Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]([S:8]([N:11]2[C:16]3[CH:17]=[C:18]([C:21]([NH:23][C:24]4[S:25][CH:26]=[C:27]([C:29]([OH:31])=[O:30])[N:28]=4)=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.S(Cl)(Cl)=O.[CH2:38](OC(C1N=C(N)SC=1)=O)[CH3:39]>C1(C)C=CC=CC=1.CN(C)C=O>[CH2:38]([O:30][C:29]([C:27]1[N:28]=[C:24]([NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[O:14][CH2:13][CH2:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:32][CH3:33])(=[O:10])=[O:9])[C:16]=3[CH:17]=2)=[O:22])[S:25][CH:26]=1)=[O:31])[CH3:39]
Reactant: CCOC(=O)c1csc(N)n1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)Nc3nc(C(=O)O)cs3)cc21
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1csc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCO3)n1

Procedure:
2-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazole-4-carboxylic acid, MS (ISP): m/e=508.3 (M−H), was prepared as described in example 1, steps 1 to 6. Step 5 was performed using thionyl chloride in toluene and dimethylformamide for the formation of the acyl chloride, and 2-amino-thiazole-4-carboxylic acid ethyl ester was used for the coupling, yielding 2-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazole-4-carboxylic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[CH:14][CH:13]=1)[CH2:5]2.C=O.[C:23]([BH3-])#[N:24].[Na+].[C:27](O)(=O)C>C1COCC1.C(OCC)(=O)C>[CH3:27][N:24]([CH3:23])[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[CH:14][CH:13]=1)[CH2:5]2
Reactant: CC(=O)O
Reactant: CCCc1ccc(N2Cc3cc(N)ccc3C2=O)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1ccc(N2Cc3cc(N(C)C)ccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-amino-2-(4-propyl-phenyl)-isoindol-1-one (89 mg, 0.33 mmol) obtained in Example 2 and formalin (0.26 ml) in THF (5 ml) was added with 95% sodium cyanoborohydride (66 mg, 1.00 mmol) and acetic acid (0.1 ml), the mixture was stirred at room temperature for 30 minutes, and then further added with acetic acid (0.1 ml), and the mixture was stirred at room temperature for 7 hours. The reaction solution was added with ethyl acetate for extraction. The ethyl acetate layer was washed with 1 N aqueous potassium hydroxide and saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform) and recrystallization (chloroform/n-hexane) to obtain 5-dimethylamino-2-(4-propyl-phenyl)-isoindol-1-one (Compound 1) as a pale yellow powdery substance (75.8 mg, yield: 77.1%).
Reaction SMILES: [I:1]Cl.[CH:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].[O-]S([O-])=O.[Na+].[Na+]>ClCCl>[I:1][C:8]1[CH:7]=[C:5]([OH:6])[C:4](=[CH:10][CH:9]=1)[CH:3]=[O:11]
Reactant: ClI
Reactant: O=Cc1ccccc1O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1ccc(I)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1 M solution of Iodine monochloride in dichloromethane (410 mL, 0.41 mol) is added to a solution of salicylaldehyde (50 g, 0.41 mol) in dichloromethane (150 mL) at 0° C. The resulting solution is warmed to room temperature and stirred overnight. The deep colored solution is discharged with saturated aqueous Na2SO3 (100 mL). The organic layer is separated, washed with water, dried over MgSO4, filtered and concentrated. The crude product is recrystallized from cyclohexane to give 4-iodosalicylaldehyde as yellow crystals (61 g, 0.25 mol). A solution of 4-iodosalicylaldehyde (12.4 g, 50 mmol) and MEM chloride (6 mL, 53 mmol) in THF (50 mL) is added to a suspension of 60% NaH (2.2 g, 55 mmol) in THF (50 mL) at 0° C. The resulting mixture is stirred at room temperature for 2 hours. Aqueous workup and concentration gives product as a liquid (15 g, 45 mmol). 1H NMR (CDCl3, 300 MHz) δ10.36 (s, 1H), 8.11 (d, 1H), 7.73 (dd, 1H), 7.03 (d, 1H), 5.37 (s, 2H), 3.88 (t, 2H), 3.52 (t, 2H), 3.36 (s, 3H). EI MS [M]+=436.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:30]3[C:29](=[O:31])[N:28]([CH2:32][CH3:33])[CH2:27][C:26]([CH3:35])([CH3:34])[O:25][C:24]=3[N:23]=[C:22]([N:36]3[CH2:42][CH:41]4[O:43][CH:38]([CH2:39][CH2:40]4)[CH2:37]3)[N:21]=2)=[CH:16][C:15]=1[F:44].C(N(CC)CC)C.[CH2:52](O)[C@@H:53]([OH:55])C>C(Cl)Cl.O>[OH:55][C@@H:53]([CH3:52])[CH2:7][O:6][C:5](=[O:11])[NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:30]3[C:29](=[O:31])[N:28]([CH2:32][CH3:33])[CH2:27][C:26]([CH3:34])([CH3:35])[O:25][C:24]=3[N:23]=[C:22]([N:36]3[CH2:37][CH:38]4[O:43][CH:41]([CH2:40][CH2:39]4)[CH2:42]3)[N:21]=2)=[CH:16][C:15]=1[F:44]
