Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH:27]=O)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][S:30]([CH2:32][S:33][CH3:34])=[O:31]>O1CCCC1>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH:27]=[C:32]([S:30]([CH3:29])=[O:31])[S:33][CH3:34])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CSCS(C)=O
Reactant: CC(C)(C)c1csc(-c2cc3cc(OCc4ccccc4C=O)ccc3o2)n1
Solvent: C1CCOC1
Product: CSC(=Cc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)S(C)=O
Temperature: 0 °C
Yield: 32.2 %

Procedure:
A mixture of 4-tert-butyl-2-[5-(2-formylphenylmethoxy)benzofuran-2-yl]thiazole (0.61 g), methyl methylsulfinylmethyl sulfide (0.46 g) and triton B (phase transfer) (0.7 g) in tetrahydrofuran (3 ml) was stirred under reflux for 5 hours. After being cooled, the resulting mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with diluted aqueous hydrochloric acid and brine, dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to column chromatography on silica gel and eluted with a mixture of ethyl acetate and chloroform (1:5). The fractions containing object compound were combined and concentrated in reduced pressure to give a syrup of 4-tert-butyl-2-[5-{2-[2-methylsulfinyl-2-methylthioethenyl)phenylmethoxy}benzofuran-2-yl]thiazole (0.25 g).
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[S:33])[CH:28]=[CH:29][CH:30]=1.C(N(CC)CC)C>>[F:23][C:24]([F:34])([F:35])[C:25]1[CH:26]=[C:27]([NH:31][C:32]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[CH:13][C:8]4[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=4[N:10]=3)[CH2:15][CH2:16]2)=[S:33])[CH:28]=[CH:29][CH:30]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4cccc(C(F)(F)F)c4)CC3)nc21

Procedure:
Pipemidic acid (25 mg, 0.0824 mmol), 3-(trifluoromethyl)phenyl isothiocyanate (12.5 μL, 0.0824 mmol) and triethylamine (23 μL, 0.165 mmol) were used. Purification on silica yielded compound 11 in Table 1, below (31 mg, 75%). 1H NMR (300 MHz, CDCl3) δ 9.32 (s, 1H), 8.72 (s, 1H), 7.41-7.35 (m, 1H), 7.29-7.21 (m, 2H), 7.21-7.16 (m, 1H), 4.37 (q, J=7.10 Hz, 2H), 4.27-3.93 (m, 8H), 1.50 (t, J=7.04 Hz, 3H) ppm.
Reaction SMILES: C(O)(=O)C.OO.[NH2:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[O:17]>O>[Cl:15][C:11]1[CH:12]=[C:13]([CH3:14])[C:8]2[C:9]([CH:10]=1)=[C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[O:17][N:7]=2
Reactant: Cc1cc(Cl)cc(C(=O)c2ccc(Cl)cc2)c1N
Agent: OO
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(Cl)cc2c(-c3ccc(Cl)cc3)onc12
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A solution of 300 ml of glacial acetic acid and 150 ml of 30% hydrogen peroxide was heated on a steam bath for 1 hr, cooled, and treated with 28.0 g (0.1 mole) of (2-amino-5-chloro-3-methylphenyl)(4-chlorophenyl)methanone. The mixture was heated to 95° C. and 450 ml of acetic acid was added to dissolve all solids. The stirred mixture was heated at 60°-70° C. for 5 hr, poured into 2.5 liters of water and let stand at ambient temperature overnight. The solid was collected by filtration, washed with water and recrystallized from 2-propanol to yield 12.3 g (44%) of fluffy, off-white solid, m.p. 151°-152° C.
Reaction SMILES: [ClH:1].[ClH:2].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]=1[NH:12][C:13]1[NH:14][CH2:15][CH2:16][N:17]=1.OO>Cl.O>[Cl:1][C:10]1[C:9]([Cl:2])=[CH:8][C:7]2[N:3]=[C:4]([NH:12][C:13]3[NH:14][CH2:15][CH2:16][N:17]=3)[NH:5][C:6]=2[CH:11]=1
Reactant: Cl
Reactant: c1ccc2[nH]c(NC3=NCCN3)nc2c1
Agent: OO
Solvent: O
Product: Clc1cc2nc(NC3=NCCN3)[nH]c2cc1Cl
Temperature: 70 °C

