Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH2:12][CH:13]([C:22]1[C:26]([CH:27]2[CH2:29][CH2:28]2)=[C:25]([CH:30]2[CH2:33][CH:32]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:31]2)[O:24][N:23]=1)[CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[O:11].O.Br.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH2:12][CH:13]([C:22]1[C:26]([CH:27]2[CH2:28][CH2:29]2)=[C:25]([CH:30]2[CH2:31][CH:32]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:33]2)[O:24][N:23]=1)[CH2:14][C:15]([OH:17])=[O:16])=[O:11]
Reactant: Cc1ccc(NC(=O)CC(CC(=O)OC(C)(C)C)c2noc(C3CC(CC(C)C)C3)c2C2CC2)c(Cl)c1
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(NC(=O)CC(CC(=O)O)c2noc(C3CC(CC(C)C)C3)c2C2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.1 %

Procedure:
tert-Butyl 4-(2-chloro-4-methylphenylcarbamoyl)-3-[4-cyclopropyl-5-(3-isobutylcyclobutyl)isoxazol-3-yl]butanoate (131 mg) and water (0.8 mL) were mixed. After an addition of 25 w/w % hydrogen bromide in acetic acid (1.64 mL) to the reaction mixture, the mixture was stirred at RT for 1.5 hr. Sodium acetate and water were added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by preparative chromatography (Eluent: methanol/chloroform=1/9) to give the title compound (97.3 mg). The specific optical rotation value of the title compound was [α]D25=+32.7° (c=1.00, methanol). The title compound was analyzed using a chiral column. The retention time of the title compound was 6.8 min., and the optical purity thereof was 95.1% ee. The condition for the analysis using the chiral column was as follows:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>CC#N>[CH3:31][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: N#Cc1ccc(NCCCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OCCCNc2ccc(C#N)cc2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 77.2 %

