[C:32](=[O:34])[O:35][C:36]1([CH3:40])[CH3:39])(=[O:41])[CH3:43]
Reactant: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C1CCOC1
Reactant: CC(=O)OC(C)(C)C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CC(=O)OC1C(C)(C)OC(=O)C12CCN(C(=O)OCc1ccccc1)CC2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-benzyl 4-ethyl piperidine-1,4-dicarboxylate (2.35 g) was dissolved in tetrahydrofuran (30 mL) and was cooled to −78° C. Lithium bis(trimethylsilyl)amide (9 mL, 1M) was added dropwise under nitrogen and the solution was stirred for 30 min at −20° C. The solution was re-cooled to −78° C. and 1,1-dimethyl-2-oxoethyl acetate (1.17 g) in tetrahydrofuran (5 mL) was added and the mixture was stirred for 30 min. The mixture was quenched (NaHCO3, 30 mL) and the mixture was extracted with ethyl acetate (2×50 mL). The extracts were combined, washed with brine, dried (MgSO4) and were concentrated in vacuo. The crude product was purified by chromatography on silica using 25-75% ethyl acetate in iso-hexane as eluant to afford the product (1.4 g).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][C@H:6]1[O:18][CH3:19])=[N+]=[N-]>CO.[OH-].[C+4].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-]>[NH2:1][CH2:4][C@H:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7][C@H:6]1[O:18][CH3:19]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1CN=[N+]=[N-]
Agent: [Pd+2]
Agent: [C+4]
Agent: [OH-]
Solvent: CO
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1CN
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a solution of cis-4-azidomethyl-1-tert-butoxycarbonyl-3-methoxypiperidine (1.5 g) in methanol (50 ml) was added 20% palladium carbon hydroxide (0.6 g), and the resulting mixture was stirred at room temperature under hydrogen atmosphere for 2 hr. 20% Palladium carbon hydroxide was filtered off and the solvent was evaporated under reduced pressure to give 1.2 g of cis-4-aminomethyl-1-tert-butoxycarbonyl-3-methoxypiperidine.
Reaction SMILES: S(O)(O)(=O)=O.CS[C:8](=[NH:10])[NH2:9].Cl[C:12]([O:14][CH3:15])=[O:13].[OH-].[Na+].[Cl:18][C:19]1([Cl:32])[CH2:21][CH:20]1[CH2:22][S:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[C:26](N)[CH:25]=1>O.CO.C(O)(=O)C>[Cl:32][C:19]1([Cl:18])[CH2:21][CH:20]1[CH2:22][S:23][C:24]1[CH:29]=[CH:28][C:27]2[NH:30][C:8]([NH:9][C:12](=[O:13])[O:14][CH3:15])=[N:10][C:26]=2[CH:25]=1
Reactant: CSC(=N)N
Reactant: COC(=O)Cl
Reactant: Nc1ccc(SCC2CC2(Cl)Cl)cc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)Nc1nc2cc(SCC3CC3(Cl)Cl)ccc2[nH]1
Reaction time: 0.25 h

Procedure:
To a mixture of 9 g of 2-methyl-2-thiopseudourea sulfate in 6 ml of H2O there is added 5.7 ml of methyl chloroformate at 0° C and the mixture is stirred for 15 minutes. Then there is added 12 ml of 25% NaOH dropwise and the mixture is stirred for 15 minutes. Then there is added 6 ml of acetic acid dropwise and the mixture is stirred for 15 minutes. Then the total amount of 4-[(2,2-dichlorocyclopropyl)methyl]thio-o-phenylenediamine from above in 50 ml of methanol is added and the mixture is refluxed for 2 hours. The alcohol is removed in vacuo and H2O is added. The resulting solid is filtered off and crystallized from glyme to yield 5.4 g, m.p. 211-213°.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[NH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[N:32]1[CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33]1>O>[CH2:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:40][N:32]1[C:23]1[CH:24]=[CH:25][C:26]([C:28]([F:30])([F:31])[F:29])=[CH:27][C:22]=1[NH:21][C:2](=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: Nc1cc(C(F)(F)F)ccc1N1Cc2ccccc2C1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1cc(C(F)(F)F)ccc1N1Cc2ccccc2C1)c1ccncc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Isonicotinoyl chloride hydrochloride (250 mg, 1.40 mmol, commercially available product) and triethylamine (287 μl, 2.07 mmol) were sequentially added at 0° C. to a dichloromethane (6 ml) solution of 2-[2-amino-4-(trifluoromethyl)phenyl]isoindoline (193 mg, 0.694 mmol), obtained as described in Referential Example 20-2. The resulting mixture was warmed to room temperature and stirred for three hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5 g, hexane/ethyl acetate=1/1). Thus, N-[2-(2-isoindolinyl)-5-(trifluoromethyl)phenyl]isonicotinamide (GIF-0620) (266 mg, quant.) was yielded as a colorless solid.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17](B(O)O)=[CH:18]4)=[CH:13][C:12]=3[O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:33][C:34]1[CH:43]=[C:42](I)[CH:41]=[CH:40][C:35]=1[C:36]([O:38][CH3:39])=[O:37]>>[OH:33][C:34]1[CH:43]=[C:42]([C:17]2[CH:16]=[CH:15][C:14]3[C:19](=[CH:20][C:11]([C:1]45[CH2:8][CH:7]6[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]6)[CH2:2]4)[CH2:10]5)=[C:12]([O:24][CH2:25][C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)[CH:13]=3)[CH:18]=2)[CH:41]=[CH:40][C:35]=1[C:36]([O:38][CH3:39])=[O:37]
Reactant: OB(O)c1ccc2cc(OCc3ccc(F)cc3)c(C34CC5CC(CC(C5)C3)C4)cc2c1
Reactant: COC(=O)c1ccc(I)cc1O
Product: COC(=O)c1ccc(-c2ccc3cc(OCc4ccc(F)cc4)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1O
Yield: 78 %