Procedure:
2-(2-Benzimidazolyl) amino-2-imidazoline dihydrochloride (13.7g, 0.05 mol) was dissolved in concentrated hydrochloric acid (100 ml) and water (100 ml). The solution was stirred and heated to 70°C. A 10% solution of hydrogen peroxide (27 ml) was added dropwise over 10 minutes resulting in precipitation of a white solid. Water (100 ml) was added to cool the reaction mixture to 60°C. A further quantity of 10% hydrogen peroxide (10.5 ml; 10% excess in all) was added. The reaction mixture was heated to 80°C for 15 minutes, and filtered whilst hot to give a solid m.p. 265°-272°C. The filtrate was cooled to give more solid m.p. 285°-292°C. Finally evaporation of the mother liquors in vacuo yielded a third quantity. All 3 solids were combined and recrystallised twice from water to yield 2-(5,6-Dichloro-2-benzimidazolyl) amino-2-imidazoline hydrochloride (7.86g; 53%) as colourless microcrystals m.p. 279° -281°C.
Reaction SMILES: CN(C)C=O.P(Br)(Br)([Br:8])=O.[CH3:11][O:12][C:13]1[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=[C:27]([CH3:35])[C:14]=1[C:15]([C:17]1[C:22]([O:23][CH3:24])=[CH:21][N+:20]([O-])=[CH:19][C:18]=1[Cl:26])=[O:16]>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]1[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=[C:27]([CH3:35])[C:14]=1[C:15]([C:17]1[C:22]([O:23][CH3:24])=[CH:21][N:20]=[C:19]([Br:8])[C:18]=1[Cl:26])=[O:16]
Reactant: COc1cc(C)c(C(=O)c2c(Cl)c[n+]([O-])cc2OC)c(OC)c1OC
Reactant: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc(C)c(C(=O)c2c(OC)cnc(Br)c2Cl)c(OC)c1OC
Yield: 743 %

Procedure:
5 ml of dimethylformamide was added to 2.5 ml of toluene, the mixture was cooled with ice, and 0.7 g (0.2 mmol) of phosphorus oxybromide was dropwise added thereto. After the mixture was stirred under cooling with ice for 10 minutes, 0.42 g (0.1 mmol) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-chloro-5-methoxypyridine-N-oxide obtained in Synthesis Example 14 (a) was added thereto. After the mixture was stirred under cooling with ice for 30 minutes, the temperature was recovered to room temperature, followed by stirring for 2 hours. 10 ml of water was added to the mixture to terminate the reaction, and ethyl acetate was added thereto for extraction. The organic layer was dried over anhydrous sodium sulfate, subjected to filtration and purified by silica gel column chromatography to obtain 0.32 g (yield 65%) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-2bromo-3-chloro-5-methoxypyridine (compound No. 245; m.p. 97-99° C.).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:10]=[C:9]([N:11]2[CH:15]([CH3:16])[C:14](=[O:17])[C:13]([CH3:19])([CH3:18])[C:12]2=[O:20])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[CH3:23][Mg]Br.C1COCC1>>[OH:17][C@:14]1([CH3:23])[C:13]([CH3:19])([CH3:18])[C:12](=[O:20])[N:11]([C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([C:2]([F:21])([F:1])[F:22])[CH:10]=2)[C@@H:15]1[CH3:16]
Reactant: CC1C(=O)C(C)(C)C(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: C[C@H]1N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C(C)(C)[C@@]1(C)O

Procedure:
Using 2-(trifluoromethyl)-4-(3,3,5-trimethyl-2,4-dioxopyrrolidin-1-yl)benzonitrile (100 mg) and methylmagnesium bromide-THF solution (3.22 mL, 1.0 mol/L), and in the same manner as in Example 2, the title compound was obtained as a colorless solid (yield: 77 mg, 73%).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH2:13]=O>C(O)=O>[Br:1][C:2]1[CH:12]=[CH:11][C:5]2[CH2:6][CH2:7][N:8]([CH3:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: C=O
Reactant: Brc1ccc2c(c1)CCNCC2
Solvent: O=CO
Product: CN1CCc2ccc(Br)cc2CC1
Temperature: 70 °C
Reaction time: 3.5 h