Procedure:
A cooled (0° C.) solution of 4-[(3-hydroxypropyl)amino]benzonitrile (from step (i) above; 17 g, 96.5 mmol) in dry MeCN (195 mL) was treated with triethylamine (9.8 g, 96.5 mmol) and then p-toluenesulfonyl chloride (20.2 g, 106 mmol). The mixture was stirred at 0° C. for 90 minutes before being concentrated in vacuo. Water (200 mL) was added to the residue, and the aqueous solution was extracted with DCM. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified by crystallisation from iso-propanol to yield 24.6 g (77%) of the title compound.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1[Cl:11].[CH:12]1([O:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[C:21](Cl)=[O:22])[CH2:16][CH2:15][CH2:14][CH2:13]1.Cl>O1CCCC1.ClCCl>[Cl:11][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Cl:10])[C:4]=1[NH:3][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:18]([O:17][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16]2)[CH:19]=1
Reactant: Nc1c(Cl)cncc1Cl
Reactant: COc1ccc(C(=O)Cl)cc1OC1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1CCCC1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
A suspension of sodium hydride (60% dispersion in oil; 2.2 g) in dry tetrahydrofuran (25 mL) at 15-20° C. is treated portionwise with a solution of 4-amino-3,5-dichloropyridine (4.5 g; that is prepared as described in Reference Example 5) in dry tetrahydrofuran (40 mL), with cooling. The mixture is stirred for a further 30 minutes, and then it is cooled to 10° C. and treated with a solution of 3-cyclopentyloxy-4-methoxybenzoyl chloride (6.4 g) in dry tetrahydrofuran (40 mL), dropwise, during 45 minutes at 10° C. The mixture is stirred at 10° C. for 30 minutes and is then treated with dilute hydrochloric acid (50 mL; 1N), followed by dichloromethane (75 mL). The layers are separated and the aqueous layer is washed with a further quantity of dichloromethane (25 mL). The combined organic layers are washed with water (50 mL), with saturated aqueous sodium bicarbonate solution (100 mL), and with water (50 mL), dried over magnesium sulfate and evaporated to dryness. The resulting residue is recrystallized from isopropanol, to give N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide (7.0 g).
Reaction SMILES: COC1NC(C)=C(C(OCC)=O)C(C2C=CC=C(Cl)C=2Cl)N=1.N1C=CC=CC=1.ClC(OCC)=O.Cl.[CH3:36][C:37]1[NH:38][C:39](=[O:61])[N:40]([C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH:41]([C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:49]=2[Cl:55])[C:42]=1[C:43]([O:45][CH2:46][CH3:47])=[O:44]>ClCCl.O1CCCC1CO>[CH3:36][CH:37]1[C:42]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:41]([C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:49]=2[Cl:55])[N:40]([C:56]([O:58][CH2:59][CH3:60])=[O:57])[C:39](=[O:61])[NH:38]1
Reactant: CCOC(=O)C1=C(C)NC(=O)N(C(=O)OCC)C1c1cccc(Cl)c1Cl
Agent: CCOC(=O)C1=C(C)NC(OC)=NC1c1cccc(Cl)c1Cl
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: OCC1CCCO1
Product: CCOC(=O)C1=C(c2cccc(Cl)c2Cl)N(C(=O)OCC)C(=O)NC1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,4-dihydro-2-methoxy-6-methyl-4-(2,3-dichlorophenyl)-5-pyrimidinecarboxylic acid, ethyl ester (1.3 g., 3.8 mmole) in dichloromethane (10 ml.) is cooled to 0° and treated with pyridine (0.6 ml., 7.58 mmole) followed by ethyl chloroformate (0.4 ml., 4.0 mmole). The cooling bath is removed and the reaction is allowed to stir at room temperature overnight. The solvent is then stripped off to provide a colorless solid. This material is dissolved in tetrahydrofuran-methanol (10 ml. of 1:4 mixture) and treated with 2N hydrochloric acid (2 ml.). The reaction is allowed to stir at room temperature for 30 minutes and the solvent is then evaporated. The residue is extracted with ethyl acetate and the combined extracts are washed with sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent is stripped and the residue is crystallized from isopropyl ether to provide 1.25 g. of 3,6-dihydro-4-methyl-6-(2,3-dichlorophenyl)-2-oxo-1,5(2H)pyrimidinedicarboxylic acid, diethyl ester as a colorless solid; m.p. 139.5°-141°. TLC(silica gel; acetone/hexanes, 50:50) Rf =0.44.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([CH2:23][OH:24])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C>ClCCl.CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH:11]([CH:23]=[O:24])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CO)CCC2c2ccc(F)cc2)cc1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N2C(C=O)CCC2c2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a stirred solution of (2RS,5SR)-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-methanol (8.12 g, 23.2 mmol) in dichloromethane (150 ml) was added triethylamine (16.2 ml, 116 mmol). To the cooled solution (0° C.) was added dropwise over a period of 15 min pyridine-SO3-complex (18.3 g, 116 mmol) dissolved in DMSO (75 ml) and the reaction mixture was stirred for 1 h at 0° C. Aqueous work-up yielded (2RS,5SR)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine-2-carboxaldehyde (8.0 g, yield 99%) as a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:34]=[C:33]([CH2:35]OS(C)(=O)=O)[O:32][N:31]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:35][C:33]2[O:32][N:31]=[C:30]([CH3:29])[CH:34]=2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: Cc1cc(COS(C)(=O)=O)on1
Product: Cc1cc(Cn2cc(C(=O)N3CCC4(CC3)OC(=O)c3cc(F)ccc34)c3ccc(Cl)cc32)on1

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with methanesulfonic acid 3-methyl-isoxazol-5-ylmethyl ester (described in Heterocycles, 23(3), 571-83; 1985) gave the title compound.
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([S:16]([CH:19]=[CH2:20])(=[O:18])=[O:17])[CH3:15]>>[CH2:14]([S:16]([CH2:19][CH2:20][P:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:18])=[O:17])[CH3:15]
Reactant: C=CS(=O)(=O)CC
Reactant: c1ccc(Pc2ccccc2)cc1
Product: CCS(=O)(=O)CCP(c1ccccc1)c1ccccc1
Reaction time: 1.75 h
Yield: 69 %

