Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:18]#[C:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:8][C:9]=1[NH:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[O:4].[CH3:24][CH:25]1[CH2:30][CH2:29][CH:28]([C:31](Cl)=[O:32])[CH2:27][CH2:26]1>CN(C1C=CN=CC=1)C.ClCCCl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:18]#[C:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:8][C:9]=1[N:10]([C:31]([CH:28]1[CH2:29][CH2:30][CH:25]([CH3:24])[CH2:26][CH2:27]1)=[O:32])[NH:11][C:12](=[O:17])[C:13]([F:14])([F:15])[F:16])=[O:4]
Reactant: CC1CCC(C(=O)Cl)CC1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1NNC(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(NC(=O)C(F)(F)F)C(=O)C1CCC(C)CC1
Temperature: 40 °C
Yield: 96.7 %

Procedure:
A mixture of 5-(3,3-dimethyl-but-1-ynyl)-3-[N′-(2,2,2-trifluoro-acetyl)-hydrazino]-thiophene-2-carboxylic acid methyl ester (2.1 g, 6.0 mmol), 4-methyl-cyclohexanecarbonyl chloride (1.45 g, 9 mmol), DMAP (1.1 g, 9 mmol) and DCE (20 mL) was heated to 40° C. for 16 h. After cooling, the mixture was concentrated and the product was purified by silica gel chromatography 0-30% EtOAc/hexanes to give 5-(3,3-dimethyl-but-1-ynyl)-3-[N-(4-methyl-cyclohexanecarbonyl)-N′-(2,2,2-trifluoro-acetyl)-hydrazino]-thiophene-2-carboxylic acid methyl ester (2.74 g, 5.8 mmol).
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([S:9][CH:10]([CH3:12])[CH3:11])([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].O1CCOCC1.[OH-].[Na+].Cl[C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23]>O>[CH:25]([O:24][C:22]([NH:1][C@@H:2]([C:6]([S:9][CH:10]([CH3:12])[CH3:11])([CH3:7])[CH3:8])[C:3]([OH:5])=[O:4])=[O:23])([CH3:27])[CH3:26]
Reactant: CC(C)OC(=O)Cl
Reactant: CC(C)SC(C)(C)[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)OC(=O)N[C@H](C(=O)O)C(C)(C)SC(C)C
Reaction time: 6 h
Yield: 64 %

Procedure:
2-(R)-Amino-3-isopropylsulfanyl-3-methyl-butyric acid (17 mmol; crude material obtained from D-penicillamine and isopropyl iodide) was dissolved in 40 mL of water and 40 mL of dioxane and pH 9.5 was adjusted by adding aqueous NaOH. Isopropyl chloroformate (22 mL; 1 M solution in toluene) was slowly added at 5° C. while maintaining pH 9.5 by addition of the appropriate amount of aqueous NaOH. Stirring was continued for 6 h at room temperature. Aqueous NaOH was added (pH 11) and the dioxane removed in vacuo followed by extraction of the remaining aqueous solution with ethyl acetate. KHSO4 was added and the acidified aqueous solution extracted with ethyl acetate several times, Evaporation of the solvent in vacuo gave a yellow oil, which was purified by HPLC (RP-18; pH 2.3; H2O/CH3OH 3/7) to give 3.0 g (64%) of the title compound as a colorless oil. (−)-APCI-MS: 276 ([M−H]−).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([C:14]([OH:16])=O)[O:7][CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:29][O:30][NH:31][CH3:32]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([C:14]([N:31]([CH3:32])[O:30][CH3:29])=[O:16])[O:7][CH2:6][CH2:5]2
Reactant: COc1cc2c(cc1Br)CCOC2C(=O)O
Reactant: CNOC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COc1cc2c(cc1Br)CCOC2C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-bromo-7-(methyloxy)-3,4-dihydro-1H-isochromene-1-carboxylic acid (5.9 g, 21 mmol) and CDI (4.0 g, 25 mmol) in 60 mL of dry DCM was stirred at r.t. for 0.5 hours and then O,N-dimethyl-hydroxylamine (2.4 g, 25 mmol) was added. The result mixture was stirred overnight. The solvents were removed under vacuum, and the residue was purified by column to give 6-bromo-N-methyl-N,7-bis(methyloxy)-3,4-dihydro-1H-isochromene-1-carboxamide.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]([C:17]([O:19][CH3:20])=[O:18])#[C:12][C:13]([O:15][CH3:16])=[O:14]>CO>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:12](=[CH:11][C:17]([O:19][CH3:20])=[O:18])[C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Product: COC(=O)C=C(Nc1ccc([N+](=O)[O-])cc1)C(=O)OC
Temperature: 25 °C
Yield: 45.9 %

