Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[O-:18][Mn](=O)(=O)=O.[K+]>O1CCOCC1>[C:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([OH:18])=[O:11])=[CH:8][C:7]=1[O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1cc(C=O)ccc1OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(C(=O)O)ccc1OC(C)(C)C
Reaction time: 16 h
Yield: 48.9 %

Procedure:
4-tert-Butoxy-3-methoxybenzaldehyde (130 mg, 0.62 mmol) was suspended in a mixture of dioxane (520 μL) and potassium hydroxide (6.5 mL of 0.20 M, 1.3 mmol). KMnO4 (150 mg, 0.93 mmol) was added and the reaction was stirred vigorously for 16 h. The reaction mixture was filtered and then concentrated to 3 mL. Hydrochloric acid (1M, 4 mL) was added and the resulting precipitate was filtered (after standing for 15 minutes) and washed with 1M HCl and a small amount of water to yield 4-tert-butoxy-3-methoxy-benzoic acid (68 mg, 49%) as a white solid. Rf=0.23 (SiO2, 40% ethyl acetate in hexanes); ESI-MS m/z calc. 224.1. found 225.2 (M+1)+. Retention time: 1.66 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 12.80 (s, 1H), 7.66-7.41 (m, 2H), 7.09 (d, J=8.8 Hz, 1H), 3.78 (s, 3H), 1.32 (s, 9H). The following compounds were synthesized using the procedures described above: 4-tert-butoxy-3-methylbenzoic acid from 4-hydroxy-3-methylbenzaldehyde, 2-fluoro-4,5-dimethoxybenzoic acid from 2-fluoro-4,5-dimethoxybenzaldehyde, 4-tert-butoxy-2-methoxybenzoic acid from 4-hydroxy-2-methoxybenzaldehyde, 4-tert-butoxy-2-fluorobenzoic acid from 2-fluoro-4-hydroxybenzaldehyde, and 4-tert-butoxybenzoic acid from 4-hydroxybenzaldehyde.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[C:12]([O:14]CC)=[O:13])[N:4]2[CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:22]=[C:3]12.[OH-].[Na+].Cl>O1CCCC1.O>[O:1]=[C:2]1[NH:7][CH:6]=[C:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[C:12]([OH:14])=[O:13])[N:4]2[CH:20]=[C:21]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[CH:22]=[C:3]12
Reactant: CCOC(=O)c1cccc(Cc2c[nH]c(=O)c3cc(-c4ccncc4)cn23)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(Cc2c[nH]c(=O)c3cc(-c4ccncc4)cn23)c1
Temperature: 80 °C

Procedure:
To a suspension of EXAMPLE 4E (30 mg, 0.08 mmol) in tetrahydrofuran (5 mL) was added NaOH (32 mg, 0.8 mmol) in water (0.5 ml). The reaction mixture was heated at 80° C. overnight. After cooling, the reaction mixture was neutralized with 1N aqueous HCl, and concentrated. The residue was separated by HPLC (0-100% gradient CH3CN in water containing 0.1% CF3CO2H to afford the title compound. MS (DCI/NH3) m/z 346 (M+H)+; 1H NMR (300 MHz, dimethylsulfoxide-d6): δ 4.19 (s, 2H), 6.59 (d, J=5.55 Hz, 1H), 7.47 (t, J=7.54 Hz, 1H), 7.68 (d, J=7.54 Hz, 1H), 7.77 (d, J=1.59 Hz, 1H), 7.82 (d, J=7.93 Hz, 1H), 7.97 (s, 1H), 8.19 (d, J=6.74 Hz, 2H), 8.33 (d, J=1.59 Hz, 1H), 8.73 (d, J=6.35 Hz, 2H), 10.74 (d, J=5.55 Hz, 1H), 12.98 (s, 1H).
Reaction SMILES: [CH2:1]([C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:14](Cl)=[O:15])[CH2:2][CH2:3][CH3:4].[Br:17][C:18]1[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][C:22]([CH2:30][NH:31][CH3:32])=[CH:23]2.C(N(CC)CC)C>C(Cl)Cl>[Br:17][C:18]1[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][C:22]([CH2:30][N:31]([CH3:32])[C:14]([C:6]1[O:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:5]=1[CH2:1][CH2:2][CH2:3][CH3:4])=[O:15])=[CH:23]2
Reactant: CCCCc1c(C(=O)Cl)oc2ccccc12
Reactant: CNCc1ccc2c(Br)c(OC)ccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1c(C(=O)N(C)Cc2ccc3c(Br)c(OC)ccc3c2)oc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-butyl-benzofuran-2-carbonyl chloride (9.0 mmol), prepared in the previous step, in 50 mL of methylene chloride was added under nitrogen dropwise over 2 h to a solution of (5-bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amine (2.52 g, 9.0 mmol), prepared in step 7 of Example 36, and triethylamine (1.26 mmol, 9.0 mmol) in 250 mL of methylene chloride at room temperature. After the addition the reaction was stirred at room temperature overnight. The reaction was extracted with 1 N HCl, 5% NaHCO3, dried (MgSO4) and the solvent removed under reduced pressure to 4.13 g of a residue. Purification of the residue on 500 g of silica gel (230-400 mesh) using 90% hexane-methylene chloride to 5% EtOAc-methylene chloride as the eluents gave 3-butyl-benzofuran-2-carboxylic acid (5-bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amide as a clear oil, MS m/z: 480 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:24]=[C:23]([O:25][CH3:26])[C:22]3[C:17](=[CH:18][C:19]([O:29][CH3:30])=[C:20]([O:27][CH3:28])[CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:31]>C(O)C.O1CCOCC1>[ClH:31].[ClH:31].[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:24]=[C:23]([O:25][CH3:26])[C:22]3[C:17](=[CH:18][C:19]([O:29][CH3:30])=[C:20]([O:27][CH3:28])[CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1
Reactant: COc1cc2nc(NC3CCN(C(=O)OC(C)(C)C)CC3)nc(OC)c2cc1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: COc1cc2nc(NC3CCNCC3)nc(OC)c2cc1OC