Procedure:
A mixture of 64 g (0.34 mole) of diphenyl phosphine and 40.2 g (0.33 mole) of highly reactive, freshly distilled vinyl ethyl sulfone monomer was irradiated in the usual manner. To suppress polymer forming side reactions the temperature of the reaction mixture was kept below 5° C. by an ice-water bath and the u.v. irradiation was limited to 105 minutes. The adduct formed crystallized from the liquid mixture by the end of the reaction period. Consequently, the reaction mixture was filtered with suction to recover the crude, crystalline product, i.e. 2-ethylsulfonylethyl diphenyl phosphine. The crude, dried product (94 g, 94) was recrystallized from 670 ml methanol to yield 69 g (69%) of the compound (of unpleasant odor) as a white crystalline solid (Table 3).
Reaction SMILES: FC(F)(F)S([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])(=O)=O.[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:34][CH2:33][C:32]([CH3:36])(O)[CH2:31][CH2:30]3)=[N:27][N:28]=2)[CH:25]=1.CCN(CC)CC>C(Cl)Cl>[F:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([C:26]([N:29]3[CH2:34][CH2:33][C:32]([CH3:36])([O:6][Si:7]([CH:8]([CH3:9])[CH3:10])([CH:11]([CH3:12])[CH3:13])[CH:14]([CH3:15])[CH3:16])[CH2:31][CH2:30]3)=[N:27][N:28]=2)[CH:25]=1
Reactant: CC1(O)CCN(c2nnc3ccc(F)cn23)CC1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[Si](OC1(C)CCN(c2nnc3ccc(F)cn23)CC1)(C(C)C)C(C)C
Yield: 96.3 %

Procedure:
Triisopropylsilyl trifluoromethanesulfonate (550 mg, 1.81 mmol) was added to a solution of Intermediate 79c (150 mg, 0.60 mmol) and Et3N (242 mg, 2.40 mmol) in a DCM (5 mL) and the mixture stirred at reflux for 1 h. The reaction mixture was diluted with DCM (30 mL), washed with water (2×), brine, dried (MgSO4), and then concentrated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give the title compound (235 mg, 96%). 1H NMR (400 MHz, CDCl3): 1.00-1.20 (21H, m), 1.40 (3H, s), 1.76-1.93 (4H, m), 3.18-3.29 (2H, m), 3.44-3.58 (2H, m), 7.03-7.12 (1H, m), 7.58-7.69 (2H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:10]=1[C:33]1[O:37][N:36]=[C:35]([C:38]([O:40]CC)=[O:39])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>C(O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[C:10]=1[C:33]1[O:37][N:36]=[C:35]([C:38]([OH:40])=[O:39])[CH:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2c(OCc3ccccc3)cc(OCc3ccccc3)cc2Oc2ccc([N+](=O)[O-])cc2)on1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)c1cc(-c2c(OCc3ccccc3)cc(OCc3ccccc3)cc2Oc2ccc([N+](=O)[O-])cc2)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.6 %

Procedure:
To a stirred solution of ethyl 5-[2,4-bis(benzyloxy)-6-(4-nitrophenoxy)phenyl]isoxazole-3-carboxylate (5 g, 9 mmol) in ethanol (150 mL) was added 1.5 M KOH solution (9 mL, 13.5 mmol, 1.5 eq). After stirring for 3 hours at room temperature, 2 M HCl solution (7.5 mL) was added and the suspension taken up in ethyl acetate was washed with brine. After drying and removal of the solvent, the residue was rinsed with a small volume of acetone and filtered off, to give after drying, the title compound (4.1 g, 86% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:15]=[CH:16][C:17]3[CH2:23][NH:22][CH2:21][CH2:20][C:18]=3[N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:24]([O:32]C(=O)C1C=CC=CC=1)(=O)[C:25]1[CH:30]=[CH:29][CH:28]=C[CH:26]=1.[N:41]1C=CC=CC=1>C(Cl)Cl>[N:41]1[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([N:22]2[CH2:21][CH2:20][C:18]3[N:19]=[C:14]([NH:13][C:5]4[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:15]=[CH:16][C:17]=3[CH2:23]2)=[O:32])[CH:26]=1
Reactant: c1ccncc1
Reactant: O=C(OC(=O)c1ccccc1)c1ccccc1
Reactant: COc1cc(Nc2ncc3c(n2)CCNC3)cc(OC)c1OC
Solvent: ClCCl
Product: COc1cc(Nc2ncc3c(n2)CCN(C(=O)c2cccnc2)C3)cc(OC)c1OC

