Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.C(N(CC)CC)C.[CH3:16][O:17][C:18]1[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]([Cl:28])[C:19]=1[C:20](Cl)=[O:21]>C1C=CC=CC=1>[CH3:16][O:17][C:18]1[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]([Cl:28])[C:19]=1[C:20]([O:7][C:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[CH:2]=1)=[O:21]
Reactant: COc1c(Cl)ccc(Cl)c1C(=O)Cl
Reactant: O=C1CCCC(=O)C1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1c(Cl)ccc(Cl)c1C(=O)OC1=CC(=O)CCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1,3-Cyclohexanedione (11.2 grams; 0.10 mole), benzene (100 ml) and triethylamine (11.1 grams; 0.10 mole) were charged into a glass reaction vessel equipped with a mechanical stirrer. 2-Methoxy-3,6-dichlorobenzoyl chloride (23.85 grams; 0.10 mole) dissolved in benzene (20 ml) was then added dropwise with stirring. After the addition was completed the reaction mixture was first stirred at ambient temperature for a period of about one hour and then at about 75°C for a period of about 20 minutes. After this time the mixture was cooled to room temperature and was filtered. The filtrate was stripped of benzene under reduced pressure to yield an oil as the residue. This oil was distilled under reduced pressure to yield the desired product 3-oxocyclohex-1-enyl 2-methoxy-3,6-dichlorobenzoate having a boiling point of 199° to 200°C at 0.45 mm of Hg pressure.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1>C(O)CCC>[Cl:1][C:2]1[NH:3][C:4]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[C:5]2[C:9]([N:10]=1)=[N:8][CH:7]=[N:6]2
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: COc1ccc(N)cc1
Solvent: CCCCO
Product: COc1ccc(Nc2[nH]c(Cl)nc3ncnc2-3)cc1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
189 mg of 2,6-dichloropurine, 4 ml of butanol and 135 mg (1.1 mol) of 4-methoxybenzenamine are mixed at room temperature and the medium is heated at a temperature of 75° C. for 5 hours and then left at room temperature overnight.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[H-].[Na+].O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: OCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCCN2CCOCC2)cc1
Temperature: 25 °C

Procedure:
To the solution of 8.0 g (51 mMol) of 1-chloro-4-nitrobenzene and 6.7 g (6.3 mL; 51 mMol) of N-hydroxyethyl-morpholine in 50 mL of DMF at 0° C. is added 2.7 g of NaH portionwise over 2.5 h. After stirring another hour at rt, the reaction mixture is poured onto 200 mL of water and stirred. The precipitated crystals are filtered and dried at 60° C. under vacuum to obtain 4-[2-(4-nitro-phenoxy)-ethyl]-morpholine. Title compound: ES-MS: 253 [M+H]+; single peak at tR=4.8 min (System 2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH:16][C:17](=[N:20][C:21]([O:23][CH3:24])=[O:22])[S:18][CH3:19])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[NH:1]=[C:2]1[C:15]([NH:16][C:17](=[N:20][C:21]([O:23][CH3:24])=[O:22])[S:18][CH3:19])=[CH:14][CH:13]=[C:4]([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])[CH:3]1[CH2:31][C:30]1[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=1
Reactant: COC(=O)N=C(Nc1ccc(C(=O)c2ccccc2)cc1N)SC
Reactant: COc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)N=C(NC1=CC=C(C(=O)c2ccccc2)C(Cc2ccc(OC)cc2)C1=N)SC
Reaction time: 3 h