Reactant: C[C@H](O)CO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN1CC(C)(C)Oc2nc(N3CC4CCC(C3)O4)nc(-c3ccc(N)c(F)c3)c2C1=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CC(C)(C)Oc2nc(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)OC[C@H](C)O)c(F)c3)c2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
A mixture of 134.43 mg (0.45 mmol) of triphosgene, 200 mg (0.45 mmol) of 4-(4-amino-3-fluorophenyl)-6-ethyl-8,8-dimethyl-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-7,8-dihydro-6H-9-oxa-1,3,6-triazabenzocyclohepten-5-one and 275.04 mg (2.72 mmol) of triethylamine in 50 ml of DCM is stirred at room temperature for 30 minutes. 134 mg (1.81 mmol) of (S)-propane-1,2-diol are added and the mixture is stirred for 2 hours at room temperature. The resulting mixture is hydrolysed with 5 ml of water and then evaporated under reduced pressure. The product is precipitated by addition of ethyl acetate/water. The product is filtered off and dried under vacuum to give 120 mg {4-[6-ethyl-8,8-dimethyl-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-oxo-5,6,7,8-tetrahydro-9-oxa-1,3,6-triazabenzocyclohepten-4-yl]-2-fluorophenyl}carbamic acid (S)-2-hydroxypropyl ester.
Reaction SMILES: NC1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].CI.C(=O)([O-])[O-].[K+].[K+].O.[CH3:31][N:32]([CH3:35])[CH:33]=O>>[CH3:31][N:32]([CH3:35])[C:33]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CN(C)C=O
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2Cl)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: CCOC(=O)Cc1cccc(Oc2ccccc2Cl)c1N(C)C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of ethyl 2-[2-amino-3-(2-chlorophenoxy)phenyl]acetate (11.8 g), methyl iodide (11.9 g) and potassium carbonate (10.7 g) in dried dimethylformamide (100 ml) was stirred at room temperature for 17 hrs. The reaction mixture was poured into water (400 ml) and extracted with diethyl ether (150 ml×2). The extract was washed with saline, dried over magnesium sulfate and evaporated in vacuo. The oily residue (12.7 g) was subjected to column chromatography on silica gel and eluted with a mixture of benzene and n-hexane (1:1) to give oily ethyl 2-[2-dimethylamino-3-(2-chlorophenoxy)phenyl]acetate (7.4 g).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[CH:5]=1.O.[OH-].[Na+].Cl>O1CCOCC1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[CH:5][C:6]=1[O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21]
Reactant: COC(=O)c1ccc(Cl)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(Cl)c(OCCc2ccc(Cl)cc2Cl)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
g (2.78 mmol) of 4-Chloro-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoic acid methyl ester was dissolved in 10 ml of dioxan. 5 ml of water and 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was heated at 60° C. for 4 h and stirred at room temperature for 16 h. The reaction solution was cooled to 0° C. and concentrated hydrochloric acid was added to give a pH of 1–2, whereupon the product precipitated from solution. The suspension was stirred for 30 min, then the product was filtered off and dried under reduced pressure.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)[C:3]#[N:4].[C:12]([C:16]#[C:17][C:18]([O:20][CH3:21])=[O:19])([O:14][CH3:15])=[O:13].C(OCC)C>CO.C(OCC)C>[ClH:11].[NH2:4][C:3]1[C:16]([C:12]([O:14][CH3:15])=[O:13])=[C:17]([C:18]([O:20][CH3:21])=[O:19])[NH:1][C:2]=1[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1
Reactant: N#CC(N)c1ccc(Cl)cc1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1[nH]c(-c2ccc(Cl)cc2)c(N)c1C(=O)OC
Product: Cl

Procedure:
Starting from 2-amino-2-(p-chlorophenyl)acetonitrile and dicarbomethoxyacetylene, the open-chain intermediate compound is obtained, m.p. 74°-76° C. (from diethyl ether). The title compound is obtained in a 48% overall yield, m.p. 216°-218° C. (from methanol/diethyl ether).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(N(CC)CC)C.Cl[C:13](OC1C=CC([N+]([O-])=O)=CC=1)=[O:14].[NH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28]>C(Cl)(Cl)Cl>[CH2:1]([NH:4][C:13]([NH:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])=[O:14])[CH:2]=[CH2:3]
Reactant: CC(C)(N)CO
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: C=CCN
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CCNC(=O)NC(C)(C)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a chloroform solution (60 mL) of allylamine (1.5 g, 26.3 mmol) were added triethylamine (4.9 mL, 35.5 mmol) and at 4° C. 4-nitrophenyl chloroformate (6.09 g, 30.2 mmol), and the mixture was stirred for an hour. To this reaction solution was added at the same temperature a chloroform solution (3 mL) of 2-amino-2-methylpropanol (2.58 g, 28.9 mmol), and the mixture was stirred overnight at room temperature. The reaction solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (ethyl acetate) to obtain the title compound (4.0 g, 88%) as a yellow oily compound.
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[S:10]([NH2:13])(=[O:12])=[O:11].[OH:14]O>C(O)(=O)C.O>[S:10]([C:2]1[S:1][C:5]2=[N+:6]([O-:14])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1)(=[O:12])(=[O:11])[NH2:13]
Reactant: OO
Reactant: NS(=O)(=O)c1cc2cccnc2s1
Solvent: CC(=O)O
Solvent: O
Product: NS(=O)(=O)c1cc2ccc[n+]([O-])c2s1
Temperature: 55 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
A mixture of thieno[2,3-b]pyridine-2 Sulfonamide (0.43 g, 2 mmol) and 30% hydrogen peroxide (1.0 ml) in acetic acid (5.0 ml) was stirred at 55° C. for 24 hours. The reaction mixture was diluted with water, chilled and the resulting solid was collected and dried; 0.35 g (76% yield); m.p. 278°-279° C.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([OH:17])=[CH:4][CH:3]=1.C[O:19][C:20]1C2C(=O)C3C(=CC=CC=3)SC=2C(OC)=C[CH:21]=1.N1C=CC=CC=1.C(Cl)(=O)C>CC(C)=O>[C:20]([O:17][C:5]1[C:6]2[S:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14](=[O:16])[C:15]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:19])[CH3:21]
Reactant: COc1ccc(OC)c2c(=O)c3ccccc3sc12
Reactant: O=c1c2ccccc2sc2c(O)ccc(Cl)c12
Solvent: CC(=O)Cl
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(Cl)c2c(=O)c3ccccc3sc12

Procedure:
1-Chloro-4-hydroxythioxanthone as prepared in Example 1 (13.1 g) and pyridine (1O g) was stirred in acetone (50 ml) at 50°. Acetyl chloride (4.3 g) was added over 0.25 h and the mixture stirred and heated under reflux for a further hour. The mixture was cooled to 20° and quenched with water (150 ml). The resulting solution was extracted with chloroform (50 ml), separated and the organic phase washed twice with water. The organic phase was evaporated to dryness under reduced pressure and the residue crystallised from methanol with a carbon treatment to afford the title compound, 4.1 g (27.0%) as a pale yellow solid of mp 141°-42°. Analysis C15H9ClO3S=304.745 Requires C 59.11% H 2.98% Cl 11.63% S 10.52% Found C 59.10% H 3.06% Cl 11.59% S 10.41%
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1.[C:26](Cl)(=[O:30])[CH2:27][CH2:28][CH3:29]>CCOCC>[C:26]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:30])[CH2:27][CH2:28][CH3:29]
Reactant: CCCC(=O)Cl
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCCCC/C=C\CCCCCCCCOC(=O)CCC
Yield: 34.2 %

Procedure:
Oleyl alcohol (40 g, Eastman) and anhydrous pyridine (10 ml) were added to a 100 ml round-bottom flask equipped with a magnetic stirrer. The mixture was stirred and cooled in an ice bath for five minutes. Butyryl chloride (15.0 g, 0.14 mol, Eastman) was added dropwise via an addition funnel. The reaction mixture was stirred for 15 minutes at 5° and at room temperature for an hour. It was then diluted with ether and filtered. The filtrate was dried over sodium sulfate. Volatiles were removed under vacuum. Distillation of the residual oil (163°-168°, 0.26-0.28 torr) gave 16.2 g (34%) of 3. NMR: δ 0.9 (m, 6 H, CH3), 1.1-2.4 (m, 32 H, CH2), 3.95 (t, J=6 Hz, CH2O), 5.3 (t, J=4.5 Hz, 2 H vinyl). IR: 3005 (olefinic-CH), 1740 (C=O), 1175 cm-1 (C--O--C)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C([O:18][C:19]1[C:20](=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:21]([OH:23])=[O:22])C.O.Cl[C:32]1C=CC=C[C:33]=1Cl>CN(C)C1C=CN=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:18][C:19]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:20]=1[C:21]([O:23][CH2:32][CH3:33])=[O:22]