Procedure:
A solution of N-(3,4,5-Trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, Intermediate 1 (75 mg, 0.24 mmol) in CH2Cl2 (1.5 mL) was cooled to 0° C. and treated with benzoic anhydride (56.7 mg, 0.251 mmol) and pyridine (22 microliter, 0.273 mmol). After 1 hour the reaction mixture was diluted with CH2Cl2 and washed with water. The organic phase was collected, dried and concentrated. The residue was purified by silica gel chromatography (15-40% acetone/CH2Cl2). The product containing fractions were concentrated to give the title compound (75 mg).
Reaction SMILES: [C:1]1([C:7]23[CH2:14][CH2:13][N:10]([CH2:11][CH2:12]2)[CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([N:22]1[CH2:27][C:26]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=2)([CH2:28][CH2:29][CH2:30]OS(C)(=O)=O)[CH2:25][O:24][C:23]1=[O:44])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[OH2:24].[Cl-:42].[CH2:15]([N:22]1[CH2:27][C:26]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=2)([CH2:28][CH2:29][CH2:30][N+:10]23[CH2:13][CH2:14][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([CH2:8][CH2:9]2)[CH2:12][CH2:11]3)[CH2:25][O:24][C:23]1=[O:44])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:15]([N:22]1[CH2:27][C:26]([CH2:28][CH2:29][CH2:30][N+:10]23[CH2:13][CH2:14][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([CH2:8][CH2:9]2)[CH2:12][CH2:11]3)([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=2)[CH2:25][O:24][C:23]1=[O:44])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-:42]
Reactant: CS(=O)(=O)OCCCC1(c2ccc(Cl)c(Cl)c2)COC(=O)N(Cc2ccccc2)C1
Reactant: c1ccc(C23CCN(CC2)CC3)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1OCC(CCC[N+]23CCC(c4ccccc4)(CC2)CC3)(c2ccc(Cl)c(Cl)c2)CN1Cc1ccccc1
Product: [Cl-]
Temperature: 50 °C
Yield: 121 %

Procedure:
A mixture of 1.2 g of 4-phenyl-1-azabicyclo[2.2.2]octane and 2 g of the compound obtained in step C of EXAMPLE 8 in 10 ml of DMF is heated to 50° C. for 3 hours. After cooling to RT, the reaction mixture is poured into water and extracted with DCM, the organic phase is washed with water, with saturated NaCl solution, twice with 2 N HCl solution, twice with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is taken up with AcOEt and the precipitate formed is wrung to give 1.56 g of the expected product. M.p.=235° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH2:4][C:5]([CH3:8])(C)N=1.C([Li])CCC.C(OC([NH:21][C@@H:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)C(Br)=O)=O)(C)(C)C.S(=O)(=O)(O)[OH:33]>O1CCCC1.CCCCCC.C(O)C>[NH2:21][C@@H:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:8][CH2:5][C:4]([O:3][CH2:2][CH3:1])=[O:33]
Reactant: O=S(=O)(O)O
Reactant: CC1=NC(C)(C)CO1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)Br)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)CC[C@@H](N)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a stirred solution of 2,4,4-trimethyl-2-oxazoline (620 μL, 4.8 mmol) in 10 mL of anhydrous tetrahydrofuran was added a 2.5 M solution of butyllithium (1.76 mL, 4.4 mmol) in hexane at -78° C. under an argon atmosphere. The reaction mixture was stirred at -78° C. for 30 min. A solution of N-(tert-Butoxycarbonyl)-2-(S)phenylglycinbromide (14) (1.08 g, 3.6 mmol) in 25 mL of anhydrous THF was added dropwise over a period of 10 min. The reaction mixture was stirred at -78° C. for 30 min, then at room temperature for 45 min, quenched with cold saturated sodium chloride aqueous solution, extracted with ether (5×5 mL). The combined ether extracts were washed with water, brine, dried over anhydrous MgSO4, concentrated under reduced pressure to give a crude 4,4-dimethyl-2-[3(R)-phenyl-3-(tert-butoxycarbamidyl)propyl-2-oxazoline. 1H NMR (CDCl3) δ 1.256 (s, 6H, 2CH3), 1.398 (s, 9H, tert-Bu), 2.05-2.35 (m, 4H), 3.879 (s, 2H), 4.670 (d, 1H, J=3.6 Hz), 5.614 (d, 1H, J=7.2 Hz), 7.20-7.34 (m, 5H); 13C NMR (CDCl3) δ 24.97, 28.18, 32.52, 54.68, 66.72, 78.80, 126.03, 126.95, 128.32, 142.34, 155.09, 165.53. To a stirred solution of this crude 4,4-dimethyl-2-[3(R)-phenyl-3-(tert-butoxycarbamidyl)propyl-2-oxazoline (1.0 g, 3.01 mmol) in 20 mL of 95% ethanol was added a solution of 2.0 mL of concentrated sulfuric acid in 18 mL of 95% ethanol at room temperature. The reaction mixture was heated to reflux for 15 h, cooled to room temperature, concentrated at reduced pressure. The residue was neutralized with 5% sodium bicarbonate solution, then basified with saturated sodium carbonate solution, extracted with methylene chloride (4×20 mL). The combined methylene chloride extracts were washed with brine, dried over anhydrous MgSO4, concentrated under reduced pressure to give 580 mg of product (76% yield for two steps) as a thick oil. 1H NMR (CDCl3) δ 1.220 (t, 3H, J=7.2 Hz, CH3), 1.694 (br, 2H, NH2), 1.92-2.04 (m, 2H), 2.24-2.34 (m, 2H), 3.901 (t, 1H, J=6.9 Hz, benzyl), 4.082 (q, 2H, J=7.2 Hz, OCH2), 7.20-7.45 (m, 5H, aryl); 13C NMR (CDCl3) δ 14.00, 31.11, 34.13, 55.25, 60.08, 126.08, 126.93, 128.33, 145.44, 173.25.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[CH3:32][Si:33]([CH3:40])([CH3:39])[CH2:34][CH2:35][O:36][CH2:37]Cl>C1COCC1.CCOC(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:37][O:36][CH2:35][CH2:34][Si:33]([CH3:40])([CH3:39])[CH3:32])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1csc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1csc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.8 %