Procedure:
To a mixture of 3-amino-4-(3-carbomethoxy-S-methylisothioureido)benzophenone (3.43 g.; 0.01 mol) in benzene (100 ml.) there is added p-methoxybenzaldehyde (1.36 g.; 0.01 mol) and p-toluenesulfonic acid monohydrate (0.1 g.). The mixture is refluxed and stirred for 3 hours. The water reaction is removed by a Dean-Stark distillation receiver. The mixture is poured into an excess of hexane and the suspension formed is filtered. The filter cake is dried to afford 3-imino-(4-methoxyphenyl)methyl-4-(3-carbomethoxy-S-methylisothioureido)benzophenone.
Reaction SMILES: [N:1]([C:4]1[NH:5][C:6]([C:10]([OH:12])=O)=[C:7]([Cl:9])[N:8]=1)=[N+:2]=[N-:3].[NH2:13][CH2:14][C:15]1[C:16]([F:32])=[C:17]([O:22][C:23]2[CH:24]=[C:25]([CH:28]=[C:29]([Cl:31])[CH:30]=2)[C:26]#[N:27])[C:18]([Cl:21])=[CH:19][CH:20]=1.ON1C2C=CC=CC=2N=N1.C([O-])(O)=O.[Na+]>>[N:1]([C:4]1[NH:5][C:6]([C:10]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][C:23]3[CH:24]=[C:25]([C:26]#[N:27])[CH:28]=[C:29]([Cl:31])[CH:30]=3)[C:16]=2[F:32])=[O:12])=[C:7]([Cl:9])[N:8]=1)=[N+:2]=[N-:3]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: [N-]=[N+]=Nc1nc(Cl)c(C(=O)O)[nH]1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(N=[N+]=[N-])nc3Cl)c2F)c1

Procedure:
A solution of 2-azido-4-chloro-1H-imidazole-5-carboxylic acid (0.26 g, 1.4 mmol), 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.44 g, 1.40 mmol), 1-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (0.32 g, 1.68 mmol) and N-hydroxybenzotriazole (0.28 g, 1.82 mmol) was stirred at RT overnight. NaHCO3 was added and the solution was extracted with 9:1 CH2Cl2:MeOH. The combined organic phase was dried (Na2SO4), filtered, and concentrated to give 2-azido-4-chloro-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide which was used without further purification after extraction. A solution of the above crude azide and catalytic Pd/CaCO3 (poisoned with lead) in EtOAc (20 mL) was then stirred under 50 psi hydrogen gas for 2 h. The solution was filtered through celite, evaporated and purified by silica gel chromatography (0-10% MeOH/CH2Cl2) to afford the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.95 (s, 1H), 7.82 (s, 1H), 7.77 (t, J=5.86 Hz, 1H), 7.48-7.54 (m, 2H), 7.46 (t, J=2.01 Hz, 1H), 7.34 (t, J=7.97 Hz, 1H), 5.82 (s, 2H), 4.49 (d, J=5.77 Hz, 2H). ES-LCMS: m/z 454.0, 456.0, 458.0 (M+1).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1>CC#N>[Br-:23].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:24][CH2:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: BrCCOC1CCCCO1
Solvent: CC#N
Product: OC(c1ccccc1)(c1ccccc1)C12CC[N+](CCOC3CCCCO3)(CC1)CC2
Product: [Br-]
Yield: 29.2 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0696 g, 0.237 mmol) and 2-[(2-bromoethyl)oxy]tetrahydro-2H-pyran (0.080 mL, 0.529 mmol) in 2 CH3CN/3 CHCl3 (5.0 mL) were reacted to give the desired product (0.0348 g, 31.6%). EI-MS m/z 422 (M+) Rt (1.85 min).
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:6])=[O:5].[C:13]1(C)C=CC=C[CH:14]=1.C([N:22](CC)CC)C>>[CH3:13][CH2:14][O:6][CH2:4][CH3:3].[C:1]1(=[O:12])[NH:22][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:1]1(=[O:12])[NH:22][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: O=C(O)c1ccccc1C(=O)O
Reactant: Cc1ccccc1
Reactant: CCN(CC)CC
Product: CCOCC
Product: O=C1NC(=O)c2ccccc21

Procedure:
An additional study was made in accordance with FIG. 2, utilizing aqueous phthalic acid solutions having about 28% by weight of phthalic acid. The toluene phase having about 10% by weight of triethylamine obtained from the extraction column was extracted with a 35% by weight phthalic acid solution having up to about 25% by weight of triethylamine. It was found that about 85-95% by weight of the triethylamine was removed from the toluene phase. The extracted toluene was further processed by feeding it to a thin film evaporator. Toluene was obtained substantially free of triethylamine which was recycled to the extraction column, while the bottom of the thin film evaporator was further processed to provide aromatic bis(ether phthalimide) and phthalimide.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=[N:8][OH:9])[NH2:7])#[N:2].[C:13](Cl)(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1>N1C=CC=CC=1>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:13]2[O:9][N:8]=[C:6]([C:5]3[CH:4]=[C:3]([CH:12]=[CH:11][CH:10]=3)[C:1]#[N:2])[N:7]=2)[CH:15]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: N#Cc1cccc(C(N)=NO)c1
Solvent: c1ccncc1
Product: N#Cc1cccc(-c2noc(-c3cccnc3)n2)c1
Temperature: 25 °C

