Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([CH:7]=O)[O:4][C:3]=1[C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[N:10]=1.C([BH3-])#N.[Na+].C(O)(=O)C.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CO>[Br:1][C:2]1[CH:6]=[C:5]([CH2:7][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[O:4][C:3]=1[C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[N:10]=1
Reactant: O=Cc1cc(Br)c(-c2nc(-c3ccc(Cl)cc3)no2)o1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Clc1ccc(-c2noc(-c3oc(CN4CCOCC4)cc3Br)n2)cc1
Reaction time: 24 h
Yield: 16.6 %

Procedure:
To a stirring solution of 5-(3-bromo-5-formyl-furan-2-yl)-3-(4-chloro-phenyl)-[1,2,4]-oxadiazole (60 mg, 0.170 mmol), sodium cyanoborohydride (10.5 mg, 0.167 mmol), acetic acid (10.0 μL, 0.173 mmol), and methanol (2.0 mL) under argon was added morpholine (50 μL, 0.57 mmol). The solution was stirred for 24 h and concentrated to dryness. The product was purified by column chromatography (2:1, hexane:ethyl acetate) to yield 12 mg (17%) of 5-(3-bromo-5-morpholinomethyl-furan-2-yl)-3-(4-chloro-phenyl)-[1,2,4]-oxadiazole as a white solid. 1H NMR (CDCl3): 8.12 (d, J=8.51 Hz, 2H), 7.49 (d, J=8.52 Hz, 2H), 6.60 (s, 1H), 3.74 (t, J=4.67 Hz, 4H), 3.67 (s, 2H), 2.56 (t, J=4.67 Hz, 4H); and to also yield 12 mg (20%) of 5-(3-bromo-5-hydroxymethyl-furan-2-yl)-3-(4-chloro-phenyl)-[1,2,4]-oxadiazole as a white solid. 1H NMR (CDCl3): 8.11 (dd, J=8.79, 2.20 Hz, 2H), 7.49 (dd, J=8.79, 2.20 Hz, 2H), 6.67 (s, 1H), 4.77 (d, J=6.32 Hz, 2H), 2.09 (t, J=6.46 Hz, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[C:8](=[C:9]([Cl:11])[CH:10]=1)[N:7]=[C:6](S)[C:5]=3[CH:13]=[CH:14][CH:15]=2.[N:16]1([CH2:21][CH2:22][CH:23]([NH2:25])C)[CH:20]=[CH:19][N:18]=[CH:17]1.[CH2:26](O)C>>[Cl:1][C:2]1[C:3]2[C:4]3[C:8](=[C:9]([Cl:11])[CH:10]=1)[N:7]=[C:6]([NH:25][CH2:23][CH2:22][CH:21]([N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)[CH3:26])[C:5]=3[CH:13]=[CH:14][CH:15]=2
Reactant: CCO
Reactant: CC(N)CCn1ccnc1
Reactant: SC1=Nc2c(Cl)cc(Cl)c3cccc1c23
Product: CC(CCNC1=Nc2c(Cl)cc(Cl)c3cccc1c23)n1ccnc1

Procedure:
A mixture of 7.0 g of 6,8-dichloro-benz[cd]indole-2-thiol, 100 ml of ethanol, 9.5 g of mercuric acetate and 4.2 g of 4-(1H-imidazol-1-yl)-2-butanamine was reacted as described in Example 1, giving 1.7 g of the desired product, mp 244°-246° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Cl:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:12]1[CH:16]2[O:17][CH2:18][CH2:19][N:15]2[CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[Cl-:9].[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N+:15]23[CH2:19][CH2:18][O:17][CH:16]2[O:12][CH2:13][CH2:14]3)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: C1CN2CCOC2O1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(C[N+]23CCOC2OCC3)cc1
Product: [Cl-]
Yield: 75.4 %

Procedure:
A solution of 1.716 g (10 mmol) 4-nitrobenzyl chloride and 1.152 g (10 mmol) tetrahydro-[1,3]oxazolo[2,3-b][1,3]oxazole in 20 ml of chloroform was stirred at the room temperature for 3 days. The precipitate was filtered off, washed twice with dichloromethane and dried. 2.161 g (75.4%) of white amorphous product was obtained, which can be further purified by recrystallisation from rectified ethanol.
Reaction SMILES: C[NH:2][CH2:3][CH2:4][NH:5][CH3:6].[S:7](Cl)([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8].[CH2:18]1COCC1>>[CH3:18][N:5]([CH3:6])[CH2:4][CH2:3][NH:2][S:7]([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C1CCOC1
Reactant: CNCCNC
Product: Cc1ccc(S(=O)(=O)NCCN(C)C)cc1
Reaction time: 16 h
Yield: 93 %

