Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].CC(O)=O.[Br:18]Br.C([O-])([O-])=O.[Na+].[Na+]>O>[Br:18][C:10]1[C:11]([CH3:13])=[CH:12][C:3]([O:2][CH3:1])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: BrBr
Reactant: COC(=O)c1ccc(C)cc1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)c(C)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A 250 ml 3-neck RBF fitted with a magnetic stirring bar, a thermometer and a dropping funnel was charged with methyl 2-methoxy-4-methylbenzoate 10b (10 g, 0.056 mol) and AcOH (70 mL). To this solution bromine (3 mL, 0.06 mol) was added drop-wise while maintaining the reaction temperature below 25° C. When bromine addition was complete, the reaction mixture was stirred at RT for 2 hours, then poured into 600 mL of cold water and the pH was adjusted to 8-9 with Na2CO3. The crude product was extracted with Et2O (3×300 mL), the combined extracts washed with brine, dried over sodium sulfate and the solvent was removed under vacuum to give methyl 5-bromo-2-methoxy-4-methylbenzoate as an orange oil, which solidified on standing (14.3 g, 99% yield, >90% purity by 1H NMR).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].Cl[C:17]1[N:22]=[CH:21][N:20]=[C:19]([NH:23][CH3:24])[CH:18]=1.Cl>O1CCOCC1>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:17]3[CH:18]=[C:19]([NH:23][CH3:24])[N:20]=[CH:21][N:22]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2ccc(N)cc2)CC1
Reactant: CNc1cc(Cl)ncn1
Agent: Cl
Solvent: C1COCCO1
Product: CCN1CCN(c2ccc(Nc3cc(NC)ncn3)cc2)CC1
Temperature: 150 °C

Procedure:
A mixture of 4-(4-ethylpiperazin-1-yl)-aniline (1 g, 4.88 mmol) (prepared in analogy to Example 238, Step 238.1), (6-chloro-pyrimidin-4-yl)-methyl-amine (1.81 g, 12.68 mmol, 1.3 eq.) and 4N HCl in dioxane (15 ml) is heated in a sealed tube to 150° C. for 5 h. The reaction mixture is concentrated, diluted with DCM and a saturated aqueous solution of sodium bicarbonate. The aqueous layer is separated and extracted with DCM. The organic phase is washed with brine, dried (sodium sulfate), filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM/MeOH, 93:7) followed by trituration in diethyl ether affords the title compound as a white solid: ESI-MS: 313.2 [MH]+; tR=1.10 min (system 1); TLC: Rf=0.21 (DCM/MeOH, 93:7).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][C@H:8]([C:10]([OH:12])=[O:11])[CH3:9].C(N(CC)CC)C.Cl>C(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([NH:7][C@H:8]([C:10]([OH:12])=[O:11])[CH3:9])=[O:4]
Reactant: C[C@H](N)C(=O)O
Reactant: CC(Br)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Br)C(=O)N[C@@H](C)C(=O)O

Procedure:
69.26 g (404 mmol) of α-bromopropionic acid chloride is added in drops at 0° C. to 30 g (336.7 mmol) of alanine and 102.2 g (1010.2 mmol) of triethylamine in 600 ml of methylene chloride. In this case, the temperature remains between 0° C.-5° C. 1000 ml of 5% aqueous hydrochloric acid is added, and the organic phase is separated. The organic phase is extracted once more with 400 ml of 5% aqueous hydrochloric acid, dried on magnesium sulfate and evaporated to dryness in a vacuum. The residue is recrystallized from acetone/diisopropyl ether.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([C:7]2[NH:11][C:10]3[CH2:12][CH2:13][CH2:14][CH2:15][C:9]=3[N:8]=2)[CH2:2]1.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[C:19]([NH2:24])[N:18]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:16][C:17]1[CH:22]=[C:21]([N:1]2[CH2:6][CH2:5][O:4][CH:3]([C:7]3[NH:8][C:9]4[CH2:15][CH2:14][CH2:13][CH2:12][C:10]=4[N:11]=3)[CH2:2]2)[N:20]=[C:19]([NH2:24])[N:18]=1
Reactant: C1CCc2[nH]c(C3CNCCO3)nc2C1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(Cl)cc(N2CCOC(c3nc4c([nH]3)CCCC4)C2)n1
Yield: 15.5 %