Procedure:
2.43 g 7-Bromo-2,3,4,5-tetrahydro-1H-benzo[d]azepine are dissolved in 4.055 g of formic acid and 3.2 mL of formaldehyde solution was added. The mixture was stirred at 70° C. for 3.5 h and continued overnight at 25° C. The mixture was concentrated, diluted with water and 10 N NaOH to adjust to a basic pH. The mixture was then extracted with tertbutylmethylether (3×) and the organic phase dried (Na2SO4), filtered and concentrated to yield 2.48 g 7-bromo-3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine as oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH2:19][CH:18]([NH2:29])[CH2:17]2)=[CH:12][CH:11]=1)[CH3:9].[C:30]1([N:36]2[CH2:41][CH2:40][N:39]([C:42](Cl)=[O:43])[CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:23])[CH2:19][CH:18]([NH:29][C:42]([N:39]3[CH2:40][CH2:41][N:36]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:37][CH2:38]3)=[O:43])[CH2:17]2)=[CH:14][CH:15]=1)[CH3:9]
Reactant: O=C(Cl)N1CCN(c2ccccc2)CC1
Reactant: CCc1ccc(C2CC(N)CN(C(=O)N3CCCC3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)N3CCN(c4ccccc4)CC3)CN(C(=O)N3CCCC3)C2)cc1

Procedure:
125 mg (50% pure, 0.15 mmol) of 5-(4-ethylphenyl)-1-(pyrrolidin-1-ylcarbonyl)piperidine-3-amine trifluoroacetate (Example 12A) and 40 mg (0.18 mmol, 1.2 eq.) of 4-phenylpiperazine-1-carbonyl chloride were reacted according to General Method 3. Yield: 13 mg (18% of theory)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:13][CH2:14][CH3:15])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC1(C)C(C)(C)OB([C:24]2[CH:36]=[CH:35][C:27]([CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:26][CH:25]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:14]([NH:13][C:4]1[C:5]([CH3:12])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=[C:2]([C:24]2[CH:25]=[CH:26][C:27]([CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:35][CH:36]=2)[CH:3]=1)[CH3:15]
Reactant: CCNc1cc(Br)cc(C(=O)OC)c1C
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCNc1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)OC)c1C
Temperature: 100 °C
Yield: 98.7 %

Procedure:
To a stirred solution of methyl 5-bromo-3-(ethylamino)-2-methylbenzoate (600 mg, 2.2 mmol) and 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine (1.0 g, 3.3 mmol) in dioxane (5 mL), aqueous 2M Na2CO3 solution (3.96 mL, 7.93 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (255 mg, 0.22 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the desired compound (800 mg, 98%).
Reaction SMILES: [H-].[Na+].[CH3:3]N(C)C=O.[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1.CI>O>[CH3:3][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(O)c1ccc(-c2ccccc2O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCOC(=O)C(O)c1ccc(-c2ccccc2OC)cc1
Reaction time: 0.25 h

Procedure:
To a stirred suspension of 0.01 moles of sodium hydride in 25 ml. of dry dimethylformamide which has been cooled to 0°C is added dropwise a solution of 0.01 moles of ethyl 2'-hydroxy-4-biphenylylglycolate in 10 ml. of dimethylformamide. The reaction mixture is stirred for 15 minutes and 0.015 moles of methyliodide is then added dropwise. The mixture is allowed to stir overnight at room temperature. 200 ml. of water is added and the resulting mixture is extracted well with ether. The ether extract is washed with water, dried over sodium sulfate, evaporated to dryness and distilled to obtain ethyl 2'-methoxy-4-biphenylylglycolate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH2:8][CH2:9][C:10]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](O)=[O:13])[CH:7]=1.S(Cl)([Cl:24])=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH2:8][CH2:9][C:10]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([Cl:24])=[O:13])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(Br)cc1CCc1c(F)cccc1C(=O)O
Solvent: C1CCOC1
Product: COc1ccc(Br)cc1CCc1c(F)cccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-[2-(5-bromo-2-methoxyphenyl)-ethyl]-3-fluorobenzoic acid (0.81 g, 2.3 mol, 1 equiv) in THF (13 mL) was added thionyl chloride (0.84 mL, 11.5 mmol, 5 equiv). The solution was heated to reflux. After one hour, the solution was cooled to room temperature and concentrated to give 2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzoyl chloride as an oil, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[N:20]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[N:20]1([CH:26]2[CH2:31][CH2:30][N:29]([C:11]([N:10]3[CH2:9][C:8]4[CH:14]=[CH:15][CH:16]=[CH:17][C:7]=4[O:6][C:5]4[CH:18]=[CH:19][C:2]([Cl:1])=[CH:3][C:4]3=4)=[O:12])[CH2:28][CH2:27]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: O=C(N1CCC(N2CCCCC2)CC1)N1Cc2ccccc2Oc2ccc(Cl)cc21
Yield: 86.9 %