Procedure:
A solution of 4-nitroaniline (6.91 g, 50 mmol) and dimethyl acetylenedicarboxylate (7.82 g, 55 mmol) in methanol (100 ml) was refluxed under heating for 24.5 hr. The reaction vessel was cooled to room temperature and allowed to stand for a day. The resulting crystals were collected by filtration to give dimethyl 2-[(4-nitrophenyl)amino]-2-butenedioate (6.43 g, 46%, yellow crystals).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19]>O1CCOCC1>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[O:12]
Reactant: NCCCCO
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: C1COCCO1
Product: O=C(NCCCCO)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
43 mmol (8.2 g) naphthalen-2-carboxylic acid chloride is dissolved in 50 mL dioxane and dropwise added to a solution of 112 mmol (10.0 g) 4-amino-butan-1-ol in 100 mL dioxane and stirred overnight at room temperature. The mixture is then poured into 200 mL of ice water and filtrated. The white solid separated is dried under vacuum.
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH:5]1[N:11]2[C:12](=[O:15])[O:13][N:14]=[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6]1)[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)Cl>[CH2:1]([S:3]([CH2:4][CH:5]1[N:11]2[C:12](=[O:15])[O:13][N:14]=[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:24])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSCC1CCCCc2noc(=O)n21
Solvent: ClCCl
Product: CCS(=O)CC1CCCCc2noc(=O)n21

Procedure:
The product of Example 38 is reacted with one equivalent of MCPBA in CH2Cl2 to generate the title material.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=O)=[CH:15][CH:14]=1.[Cl:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1C(OC)=O.CCOCC>C1COCC1>[Cl:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:20](=[O:22])[CH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: COC(=O)c1ccccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)c2ccccc2Cl)cc1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 16 %

Procedure:
230 ml of a 2M solution of NaHMDS in THF are introduced under nitrogen in a 250 ml of THF. The solution is cooled to −60° C. and then 30.5 g of (4-methoxyphenyl)acetic acid in 120 ml of THF are added at this temperature. After 1 h 30 min at −60° C., 29.8 g of methyl 2-chlorobenzoate are added and the mixture is stirred at −60° C. for 45 min and then allowed to return to 0° C. The reaction medium is poured on to 500 ml of ice-cold 2N HCl, extraction is carried out with ether and the extract is washed with water and then with a saturated aqueous sodium chloride solution. After drying and concentrating to dryness, purification is carried out by chromatography on silica (gradient: heptane up to heptane/AcOEt 80/20). 7.3 g of the expected compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH2:19]([N:21]([CH2:35][CH3:36])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[NH:28][C:29]([CH:33]=O)=[C:30]([CH3:32])[CH:31]=1)=[O:26])[CH3:20]>C(O)C.N1CCCCC1>[CH2:35]([N:21]([CH2:19][CH3:20])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[NH:28][C:29]([CH:33]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:13][C:12]2=[O:18])=[C:30]([CH3:32])[CH:31]=1)=[O:26])[CH3:36]
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Reactant: CCN(CC)CCNC(=O)c1cc(C)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCNC(=O)c1cc(C)c(C=C2C(=O)Nc3cccc(-c4cccc(OC)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.9 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (40 mg, 34%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:30]([CH3:31])=[CH:29][C:15]2[N:16]=[C:17](C3C=CC4N(C)N=NC=4C=3)[S:18][C:14]=2[C:13]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:39][N:40]1[C:44]2[CH:45]=[C:46](B3OC(C)(C)C(C)(C)O3)[CH:47]=[CH:48][C:43]=2[N:42]=[N:41]1>>[C:1]([O:5][C@@H:6]([C:12]1[C:30]([CH3:31])=[CH:29][C:15]2[N:16]=[C:17]([C:46]3[CH:47]=[CH:48][C:43]4[N:42]=[N:41][N:40]([CH3:39])[C:44]=4[CH:45]=3)[S:18][C:14]=2[C:13]=1[C:32]1[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cn1nnc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)nnn4C)sc2c1-c1ccc(Cl)cc1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4nnn(C)c4c3)sc2c1-c1ccc(Cl)cc1

Procedure:
Prepared in a manner similar to (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)benzo[d]thiazol-6-yl)acetate, but using 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d][1,2,3]triazole instead of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d][1,2,3]triazole. 1H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 8.11 (d, J=8.7 Hz, 1H), 7.96 (d, J=7.6 Hz, 2H), 7.60-7.45 (m, 4H), 5.18 (s, 1H), 4.39 (s, 3H), 4.28-4.17 (m, 2H), 2.63 (s, 3H), 1.26 (t, J=8 Hz, 3H), 0.99 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:24]2[C:29](=[O:30])[CH2:28][CH:27]([C:31](F)(F)F)[CH2:26][C:25]=2[OH:35])[NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[O:12])=[CH:5][CH:4]=1)#[N:2].[CH3:36][O:37][C:38]1[CH:39]=C(C2CC(=O)CC(=O)C2)[CH:41]=[C:42]([O:46][CH3:47])[C:43]=1[O:44][CH3:45]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:24]2[C:29](=[O:30])[CH2:28][CH:27]([C:31]3[CH:39]=[C:38]([O:37][CH3:36])[C:43]([O:44][CH3:45])=[C:42]([O:46][CH3:47])[CH:41]=3)[CH2:26][C:25]=2[OH:35])[NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:21])[F:23])[CH:15]=2)=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(C(NC(=O)Nc2cccc(C(F)(F)F)c2)C2=C(O)CC(C(F)(F)F)CC2=O)cc1
Reactant: COc1cc(C2CC(=O)CC(=O)C2)cc(OC)c1OC
Product: COc1cc(C2CC(=O)C(C(NC(=O)Nc3cccc(C(F)(F)F)c3)c3ccc(C#N)cc3)=C(O)C2)cc(OC)c1OC