Procedure:
To 10.5 g of N,N′-dimethylethylenediamine in 250 ml of THF was added 26 g of tosylchloride (TsCl) in small portions at room temperature. After 16 hours, solvents were evaporated and the residue was apportioned between H2O and CH2Cl2. A CH2C2 layer was separated and washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. About 26.5 g of N,N-dimethyl-N′-tosylethylenediamine (93%) was produced. The reaction steps are shown below:
Reaction SMILES: [CH2:1]([N:8]([CH3:34])[C:9]([C:11]1[N:15]=[C:14]([C@H:16]([CH2:25][CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[O:13][N:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:8]([CH3:34])[C:9]([C:11]1[N:15]=[C:14]([C@H:16]([CH2:25][CH2:26][CH2:27][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:17][C:18]([OH:20])=[O:19])[O:13][N:12]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(Cc1ccccc1)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 86.8 %

Procedure:
A solution of tert-butyl (3R)-3-(3-{[benzyl(methyl)amino]carbonyl}-1,2,4-oxadiazol-5-yl)-6-cyclohexylhexanoate (Preparation 33) (296 mg, 0.63 mmol) in dichloromethane (4 ml) was treated with trifluoroacetic acid (1 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 17 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene to afford the title compound (226 mg).
Reaction SMILES: [OH:1][C:2]1([C:29]2[S:33][C:32]([S:34][CH3:35])=[N:31][CH:30]=2)[CH2:7][CH2:6][CH:5]([N:8]2[CH2:11][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[O:14])[CH2:9]2)[CH2:4][CH2:3]1.O.[OH:37]OS([O-])=O.[K+]>CO>[OH:1][C:2]1([C:29]2[S:33][C:32]([S:34]([CH3:35])=[O:37])=[N:31][CH:30]=2)[CH2:3][CH2:4][CH:5]([N:8]2[CH2:9][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=3)=[O:14])[CH2:11]2)[CH2:6][CH2:7]1
Reactant: O=S([O-])OO
Reactant: CSc1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1
Agent: [K+]
Solvent: CO
Solvent: O
Product: CS(=O)c1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
N-({1-[4-Hydroxy-4-(2-methylsulfanyl-thiazol-5-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (less polar isomer, 45a, 100 mg, 0.19 mmol) in MeOH (1 mL) and water (1 mL) was treated with OXONE (Aldrich, 230 mg, 0.38 mmol) at room temperature for 6 hours. The reaction mixture was partitioned between DCM and saturate NaHCO3. The organic layer was separated and the aqueous layer was extracted 3 times with chloroform and IPA “cocktail” (˜3:1, v/v). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compounds as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:20](=[O:28])[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:7]=1)=[O:5])[CH3:2].[H][H]>C(O)(=O)C.O=[Pt]=O>[CH2:1]([O:3][C:4]([CH:6]1[C:12]2[NH:13][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8]([C:20](=[O:28])[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccccc21
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CCOC(=O)C1CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1c2CCCC1

Procedure:
A solution of 3-(4-fluoro-benzoyl)-1,2,3,6-tetrahydro-azepino[4,5-b]indole-5-carboxylic acid ethyl ester (Example 5, 1.3 g, 3.4 mmol) in 60 mL of glacial acetic acid containing 500 mg of Adams catalyst was subjected to hydrogenation for 14 hours at room temperature and under 45psi of hydrogen. (Boekelheide, V. and Liu, C-T, J. Am. Chem. Soc. 1952, 74, 4920-4922). The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The crude product was purified by preparative normal-phase HPLC eluting with 40% EtOAc-Hexane . 1H-NMR(CDCl3): δ 7.99 (1H, s), 7.40-7.37 (2H, m), 7.11-7.06 (2H, m), 4.22-4.15 (4H, m), 3.54 (1H, m), 2.75 (1H, m), 2.54-2.45 (2H, m), 2.31 (2H, m), 1.76 (4H, m), 1.61 (2H, m), 1.32 (3H, m); MS (ES): 385 (MH+).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:8]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH2:6][CH3:7])[C:4](=[O:22])[CH2:3]1)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>N1C=CC=CC=1>[C:23]([O:1][C@@H:2]1[C@H:8]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH2:6][CH3:7])[C:4](=[O:22])[CH2:3]1)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](O)CC2=O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(=O)c1ccccc1)CC2=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 102 g of 15α-hydroxy-18-methyl-4-estrene-3,17-dione in 500 ml of pyridine is combined under ice cooling with 50.9 ml of benzoyl chloride and stirred for one hour under cooling. Then 9 ml of water is added dropwise and the mixture is stirred for another hour. The reaction solution is then stirred into ice water, the thus-formed precipitate is suctioned off, washed with water, and dried, thus obtaining 146 g of crude 15α-benzoyloxy-18-methyl-4-estrene-3,17-dione.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:28]=[C:27]([O:29][CH2:30][O:31][CH3:32])[CH:26]=[CH:25][C:6]=1[C:7](=[O:24])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][O:18][CH3:19])=[C:12]([O:20][CH2:21][O:22][CH3:23])[CH:11]=1>[Pd]>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:28]=[C:27]([O:29][CH2:30][O:31][CH3:32])[CH:26]=[CH:25][C:6]=1[C:7](=[O:24])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][O:18][CH3:19])=[C:12]([O:20][CH2:21][O:22][CH3:23])[CH:11]=1
Reactant: COCOc1ccc(C(=O)C=Cc2ccc(OCOC)c(OCOC)c2)c(OCOC)c1
Agent: [Pd]
Product: COCOc1ccc(C(=O)CCc2ccc(OCOC)c(OCOC)c2)c(OCOC)c1
Yield: 97.4 %