Reactant: CCOc1ccc(OC)cc1C(=O)O
Reactant: Clc1ccccc1Cl
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Product: CCOC(=O)c1cc(OC)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 180 °C
Reaction time: 4 h
Yield: 170 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (514 mg), ethyl 5-methoxysalicylic acid (1.35 g), and 4-dimethylaminopyridine (843 mg) were suspended in o-dichlorobenzene (8 ml), and the suspension was stirred at 180° C. for 4 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (152 mg, yield 170%).
Reaction SMILES: [CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([OH:18])[CH:11]=2)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.[CH3:19][C:20]([CH3:40])([CH3:39])[CH2:21][C:22]1[N:27]=[C:26]([CH2:28]O)[CH:25]=[CH:24][C:23]=1[C:30]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=1[F:38].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.C(OCC)(=O)C.CCCCCC>[CH:1]1([CH:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:28][C:26]3[CH:25]=[CH:24][C:23]([C:30]4[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=4[F:38])=[C:22]([CH2:21][C:20]([CH3:40])([CH3:39])[CH3:19])[N:27]=3)[CH:11]=2)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:2][CH2:3]1
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2CC(C)(C)C)c1
Reactant: COC(=O)CC(c1ccc(OC)c(O)c1)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)CC(c1ccc(OC)c(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1)C1CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.3 %

Procedure:
Under a nitrogen atmosphere, to a solution of methyl 3-cyclopropyl-3-(3-hydroxy-4-methoxyphenyl)propanoate (168 mg) and (6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methanol (202 mg) in toluene (15 mL) were added 1,1′-(azodicarbonyl)dipiperidine (268 mg) and tributylphosphine (262 and the mixture was stirred at room temperature for 15 hr. Hexane and ethyl acetate were added to the reaction mixture, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (190 mg) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[NH2:1][C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH2:7][CH2:6][CH:5]([N:17]2[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)=[O:23])[CH2:18]2)[CH2:4][CH2:3]1
Reactant: COc1cccc(C2(N)CCC(=O)CC2)c1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: COc1cccc(C2(N)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-amino-4-(3-methoxy-phenyl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CI.[C:16](=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([S:13][CH3:16])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(S)cnn(C(C)(C)C)c1=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CSc1cnn(C(C)(C)C)c(=O)c1C
Temperature: 25 °C

Procedure:
The crude product 2.0 g (0.01 mol) of 2-tert.-butyl-5-mercapto-4-methyl-3(2H)-pyridazinone as synthesized in the above and 1.4 g (0.01 mol) of methyl iodide were dissolved in 20 ml of dimethylformamide and then added with 2.0 g of sodium carbonate with stirring at room temperature. The reaction liquid was stirred for 3 hours at 70° C. After allowing to cool the reaction liquid was poured into 200 ml of water and extracted with 50 ml of benzene. The benzene layer was washed successively with 50 ml of 10% sodium hydroxide, 50 ml of 1N hydrochloric acid and 100 ml of water, dried over anhydrous sodium sulfate and freed of solvent by distillation to give 2.0 g of a crude product. The crude product was recrystallized from 20 ml of isopropyl ether to give 1.4 g of 2-tert.-butyl-4-methyl-5-methylthio-3(2H)-pyridazinone.
