Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[CH2:12][S:13][C@@H:14]2[C@H:21]([NH:22][C:23](=[O:34])[C:24](=[N:31][O:32][CH3:33])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:20](=[O:35])[N:15]2[C:16]=1[C:17]([OH:19])=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P([O-])([O-])([O-])=O.[C:41]([O-])(=O)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CS(C)=O>[C:1]([O:9][CH2:10][C:11]1[CH2:12][S:13][C@@H:14]2[C@H:21]([NH:22][C:23](=[O:34])[C:24](=[N:31][O:32][CH3:33])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:20](=[O:35])[N:15]2[C:16]=1[C:17]([O:19][CH:41]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccccc1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)c3ccccc3)CS[C@H]12)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(=O)c3ccccc3)CS[C@H]12)c1ccccc1

Procedure:
3-Benzoyloxymethyl-7β-(2-methoxyimino-2-phenylacetamido)-ceph-3-em-4-carboxylic Acid (syn-isomer) as a white powder (48%) [α]D + 46.5° (c 0.9 in DMSO) λmax. (pH 6 phosphate buffer) 232.5 (ε 22,400) and 258.5 nm (ε 21.400) λmax. (Nujol) 1780 (β-lactam), 1720 and 1265 (benzoate), 1705 (CO2H), 1675 and 1532 cm-1 (CONH) τ (DMSO-d6, 100 MHz) 0.16 (doublet, J 8 Hz; NH) 4.06 (double doublet J 5 and 8 Hz; C-7H), 4.70 (doublet; J5 Hz; C-6 H), 6.03 (singlet; NOCH3), and 6.14 and 6.44 [2 doublets (branches of quartet), J 18 Hz; C-2 CH2 ].
Reaction SMILES: [Li]CCCC.CC1(C)CCCC(C)(C)N1.[F:16][C:17]1[C:25]([CH3:26])=[C:24]([F:27])[CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].[S:28]1[CH:32]=[CH:31][N:30]=[C:29]1[CH:33]=[O:34]>C1COCC1>[F:16][C:17]1[C:25]([CH3:26])=[C:24]([F:27])[C:23]([CH:33]([OH:34])[C:29]2[S:28][CH:32]=[CH:31][N:30]=2)=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]
Reactant: Cc1c(F)ccc(C(=O)O)c1F
Reactant: O=Cc1nccs1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(F)c(C(=O)O)cc(C(O)c2nccs2)c1F
Temperature: -78 °C

Procedure:
A solution of 1.9 M n-BuLi (3.8 ml, 7.2 mmol) in hexanes was added at −30° C. to a stirred solution of 2,2,6,6-tetramethylpiperidine (1.2 g, 9.0 mmol) in THF and the mixture was stirred for an hour at the same temperature. After cooling to −78° C., a solution of 2,4-difluoro-3-methylbenzoic acid (Intermediate 46, 0.5 g, 3.0 mmol) in THF was added slowly at and the mixture was stirred for another 2 h at the same temperature. To this mixture, a solution of thiazole-2-carboxaldehyde (0.8 g, 7.2 mmol) in THF was added dropwise over a period of 10 mins and the mixture was brought to the room temperature. The reaction mixture was quenched with 1.5N hydrochloric acid and the organic layer was separated, the aqueous layer was extracted with ethyl acetate (3×10 mL) and the combined organic layer was dried over sodium sulfate. Removal of solvent afforded the title compound as colorless product. Yield: 0.42 g (51%).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:24])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[NH:18][CH:17]=[CH:16]4)[CH:7]=2)[CH2:3][CH2:2]1.Br[CH2:26][CH:27]1[CH2:30][CH2:29][CH2:28]1>>[CH:27]1([CH2:26][N:18]2[CH:17]=[CH:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:8]4[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=4[CH3:12])[C:5]([NH:4][CH:1]4[CH2:2][CH2:3]4)=[O:24])[CH:14]=3)[C:19]2=[O:23])[CH2:30][CH2:29][CH2:28]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)[nH]ccc2c1
Reactant: BrCC1CCC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CCC3)ccc2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 123 using the product of Example 11 and (bromomethyl)cyclobutane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[CH:18]=2)([NH2:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.N1C=CC=CC=1.[F:34][C:35]([F:49])([F:48])[C@:36]([O:46][CH3:47])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:37](Cl)=[O:38]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:16][C:37](=[O:38])[C@@:36]([O:46][CH3:47])([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:35]([F:48])([F:49])[F:34])([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:20]=[C:19]([F:27])[CH:18]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reactant: CO[C@](C(=O)Cl)(c1ccccc1)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CO[C@](C(=O)N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1)(c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To racemic 1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine (obtained as described in Example 1, Procedure 1) (55 mg, 0.14 mmol) in DCM (1 mL) was added pyridine (56 μL, 55 mmol) and (R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl chloride (52 μL, 0.22 mmol). The reaction was stirred at room temperature for 14 h and the reaction mixture filtered through a silica plug elution with DCM. (S)-N-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3,3,3-trifluoro-2-methoxy-2-phenylpropanamide was crystallized from ether heptane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([C:48]([N:50]2[CH2:55][C@H:54]([CH3:56])[O:53][C@H:52]([CH3:57])[CH2:51]2)=[O:49])=[CH:44][C:43]=1[CH3:58]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[CH:46][C:45]([C:48]([N:50]6[CH2:55][C@H:54]([CH3:56])[O:53][C@H:52]([CH3:57])[CH2:51]6)=[O:49])=[CH:44][C:43]=5[CH3:58])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: Cc1cc(C(=O)N2C[C@@H](C)O[C@@H](C)C2)ccc1Br
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4C[C@@H](C)O[C@@H](C)C4)cc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (50 mg) and (4-bromo-3-methyl-phenyl)-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-methanone (44 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-methyl-phenyl]-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-246) as a pale yellow powder (22 mg, 45%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22]>>[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:22]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3cccc(Cl)c3)c2)CC1
Yield: 82.7 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 3-chlorobenzoyl chloride (120 mg, 0.687 mmol), 67.6 mg (83%) of the title compound were recovered.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[CH3:9][O-:10].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:10][CH3:9])[CH:7]=1
Reactant: C[O-]
Reactant: Brc1cncc(Br)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cncc(Br)c1
Temperature: 100 °C
Yield: 66 %