Procedure:
A solution of 4-(4,6,7-trimethoxy-quinazolin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.2 g, 0.48 mmol) in ethanol (5 mL) and 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ESI): 319.4 [M+H]+.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][N:6](C(OCC2C=CC=CC=2)=O)[CH2:5]1)([OH:3])=[O:2].[CH2:19](OC(C1CCCN1)=O)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:19]([O:3][C:1]([CH:4]1[CH2:8][CH2:7][NH:6][CH2:5]1)=[O:2])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCOC(=O)C1CCCN1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)C1
Product: CCCCCCOC(=O)C1CCNC1

Procedure:
By substituting the 3-carboxy-1-phenylmethyloxycarbonylpyrrolidine obtained in Example 10 for the 2-[(hexyloxy)carbonyl]pyrrolidine in the procedure of Example 1, 3-[(hexyloxy)carbonyl]pyrrolidine is obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br.C([O-])([O-])=O.[Na+].[Na+]>>[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C@H:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1)[CH3:11])=[O:8]
Reactant: Fc1cccc(CBr)c1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2Cc2cccc(F)c2)cc1
Yield: 59 %

Procedure:
The title compound (D23) (40 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((S)-1-((R)-piperidine-2-carboxamido)ethyl)benzoate (D12) (50 mg, 0.17 mmol) and 3-fluorobenzyl bromide (0.042 ml, 0.34 mmol). (Na2CO3: 2.5 eq; reaction time: 3 hrs; 60° C.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].COCN[C:19]([C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[S:24][CH:25]=1)=[O:20]>C1COCC1>[C:26]1([C:23]2[S:24][CH:25]=[C:21]([C:19]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)=[O:20])[N:22]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1cc([Mg]Br)cc(OC)c1OC
Reactant: COCNC(=O)c1csc(-c2ccccc2)n1
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2csc(-c3ccccc3)n2)cc(OC)c1OC
Yield: 27.3 %