Procedure:
The title compound of Example 2 (0.6 g, 2.0 mmol) was combined with 1,4'-bipiperidine (0.38 g, 2.2 mmol) and the reaction was carried out by the method of Example 4. Following chromatographic purification, 0.74 g of the title product was obtained as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=2[Cl:43])[O:7][CH:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([C:29]5[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=5)[CH:23]=4)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][O:4]1.[NH:44]1[CH:48]=[CH:47][N:46]=[CH:45]1.[H-].[Na+]>CS(C)=O>[Cl:43][C:37]1[CH:38]=[C:39]([Cl:42])[CH:40]=[CH:41][C:36]=1[C:3]1([CH2:2][N:44]2[CH:48]=[CH:47][N:46]=[CH:45]2)[O:7][CH:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:17][CH2:18][N:19]([C:22]4[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([C:29]5[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=5)[CH:23]=4)[CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][O:4]1
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(-c2cc(N3CCN(c4ccc(OCC5COC(CBr)(c6ccc(Cl)cc6Cl)O5)cc4)CC3)nc(C)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc(-c2cc(N3CCN(c4ccc(OCC5COC(Cn6ccnc6)(c6ccc(Cl)cc6Cl)O5)cc4)CC3)nc(C)n2)cc1
Temperature: 130 °C
Reaction time: 26 h
Yield: 51 %

Procedure:
6.21 g (9.1 mmol) of 2-bromomethyl-2-(2,4-dichlorophenyl)-4-[4-(4-(2-methyl-4-(4-tolyl)pyrimidin-6-yl)piperazin-1-yl)phenoxymethyl]-1,3-dioxolane (mixture of cis/trans diastereomers) were reacted with 1.244 g (18.3 mmol) of imidazole and 0.55 g (18.2 mmol) of an 80% strength sodium hydride/oil dispersion in 26 ml of absolute dimethyl sulfoxide as described in Example 8b. After stirring for 26 hours at 130° C., the dimethyl sulfoxide (DMSO) was removed by distillation in an oil-pump vacuum. The residue remaining was taken up in CH2Cl2 /water. After thorough mixing and subsequent separation of the phases, the aqueous solution was extracted three times with CH2Cl2. The combined CH2Cl2 extracts were evaporated in vacuo. The residue remaining (4.30 g) was chromatographed on a silica gel S/CH2Cl2 column (diamter 2.0 cm, height 20 cm) with elution using CH2Cl2 and CH2Cl2 /C2H5OH mixtures (0.5-3.0% by volume of C2H5OH). The fractions containing the diastereomer racemates (check using TLC) were combined and evaporated in vacuo. In this fashion, 3.12 g (=51% yield) of 2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-4-[4-(4-(2-methyl-4-(4-tolyl)pyrimidin-6-yl)piperazin-1-yl)phenoxymethyl]-1,3-dioxolane (mixture of cis/trans diastereomers) were obtained as a viscous oil;
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([Cl:21])=[CH:11][C:12]([Cl:20])=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[N:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:22]1CCOCC1>O>[CH2:1]([O:8][C:9]1[C:10]([Cl:21])=[CH:11][C:12]([Cl:20])=[C:13]2[C:18]=1[N:17]=[C:16]([CH:19]=[O:22])[CH:15]=[N:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCO1
Reactant: Cc1cnc2c(Cl)cc(Cl)c(OCc3ccccc3)c2n1
Solvent: O
Product: O=Cc1cnc2c(Cl)cc(Cl)c(OCc3ccccc3)c2n1
Yield: 59 %