Procedure:
To a solution of 3,5-dibromopyridine (10.0 g, 42.2 mmol) in DMF (10 mL) in a flask with a distillation head was added NaOMe solution 25% wt/wt (10 mL) and the mixture was heated to 100° C. for 3 hours. At the end of 3 hours ˜8 mL of MeOH was collected. The DMF solution was cooled to room temperature and diluted with H2O (25 mL) and extracted with MTBE (2×25 mL). The combined organic layers were washed with H2O (2×25 mL), dried over Na2SO4, filtered and concentrated. The residue was then dried under high vacuum for 10 hours to give the title compound (5.2 g, 66%). 1H NMR (400 MHz, DMSO-D6) δ 8.26-8.31 (m, 2H) 7.69-7.72 (m, 1H) 3.84 (s, 3H).
Reaction SMILES: [C:1](=O)([O:7]C1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][CH2:4][O:5][CH3:6].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH3:35][C:36]1[CH:72]=[CH:71][CH:70]=[CH:69][C:37]=1[CH2:38][NH:39][C:40]([C@@H:42]1[C:46]([CH3:48])([CH3:47])[S:45][CH2:44][N:43]1[C:49](=[O:68])[C@@H:50]([OH:67])[C@@H:51]([NH:59][C:60](=[O:66])[C@H:61]([CH:63]([CH3:65])[CH3:64])[NH2:62])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:41]>CN(C=O)C.C(OCC)(=O)C>[CH3:35][C:36]1[CH:72]=[CH:71][CH:70]=[CH:69][C:37]=1[CH2:38][NH:39][C:40]([C@@H:42]1[C:46]([CH3:48])([CH3:47])[S:45][CH2:44][N:43]1[C:49](=[O:68])[C@@H:50]([OH:67])[C@@H:51]([NH:59][C:60](=[O:66])[C@@H:61]([NH:62][C:1]([O:2][CH2:3][CH2:4][O:5][CH3:6])=[O:7])[CH:63]([CH3:65])[CH3:64])[CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)=[O:41]
Reactant: COCCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@@H](N)C(C)C)CSC1(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCCOC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)N1CSC(C)(C)[C@H]1C(=O)NCc1ccccc1C)C(C)C
Reaction time: 8 h