Procedure:
A mixture of 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid (5 mmol), EDCI (6 mmol) and HOBt (5 mmol) in CH2Cl2 (50 mL) was stirred for 10 min. To this solution, NMM (5 mmol) and HNCH3OCH3 (5 mmol) were added and stirring continued at RT for 6-8 h. The reaction mixture was diluted with CH2Cl2 (100 mL) and sequentially washed with water, satd. NaHCO3, brine and dried over MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to get 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid methoxymethylamide. A solution of 2-phenyl-4,5-dihydrothiazole-4-carboxylic acid methoxymethylamide (1 equiv) in CH2Cl2 was cooled to 0° C., and distilled DBU (2 equiv) was added. Bromotrichloromethane (1.7 equiv) was then introduced dropwise via syringe over 10 min. The reaction mixtures were allowed to warm to RT and stirred overnight. Upon washing with satd. aqueous NH4Cl (2×50 mL), the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic layers were dried on MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography as needed providing 2-phenyl-thiazole-4-carboxylic acid methoxymethylamide (73.6%). 1H NMR (300 MHz, CDCl3) δ 8.01 (s, 1H), 7.99-7.96 (m, 2H), 7.47-7.44 (m, 3H), 3.88 (s, 3H), 3.49 (s, 3H). MS (ESI) m/z 271.0 (M+Na)+. To a solution of 3,4,5-trimethoxyphenylmagnesium bromide (0.5 N, 3 mL) in 2 mL THF was charged a solution of 2-phenyl-thiazole-4-carboxylic acid methoxymethylamide (1 mmol) in 3 mL THF at 0° C. The mixtures were stirred for 30 min until amides disappeared on TLC plates. The reaction mixture was quenched with satd. NH4Cl, extracted with ethyl ether, dried with MgSO4. The solvent was removed under reduced pressure to yield a crude product, which was purified by column chromatography to obtain pure compound 1h. Yield: 27.3%. 1H NMR (300 MHz, CDCl3) δ 8.29 (s, 1H), 8.03 (q, 2H), 7.80 (s, 2H), 7.49-7.47 (m, 3H), 3.96 (s, 6H), 3.97 (s, 3H). MS (ESI) m/z 378.1 (M+Na)+.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][C:5]([C:10](O)=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C)C=O>[ClH:16].[N:2]12[CH2:9][CH2:8][C:5]([C:10]([Cl:1])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2
Reactant: O=C(O)C12CCN(CC1)CC2
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C12CCN(CC1)CC2

Procedure:
Quinuclidine-4-carboxylic acid hydrochloride (0.192 g, 0.001 mole) was suspended in dichloromethane (5 ml) and dimethylformamide (1 drop) and oxalyl chloride (0.436 ml. 0.635 g, 0.005 mole) were added. The resulting suspension was heated to reflux under an atmosphere of argon for six hours. Following concentration of the suspension in vacuo the residue was suspended in dichloromethane, concentrated in vacuo and finally dried in vacuo to give the title compound as a pale brown solid.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[F:9][C:10]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][C:11]=1[NH2:12]>C(OCC)(=O)C>[F:9][C:10]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][C:11]=1[N:12]=[C:2]=[O:3]
Reactant: COC(=O)Oc1cc(N)c(F)cc1Cl
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)Oc1cc(N=C=O)c(F)cc1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
A solution of trichloromethyl chloroformate (19 ml, 158 mmol) in ethyl acetate (200 ml) was charged into a 500 ml-three neck flask equipped with a dropping funnel and a distillation apparatus and a solution of 2-fluoro-4-chloro-5-methoxycarbonyloxianiline (21.9 g, 100 mmol) in ethyl acetate (100 ml) was added dropwise in 20 minutes. After completion of addition, the mixture was heated at 80° C. and ethyl acetate was distilled off. After cooling, carbon tetrachloride (150 ml) was added and allowed the mixture to stand overnight. After removal of indissolved substances by filtration, the solvent was distilled off from filtrate under reduced pressure, whereby light brown solid of 2-fluoro-4-chloro-5-methoxycarbonyloxyphenyl isocyanate (20.6 g, yield 84%) was obtained.
Reaction SMILES: [C:1]([C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])([CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:5][CH2:6]C(O)=O)(=[O:3])[CH3:2].C([O-])(=O)C.[K+]>C(OC(=O)C)(=O)C>[C:1]([C:4]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:5][CH2:6][C:12](=[O:14])[CH2:11][CH2:10]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(CCC(=O)O)(CCC(=O)O)C(C)=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C1(C(C)=O)CCC(=O)CC1
Temperature: 145 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of Step 2 product (1 eq) in acetic anhydride (2.5 v/w) under nitrogen was added potassium acetate (0.02 eq). The reaction mixture was heated to, and stirred at the reflux temperature (145° C.) for 2 hours. The resultant solution was concentrated in vacuo, and purged with toluene to afford a brown oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([CH3:33])([CH3:32])[C:29]([OH:31])=[O:30])=[CH:24][C:23]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>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>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:27]2[CH:26]=[C:25]([C:28]([CH3:33])([CH3:32])[C:29]([OH:31])=[O:30])[CH:24]=[CH:23][C:22]=2[F:21])[CH:3]=1
Reactant: CC(C)(C(=O)O)c1ccc(F)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
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: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cc(C(C)(C)C(=O)O)ccc2F)n1
Yield: 29 %