Procedure:
3-Cyano-N′-hydroxybenzimidamide (0.322 g, 1 mmol) was dissolved in pyridine (10 mL) and nicotinoyl chloride (Aldrich, 0.141 g, 1 mmol) was added. The reaction mixture was heated to reflux for 3 hours and cooled to room temperature. The cooled reaction mixture was quenched with water (25 mL) and filtered. The solid was further purified with flash column chromatography (5% methanol/dichloromethane) to give the titled compound. 1H NMR (300 MHz, DMSO-d6) δ 7.75-7.71 (dd, J=5.7, 4.1 Hz, 1 H), 7.85 (t, J=7.8 Hz, 1 H), 8.15-8.12 (d, J=7.8 Hz, 1 H) 8.44-8.42 (m, 1 H), 8.50 (m, 1 H), 8.60-8.56 (m, 1 H), 8.93-8.91 (dd, J=1.7 Hz, 1 H), 9.37-9.38 (d, J=1.7 Hz, 1 H) ppm; MS (DCI/NH3) m/z 249 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:1][C:2]1[N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)[C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Reactant: Cc1nc2ccccc2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc2ccccc2c(=O)n1CCOc1ccc([N+](=O)[O-])cc1
Yield: 59 %

Procedure:
The title compound (1.2 g, 60%) was prepared from 2-methyl-4-oxo-3,4-dihydroquinazoline (1.0 g, 6.25 mmol) and 4-[2-bromoethoxy]nitrobenzene (1.69 g, 6.9 mmol) and K2CO3 (1.73 g, 12.5 mmol) as a base by a similar procedure to that described in preparation 1.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:14][C:15]([O:18][C:19]([N:21]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:22]([C:30]1[C:35]([F:36])=[C:34](Cl)[N:33]=[C:32]([Cl:38])[N:31]=1)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])([CH3:17])[CH3:16]>CN(C=O)C.C(OCC)C>[CH3:17][C:15]([O:18][C:19]([N:21]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:22]([C:30]1[C:35]([F:36])=[C:34]([NH:4][CH:1]([CH3:3])[CH3:2])[N:33]=[C:32]([Cl:38])[N:31]=1)[C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])=[O:20])([CH3:14])[CH3:16]
Reactant: CC(C)N
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F
Yield: 94.9 %

Procedure:
To a vigorously stirred solution of isopropyl amine (83 μL, 1.21 mmol) in DMF (6 mL) at 0° C. was added DIPEA (0.24 mL, 1.33 mmol) followed immediately by tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (600 mg, 1.21 mmol). When the reaction was complete as determined by LCMS, the reaction mixture was diluted with diethyl ether (˜40 mL) and washed with water (3×40 mL). The combined three aqueous layers were back-extracted once with diethyl ether, and then the combined organics were dried (Na2SO4) and concentrated in vacuo. This crude product was purified by flash chromatography (Combiflash, 5-60% ethyl acetate/hexanes, 1% triethylamine) to provide tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[(1-methylethyl)amino]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (597 mg, 95%). LCMS: (M+H)+: 520.2.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:17][CH:16]([NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH3:28])=[O:26])=[N:23][CH:24]=4)[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[BH3-][C:30]#N.[Na+].C(O)(=O)C>CC#N.O.C=O>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:15][CH:16]([N:18]([CH3:30])[C:19]4[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH3:28])=[O:26])=[N:23][CH:24]=4)[CH2:17]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: [BH3-]C#N
Reactant: CNC(=O)c1ccc(NC2CN(C(=O)N3CCCN(C4CCC4)CC3)C2)cn1
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC#N
Product: CNC(=O)c1ccc(N(C)C2CN(C(=O)N3CCCN(C4CCC4)CC3)C2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 19 %