Procedure:
A solution of 2-(2-morpholinyl)-4,5,6,7-tetrahydro-1H-benzimidazole (0.8 g, 3.86 mmol), 4,6-dichloro-2-pyrimidinamine (0.633 g, 3.86 mmol) and Hunig's base (1.681 mL, 9.65 mmol) in ethanol (19.3 mL) was heated at 85° C. overnight. The mixture was concentrated and chromatographed (eluent EtOAc+NH4OH) to afford the title compound (200 mg). LC-MS (ES) m/z=335 [M+H]+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[Cl:29])[N:25](COCC[Si](C)(C)C)[N:24]=[C:23]2[NH:38][C:39](=[O:43])[CH2:40][CH2:41][CH3:42].C(OCC)(=O)C>O1CCCC1>[Br:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][C:28]=1[Cl:29])[NH:25][N:24]=[C:23]2[NH:38][C:39](=[O:43])[CH2:40][CH2:41][CH3:42]
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(Br)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(Cl)c(Br)cc12
Temperature: 67 °C

Procedure:
12.6 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 940 mg of N-[5-bromo-6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 30 cm3 of tetrahydrofuran. The medium is then maintained at 67° C. for 19 hours and is then allowed to return to room temperature and 50 cm3 of ethyl acetate are added. The organic phase is washed with 2×50 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 50 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2 kPa; 45° C.). The residue is purified by chromatography under an argon pressure of 50-kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.) and the residue is taken up in 15 cm3 of diisopropyl ether, filtered off on a sinter funnel and washed successively with 5 cm3 of ethyl acetate and then with 2×10 cm3 of diisopropyl ether. After drying (90 Pa; 50° C.), 460 mg of N-(5-bromo-6-chloro-1H-indazol-3-yl)butanamide are obtained in the form of a white solid melting at 250° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][C:5]([CH2:11][OH:12])=[CH:4][C:3]=1[O:13][CH2:14][CH3:15]>CN(C=O)C.O=[Mn]=O>[NH2:1][C:2]1[C:3]([O:13][CH2:14][CH3:15])=[CH:4][C:5]([CH:11]=[O:12])=[CH:6][C:7]=1[O:8][CH2:9][CH3:10]
Reactant: CCOc1cc(CO)cc(OCC)c1N
Agent: O=[Mn]=O
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)cc(OCC)c1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (4-amino-3,5-diethoxy-phenyl)-methanol (0.79 g, 3.74 mmol, 1.0 equiv) in DMF (20 mL) was added activated MnO2 (1.63 g, 18.70 mmol, 5.0 equiv). The reaction mixture was stirred for 24 h at rt, filtered through Hyflo Super Cel, the filtrate extracted with ethyl acetate (3×50 mL) and the combined organic phases dried over Mg504 providing 0.69 g (88%) of the title compound. 1H NMR (300 MHz, DMSO): δ 1.46 (t, J=7.0 Hz, 3H), 4.15 (q, J=7.0 Hz, 2H), 4.50 (br s, 2H), 7.04 (s, 2H), 9.70 (s, 1H). MS (ISP): 210.0 [M+H]+.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1.O>CO>[CH3:1][O:2][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1
Reactant: Cc1ccc(CCl)cc1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCc1ccc(C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of NaOMe (1.6 g, 29.63 mmol) in dry MeOH (40 mL) under inert atmosphere was added 4-chloromethyl-1-methyl-2-nitro-benzene (5.0 g, 26.94 mmol). The reaction mixture was stirred at room temperature for 16 h. Water was added and EtOH was removed under reduced pressure. The crude product was extracted with DCM (2 times) and the organic layer was washed with water, then with a saturated solution of NaCl, dried over MgSO4 and concentrated to give intermediate II-l as yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.94 (s, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.32 (d, J=7.8 Hz, 1H), 4.48 (s, 2H), 3.41 (s, 3H), 2.58 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9](O)[C:10]1[N:14]([CH2:15][CH2:16][C:17]([O:19]C)=O)[C:13]2[C:21]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:22][CH:23]=[CH:24][C:12]=2[N:11]=1.C1(P([N:45]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.Cl.C(N=C=NCCCN(C)C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]2=[N:11][C:12]3[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[C:13]=3[N:14]2[CH2:15][CH2:16][C:17](=[O:19])[NH:45]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)c1cccc2nc(C(O)c3ccc(Cl)cc3Cl)n(CCC(=O)OC)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CCN(CC)c1cccc2nc3n(c12)CCC(=O)NC3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.3 %