Procedure:
A suspension of the 2-methyl product from Step B (93 mg, 0.291 mmol) and SeO2 (100 mg) in dioxane (4 mL) and H2O (0.4 mL) was heated under reflux for 3 h. The mixture was cooled, filtered (celite), and concentrated. Dichloromethane was added and the insoluble material was filtered off. The solvent was evaporated and the residue purified by SiO2-gel chromatography (dichloromethane) to yield the desired aldehyde as an off-white solid (57 mg, 59%).
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:6]2[O:7][CH:8]=[C:9]([C:11]3([C:14]([O:16]CC)=[O:15])[CH2:13][CH2:12]3)[N:10]=2)[CH2:5][CH2:4]1.Cl>O1CCCC1.O>[CH:3]1([C:6]2[O:7][CH:8]=[C:9]([C:11]3([C:14]([OH:16])=[O:15])[CH2:13][CH2:12]3)[N:10]=2)[CH2:4][CH2:5]1
Reactant: CCOC(=O)C1(c2coc(C3CC3)n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(c2coc(C3CC3)n2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.3 %

Procedure:
An aqueous solution of sodium hydroxide (4N, 5 mL) was added to a solution of ethyl 1-(2-cyclopropyloxazol-4-yl)cyclopropanecarboxylate (200 mg, 0.9 mmol) in tetrahydrofuran and water (4 mL, 1:1). The reaction mixture was stirred at room temperature for 12 h. The mixture was acidified with an aqueous solution of hydrochloric acid (4N), extracted with ethyl acetate, dried and concentrated under reduced pressure to afford the title compound (150 mg). MS (ES+APCI) (M+H) 194.1; LCMS retention time: 3.515 min (Method Q1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][C:4]=2[N:3]=[C:2]1[SH:14])[CH:11]=[CH:10][CH:9]=[CH:8]3.[ClH:15].[Cl:16][CH2:17][C:18]1[NH:19][CH:20]=[CH:21][N:22]=1>CN(C)C=O.C1(C)C=CC=CC=1>[ClH:16].[ClH:15].[NH:22]1[CH2:21][CH2:20][N:19]=[C:18]1[CH2:17][S:14][C:2]1[NH:3][C:4]2[CH:13]=[C:12]3[C:7](=[CH:6][C:5]=2[N:1]=1)[CH:8]=[CH:9][CH:10]=[CH:11]3
Reactant: Sc1nc2cc3ccccc3cc2[nH]1
Reactant: ClCc1ncc[nH]1
Agent: Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: c1ccc2cc3[nH]c(SCC4=NCCN4)nc3cc2c1
Temperature: 25 °C
Yield: 58.1 %

Procedure:
10.0 g 1H-Naphth[2,3-d]imidazole-2-thiol and 8.0 g of 2-chloromethylimidazole-hydrochloride were heated for 3 hours at 90° in 50 ml of dimethylformamide. The reaction mixture was cooled to room temperature and then diluted with 200 ml of toluene. The residue was suction filtered, washed well with toluene, and crystallized from 700 ml of methanol, with the addition of 300 ml of ether. 10.3 g of 2-[(2-Imidazoline-2-ylmethyl)thio]-1H-naphth[2,3-d]imidazoldihydrochloride having an m.p. of 227°-228° were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:25])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16].Cl>CO.O>[Cl:1][C:2]1[C:3](=[O:25])[NH:4][N:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:17])([F:18])[F:16]
Reactant: O=c1c(Cl)c(Oc2ccccc2C(F)(F)F)cnn1C1CCCCO1
Agent: Cl
Solvent: O
Solvent: CO
Product: O=c1[nH]ncc(Oc2ccccc2C(F)(F)F)c1Cl
Temperature: 110 °C
Reaction time: 4 h
Yield: 101.2 %