Procedure:
Catalytic reduction of 5.05 g of the 2',3,4,4'-tetrakis(methoxymethoxy)chalcone obtained as the intermediate in Specific Example 19 was carried out by using 1.76 g of 5% palladium/carbon according to customary procedures. After the reaction, the reaction liquid was filtered and the solvent was removed from the filtrate by distillation to obtain 4.94 g (yield=97.3%) of 1-[2,4-bis(methoxymethoxy)phenyl]-3-[3,4-bis(methoxymethoxy)phenyl]-1-propanone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=O)[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[C:32]([CH3:33])=[C:31]([CH:34]=[C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[CH:16][C:8]=4[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[NH:12][C:11]3=[O:17])[NH:30][C:29]=2[CH3:36])=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)c(C)c1C(=O)NCCN1CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.2 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (68.5 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide as a yellow solid (90.0 mg, 76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1/[N:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Li][C:18]([CH3:21])([CH3:20])[CH3:19].O>C1COCC1.CCCCC>[CH3:19][C:18]([CH3:21])([CH3:20])[CH:6]([NH:5][C:4]1[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=1[O:2][CH3:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1ccccc1/N=C/c1ccccc1
Reactant: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: O
Product: COc1ccccc1NC(c1ccccc1)C(C)(C)C
Temperature: -80 °C
Yield: 92.8 %

Procedure:
To a solution of 1.27 g (6.00 mmol) of 9 in 40 mL of THF, 4.20 mL (6.30 mmol) of 1.5 M tBuLi in pentane was added with vigorous stirring at −80° C. The mixture was slowly warmed to room temperature, and then 2 mL of water was added. The resulting mixture was evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um, eluent: from hexanes to hexanes-diethyl ether=40:1, vol.) to yield 1.50 g (93%) of B1.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:37]=[CH:36][C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:24][CH2:25][C:26]4[CH:35]=[CH:34][C:29]5[C:30]([OH:33])=[N:31][O:32][C:28]=5[CH:27]=4)=[C:17]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:18]=3)=[O:12])=[C:9]([OH:38])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:46](Cl)([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.Cl>C(Cl)Cl.O>[CH:1]1([O:6][C:7]2[CH:37]=[CH:36][C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:24][CH2:25][C:26]4[CH:35]=[CH:34][C:29]5[C:30](=[O:33])[N:31]([C:46]([C:47]6[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=6)([C:59]6[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=6)[C:53]6[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=6)[O:32][C:28]=5[CH:27]=4)=[C:17]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:18]=3)=[O:12])=[C:9]([OH:38])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CCc1cc(C(=O)c2ccc(OC3CCCC3)cc2O)ccc1OCc1ccc2c(O)noc2c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(O)CCc1cc(C(=O)c2ccc(OC3CCCC3)cc2O)ccc1OCc1ccc2c(=O)n(C(c3ccccc3)(c3ccccc3)c3ccccc3)oc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
5.80 g of 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl} propanoic acid was suspended in 58 mL of methylene chloride, to which 6.2 mL of triethylamine was added at room temperature followed by addition of 3.44 g of trityl chloride in an ice bath, and this mixture was stirred for 30 minutes at room temperature. The reaction mixture to which water was added was adjusted to pH 3 with 6M hydrochloric acid, and the organic phase was separated therefrom. After the resultant organic phase was washed with water, the solvent was distilled out under reduced pressure. The resultant residue was washed with hexane and then purified by silica gel column chromatography [eluent; chloroform:ethanol=50:1] to yield 6.83 g of 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-oxo-2-trityl-2,3-dihydro-1,2-benzisoxazol-6-yl)methoxy]phenyl} propanoic acid as yellow solid.
Reaction SMILES: OO.[OH:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[N:7]([OH:12])[C:6]([CH3:14])([CH3:13])[CH2:5]1.[CH3:15]S(C)=O>CCCCCCC.C(OCC)(=O)C>[CH3:15][O:12][N:7]1[C:8]([CH3:10])([CH3:11])[CH2:9][CH:4]([OH:3])[CH2:5][C:6]1([CH3:14])[CH3:13]
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: CS(C)=O
Agent: OO
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CON1C(C)(C)CC(O)CC1(C)C
Reaction time: 0.42 h
Yield: 79 %