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([Cl:14])[CH:10]=[C:9]([Cl:15])[C:3]=1[O:4][CH2:5][CH:6]1[CH2:8][O:7]1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(O)C>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:27]([CH2:8][CH:6]([OH:7])[CH2:5][O:4][C:3]2[C:9]([Cl:15])=[CH:10][C:11]([Cl:14])=[C:12]([Cl:13])[C:2]=2[Cl:1])[CH2:26][CH2:25]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: Clc1cc(Cl)c(OCC2CO2)c(Cl)c1Cl
Solvent: CCO
Product: COc1ccccc1N1CCN(CC(O)COc2c(Cl)cc(Cl)c(Cl)c2Cl)CC1
Yield: 44.3 %

Procedure:
To a solution of 2-((2,3,4,6-tetrachlorophenoxy)methyl)oxirane (45 mg, 0.16 mmol) in ethanol (0.50 mL) was added 4-(2-methoxyphenyl)piperazine (33 μL, 0.19 mmol) at room temperature. The mixture was stirred under reflux for 1 hr. The reaction mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give HUHS1007 (34 mg, 44%).
Reaction SMILES: CC(C)([O-:4])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].CC(OO)(C)C>C1COCC1>[Cl:7][C:8]1[C:9]([N+:14]([O-:16])=[O:15])=[CH:10][NH:11][C:12](=[O:4])[CH:13]=1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)[O-]
Agent: CC(C)(C)OO
Agent: [K+]
Solvent: C1CCOC1
Product: O=c1cc(Cl)c([N+](=O)[O-])c[nH]1
Temperature: 35 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
Anhydrous THF (50 mL) in a 500-mL round-bottom flask was cooled to −78° C. and anhydrous NH3 (gas) was bubbled into until saturated (about 20 minutes). Potassium t-butoxide (6.5 g, 57.9 mmol) was added portion wise and the mixture was allowed to warm to ˜35° C. To a solution of 4-chloro-3-nitropyridine (3.498 g, 22 mmol) in dry THF (20 mL) at 0° C. was added tBOOH (4.4 mL, 22 mmol) (5M in decane) over 10 minutes. This solution was then added dropwise to the prepared KOtBu solution over a period of 15 minutes, then stirred for 2 hours at ˜35° C., followed by quenching the reaction with 5 mL of saturated aqueous NH4Cl solution. The reaction was allowed to stir at room temperature overnight. Volatiles were removed under reduced pressure and the residue was made weakly acidic with saturated aqueous NH4Cl solution. The solid was filtered and washed with cold water. The title compound was obtained as a tan-powder, dried under high vacuum overnight, and used for the next reaction without further purification. (1.36 g, 35% yield).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:9][C:10](=[O:29])[C:11]([C:17](=[O:28])[C:18]1[C:23](F)=[C:22]([F:25])[CH:21]=[C:20]([F:26])[C:19]=1[F:27])=[CH:12][NH:13][CH:14]1[CH2:16][CH2:15]1)[CH3:8]>C1COCC1.O1CCOCC1>[CH2:7]([O:9][C:10]([C:11]1[C:17](=[O:28])[C:18]2[C:23](=[C:22]([F:25])[CH:21]=[C:20]([F:26])[C:19]=2[F:27])[N:13]([CH:14]2[CH2:16][CH2:15]2)[CH:12]=1)=[O:29])[CH3:8]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)c(F)cc(F)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C2CC2)c2c(F)cc(F)c(F)c2c1=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 83.9 %

Procedure:
Potassium tert-butoxide (2.36 g, 21 mmol) was slowly added to a stirred solution of example 1b (6.62 g, 20 mmol) in 1:1 THF/dioxane (60 mL) at 0° C. The reaction mixture was stirred at 0° C. for 5 h. The precipitate was collected by filtration to give 5.22 g (79%) of clean desired product as a beige solid. The filtrate contained product contaminated with some starting material and was concentrated in vacuo. The residue (1.3 g) was treated by potassium tert-butoxide (350 mg, 3.12 mmol) in 1:1 THF/dioxane (60 mL) for 18 h. Purification by silica gel chromatography gave an additional 1.1 g (18%) of the title compound as a beige solid. 1H NMR (400 MHz, DMSO-d6): δ 8.41 (s, 1H), 8.09-8.19 (m, 1H), 4.21 (q, 211, J=7.2 Hz), 3.88-3.97 (m, 1H), 1.27 (t, 3H, J=7.2 Hz), 1.08-1.14 (m, 4H). MS (ES) [m+H] calc'd for C15H12F3NO3, 312; found 312.