Procedure:
To a stirred solution of methyl 3-{2-[(2,4-dichlorophenyl)(hydroxy)methyl]-7-(diethylamino)-1H-benzimidazol-1-yl}propanoate (1.00 g, 2.15 mmol) and diphenylphosphoryl azide (1.39 mL, 6.46 mmol) in toluene (11 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (966 μL, 6.46 mol) at room temperature. After 12 h, the reaction mixture was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 0-35% ethyl acetate/n-hexane gradient mixture. A solution of the obtained compound was stirred in the presence of 1.9% palladium on fibroin (200 mg) under hydrogen atmosphere at room temperature for 17 h. The catalyst was removed and the filtrate was concentrated in vacuo. The residue was dissolved in tetrahydrofuran (10 mL) and aqueous sodium hydroxide (8 M, 0.5 mL) was added at room temperature. After 15 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in N,N-dimethylformamide (10 mL) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (973 mg, 5.08 mmol) was added at room temperature. After 6 h, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (155 mg, 1.02 mmol) was added. After 2 h, the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 0-35% ethyl acetate/n-hexane gradient mixture to afford the desired product as pale yellow solid (334 mg, 0.801 mmol, 39%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[O:10]1[CH2:15][CH:14]=[C:13]([C:16]([CH3:21])([CH3:20])[CH2:17][CH:18]=O)[CH2:12][CH2:11]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:18]/[CH2:17][C:16]([C:13]1[CH2:14][CH2:15][O:10][CH2:11][CH:12]=1)([CH3:21])[CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(CC=O)C1=CCOCC1
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C/N=C/CC(C)(C)C1=CCOCC1
Yield: 98.6 %

Procedure:
Step F In a manner similar to the method described in Example 1a, glycine tert-butyl ester (2 g, 15.5 mmol) was reacted with 3-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-butyraldehyde (2.6 g, 15.5 mmol) in CH2Cl2 at room temperature for 5 h to give [3-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a yellow oil (4.3 g, 100%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[NH+]([O-])N1)C.[CH:25]1([C:28]([OH:30])=O)[CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.FC(F)(F)C([O-])=O.[Cl:47][C:48]1[CH:65]=[CH:64][CH:63]=[C:62]([Cl:66])[C:49]=1[CH2:50][O:51][C:52]1[CH:53]=[CH:54][C:55]2[N:59]=[C:58]([NH3+:60])[NH:57][C:56]=2[CH:61]=1>CN(C)C=O>[Cl:47][C:48]1[CH:65]=[CH:64][CH:63]=[C:62]([Cl:66])[C:49]=1[CH2:50][O:51][C:52]1[CH:53]=[CH:54][C:55]2[N:59]=[C:58]([NH:60][C:28]([CH:25]3[CH2:27][CH2:26]3)=[O:30])[NH:57][C:56]=2[CH:61]=1
Reactant: [NH3+]c1nc2ccc(OCc3c(Cl)cccc3Cl)cc2[nH]1
Reactant: O=C(O)C1CC1
Agent: CN(C)C(N(C)C)=[N+]1N[NH+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nc2ccc(OCc3c(Cl)cccc3Cl)cc2[nH]1)C1CC1
Temperature: 20 °C
Yield: 28.7 %