Procedure:
A solution of 8.6 g (76 mmol) of 30% aqueous hydrogen peroxide is added dropwise, under nitrogen, over a 35-minute period to a mixture of 10.0 g (58.1 mmol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 17.8 g (64.0 mmol) of ferrous sulfate heptahydrate, and 200 ml of dimethyl sulfoxide which is initially at 25° C. A water bath is used to keep the reaction temperature from exceeding 33° C. during the peroxide addition. The reaction mixture is then stirred for 25 minutes and partitioned between methylene chloride (200 ml) and water (100 ml). The aqueous layer is extracted with methylene chloride (100 ml). The combined organic layers are dried over anhydrous magnesium sulfate and concentrated at reduced pressure. The crude product is purified by flash chromatography on silica gel (10:1 heptane/ethyl acetate, then 4:1 heptane/ethyl acetate) to afford 8.6 g (79% yield) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[CH:20]=[CH:19][N:18]([CH:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[C:14]2=[CH:15][N+:16]=1[O-])[CH3:2].COS(OC)(=O)=O.O.[C-:36]#[N:37].[K+]>C1(C)C=CC=CC=1.[OH-].[Na+]>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[CH:20]=[CH:19][N:18]([CH:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[C:14]2=[C:15]([C:36]#[N:37])[N:16]=1)[CH3:2]
Reactant: [C-]#N
Reactant: CCCC(CCC)n1ccc2cc(-c3c(CC)cccc3CC)[n+]([O-])cc21
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CCCC(CCC)n1ccc2cc(-c3c(CC)cccc3CC)nc(C#N)c21
Temperature: 90 °C
Reaction time: 12 h

Procedure:
To a solution of 5-(2,6-diethyl-phenyl)-1-(1-propyl-butyl)-1H-pyrrolo[2,3-c]pyridine 6-oxide (220 mg, 0.6 mmol) in toluene (3 mL), is added dimethylsulfate (69 μL, 0.72 mmol), and the mixture is heated to 90° C. for 2 h. All volatiles are removed under reduced pressure. The residue is treated with water (2 mL), 10 M NaOH (20 drops) and KCN (200 mg, 3.1 mmol). The mixture is stirred for 12 h at room temperature. The product is extracted with EtOAc several times. The combined organic extracts are washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Chromatography of the residue on silica gel (Hexane/EtOAc, 1:1) gives 5-(2,6-diethyl-phenyl)-1-(1-propyl-butyl)-1H-pyrrolo[2,3-c]pyridine-7-carbonitrile as a colorless oil: 1H NMR (CDCl3) 7.66 (s, 1H), 7.50 (d, J=3 Hz, 1H), 7.32 (t, J=7 Hz, 1H), 7.16 (d, J=7 Hz, 2H), 6.70 (d, J=3 Hz, 1H), 5.34 (m, 1H), 2.32 (m, 4H), 1.92 (m, 4H), 1.44 (m, 2H), 1.21 (m, 2H), 1.02 (t, J=7 Hz, 6H), 0.95 (t, J=7 Hz, 6H); LCMS m/z 374.27 (3.06 min).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]([CH3:10])[CH3:9])=[CH:6][CH:7]=1.[C:11]([NH:16][NH2:17])([O:13][CH2:14][CH3:15])=[O:12]>O>[ClH:1].[C:11]([NH:16][NH:17][C:2]1[N:3]=[N:4][C:5]([N:8]([CH3:10])[CH3:9])=[CH:6][CH:7]=1)([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)NN
Reactant: CN(C)c1ccc(Cl)nn1
Solvent: O
Product: CCOC(=O)NNc1ccc(N(C)C)nn1
Product: Cl
Temperature: 160 °C

