Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:13]2[C:8](=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([NH2:17])[CH2:5]1)(=O)C.[OH-].[K+].O>CCO>[NH2:17][C:6]1[CH:5]=[N:4][C:13]2[C:8]([CH:7]=1)=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:11][CH:12]=2
Reactant: CC(=O)N1CC(N)=Cc2c1cccc2[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cnc2cccc([N+](=O)[O-])c2c1

Procedure:
N-Acetyl-3-amino-5-nitroquinoline, as described above in Step B, (5.89 g, 25.5 mmol) was dissolved in EtOH (200 mL) and KOH (2 N aqueous solution, 19.2 mL, 38.4 mmol) was added. The reaction mixture was heated to reflux for 48 hours, cooled, poured into water, and concentrated to in vacuo to remove the EtOH. The resulting solid was collected by filtration and dried to afford the desired product.
Reaction SMILES: ClCC([NH:5][CH2:6][C:7]1[C:8]([OH:28])=[C:9]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:10]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:11][C:12]=1[C:13]([CH3:16])([CH3:15])[CH3:14])=O.Cl>C(O)C>[NH2:5][CH2:6][C:7]1[C:12]([C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:11][C:10]([C:17]([CH3:18])([CH3:19])[CH3:20])=[C:9]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:8]=1[OH:28]
Reactant: CC(C)(C)c1cc(C(C)(C)C)c(-c2ccc(Cl)cc2)c(O)c1CNC(=O)CCl
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(C(C)(C)C)c(-c2ccc(Cl)cc2)c(O)c1CN
Temperature: 75 °C

Procedure:
To a mixture of 0.30 g (0.71 mmol) of the product from Step C in 20 mL ethanol was added 3 mL conc. hydrochloric acid and the resulting solution was stirred and heated overnight at 75° C. The reaction mixture was then cooled to room temperature, concentrated in vacuo and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was separated and re-extracted with EtOAc. The organic layers were combined, dried Na2SO4), filtered and evaporated in vacuo to afford the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH2:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:13][C:14]1[C:19]([CH2:20][CH:21]=O)=[C:18](Cl)[N:17]=[CH:16][N:15]=1>C(O)C>[Si:1]([O:8][CH2:9][C@@H:10]([N:12]1[C:18]2[N:17]=[CH:16][N:15]=[C:14]([Cl:13])[C:19]=2[CH:20]=[CH:21]1)[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=CCc1c(Cl)ncnc1Cl
Reactant: C[C@H](N)CO[Si](C)(C)C(C)(C)C
Solvent: CCO
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c(Cl)ncnc21
Yield: 67 %

Procedure:
(S)-2-tert-Butyldimethylsilyloxy-1-methylethylamine (120 g, 636 mmol) was added to (4,6-dichloropyrimidin-5-yl)acetaldehyde (52.8 g, 276 mmol) in ethanol (500 mL). The mixture was heated to reflux for 45 minutes. The reaction mixture was evaporated in vacuo then the residue was diluted with water (400 mL) and extracted with ethyl acetate (600 mL). The organic extract was evaporated in vacuo and the crude material was purified by column chromatography on silica gel (gradient of pentane:EtOAc 90:10 to 80:20) to afford the title compound as a yellow liquid in 67% yield, 60.4 g.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]#N)=[CH:10][C:4]=2[O:3]1.[OH2:13]>C(O)=O.[Al].[Ni]>[O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[O:13])=[CH:10][C:4]=2[O:3]1
Reactant: O
Reactant: N#Cc1ccc2[nH]c(=O)oc2c1
Agent: [Ni]
Agent: [Al]
Solvent: O=CO
Product: O=Cc1ccc2[nH]c(=O)oc2c1
Yield: 97 %