Procedure:
A solution of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2,4-dichlorophenyl)-ethyl]amine (0.24 g), 2-[4-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-methyl-propionic acid (0.4 g), Cs2CO3 (1.01 g) and tetrakis(triphenylphosphine)palladium (0) (100 mg) in water (20 mL)/DME (80 mL) is heated at 90° C. for 16 h. The solution is poured into water and extracted with EtOAc (2×200 mL). The organic layer is dried over sodium sulfate, filtered, evaporated in vacuo. The residue is chromatographed on silica gel eluting with EtOAc to afford 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-4-fluoro-phenyl)-2-methyl-propionic acid (100 mg), which is dissolved in THF (4 mL) and treated with 4 N HCl in 1,4-dioxane (1 mL). The mixture is concentrated in vacuo and the residue is suspended in ether (25 mL). The solid is formed and filtered under nitrogen to afford 2-(3-{6-[2-(2,4-Dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-4-fluoro-phenyl)-2-methyl-propionic acid hydrochloride (67 mg, Example 99). MS: 478 (M+H); 1H NMR (300 MHz, NMR, CD3OD) □7.8, (d, 1H, J=0.3 Hz); 7.4 (m, 2H); 7.35 (s, 1H); 7-7.15 (m, 4H); 6.6 (s, 1H); 4.2 (s, 3H); 3.6 (m, 2H); 3.05 (t, 2H); 1.65 (s, 6H). IC50=0.5 nM
Reaction SMILES: C([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[CH:11]=2)[CH2:6]1)(=O)C.[ClH:17]>>[ClH:17].[N+:14]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH2:6][CH:5]([NH2:4])[CH2:13]2)([O-:16])=[O:15]
Reactant: CC(=O)NC1Cc2ccc([N+](=O)[O-])cc2C1
Agent: Cl
Product: NC1Cc2ccc([N+](=O)[O-])cc2C1

Procedure:
N-Acetyl-5-nitro-2-indanamine, 1.5 g. (0.007 mole) as prepared in Example 9 was refluxed in 10% hydrochloric acid for 3 hours. The mixture was evaporated and the crystalline residue recrystallized from methanol-ether to yield 5-nitro-2-indanamine hydrochloride, dec.>280° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(Cl)(Cl)[Cl:16]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([Cl:16])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: ClC(Cl)Cl
Product: COc1ccc(CC(=O)Cl)cc1OC

Procedure:
(3,4-dimethoxyphenyl)acetyl chloride is prepared according to the method described in Example 8 using 3,4-dimethoxyphenylacetic acid (2.85 g, 14.5 mmol) to give a brown oil which is dissolved in chloroform (10 mL). This solution is refluxed for 3 hours with a solution of (±)-trans-[2-(4-morpholinyl)]cyclohexanethiol (2.8 g, 14 mmol) in chloroform (10 mL) under nitrogen. The reaction mixture is partitioned between 1M sodium hydroxide solution (100 mL) and dichloromethane (80 mL). The organic layer is separated and the aqueous is washed with more dichloromethane (2×50 mL). The combined dichloromethane extracts are dried over sodium sulfate, and the solvent is removed to leave the crude free ester. This is purified by column chromatography and converted to the hydrochloride salt by treatment with HCl in ether. The product is recrystallised from hot ethyl acetate/methanol to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[C:4]#N.C(O)=[O:13].O.[Al]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:13]
Reactant: N#Cc1c(Cl)cc(Cl)cc1Cl
Reactant: O=CO
Agent: [Al]
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 100 °C
Yield: 93 %

Procedure:
Add 2,4,6-trichlorobenzonitrile (206 mg, 1.0 mmol) to 96% formic acid (5 mL, 96%) and water (1 mL). Add nichol/aluminum alloy (206 mg) to the mixture. Heat at 100° C. for 4 hours. Dilute with ethyl acetate and filter through Celite®. Extract the filtrate with 1 N sodium hydroxide and saturated aqueous sodium chloride, dry (sodium sulfate), filter, and concentrate to give 2,4,6-trichlorobenzaldehyde (195 mg, 93%). 1H NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 7.99 (s, 1H), 7.61 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([CH3:21])([CH3:20])[CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:22]1[CH:26]=[CH:25][N:24]=[C:23]1[Na].O>C(O)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:9])([C:11]([CH3:21])([CH3:20])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:10][N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)=[CH:4][CH:3]=1
Reactant: CC(C)(Cc1ccc(Cl)cc1)C1(c2ccc(Cl)cc2)CO1
Reactant: [Na]c1ncc[nH]1
Solvent: CCCO
Solvent: O
Product: CC(C)(Cc1ccc(Cl)cc1)C(O)(Cn1ccnc1)c1ccc(Cl)cc1
Yield: 34.9 %