Procedure:
Methoxyethyl p-nitrophenyl carbonate (112 mg), HOBt (41 mg), triethylamine (104 μl) were added to a solution of H-Val-Apns-Dmt-NHBzl(2-Me) obtained in the step 2 of Example 8 in DMF (5 ml) and the mixture was stirred overnight. After the addition of ethyl acetate, the reaction mixture was washed with 3% Na2CO3, 1N HCl, and 5% NaCl and dried over MgSO4. After filtration and concentration, the residue was purified using silica gel column chromatography and reprecipitated from ethyl acetate/n-hexane to obtain the title compound (130 mg).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7](=[O:16])[C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10](Cl)[N:9]=1>>[Cl:14][C:12]1[CH:13]=[C:8]([C:7]([O:6][CH3:5])=[O:16])[N:9]=[C:10]([C:7]([O:6][CH3:5])=[O:16])[CH:11]=1
Reactant: COC(=O)c1cc(Cl)cc(Cl)n1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)cc(C(=O)OC)n1
Temperature: 80 °C

Procedure:
N-Ethyl-4-pyridone-2,6-dicarboxylic acid, prepared in Step A of Example 36, was treated with thionyl chloride and heated at 80° C. as described in the literature. The excess thionyl chloride was removed under reduced pressure and the remaining residue was cooled to 0° C. The product was slowly poured into cold methanol with vigorous stirring. The solvent was then removed in vacuo and the crude product was purified by silica gel column chromatography. Two products were isolated: the higher Rf product was 4,6-dichloropicolinic acid methyl ester while the lower Rf product was the title compound.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[F:7][C:8]1([CH:20]([CH3:24])[C:21](O)=[O:22])[CH2:13][CH:12]=[CH:11][CH:10]=[C:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O.C(Cl)Cl>[F:7][C:8]1([CH:20]([CH3:24])[C:21]([Cl:4])=[O:22])[CH2:13][CH:12]=[CH:11][CH:10]=[C:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C(=O)O)C1(F)CC=CC=C1c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C(=O)Cl)C1(F)CC=CC=C1c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (3.8 g, 30 mmol) was combined with methylene chloride (30 mL). The resulting mixture was cooled to 0° C. and dimethylformamide (10 drops) was added. After 5 minutes of stirring a solution of 2-fluoro-α-methyl-biphenylacetic acid (3.0 g, 12 mmol) in methylene chloride (30 mL) was added dropwise over a 30 minute period. The reaction mixture was allowed to warm to room temperature and stirred overnight. The solvent was evaporated to give the product in a quantitative yield as a yellow solid. 1H NMR (CDCl3) δ: 1.58 (d, 3 H), 4.20 (q, 1H), 7.11 (t, 2H), 7.33-7.47 (m, 4H), 7.54 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:22](=[O:23])[O:24][CH2:25][CH3:26])=[C:3]([C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[NH:4]2)=[CH:9][CH:8]=1
Reactant: Cc1cccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)Nc1c(C(=O)c2cccc(C)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 3-amino-6-chloro-2-(3-methylbenzoyl)-1H-indole (step 2) and ethyl chloroformate.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:21])=[CH:4][C:5]([F:20])=[C:6]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)[CH:7]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.[Cl-].[NH4+].C(O)C.O>[Cl:21][C:3]1[C:2]([NH:1][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:7][C:6]([C:8]2[C:9](=[O:19])[N:10]([CH3:18])[C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)=[C:5]([F:20])[CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc(N)c(Cl)cc2F)c1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(C(F)(F)F)ccc(-c2cc(NS(C)(=O)=O)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
0.9 g (2.8 mmol) of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone and 0.6 g (5.9 mmol) of triethylamine were dissolved in 20 ml of dichloromethane, and 0.7 g (6.1 mmol) of methylsulfonyl chloride was dropwise added thereto under cooling with ice. The mixture was stirred at room temperature for 2 hours and then diluted with an aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate. After washing with water and a saturated sodium chloride aqueous solution, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. Then, the obtained crude crystals of the bissulfone compound were dissolved in 25 ml of ethanol, and 10 ml (5.0 mmol) of a 0.5N sodium hydroxide aqueous solution was added at room temperature, followed by stirring for 1 hour. The mixture was poured into water, acidified with citric acid and extracted with ethyl acetate After washing with water, the organic layer was dried over anhydrous magnesium sulfate Ethyl acetate was distilled off under reduced pressure. Then, the obtained crude crystals were washed with n-hexane to obtain 0.80 g (yield: 72%) of the desired product. Melting point: 113-114° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br.Br[CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[C:15]([Cl:27])[CH:14]=1)=[O:11].[Cl:28][C:29]1[CH:30]=[C:31]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:33][C:34]=1[OH:35].CN(C=O)C>ClCCl>[Cl:28][C:29]1[CH:30]=[C:31]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=[CH:33][C:34]=1[O:35][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[C:15]([Cl:27])[CH:14]=1)=[O:11]
Reactant: CCN(CC)CCOc1ccc(NC(=O)CBr)cc1Cl
Reactant: Oc1ccc(-c2ccccc2)cc1Cl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(-c3ccccc3)cc2Cl)cc1Cl