Procedure:
5-({1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-yl}amino)-N-methylpyridine-2-carboxamide (34 mg, 92 μmol) was dissolved in 1:1 MeCN/water (3 ml) and formaldehyde (50 μl of a 37% wt. soln, 1.8 mmol) followed by NaBH3CN (34 mg, 0.56 mmol) were added. After 10 minutes, acetic acid (40 μl, 0.72 mmol) was added and the reaction stirred at room temperature for 16 hours. The reaction mixture was concentrated at reduced pressure and purified by FCC (DCM/MeOH/NH3 gradient, 98:2:1 to 90:10:1) giving the title compound as colourless oil (7 mg, 19%).
Reaction SMILES: [OH:1][CH:2]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)[CH:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]2=[O:20])[CH2:7][CH2:6]1)[CH3:4].C(N([CH2:36][CH3:37])CC)C.CN(C)C=[O:41]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[OH:1][CH:2]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)[CH:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([C:36](=[O:41])[CH3:37])[C:12]2=[O:20])[CH2:7][CH2:6]1)[CH3:4]
Reactant: CN(C)C=O
Reactant: COc1ccc(C(O)C(C)N2CCC(n3c(=O)[nH]c4ccccc43)CC2)cc1OC
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(C(O)C(C)N2CCC(n3c(=O)n(C(C)=O)c4ccccc43)CC2)cc1OC

Procedure:
A solution of 2.0 g of 1-[3-hydroxy-3-(3,4-dimethoxyphenyl)-2-propyl]-4-(2-keto-1-benzimidazolinyl)-piperidine and 0.6 g of 4-dimethylaminopyridine in 10 ml of dimethylformamide is stirred at room temperature for 12 hours. Dimethylformamide is distilled away under reduced pressure to obtain a residue. The residue is dissolved in 20 ml of ethyl acetate. To the solution is added 0.6 g of triethylamine. The mixture is washed five times with 20 ml of water and dried. Recrystallization of the crystals from a mixture of dioxane and ether (1:1) yields 1.21 g of 1-[3-hydroxy-3-(3,4-dimethoxyphenyl)-2-propyl]-4-(3-acetyl-2-keto-1-benzimidazolinyl)-piperidine.
Reaction SMILES: [CH3:1][C:2]1([C:12]([O:14][CH3:15])=[O:13])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.[H][H]>C(O)(=O)C.OS(O)(=O)=O>[CH3:1][C:2]1([C:12]([O:14][CH3:15])=[O:13])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1
Reactant: COC(=O)C1(C)Cc2ccccc2C1=O
Reactant: [H][H]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)C1(C)Cc2ccccc2C1

Procedure:
A solution of the methyl 2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2.04 g, 9.99 mmol) in glacial acetic acid (22 mL) and concentrated H2SO4 (2 mL) was hydrogenated on a Parr apparatus under 50 psi of hydrogen using 10% palladium on carbon (50% H2O, 0.200 g) as the catalyst. After 4 hours the reaction was filtered to remove the catalyst and washed 2× methanol, then concentrated to remove most of the acetic acid. The residue was neutralized using saturated Na2CO3 and the organics extracted twice with 25 mL ethyl acetate, then the combined organics washed with brine, dried (Na2SO4), filtered and concentrated to 2.0 g of methyl 2-methyl-2,3-dihydro-1H-indene-2-carboxylate.
Reaction SMILES: ClCCl.B(Br)(Br)Br.C(Cl)(Cl)Cl.C[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:25]([CH3:26])=[N:24][N:23]3[CH:27]=[N:28][N:29]=[C:22]3[CH:21]=2)=[CH:16][CH:15]=1>O>[CH3:26][C:25]1[C:20]([C:17]2[CH:18]=[CH:19][C:14]([OH:13])=[CH:15][CH:16]=2)=[CH:21][C:22]2[N:23]([CH:27]=[N:28][N:29]=2)[N:24]=1
Reactant: COc1ccc(-c2cc3nncn3nc2C)cc1
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1nn2cnnc2cc1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
1.5 ml (1.41 mol) of a dichloromethane solution of 1 M boron tribromide was added to a chloroform solution (4 ml) of 107 mg (0.47 mmol) of the obtained 7-(4-methoxyphenyl)-6-methyl-[1,2,4]triazolo[4,3-b]pyridazine, and stirred overnight at room temperature. Water was added to the reaction liquid, extracted with chloroform, and the organic layer was washed with saturated saline water. This was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 68 mg of a crude product of 4-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)-phenol.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17]C[CH2:15][C@H:14]4[CH3:18])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][C:22]1[CH:23]=[CH:24][C:25](=[O:28])[NH:26][CH:27]=1.N1NC(=O)C=CC=1>>[CH:14]([N:13]([CH3:17])[C@H:11]1[CH2:12][C@H:9]([C:7]2[S:8][C:4]3[CH:3]=[C:2]([N:26]4[CH:27]=[C:22]([CH3:21])[CH:23]=[CH:24][C:25]4=[O:28])[CH:20]=[CH:19][C:5]=3[N:6]=2)[CH2:10]1)([CH3:18])[CH3:15]
Reactant: Cc1ccc(=O)[nH]c1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Agent: O=c1cccn[nH]1
Product: Cc1ccc(=O)n(-c2ccc3nc([C@H]4C[C@H](N(C)C(C)C)C4)sc3c2)c1