Procedure:
A mixture of 2-oxo-2,3-dihydro-1,3-benzoxazole-6-carbonitrile (Intermediate 6, 220 mg; 1.37 mmol) and aluminium/nickel 1:1 alloy (223.6 mg; 2.61 mmol) in 2.25 ml of formic acid and 0.75 ml of water is stirred at 90° C. for 24 hr. The solid is filtered and washed with ethanol. The filtrate is concentrated in vacuo and dried overnight at 45° C. in a vacuum dessicator. The solid obtained (219 mg; 97% yield) is pure enough as to prosecute with the synthesis.
Reaction SMILES: C(C(NC(C1C=C(F)C=CC=1S[S:20][N:21]([C:30](=[O:38])[C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][CH:32]=1)[CH:22]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:23]([OH:25])=[O:24])=O)CC(C)C)(O)=O.BrBr>C(#N)C.ClCCl>[CH3:28][CH:27]([CH3:29])[CH2:26][C@H:22]([N:21]1[C:30](=[O:38])[C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[S:20]1)[C:23]([OH:25])=[O:24]
Reactant: CC(C)CC(NC(=O)c1cc(F)ccc1SSN(C(=O)c1cccc(F)c1)C(CC(C)C)C(=O)O)C(=O)O
Agent: BrBr
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)C[C@@H](C(=O)O)n1sc2ccc(F)cc2c1=O
Yield: 137.3 %

Procedure:
Following the general method of Example 3, a slurry of {s-(R*,R*)]-2-{-[2-(1-carboxy-3-methyl-butylcarbamoyl)-4-fluorophenyldisulfanyl]-5-fluorobenzoylamino}-4-methyl-pentanoic acid (2.1 g, 3.6 mmol) (from Preparation 21) in 8 mL acetonitrile and 25 mL dichloromethane was treated with bromine (0.7 g, 4.4 mmol) in 15 mL dichloromethane. The crude compound was recrystallized from methanol/water to afford 1.4 g of the title compound, mp 161-162° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:10][C:11]([CH3:13])=O>CO>[C:11](=[N:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)([CH3:13])[CH3:10]
Reactant: COc1ccc(N)cn1
Reactant: CC(C)=O
Solvent: CO
Product: COc1ccc(N=C(C)C)cn1
Yield: 80.6 %

Procedure:
To a solution of 5-amino-2-methoxypyridine (18 g, 161 mmol) in methanol (80 mL) was added acetone (20 mL, 177 mmol). The reaction was heated at reflux for 24 hours and the volatiles were concentrated in vacuo to provide 21.3 g of isopropylidene-(6-methoxy-pyridin-3-yl)-amine. 1H NMR (CDCl3) δ 7.59 (d, 1H), 7.31 (m, 1H), 6.70 (d, 1H), 3.91 (s, 3H), 2.20 (s, 3H), 1.85 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:37])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[N:9]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])(=[O:19])=[O:18])[C:8]1=[O:30].O>N1C=CC=CC=1>[Cl:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[O:28][CH3:29])(=[O:19])=[O:18])[C:8](=[O:30])[C:7]2([NH:6][C:1]([CH2:2][CH3:3])=[O:4])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:37]
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(N)(c3ccccc3Cl)c3cc(Cl)ccc32)c(OC)c1
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCC(=O)NC1(c2ccccc2Cl)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.08 g of propionyl chloride is added to a solution of 0.33 g of the compound obtained in EXAMPLE 3 in 3 ml of pyridine and the reaction mixture is stirred for 1 hour at RT. It is poured into water, extracted with AcOEt, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (98/2; v/v) as the eluent to give the expected product after crystallization from a DCM/iso ether mixture. m=0.18 g. M.p.=188° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[CH:13]=[C:14]([CH2:16]O)[O:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]2[CH:13]=[C:14]([CH2:16][N:24]3[C:20](=[O:30])[C:21]4[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:23]3=[O:25])[O:15][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1cc2ccc(OCc3ccccc3)cc2o1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cc2ccc(OCc3ccccc3)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a tetrahydrofuran (300 mL) solution of (6-benzyloxy-benzofuran-2-yl)-methanol (14.2 g, 55.8 mmol) described in Production Example 1-2-2 were added phthalimide (9.03 g, 61.4 mmol), triphenylphosphine (17.6 g, 67 mmol) and diethylazodicarboxylate (29.2 g, 67 mmol) at 0° C., which was stirred at room temperature for 7 hours 30 minutes. To the reaction mixture was added water at room temperature followed by extraction with ethyl acetate. After washing the organic layer with water and sat. NaCl, the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=3:1) to obtain a mixture of the title compound and a by-product (14.3 g) as a white solid. This was then used in the next reaction without additional purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[NH:15][CH2:16][CH3:17].[CH:18](O)=O>CCOC(C)=O>[CH2:16]([N:15]1[C:3]2[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:2]=2[N:1]=[CH:18]1)[CH3:17]
Reactant: CCNc1cc(C(=O)OC)cc([N+](=O)[O-])c1N
Reactant: O=CO
Solvent: CCOC(C)=O
Product: CCn1cnc2c([N+](=O)[O-])cc(C(=O)OC)cc21
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 79 %