Procedure:
Following the procedure of Example 1(c), but reacting 560 mg (1.41 mmol) of 7-(1-adamantyl)-6-(4-fluorobenzyl)oxy-2-naphthylboronic acid with 330 mg (1.17 mmol) of methyl 2-hydroxy-4-iodobenzoate, 490 mg (78%) of the expected ester were obtained, which ester had a melting point of 189°-91° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COCCOC[N:16]1[C:20]2[CH:21]=[CH:22][C:23]([NH2:33])=[C:24]3[C:25](=[O:32])[C:26]4[C:31]([C:18]([C:19]=23)=[N:17]1)=[CH:30][CH:29]=[CH:28][CH:27]=4.C(N(CC)CC)C.Cl>C(Cl)Cl>[C:1]([NH:33][C:23]1[CH:22]=[CH:21][C:20]2[NH:16][N:17]=[C:18]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25](=[O:32])[C:24]=1[C:19]=23)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COCCOCn1nc2c3c(c(N)ccc31)C(=O)c1ccccc1-2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc2[nH]nc3c2c1C(=O)c1ccccc1-3)c1ccccc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Benzoyl chloride is added to a solution of 2-(methoxyethoxymethyl)-5-aminoanthra[1,9cd]pyrazol-6-(2H)one and triethylamine in methylene chloride at 0° C. The mixture is stirred for 16 hours, quenched with water, and extracted with ethyl acetate (×2). The combined organic layer is washed with sodium bicarbonate solution, and brine, dried and evaporated. The crude reaction mixture is then taken in aqueous 6N hydrochloric acid, and heated at 80° C. for 4 hours. After cooling, the mixture is extracted with ethyl acetate (×2), washed with brine, dried, and evaporated. The reside is chromatographed on silica gel to furnish the desired amide as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].O>C1COCC1.O.[Fe]>[Cl:18][C:13]1[CH:12]=[C:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:16]=[CH:15][C:14]=1[F:17]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(F)c(Cl)c2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccc(F)c(Cl)c2)cc1
Yield: 97.6 %

Procedure:
To a solution of 3-chloro-4-fluorophenyl 4-nitrophenyl ether (Intermediate 7, 2.48 g) in THF/water (40 mL/10 mL) was added Fe power (11.2 g, 200 mmol) and ammonium chloride (10.7 g, 200 mmol and the mixture was heated at reflux for 4 hours. After filtration, the solvent was concentrated to give a residue and poured into 50 mL of water. The mixture was extracted with ethyl acetate (3 times 50 mL) and the combined organic phases were washed and dried over magnesium sulphate. Removal of the solvent afforded the title compound (2.15 g) which was directly used in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14]N(C3C=CC(OC)=CC=3)CN(C3C=CC(OC)=CC=3)[CH2:10]2)=[CH:5][CH:4]=1.ClC(OC(Cl)(Cl)Cl)=[O:33].[CH:39]([NH:42][C:43]([NH:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[S:44])([CH3:41])[CH3:40].[OH-].[Na+]>>[CH:39]([N:42]=[C:43]1[N:45]([CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:14](=[O:33])[N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][S:44]1)([CH3:41])[CH3:40]
Reactant: COc1ccc(N2CN(c3ccc(OC)cc3)CN(c3ccc(OC)cc3)C2)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)NC(=S)NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(N2CSC(=NC(C)C)N(Cc3ccccc3)C2=O)cc1
Yield: 155.8 %