Procedure:
a solution of 270 mg of 1-[bis(dimethylamino)methylidene]-2,3-dihydro-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium-3-oxide hexafluorophosphate, 61 mg of cyclopropanecarboxylic acid and 176 mg of diisopropylethylamine in 40 cm3 of N,N-dimethylformamide is stirred for one hour at a temperature close to 20° C. Then 250 mg of 6-[(2,6-dichlorobenzyl)oxy]-1H-benzimidazol-2-aminium trifluoroacetate is added and the orange solution obtained is stirred for about twenty hours at about 20° C. After concentration under reduced pressure (0.2 kPa), the residue is taken up in 40 cm3 of water and the mixture obtained is extracted three times with 40 cm3 of ethyl acetate. The combined organic phases are washed three times with 40 cm3 of water, then dried over magnesium sulphate, filtered and concentrated under reduced pressure. After purification of the residue by flash chromatography on silica [eluent: dichloromethane/methanol (95/5 by volume)], we obtain 64 mg of N-{6-[(2,6-dichlorobenzyl)oxy]-1H-benzimidazol-2-yl}cyclopropanecarboxamide in the form of a white powder, which has the following characteristics:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[CH:10])[CH2:4][CH2:3]1.Br[C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([CH3:21])[CH:20]=1)[C:17](=[O:22])[N:16]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1)[CH2:15]2.C(Cl)(Cl)Cl.CO>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:21][C:19]1[CH:20]=[C:12]([C:10]#[C:9][CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:13]=[C:14]2[C:18]=1[C:17](=[O:22])[N:16]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:32])[F:33])=[CH:26][CH:25]=1)[CH2:15]2
Reactant: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: C#CCN1CCN(C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1cc(C#CCN2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 100 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
A mixture of 1-methyl-4-prop-2-ynyl-piperazine (0.033 mL, 0.33 mmol), 5-bromo-7-methyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.100 g, 0.25 mmol), PdCl2(PPh3)2 (0.011 g, 0.015 mmol), and CuI (0.0028 g, 0.015 mmol) in diisopropyl amine (4 mL) was stirred at 100° C. for 2 h. Workup and silica gel column chromatography using 10:1 CHCl3-MeOH afforded 7-Methyl-5-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.076 g, 67%).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[CH2:3][CH:4]([OH:6])[CH3:5].C(Cl)Cl.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O>O>[CH3:1][CH:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:11])[CH3:12])[CH2:3][C:4](=[O:6])[CH3:5]
Reactant: CC(C)=CCCC(C)CC(C)O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)CC(C)CCC=C(C)C
Reaction time: 3 h

Procedure:
A solution of 47 g. of 4,8-dimethylnon-7-en-2-ol in 250 ml. of methylene chloride is cooled to about 10° as a solution of 46.4 g. of sodium dichromate in 125 ml. of water is added. The mixture is at about 10° as a solution of 46.3 g. of sulfuric acid in 100 ml. of water is added over about 45 minutes. The mixture is allowed to attain room temperature and, after about 3 hours, the organic layer is separated and the aqueous layer is extracted with methylene chloride. The combined organic materials are washed with saturated potassium bicarbonate, water and saturated sodium chloride, dried over magnesium sulfate and evaporated to yield 4,8-dimethylnon-7-en-2-one.
Reaction SMILES: [CH3:1][C:2]([OH:10])([CH:4]=[CH:5][C:6]([CH3:9])([OH:8])[CH3:7])[CH3:3].[CH:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH2:12]([CH:11]1[O:10][C:2]([CH3:3])([CH3:1])[CH:4]=[CH:5][C:6]([CH3:9])([CH3:7])[O:8]1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC(C)(O)C=CC(C)(C)O
Reactant: CCCCCC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC1OC(C)(C)C=CC(C)(C)O1
Yield: 70.3 %

Procedure:
A mixture of 720 g (5 moles) of 2,5-dimethylhex-3-ene-2,5-diol, 3 g of p-toluenesulfonic acid, 500 g (5 moles) of n-hexanal and 1 l of toluene was refluxed, and the resulting water of reaction (115 ml) was separated off in the course of 5.5 h. The mixture was then left to cool, 10 ml of a 25% strength aqueous sodium hydroxide solution were added, the mixture was washed neutral with a little water and the toluene was removed under reduced pressure at from 50° to 60° C. The residue obtained was distilled under 0.1 mbar to give 796 g of 2-pentyl-4,4,7,7-tetramethyl-4,7-dihydro-1,3-dioxepin of boiling point 75° C./0.1 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCCC)[NH:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[CH3:33][NH:34][CH2:35][CH:36]([OH:43])[CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:34]([CH2:35][CH:36]([OH:43])[CH2:37][N:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)[CH3:33])=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1
Reactant: CCCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CNCC(O)CN1CCCC1
Product: CN(CC(O)CN1CCCC1)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(2-hydroxy-3-pyrrolidin-1-yl-propyl)-methyl-amino]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazolidin-4-one and 1-Methylamino-3-pyrrolidin-1-yl-propan-2-ol following General Procedure B.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13]C)=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:15]#[N:16])=[CH:10]2)=[CH:5][CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-].O.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]([OH:13])=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:15]#[N:16])=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(C#N)cc2c1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc2ccc(C#N)cc2c1O
Temperature: 0 °C
Reaction time: 18 h
Yield: 86.7 %