Procedure:
To a solution of methyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)thiazole-4-carboxylate (14 g, 31.1 mmol) in THF (150 mL) was added TEA (6.3 g, 62.1 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (7.77 g, 46.6 mmol). The mixture was stirred at r.t. for 4 h. The mixture was diluted with EtOAc (400 mL) and washed with 3% HCl, water and brine. Evaporation of solvent gave 18.2 g of product. LC/MS (APCI): m/z 580.9 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([CH3:21])=[C:10]1[C:22](OCC)=[O:23].[C:27]1([N:33]=[C:34](Cl)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:20][C:13]1[NH:12][C:11]2[CH:21]=[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:22](=[O:23])[C:10]=2[CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1OC
Reactant: ClC(=Nc1ccccc1)c1ccccc1
Product: CCOC(=O)C1=C(C)Nc2cc(-c3ccccc3)n(-c3ccccc3)c(=O)c2C1c1ccccc1OC

Procedure:
This product is obtained using the procedure of Example 1 from diethyl 1,4-dihydro-4-(2-methoxyphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate and N-phenylbenzimidoyl chloride (3.1 g, 12.6%).
Reaction SMILES: C([O:8][C:9]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:39][CH2:38][N:37]([CH:40]([CH3:42])[CH3:41])[CH2:36][CH2:35]2)=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12])C1C=CC=CC=1.C(Cl)(Cl)Cl>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:35][CH2:36][N:37]([CH:40]([CH3:42])[CH3:41])[CH2:38][CH2:39]2)=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCN(C(C)C)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCN(C(C)C)CC2)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a solution mixture of the obtained methyl 2-(2-(benzyloxy)-5-(1-isopropylpiperidin-4-yl)benzamido)-4-phenylbenzoate (0.12 g) in ethyl acetate (1.5 mL) and methanol (1.5 mL), 10% palladium-carbon (0.12 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 1 hour. Chloroform was added to the reaction mixture, and the insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure to obtain 0.086 g of methyl 2-(2-hydroxy-5-(1-isopropylpiperidin-4-yl)benzamido)-4-phenylbenzoate as an orange solid.