Procedure:
Methyl 4-amino-3-(ethylamino)-5-nitrobenzoate (D205) (850 mg, 3.55 mmol, 1 equiv) was dissolved in formic acid (20 ml) and the resulting solution was stirred at 100° C. for 45 min then cooled to room temperature and diluted with AcOEt (200 ml). The organic phase was washed with a 2N aqueous NaOH solution, dried over MgSO4 and concentrated in vacuo to give methyl 1-ethyl-4-nitro-1H-benzimidazole-6-carboxylate (D206) (700 mg, 79%) as a tan solid which was used in the next step without further purification. [M+H]+=250.1, RT=2.41 min.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH:8]([CH3:12])[C:9](Cl)=[O:10])[N:3]=1.[O:13]=[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH:8]([CH3:12])[C:9]([CH:19]2[C:14](=[O:13])[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18]2)=[O:10])[N:3]=1
Reactant: Cc1cc(C)n(C(C)C(=O)Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: Cc1cc(C)n(C(C)C(=O)C2CN(C(=O)OC(C)(C)C)CCC2=O)n1
Yield: 23.9 %

Procedure:
tert-Butyl 3-(2-(3,5-dimethyl-1H-pyrazol-1-yl)propanoyl)-4-oxopiperidine-1-carboxylate (0.248 g, 23.87% yield) was synthesised from 2-(3,5-dimethyl-1H-pyrazol-1-yl)propanoyl chloride (0.5 g, 2.97 mmol, example 104b) and tert-butyl 4-oxopiperidine-1-carboxylate (1.185 g, 5.95 mmo) by the general procedure for the preparation of diketones.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[N:10][C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=12.C(N(CC)CC)C.[N:31]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:1][C@H:2]1[N:3]([C:8]2[C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:12]=3[C:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:10][N:9]=2)[CH2:4][CH2:5][N:6]([C:37]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:38])[CH2:7]1
Reactant: C[C@@H]1CNCCN1c1nnc(-c2ccccc2)c2ccncc12
Reactant: O=C(Cl)N1CCCCC1
Solvent: CCN(CC)CC
Product: C[C@@H]1CN(C(=O)N2CCCCC2)CCN1c1nnc(-c2ccccc2)c2ccncc12

Procedure:
Using methods described in Example 18, and starting with (R)-4-(2-methylpiperazin-1-yl)-1-phenylpyrido[4,3-d]pyridazine 16 (125 mg, 409 μmol, triethylamine (80 μl, 614 μmol), and piperidine-1-carbonyl chloride (67 μl, 532 μmol) afforded (R)-(3-methyl-4-(1-phenylpyrido[4,3-d]pyridazin-4-yl)piperazin-1-yl)(piperidin-1-yl)methanone 38. MS 416.2 (calc'd) 417.3 (M+H, found).
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:20][NH:21][NH:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].O>CN(C1C=CN=CC=1)C.ClCCCl>[CH:1]1([C:4]([N:21]([CH3:20])[NH:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[O:6])[CH2:3][CH2:2]1
Reactant: CNNC(=O)OCc1ccccc1
Reactant: O=C(O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: O
Product: CN(NC(=O)OCc1ccccc1)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.5 %