Procedure:
A solution of 4-chloro-2-(tetrahydro-pyran-2-yl)-5-(2-trifluoromethyl-phenoxy)-2H-pyridazin-3-one (4.78 g, 12.78 mmol) in methanol (25.5 mL, 0.5M) was treated with a 6N aqueous hydrochloric acid solution (10.6 mL, 1.2M). The reaction solution was heated to 110° C., where it stirred for 4 h and was then allowed to cool down to 25° C. The reaction was diluted with water (250 mL) and extracted with a 90/10 methylene chloride/methanol solution (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and dried in vacuo to afford 4-chloro-5-(2-trifluoromethyl-phenoxy)-2H-pyridazin-3-one (3.76 g, 100%) as a white solid; ES+-HRMS m/e calcd for C11H6N2O2F3Cl [M+H+] 291.0143, found 291.0142. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.41-7.51 (m, 2H), 7.74 (t, J=8.2 Hz, 1H), 7.79 (s, 1H), 7.86 (d, J=7.8 Hz, 1H), 13.59 (br. s., 1H).
Reaction SMILES: [F:1][C:2]1([F:22])[C:4]2([C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7](NC(OC(C)(C)C)=O)[CH2:6][CH2:5]2)[CH2:3]1.Cl>ClCCl.O1CCOCC1>[F:22][C:2]1([F:1])[C:4]2([C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH2:6][CH2:5]2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)NN1CCC2(CC2(F)F)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: FC1(F)CC12CCNc1ccccc12
Yield: 890.3 %

Procedure:
0.105 g of tert-butyl 2,2-difluoro-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-quinoline]-1′-carbamate is dissolved in 5 ml of dichloromethane and then 7.78 ml of a 4N solution of hydrochloric acid in dioxane are added. Stirring is maintained for 14 hours. After evaporating, the residue is taken up in dichloromethane and then hydrolyzed with a saturated solution of sodium hydrogencarbonate in water. The mixture is extracted twice with dichloromethane. The organic phases are combined, washed with water and then with a saturated solution of sodium hydrogencarbonate in water and then dried over magnesium sulfate and the solvent is evaporated under reduced pressure. 0.588 g of 2,2-difluoro-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-quinoline] is obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH:8]=[CH2:9].[OH:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[C:13]=1[C:22]([O:24][CH3:25])=[O:23]>C(C(C)=O)C>[CH2:7]([O:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[C:13]=1[C:22]([O:24][CH3:25])=[O:23])[CH:8]=[CH2:9]
Reactant: COC(=O)c1cccc(O)c1C(=O)OC
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1cccc(C(=O)OC)c1C(=O)OC

Procedure:
The starting material can be prepared as follows: 225 g of potassium carbonate and 98 g of allyl bromide are added to a solution of 170.0 g of dimethyl 3-hydroxy-phthalate in 400 ml of methyl ethyl ketone. The mixture is heated to the reflux temperature for 18 hours, whilst stirring, and then filtered, the filter residue is washed with methyl ethyl ketone and the filtrate, combined with the wash liquid, is evaporated under reduced pressure. The residual oily crude product is distilled under reduced pressure; dimethyl 3-allyloxyphthalate is obtained as the main fraction; boiling point 126°-130°/0.015 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[C:21]([Cl:40])=[C:22]([C:36]([Cl:39])=[CH:37][CH:38]=1)[CH2:23][CH:24]1[CH2:28][CH2:27][N:26]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[C:25]1=[O:35]>>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:19][C:20]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:22]([CH2:23][CH:24]3[CH2:28][CH2:27][N:26]([CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[C:25]3=[O:35])[C:21]=2[Cl:40])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Nc1ccc(Cl)c(CC2CCN(C3CCCCC3)C2=O)c1Cl
Solvent: c1ccncc1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ccc(Cl)c(CC2CCN(C3CCCCC3)C2=O)c1Cl
Yield: 47.2 %

Procedure:
Using the procedure to synthesize Example 207 and using reagents 3-Chloro-2-methyl-benzenesulfonyl chloride (194 mg, 0.84 mmol), pyridine (0.07 mL, 0.84 mmol), and 3-(3-Amino-2,6-dichloro-benzyl)-1-cyclohexyl-pyrrolidin-2-one (Example 192) (240 mg, 0.70 mmol) affords 175 mg (47%) of the title compound: Mass spectrum (apci) m/z=529.05 (M+H).