Procedure:
A solution of Example 1A (1 g) in methylene chloride (100 mL) at 0° C. was treated with AlCl3, stirred for 4 h at 0° C. and at room temperature for 18 h, poured into water (200 mL) containing 6N HCl (20 mL), stirred for 1 h and diluted with methylene chloride (100 mL). The layers were separated, and the organic layer was washed with brine and dried (MgSO4) to provide 810 mg of the title compound as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([OH:11])[C:2]=1[OH:1]
Reactant: CO
Reactant: O=C(O)c1cccc(O)c1O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(O)c1O
Temperature: 25 °C

Procedure:
50 g of 2,3-dihydroxybenzoic acid in 450 ml of methanol is mixed drop by drop with 50 ml of thionyl chloride at room temperature. Then, the solution is heated for five hours to 60° C. and still stirred overnight at room temperature. The solvent is completely removed in a vacuum, and the remaining oil is taken up in diethyl ether and extracted with saturated sodium bicarbonate solution. After washing with brine, drying with sodium sulfate and removal of the solvent in a vacuum, 46 g of 2,3-dihydroxybenzoic acid-methyl ester is obtained. The latter is mixed in 575 ml of DMF and 20.2 ml of dibromomethane with 56.7 g of potassium carbonate, and it is heated for five hours under argon to 100° C. Then, it is stirred overnight at room temperature. After mixing with water, it is extracted three times with ethyl acetate. The organic phase is washed several times with water and dried on sodium sulfate. The solvent is removed in a vacuum, and 50.2 g of 1,3-benzodioxole-4-carboxylic acid-methyl ester is obtained as a brown solid.
Reaction SMILES: COC1C=C([C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH2:13])=[S:12])C=CC=1.[C:18](Cl)(=[O:22])[C:19](Cl)=[O:20].C[C:25](C)=[O:26]>>[CH3:25][O:26][C:15]1[CH:14]=[C:10]([C:11]2[S:12][C:18](=[O:22])[C:19](=[O:20])[N:13]=2)[CH:9]=[CH:17][CH:16]=1
Reactant: COc1cccc(-c2ccccc2C(N)=S)c1
Reactant: CC(C)=O
Reactant: O=C(Cl)C(=O)Cl
Product: COc1cccc(C2=NC(=O)C(=O)S2)c1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
7.3 g of 3-methoxyphenylthiobenzamide [preparation similar to Example 65B)] were dissolved in 50 ml acetone and cooled to -20° C. in a nitrogen atmosphere. A solution of 4 ml oxalyl chloride in 40 ml acetone were added slowly dropwise to this solution. Then it was stirred for 1 hour at 20° C. The crystals that settled out were drawn off and the mother liquor concentrated to approximately one-third of the original volume. A further crystal fraction was obtained. In all, 5 g of 2-(3-methoxyphenyl)-1,3-thiazole-4,5-dione were obtained as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=O)[C:9]([CH3:25])([CH3:24])[CH2:8]2)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40].N12CCCN=C1CCCCC2>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:23]=[CH:22][CH:21]=[C:17]([C:18](=[O:20])[NH:42][S:39]([CH3:38])(=[O:41])=[O:40])[CH:16]=1)[C:9]([CH3:24])([CH3:25])[CH2:8]2)=[O:4]
Reactant: CS(N)(=O)=O
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)O)c1)N2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)NS(C)(=O)=O)c1)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 111.9 %

Procedure:
A solution of 3-(6-(methoxycarbonyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (150 mg, 0.44 mmol) and 1,1′-carbonyldiimidazole (214 mg, 1.32 mmol) in tetrahydrofuran (3 mL) was heated to 60° C. for 2 h, then was cooled to room temperature and treated with methanesulfonamide (54.2 mg, 0.57 mmol, 1.3 eq.). After stirring for 10 min, the reaction mixture was treated with dropwise addition of a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (221 mg, 1.45 mmol) in tetrahydrofuran (1 mL). Upon completion of addition, the resultant mixture was stirred overnight. Thin layer chromatography (petroleum ether:ethyl acetate=1:1) showed the reaction was complete. The reaction mixture was quenched with brine and acidified with 1N hydrochloric acid solution to pH=5, extracted with ethyl acetate (twice). The combined organic layers were washed with brine for 3 times, dried over anhydrous sodium sulfate. Removal of the solvent in vacuo gave 205 mg of methyl3,3-dimethyl-2-(3-(methylsulfonylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a white solid, which was purified by column chromatography (petroleum ether:ethyl acetate=2:1 to 1:1) to afford 58 mg of white solid, which was used in next step.