Procedure:
Cyclopropanecarboxylic acid (600 mg, 6.97 mmol), DMAP (170 mg, 1.39 mmol) and EDC.HCl (1.19 g, 7.67 mmol) were added in that order to a stirred solution of benzyl 2-methylhydrazinecarboxylate hydrochloride (JOC, 2013, 78, 3541-3552.) (1.80 g, 8.37 mmol) in DCE (10 mL) and the reaction mixture was stirred at 25° C. for 12 h. Water was added to the reaction mixture and the mixture extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered, concentrated and the residue was purified by column chromatography on silica (100-200 mesh) eluting with 30% hexane in EtOAc to afford the title compound as a colourless gum (1.6 g, 80%): 1H NMR (300 MHz, DMSO-d6) δ10.01 (bs, 1H), 7.37 (s, 5H), 5.18 (s, 2H), 2.97 (s, 3H), 1.98-1.89 (m, 1H), 0.70-0.68 (m, 4H); ESIMS m/z 247.0 ([M−H]−); IR (thin film) 3502, 2928, 1736 cm−1.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.Cl[CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH3:16])=[O:14]>CO>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[N:1]=2)[N:4]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: COC(=O)CC(=O)CCl
Solvent: CO
Product: COC(=O)Cc1cn2nc(Cl)ccc2n1
Yield: 52 %

Procedure:
10.1 g of 3-amino-6-chloropyridazine was suspended in 120 ml of methanol; 23.5 g of methyl 4-chloroacetoacetate was added, followed by heating and refluxing for 20 hours. After cooling, the mixture was concentrated under reduced pressure; the residue was ajusted to pH 7 by the addition of an aqueous solution of sodium hydrogen carbonate, followed by extraction with ethyl ether; the extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with hexane:ethyl acetate (1:4). The desired fraction was collected to yield 9.15 g of methyl 6-chloroimidazo[1,2-b]pyridazin-2-acetate was dissolved in 10 ml of N,N-dimethylformamide; while the solution was stirred under ice water cooling conditions, 3.5 g of a 60% sodium hydride dispersion in mineral oil was add little by little, followed by stirring at room temperature for 30 minutes. Under ice water cooling conditions, 6.3 ml of methyl iodide was added, followed by stirring at room temperature for 5 hours. Ice water was poured, followed by extraction with ethyl acetate; the extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with hexane:ethyl acetate (1:1). The desired fraction was collected and concentrated to yield 14.1 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([NH:6][C:7]2[S:8][C:9]3[CH2:23][CH2:22][C:12]4[N:13]=[C:14]([NH:16][C:17]([NH:19][CH2:20][CH3:21])=[O:18])[S:15][C:11]=4[C:10]=3[N:24]=2)=[CH:4][CH:3]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7]2[S:8][C:9]3[CH:23]=[CH:22][C:12]4[N:13]=[C:14]([NH:16][C:17]([NH:19][CH2:20][CH3:21])=[O:18])[S:15][C:11]=4[C:10]=3[N:24]=2)=[CH:25][CH:26]=1
Reactant: CCNC(=O)Nc1nc2c(s1)-c1nc(Nc3ccc(Br)cc3)sc1CC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: CCNC(=O)Nc1nc2ccc3sc(Nc4ccc(Br)cc4)nc3c2s1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a suspension of N-[7-(4-bromoanilino)-4,5-dihydro[1,3]thiazolo[4′,5′: 3,4]benzo[d][1,3]thiazol-2-yl]-N′-ethylurea (27 mg, 0.060 mmol) in toluene (2.0 mL) was added DDQ (28 mg, 0.125 mmol). The reaction mixture was stirred at about 20° C. for about 2 hrs. The reaction mixture was pumped down in vacuo and purified by preparative HPLC. 7 mg (26%, 2 steps) pure product was isolated. LC/MS 448 and 450 (MH+); RP-HPLC 18.09 min.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:13].[CH3:14][Mg]Br>CCOCC>[OH:13][C:7]1([CH3:14])[C:8]2[C:3](=[C:2]([CH3:1])[CH:11]=[C:10]([CH3:12])[CH:9]=2)[CH2:4][CH2:5][CH2:6]1
Reactant: C[Mg]Br
Reactant: Cc1cc(C)c2c(c1)C(=O)CCC2
Solvent: CCOCC
Product: Cc1cc(C)c2c(c1)C(C)(O)CCC2
Yield: 97 %