Procedure:
65 mg (0.47 mmol) of potassium carbonate was added to a solution of 70 mg (0.159 mmol) of 2-bromo-N-[3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-acetamide-hydrobromide (intermediate product Z1c) and 64 mg (0.314 mmol) of 3-chloro-biphenyl-4-ol in 1 mL of abs. DMF and the mixture was stirred for 1 hour at 40° C. and for 15 hours at RT. The reaction mixture was diluted with dichloromethane, the org. phase was washed with sat. aqueous sodium bicarbonate solution and water and dried over magnesium sulphate. Column chromatography (silica gel, dichloromethane/MeOH 9:1) yielded the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:18])=O.CN(C)C=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5]([Cl:18])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(OC)c(C(=O)O)cc1OC
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(OC)c(C(=O)Cl)cc1OC
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2,4,5-Trimethoxybenzoic acid (500 g) was suspended in dried toluene (2 l) and to the suspension, thionyl chloride (206 ml) and N,N-dimethylformamide (1.0 ml) were added at room temperature, and the mixture was stirred at 80° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. To the resultant residue, n-hexane was added and through co-boiling the mixture, 2,4,5-trimethoxybenzoyl chloride was obtained. To the resultant compound, 2-amino-4-methoxycarbonyl-1,3-thiazole (372.7 g) and 1,2-dichloroethane (4.5 l) were added and the mixture was refluxed for 6 hours. After completion of reaction, the reaction mixture was allowed to cool. Crystals so precipitated were collected by filtration, washed with 1,2-dichloroethane, and air-dried. The crystals were suspended in water (8 l) and to the suspension, ice (2 kg) was added. While cooling, a solution of sodium hydroxide (94 g) in water (850 ml) was added thereto to thereby adjust the pH of the suspension at about 7.5. Subsequently, the mixture was stirred for 3 hours at room temperature. Crystals so precipitated were collected by filtration, washed with water, and air-dried to thereby obtain the title compound (702.7 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=O)[CH3:9])=[CH:4][CH:3]=1.[CH3:22][C:23]([S@:26]([NH2:28])=[O:27])([CH3:25])[CH3:24]>C1COCC1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13](=[N:28][S@@:26]([C:23]([CH3:25])([CH3:24])[CH3:22])=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: C[C@H](NCCC(=O)c1ccc(F)cc1)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](NCCC(=N[S@](=O)C(C)(C)C)c1ccc(F)cc1)c1ccc(Br)cc1
Yield: 73.3 %

Procedure:
A mixture of (S)-3-(1-(4-bromophenyl)ethylamino)-1-(4-fluorophenyl)propan-1-one (14.5 g, 0.04 mol), (R)-2-methylpropane-2-sulfinamide (5.5 g, 0.046 mol), and Ti(OEt)4 (18 g, 0.08 mmol) in THF (150 mL) was heated to reflux overnight. The mixture was treated with brine, and the precipitate was filtered. The filtrate was concentrated to give (R)—N-(3-((1S)-1-(4-bromophenyl)ethylamino)-1-(4-fluorophenyl)propylidene)-2-methylpropane-2-sulfinamide (13.3 g, 59%), which was used for the next step without purification.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[CH:5]=[C:4]([O:17][CH2:18][CH:19]2[CH2:21][O:20]2)[CH:3]=1.FC(F)(F)C(O)=[O:25]>>[OH:20][CH:19]([CH2:21][OH:25])[CH2:18][O:17][C:4]1[CH:3]=[C:2]([OH:1])[C:15]2[C:14](=[O:16])[C:13]3[C:8]([O:7][C:6]=2[CH:5]=1)=[CH:9][CH:10]=[CH:11][CH:12]=3
Reactant: O=c1c2ccccc2oc2cc(OCC3CO3)cc(O)c12
Reactant: O=C(O)C(F)(F)F
Product: O=c1c2ccccc2oc2cc(OCC(O)CO)cc(O)c12
Temperature: 50 °C
Reaction time: 4 h
Yield: 62.7 %