Procedure:
The title compound was prepared according to the procedure described in Example 22, except for substituting the product of Example 52A for the product of Example 1E and substituting 5-methyl-2-pyridone for 3(2H)-pyridazinone. 1H NMR (400 MHz, CDCl3) δ ppm 8.02 (d, J=8.59 Hz, 1H) 7.88 (d, J=2.15 Hz, 1H) 7.42 (dd, J=8.59, 1.84 Hz, 1H) 7.26-7.30 (m, 1H) 7.15 (s, 1H) 6.62 (d, J=9.21 Hz, 1H) 3.51-3.64 (m, 1H) 3.13-3.27 (m, 1H) 2.90-3.02 (m, 1H) 2.62-2.72 (m, 2H) 2.28-2.40 (m, 2H) 2.13 (s, 3H) 2.12 (s, 3H) 1.02 (d, J=6.44 Hz, 6H). MS: (M+H)+=368.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][C:5](=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[C:6]2=[O:13].[H][H]>C(OC(=O)C)C.C(O)(=O)C.[Pd]>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]2[C:3]=1[CH2:4][CH:5]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[C:6]2=[O:13]
Reactant: COc1ccc(C=C2Cc3c(C)cc(C)c(O)c3C2=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(CC2Cc3c(C)cc(C)c(O)c3C2=O)cc1