Procedure:
Following the procedure of Example 1, step 1, 25.20 g (0.145 ml) of 5,7-dimethyltetralone in 200 ml of anhydrous ether was reacted with 60.3 ml of 3.0M methyl magnesium bromide in ether to give 26.64 g (97%) of the title product as an orange oil. NMR δ(CDCl3) 1.56 (3H, s), 1.70 (1H, s), 1.78-2.04 (4H, m), 2.20 (3H, s), 2.30 (3H, s), 2.60 (2H, m), 6.90 (1H, s), 7.30 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][Cl:9])=[C:6]([CH3:10])[CH:5]=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:7]([CH2:8][Cl:9])=[C:6]([CH3:10])[CH:5]=[CH:4][N+:3]=1[O-:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccnc(C)c1CCl
Solvent: ClC(Cl)Cl
Product: Cc1cc[n+]([O-])c(C)c1CCl
Temperature: 0 °C
Reaction time: 4 h

Procedure:
The 2,4-dimethyl-3-chloromethylpyridine (21.5 g, 138 mmol) was dissolved in CHCl3 (800 mL) and cooled under nitrogen to 0° C. and m-chloroperbenzoic acid (55%, 35 g) was added in small portions. The reaction was stirred for 4 hours. The solution was extracted twice with saturated aqueous sodium bicarbonate (500 mL). The organic phase was dried with MgSO4, filtered and the solvent removed under reduced pressure. The residue was chromatographed on silica gel packed in 98:2 CH2 Cl2 :MeOH and eluted with same. The appropriate fractions were combined and the solvent was removed under reduced pressure the give the desired 2,4-dimethyl-3-chloromethylpyridine-N-oxide.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:24][CH2:23][C:11]2([C:15](=[O:16])[NH:14][CH2:13][CH:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7].[CH3:34]I>>[F:31][C:28]([F:29])([F:30])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:27]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([CH3:34])[CH2:13][CH:12]2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:23][CH2:24]1)=[O:7]
Reactant: CI
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCC2c1ccccc1
Product: CN1CC(c2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=485.3 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-phenyl-2,8-diaza-spiro[4.5]decan-1-one and methyl iodide.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([NH2:21])[CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].C(OC(N1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42])=O)C>C(#N)C.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:21]3[C:36](=[O:37])[C:35]4[C:34](=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:33]3=[O:42])[CH2:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: COc1ccc(C(N)CS(C)(=O)=O)cc1OC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(C(CS(C)(=O)=O)N2C(=O)c3ccccc3C2=O)cc1OC1CCCC1