Procedure:
A mixture of 1.57 g (0.01 moles) 3-chloro-6-dimethylaminopyridazine and 2.08 g (0.02 moles) monocarbethoxyhydrazine is warmed up for half an hour at 160° C. The resulting mixture is cooled, water added thereto, the solid which separates filtered away and the filtrate neutralized with NaHCO3 until a final pH 7. The mixture is then extracted with chloroform; the organic extract dried over sodium sulphate and the solvent evaporated. The residual oil is purified by chromatography on silica gel, eluting with a mixture of chloroform:methanol 8.5:1.5. The unitary fractions on thin layer chromatography with the same Rf are collected together, evaporated and the residue treated while warm with ethyl ether, and the residue filtered off. By addition of hydrogen chloride to the filtrate, 3-(2-carbethoxyhydrazino)-6-dimethylaminopyridazine hydrochloride precipitates with good yields melting at 215°-217° C (with dec).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Cl[CH2:45][C:46]1[N:51]=[CH:50][CH:49]=[CH:48][N:47]=1.BrCC1OC(C(F)(F)F)=CC=1>>[N:47]1[CH:48]=[CH:49][CH:50]=[N:51][C:46]=1[CH2:45][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: ClCc1ncccn1
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2ncccn2)c2ccccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1H)-one, and 2-(chloromethyl)pyrimidine to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, (pyrimidin-2-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (84%) as a colorless solid: mp 203-205° C.; 1H NMR (300 MHz, CDCl3) δ8.68 (d, J=4.9 Hz, 2H), 7.24-7.15 (m, 3H), 7.03 (dd, J=7.5, 7.5 Hz, 1H), 6.75 (s, 1H), 6.73 (d, J=7.7 Hz, 1H), 6.42 (s, 1H), 5.22 (ABq, 2H), 4.89 (ABq, 2H), 4.53 (t, J=8.6 Hz, 2H), 3.07-2.93 (m, 2H) 13C NMR (75 MHz, CDCl3) δ178.0, 164.6, 161.6, 161.1, 157.4, 142.2, 132.9, 128.4, 123.7, 123.2, 120.5, 119.7, 119.7, 119.4, 108.7, 93.0, 80.5, 72.2, 57.7, 45.7, 29.0; MS (ES+) m/z 372.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH:15]=[C:16]3[O:21][C:20](=[O:22])[CH2:19][O:18][C:17]3([CH3:24])[CH3:23])[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C-]#N.[K+]>C(#N)C.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH:15]3[C:20](=[O:22])[CH2:19][O:18][C:17]([CH3:23])([CH3:24])[C:16]3=[O:21])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1C=C1OC(=O)COC1(C)C
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)COC(C)(C)C1=O
Yield: 89.9 %

Procedure:
To a suspension of 6-[1-(4′-chloro-4-methylbiphenyl-3-yl)methylidene]-5,5-dimethyl-[1,4]dioxan-2-one (1.5 g, 4.38 mmol) in anhydrous acetonitrile (22 ml) is added triethylamine (0.67 ml, 4.81 mmol) and potassium cyanide (30 mg, 0.46 mmol). The reaction mixture is stirred under reflux for two hours. The cooled mixture is diluted with ethyl acetate, and 0.5N aqueous hydrochloric acid is added at 0° C. The organic layer is separated and the aqueous phase extracted twice with ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate, filtered and the filtrate evaporated in vacuo. The residue is purified by flash chromatography (heptane/ethyl acetate 1:1 ratio) to afford 4-(4′-chloro-4-methylbiphenyl-3-yl)-2,2-dimethylpyran-3,5-dione (1.35 g) as a foam. A sample of the product is stirred in hexane/diisopropyl ether (4:1 ratio) and filtered to give a white solid with a melting point of 186-188° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]3[CH:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:29]1([C:19]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:27]3[CH:23]([CH2:24][N:25]([C:9](=[O:11])[CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O)Cc1ccccc1F
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3F)CC12
Reaction time: 0.33 h
Yield: 51.1 %

Procedure:
N,N'-Carbonyldiimidazole (1.14 g) is added to a solution of 2-fluorophenylacetic acid (1.08 g) in dry dichloromethane (30 cc) cooled to +5° C. The mixture is stirred for 20 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.3 g) and triethylamine (1.98 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 72 hours and then washed with water (2×150 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from a mixture of acetonitrile (30 cc) and isopropyl ether (50 cc). The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(2-fluorophenyl)acetyl]-4-perhydroisoindolone (1.53 g) is obtained in the form of white crystals melting at 186° C.