Procedure:
Similarly, 1.4 g (0.0033 mole) of 1,3,5-tris(p-methoxyphenyl)-hexahydro-s-triazine, 1 g (0.005 mole) of trichloromethyl chloroformate, 2.1 g (0.01 mole) of 1-isopropyl-3-benzylthiourea, and 9 ml of a 10% sodium hydroxide solution were used to obtain 1.9 g (52% yield) of 2-isopropylimino-3-benzyl-5-(p-methoxyphenyl)tetrahydro-1,3,5-thiadiazin-4-one (compound No. 356) of the formula, ##STR157## as white crystals melting at 114° C.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[F:6][C:7]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:8]=1[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([CH:17]=O)[CH2:13][CH2:12]1)=[O:10].Cl.N[OH:26]>O.C(O)C>[F:6][C:7]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:8]=1[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([CH:17]=[N:5][OH:26])[CH2:13][CH2:12]1)=[O:10]
Reactant: O=CN1CCC(C(=O)c2ccc(F)cc2F)CC1
Reactant: [NH4+]
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(c1ccc(F)cc1F)C1CCN(C=NO)CC1
Yield: 75.5 %

Procedure:
A solution of 12 g of ammonium acetate in 45 ml of water was added to a solution of 15 g of 4-(2,4-difluorobenzoyl)-1-formylpiperidine and 6 g of hydroxylamine hydrochloride in 35 ml of ethanol. The mixture was heated for 18 hrs. at 90°, with stirring. The solvent was evaporated in vacuum until precipitation occurred. Water (500 ml) was added. The mixture was filtered, washed with 300 ml of water and dried in vacuum over phosphorous pentoxide to yield 12 g (75.5%) of product. Recrystallization from ethanol and water yielded the analytical sample, mp, 185°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[Cl-].[NH4+]>[Fe].O>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:9][CH2:10][N:11]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Temperature: 80 °C
Yield: 82.2 %

Procedure:
[1-(4-Nitro-benzenesulfonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.5 g, 1.3 mmol) was suspended in a 5:1 mixture of ethanol and water (20 ml). To this solution was added iron powder (0.22 g, 3.4 mmol) followed by saturated ammonium chloride solution (3 ml) and the mixture was heated to 80° C. for three hours. After this time, the reaction mixture was cooled to room temperature and filtered through a pad of celite, the celite was washed with ethanol (10 ml) and EtOAc (50 ml) and the solution was concentrated under vacuum. The resulting residue was suspended in water (10 ml) and the solid precipitate collected by filtration and dried under vacuum to give the title compound (0.38 g, 78% yield) as a white solid. Tr=1.84 min, m/z (ES+) (M+Na)+ 378.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14](Cl)=[C:15]([F:20])[CH:16]=2)[N:11]([CH:22]2[CH2:24][CH2:23]2)[C:10]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:30][C:31](=[O:38])[NH:32][CH:33]1[CH2:37][CH2:36][NH:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27].C(N(CC)CC)C>CN(C=O)C.O>[C:26]([O:30][C:31](=[O:38])[NH:32][CH:33]1[CH2:37][CH2:36][N:35]([C:14]2[CH:13]=[C:12]3[C:17]([C:18](=[O:19])[N:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:10](=[O:25])[N:11]3[CH:22]3[CH2:24][CH2:23]3)=[CH:16][C:15]=2[F:20])[CH2:34]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=c1c2cc(F)c(Cl)cc2n(C2CC2)c(=O)n1OCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(c2cc3c(cc2F)c(=O)n(OCc2ccccc2)c(=O)n3C2CC2)C1
Temperature: 70 °C
Yield: 46.6 %

Procedure:
A solution of 3-benzyloxy-7-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione (Example E-3, 0.15 g, 0.42 mmol) in DMF (3.0 mL) was reacted with pyrrolidin-3-yl-carbamic acid tert-butyl ester (0.700 g, 3.5 mmol) and triethylamine (0.70 mL, 5.0 mmol) then heated to 70° C. overnight. The mixture was then cooled, diluted with H2O, and extracted with ethyl acetate. The organic layers were combined, dried with sodium sulfate, and concentrated. The residue was then purified by column chromatography (silica gel, 1:1 hexanes/ethyl acetate) to provide 0.10 g of the title compound as a solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][N+:4]=1[O-])[CH3:2]>CCO.[NH4+].[Cl-].C(Cl)Cl.CO.[Fe]>[CH2:1]([C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1cc([N+](=O)[O-])cc[n+]1[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCO
Solvent: ClCCl
Product: CCc1cc(N)ccn1

Procedure:
A solution of 388.0 g (2.3 mol) 2-ethyl-4-nitro-pyridine-1-oxide in 3.0 L EtOH and 1.0 L saturated NH4Cl solution (1.0 L) is stirred with 647.5 g (11.6 mol) iron powder. This mixture is refluxed for 3 h. The iron powder is filtered off with Celite®, and the solvent is removed from the filtrate in vaccuo to afford a crude oil. This oil is diluted with DCM/MeOH (1.0 L, 10:1) and the undissolved NH4Cl is removed by filtration, the filtrate is dried in vaccuo to afford the title compound. Yield: 200.0 g (71%).