Procedure:
1-hydroxy-3-(oxiran-2-ylmethoxy)-9H-xanthen-9-one (30 mg, 0.11 mmol) synthesized in Step 2 of Example 2 and 50% trifluoroacetic acid (TFA) (5 mL) were charged to a round-bottom flask, followed by stirring at 50° C. for 4 hours. After the reaction was completed, the solvent was removed, followed by drying under reduced pressure to give the title compound (20 mg, 62.7%) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.C[Si]([N:27]=[C:28]=[S:29])(C)C.[ClH:30].CCO.Cl>C1C=CC=CC=1.O.CCO.CCOCC>[CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([C:28](=[S:29])[NH2:27])[C:6]=2[N:5]=[CH:4][CH:3]=1.[ClH:30]
Reactant: Cc1ccnc2c1CCCC2
Reactant: C[Si](C)(C)N=C=S
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1ccnc2c1CCCC2C(N)=S
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-methyl-5,6,7,8-tetrahydroquinoline (5.83 g., 0.04 mole) in dry benzene (40 ml.) was cooled to 0° and to the stirred solution was added dropwise a 15% w/w solution of butyl lithium in hexane (17.5 ml., 0.04 mole) under an atmosphere of nitrogen. The red reaction mixture was stirred at 0° for a further 30 minutes. Trimethylsilylisothiocyanate (5.6 ml., 0.04 mole) was then added dropwise, maintaining the temperature at 0°. After an additional 30 minutes, the mixture was allowed to warm to room temperature and diluted with water (40 ml.) The pH was adjusted to 2.0 by addition of conc. HCl and the benzene layer separated and discarded. The aqueous phase was adjusted to pH 10.0 by adding anhydrous Na2CO3 and extracted with CHCl3 (3 × 40 ml.). The CHCl3 solution was then dried (MgSO4), filtered and evaporated (reduced pressure) to afford an oil (5.77 g.). Addition of ether caused crystallisation of the title compound as colourless needles. Filtration afforded 0.69 g. of base which was converted to the hydrochloride by dissolving in a minimum of EtOH, adding EtOH/HCl until just acid followed by ether to induce crystallisation. Filtration provided the title compound hydrochloride as colourless needles, (0.64 g.), m.p. 213° C. Analysis: Found: C, 54.95; H, 6.40; N, 11.52 C11H14N2S.HCl requires C, 54.42; H, 6.23; N, 11.54%
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]#[N:19])[CH:14]=3)[C:9]2=[O:20])[CH2:6][CH2:5][C:4](=[O:21])[NH:3]1.[ClH:22].O>CN(C=O)C.[Pd]>[ClH:22].[NH2:19][CH2:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:20])[N:8]([CH:7]1[CH2:6][CH2:5][C:4](=[O:21])[NH:3][C:2]1=[O:1])[C:16]2=[O:17]
Reactant: N#Cc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 85 %

Procedure:
A mixture of 2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carbonitrile (1.00 g, 3.53 mmol), 4N HCl (4.5 mL), 10% Pd—C (0.1 g) and decolorizing carbon (0.06 g) in DMF (30 mL) was hydrogenated at 50 psi overnight. Water (5 mL) was added, and the reaction mixture was filtered through Celite. The filter was washed with methanol (10 mL). The filtrate was concentrated, and the residue was co-evaporated with ethanol (4×5 mL). The resulting solid was triturated with ethanol (5 mL) for 1 hour, filtered, washed with additional ethanol (10 mL), and dried to give 0.97 g of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride as a white solid, in 85% yield; mp>260° C.; 1H NMR (DMSO-d6) δ 2.05-2.12 (m, 1H), 2.45-2.63 (m, 2H), 2.83-2.98 (m, 1H), 4.24 (s, 2H), 5.18 (dd, J=12.6 Hz, J=5.4 Hz, 1H), 7.96-8.03 (m, 2H), 8.11 (s, 1H), 8.73 (br, 3H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 41.7, 49.1, 123.6, 123.9, 131.0, 131.5, 135.4, 141.5, 166.8, 166.9, 169.8, 172.7; Anal. Calcd for C14H14N3O4Cl+0.15H2O: C, 51.51; H, 4.42; N, 12.87. Found: C, 51.16; H, 4.40; N, 12.59.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](Cl)=[O:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][C:10](=[O:11])[N:9]([CH3:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccccn1
Product: CN(C(=O)Oc1ccccn1)c1ccccc1

Procedure:
The title product was prepared from 2-hydroxypyridine and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (57%, colorless oil). HPLC-MS: m/z=229.1 (M+23); Rt: 2.80 min.