Procedure:
2-[1-(3-Cyclopentyloxy-4-methoxyphenyl)-2-methylsulfonylethyl]isoindoline-1,3-dione was prepared by the procedure of Example 5 from 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-methylsulfonylethylamine (1.0 g, 3.2 mmol), sodium hydrogen carbonate (281 mg, 3.34 mmol) and N-ethoxycarbonyl phthalimide (732 mg, 3.3 mmol) in acetonitrile and water (4 mL each). The product was obtained as a white solid (314 mg, 22% yield): mp, 173.0-175.0° C.; 1H NMR (CDCl3); δ 1.61-2.05 (m, 8H, C5H8), 2.84 (s, 3H, CH3), 3.80 (dd, J=4.9, 14.4 Hz, 1H, CHH), 3.83 (s, 3H, CH3), 4.54 (dd, J=9.9, 14.4 Hz, 1H, CHH), 4.77-4.82 (m, 1H, OCH), 5.90 (dd, J=4.9, 9.9 Hz, 1H, NCH), 6.82 (d, J=8.3 Hz, 1H, Ar), 7.09-7.17 (m, 2H, Ar), 7.69-7.75 (m, 2H, Ar), 7.81-7.86 (m, 2H, Ar); 13C NMR (CDCl3) δ 24.08, 32.77, 41.53, 48.98, 54.99, 56.03, 80.59, 111.92, 114.57, 120.37, 123.55, 129.55, 131.67, 134.20, 148.02, 150.38, 167.82; Anal Calcd for C23H25NO6S+0.1 CH2Cl2 : C, 61.38; H, 5,62; N, 3.10. Found: C, 61.05; H, 5.60; N, 2.96.
Reaction SMILES: C[O:2][C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:26](=[CH:27][CH:28]=1)[O:25][C:11]1([CH2:17][CH2:16][CH2:15][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:29].Cl>CC(O)=O>[CH2:18]([N:14]1[CH2:15][CH2:16][CH2:17][C:11]2([CH2:10][C:9](=[O:29])[C:8]3[C:26](=[CH:27][CH:28]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:30])=[O:2])[CH:7]=3)[O:25]2)[CH2:12][CH2:13]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccccc3)CC1)O2
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3ccccc3)CC1)O2
Yield: 106.1 %

Procedure:
(±)-(E)-3-[1′-Benzyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid methyl ester (480 mg, 1.18 mmol) was hydrolyzed with aqueous 20% HCl solution and AcOH following the procedure described in Example 22, Step A, giving (±)-(E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid (490 mg) as a white solid (hydrochloride salt).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:37])[C:5]([CH3:36])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:32]C(=O)C)=[C:17]([CH:31]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:30])([F:29])[F:28])=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:37])[C:5]([CH3:36])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:32])=[C:17]([CH:31]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]([F:28])([F:30])[F:29])=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccccc3C(F)(F)F)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccccc3C(F)(F)F)c2)=C(C)C1=O
Yield: 97.9 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-2-trifluoromethylaniline (0.100 g, 0.193 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.090 g, 0.189 mmol, 98%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:18])[NH:8][N:9]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:11]=1)=O)C.O.[NH2:20][NH2:21]>C(O)C>[O:18]=[C:7]1[C:6]([C:4]([NH:20][NH2:21])=[O:3])=[CH:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:9][NH:8]1
Reactant: CCOC(=O)c1cc(-c2ccncc2)n[nH]c1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cc(-c2ccncc2)n[nH]c1=O
Temperature: 25 °C

Procedure:
10 g of 3-oxo-6-pyridin-4-yl-2,3-dihydro-pyridazine-4-carboxylic acid ethyl ester are dissolved in 150 ml of ethanol, 4.2 ml of hydrazine hydrate is added and the mixture is refluxed for 5 hours. After cooling to room temperature, the solid is collected by filtration and dried in vacuo at 40° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][O:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][OH:10].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[CH2:4][O:5][CH2:6]/[CH:7]=[CH:8]/[CH:9]=[O:10]
Reactant: COC(=O)COC/C=C\CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: COC(=O)COC/C=C/C=O
Temperature: 25 °C
Reaction time: 23 h
Yield: 20.1 %

Procedure:
To a solution of 1.57 g of 2-[4-hydroxy-(Z)-2-buten-1-yloxy]acetic acid methyl ester in 157 ml of benzene, 7.90 g of celite and 4.87 g of pyridinium chlorochromate were added, followed by stirring at room temperature for 23 hours. The insoluble matter was removed by filtration and the solvent in the filtrate was evaporated under reduced pressure. After the was dissolved in ethyl acetate, the insoluble matter was removed by filtering trough celite to obtain 311 mg of the desired crude product as a brown oily substance.