Procedure:
30 g (0.0935 mol) of 2-(4-chlorophenyl)-2-(4-chlorophenyl-tert.-butyl)-oxirane in 40 ml of n-propanol are added dropwise to a solution of 7.7 g (0.108 mol) of imidazolyl-sodium in 60 ml of n-propanol at the reflux temperature. The reaction mixture is stirred under reflux for a further 48 hours and cooled, water is added, and the mixture is extracted with methylene chloride. The organic phase is dried over sodium sulphate and concentrated in vacuo. The oily residue is stirred in diisopropyl ether. The crystalline precipitate formed is filtered off under suction and dried. 12.7 g (35% of theory) of 2,4-bis(4-chlorophenyl)-3,3-dimethyl-1-(imidazol-1-yl)-butan-2-ol of melting point 174° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=O.[CH2:24]([O:26][C:27](=[O:39])[CH2:28][C:29](=O)[CH2:30][CH2:31][CH2:32][N:33]1[CH:37]=[CH:36][N:35]=[CH:34]1)[CH3:25].S(=O)(=O)(O)O>C(O)(=O)C>[CH2:24]([O:26][C:27]([C:28]1[C:29]([CH2:30][CH2:31][CH2:32][N:33]2[CH:37]=[CH:36][N:35]=[CH:34]2)=[N:1][C:2]2[C:3]([C:4]=1[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=[CH:16][C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)=[O:39])[CH3:25]
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Reactant: CCOC(=O)CC(=O)CCCn1ccnc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(CCCn2ccnc2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
To a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone (453 mg), 6-(1-imidazolyl)-3-oxohexanoic acid ethyl ester (320 mg) and acetic acid (5 ml), concentrated sulfuric acid (0.03 ml) was added, followed by stirring at 100° C. for 2 hours. After the reaction mixture was concentrated under reduced pressure, the residue was poured over water, alkalinized with 2N sodium hydroxide and then extracted with chloroform. The chloroform layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residual oily substance was subjected to silica gel column chromatography and eluted with chloroform-methanol (50:1, v/v) to yield 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-[3-(1-imidazolyl)propyl]quinoline-3-carboxylic acid ethyl ester (310.0 mg, 43%), which was then recrystallized from ethyl acetate-hexane to yield a colorless prismatic crystal having a melting point of 164° to 165° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][C:8]1[CH:25]=[CH:24][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:23][CH:22]=[N:21][CH:20]=3)=[CH:15][CH:14]=2)=[CH:10][CH:9]=1.[CH3:26][O:27][C:28](=[O:33])[CH2:29][CH2:30][CH2:31]Br>ClCCl.C(N(CC)CC)C>[CH3:26][O:27][C:28](=[O:33])[CH2:29][CH2:30][CH2:31][N:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][C:8]1[CH:25]=[CH:24][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:23][CH:22]=[N:21][CH:20]=3)=[CH:15][CH:14]=2)=[CH:10][CH:9]=1
Reactant: c1ncc(-c2ccc(Oc3ccc(OC[C@H]4CCCN4)cc3)cc2)o1
Reactant: COC(=O)CCCBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCN1CCC[C@@H]1COc1ccc(Oc2ccc(-c3cnco3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
To a solution of (5-{4-[4-((R)-1-pyrrolidin-2-ylmethoxy)-phenoxy]-phenyl}-oxazole (150 mg, 0.4 mmol) in anhydrous dichloromethane (0.5 mL) was added methyl-4-bromobutyrate (80 mg, 0.44 mmol) in dichloromethane (0.5 mL) and triethylamine (81 mg, 0.8 mmol. The resulting mixture was purged with nitrogen and stirred at rt for 16 h. dichloromethane was removed in vacuo and crude mixture was partioned between EtOAc and water. EtOAc layer was removed, washed with brine, dried over anhydrous MgSO4 and concentrated. The crude mixture was purified by silica gel flash chromatography (40% EtOAc/Hexane) to obtain the title product as yellow oil (95 mg, 55%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@H:27]([CH2:28][OH:29])[CH2:26][CH2:25][C:24]4=[O:30])=[CH:19][C:18]=3[S:31]([CH3:34])(=[O:33])=[O:32])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.S(C1C=CC(C)=CC=1)(O[CH3:39])(=O)=O>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@H:27]([CH2:28][O:29][CH3:39])[CH2:26][CH2:25][C:24]4=[O:30])=[CH:19][C:18]=3[S:31]([CH3:34])(=[O:33])=[O:32])=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@H]4CO)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Product: COC[C@@H]1CCC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)c(S(C)(=O)=O)c1
Yield: 27.7 %

Procedure:
Using (S)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-methanesulfonylphenyl}-5-hydroxymethylpyrrolidin-2-one (530 mg) described in Example 274 and methyl tosylate (203 mg) and by the reaction and treatment in the same manner as in Example 36, the title compound (151 mg) was obtained.