Procedure:
16.09 Grams of 2,3-dihydro-4,6-dimethyl-7-hydroxy-2-(4-methoxybenzylidene)-1H-inden-1-one was dissolved in a mixed solvent of 150 ml of ethylacetate with 100 ml of acetic acid, this solution was let subjected to catalytic reduction at room temperature under 3 atmospheric hydrogen gas pressure in the presence of 1.5 g of palladium black as the hydrogenation catalyst. After the catalytic reduction, the catalyst was removed by filtration, and the filtrate was concentrated by removing the solvent under reduced pressure. The residue thus obtained was purified by a silica gel column chromatography (eluent: n-hexane: ethyl acetate=9:1) to obtain 8.5 g of 2,3-dihydro-4, 6-dimethyl-7-hydroxy-2-(4-methoxybenzyl)-1H-inden-1-one as in the form of colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][CH:8]2[CH2:12][O:11][S:10](=[O:13])[N:9]2[CH:14]([CH:22]([CH3:24])[CH3:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:5][CH:4]=1.O.C([O-])(O)=[O:29].[Na+].C(Cl)Cl>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[CH2:12][O:11][S:10](=[O:29])(=[O:13])[N:9]2[CH:14]([CH:22]([CH3:23])[CH3:24])[C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])=[CH:25][CH:26]=1
Reactant: COc1ccc(CC2COS(=O)N2C(C(=O)OC(C)(C)C)C(C)C)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: COc1ccc(CC2COS(=O)(=O)N2C(C(=O)OC(C)(C)C)C(C)C)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
t-Butyl 2-(4-(4-methoxybenzyl)-2-oxo-(1,2,3) oxathiazolidin-3-yl)-3-methylbutyrate (2.2 g; 5.7 mmol) was dissolved in acetonitrile (15 ml) and the reaction solution was cooled to 0° C. Then NaIO4 (1.47 g; 6.8 mmol), RuCl3.H2O (128.5 mg; 0.57 mmol) and water (15 ml) were added. The reaction solution was stirred at 0° C. for 5 minutes and then at RT for 30 minutes. This was followed by addition of NaHCO3 solution, extraction with CH2Cl2 (3×) and drying of the organic phase over NaSO4 and concentration in a rotary evaporator. The crude product was filtered through an SiO2 cartridge (10 g). t-Butyl 2-(4-(4-methoxybenzyl)-2,2-dioxo-(1,2,3)oxathiazolidin-3-yl)-3-methylbutyrate (2.02 g; 5.0 mmol) was obtained as a yellow oil. MS: 417.45 (M+NH4+); Rt: 1.86 min (method: gradient 0 min 96% H2O (0.05% TFA) 2.0 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 4% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: CS(N1C2C(=CC=CC=2)C=C1[CH2:14][O:15][CH:16]1[CH:21]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])=[CH:24][CH:23]=2)[CH2:20][CH2:19][N:18](C(OCC2C=CC=CC=2)=O)[CH2:17]1)(=O)=O.[F-].C([N+:57]([CH2:66][CH2:67][CH2:68][CH3:69])([CH2:62][CH2:63][CH2:64][CH3:65])[CH2:58][CH2:59][CH2:60]C)CCC.[O:70]1CCC[CH2:71]1>>[CH3:41][O:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][O:32][CH2:31][CH2:30][CH2:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH:21]2[CH2:20][CH2:19][NH:18][CH2:17][CH:16]2[O:15][CH2:14][C:66]2[N:57]([CH2:58][CH2:59][CH2:60][O:70][CH3:71])[C:62]3[C:68]([CH:67]=2)=[CH:69][CH:65]=[CH:64][CH:63]=3)=[CH:23][CH:24]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C1CCOC1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2cc3ccccc3n2S(C)(=O)=O)cc1
Agent: [F-]
Product: COCCCn1c(COC2CNCCC2c2ccc(OCCCOCc3ccccc3OC)cc2)cc2ccccc21

Procedure:
The solution of 0.160 g of benzyl 3-(1-methanesulphonyl-1H-indol-2-ylmethoxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 11 ml of tetrahydrofuran is admixed with 0.44 ml of tetrabutylammonium fluoride solution (1M in tetrahydrofuran) and stirred at reflux over 20 hours. The reaction mixture is cooled, poured onto brine (40 ml) and extracted with ethyl acetate (2×40 ml). The organic phases are washed with brine (1×40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as an orange oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.18 (1:2 EtOAc-heptane); Rt=26.90 (II).
Reaction SMILES: C([O:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:12]([C:22]([O:24][CH3:25])=[O:23])[CH2:11]1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[C:18]([O:17][C:15]([N:13]1[CH2:14][C@@H:10]([OH:9])[CH2:11][C@H:12]1[C:22]([O:24][CH3:25])=[O:23])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)[C@@H]1C[C@H](OC(=O)c2ccccc2)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a solution of (2S,4S)-4-benzoyloxy-1-t-butoxycarbonyl-2-methoxycarbonylpyrrolidine (30.0 g) in methanol (600 ml) was added potassium carbonate (11.9 g) and the mixture was stirred at room temperature for 1 hour. The solution was diluted with ethyl acetate (1 l) and washed with water. The organic phase was washed with brine. The aqueous phase was saturated with sodium chloride, extracted with chloroform and washed with brine. The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to give an oil. The oil was chromatographed on a silica gel (500 g) column with a mixture of n-hexane and ethyl acetate (1:1) as an eluent to give (2S,4S)-1-t-butoxycarbonyl-4-hydroxy-2- methoxycarbonylpyrrolidine (20.7 g) as colorless crystal.