Procedure:
The title compound is prepared in analogy to 1-((4-cyanophenyl)(2-hydroxy-6-oxo-4-(tri-fluoromethyl)cyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 12), using 5-(3,4,5-trimethoxyphenyl)cyclohexane-1,3-dione (300 mg, 1.08 mmol) as starting material. Yield: 590 mg; ESI mass spectrum [M+H]+=596, Retention time HPLC: 0.76 min (V011_S01).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][N:24]=1>CN(C=O)C>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:4]2[C:5]3[C:10](=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][CH:6]=3)[C:2]([I:1])=[N:3]2)=[N:24][CH:25]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Reactant: Fc1ccc(CCl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2c1c(I)nn2Cc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.3 %

Procedure:
To a solution of 3-iodo-4-nitro-1H-indazole (1.0 g, 3.46 mmol) in DMF (20 mL) was added potassium carbonate (0.956 g, 6.92 mmol) and 2-(chloromethyl)-5-fluoropyridine hydrochloride (0.630 g, 3.46 mmol). The mixture was stirred at ambient temperature for 18 hours under nitrogen. The mixture was concentrated under vacuum and then diluted water (300 mL). The precipitated solids were collected by filtration and washed with water. The material was dried under high vacuum for 16 hours to give 1-((5-fluoropyridin-2-yl)methyl)-3-iodo-4-nitro-1H-indazole (0.968 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][CH:14]=1.[Br:16]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:16][C:13]1[CH:14]=[C:9]([O:8][C:7]2[CH:6]=[CH:5][N:4]=[N:3][C:2]=2[CH3:1])[C:10]([NH2:15])=[N:11][CH:12]=1
Reactant: Cc1nnccc1Oc1cccnc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nnccc1Oc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.9 %

Procedure:
3-(3-Methylpyridazin-4-yloxy)pyridin-2-amine (0.50 g, 2.5 mmol) was dissolved in DMF (7 mL). N-Bromosuccinimide (0.46 g, 2.6 mmol) was added and the solution stirred at ambient temperature for 5 minutes. The solution was diluted with water and filtered through celite (rinsing with chloroform). The solution was extracted with chloroform, dried (Na2SO4), filtered and concentrated. Flash chromatography gave 5-bromo-3-(3-methylpyridazin-4-yloxy)pyridin-2-amine (0.66 g, 95%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[CH:6][O:5][N:4]=1.[CH2:8]([NH:15][C:16]([C:18]1[S:22][C:21]([N:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]2=[O:30])=[N:20][C:19]=1[CH3:31])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[O:5]1[CH:6]=[N:7][C:3]([CH2:2][O:29][C:26]2[CH:27]=[CH:28][N:23]([C:21]3[S:22][C:18]([C:16]([NH:15][CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[O:17])=[C:19]([CH3:31])[N:20]=3)[C:24](=[O:30])[CH:25]=2)=[N:4]1
Reactant: ClCc1ncon1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Product: Cc1nc(-n2ccc(OCc3ncon3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 20 %

Procedure:
Following the procedure as described in Example 21, making variation only as required to use 3-(chloromethyl)-1,2,4-oxadiazole in place of 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole to react with N-benzyl-2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxamide, the title compound was obtained as a colorless solid in 20% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.81 (t, J=5.9 Hz, 1H), 8.66 (d, J=8.1 Hz, 1H), 7.36-7.17 (m, 6H), 6.42 (dd, J=8.1, 2.8 Hz, 1H), 6.33 (d, J=2.8 Hz, 1H), 5.26 (s, 2H), 4.38 (d, J=5.9 Hz, 2H), 2.55 (s, 3H); MS (ES+) m/z 424.1 (M+1).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[C:9]([O:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[C:22]([NH:25][C:26]1[CH:36]=[CH:35][CH:34]=[C:28]2[C:29]([O:31][C:32](=O)[C:27]=12)=[O:30])(=[O:24])[CH3:23].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:22]([NH:25][C:26]1[CH:36]=[CH:35][CH:34]=[C:28]2[C:27]=1[C:32](=[O:31])[N:1]([CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[C:9]([O:17][CH2:18][CH:19]3[CH2:21][CH2:20]3)[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5])[C:29]2=[O:30])(=[O:24])[CH3:23]
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Reactant: NC(CC(=O)O)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc2c1C(=O)N(C(CC(=O)O)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Reaction time: 2 h
Yield: 147.4 %

Procedure:
To a solution of 3-amino-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionic acid (500 mg, 1.0 mmol) in acetic acid (10 ml) was added 3-acetamido-phthalic anhydride (390 mg, 1.9 mmol) and sodium acetate (160 mg, 1.9 mmol). The mixture was heated at reflux temperature overnight. The solvent was removed in vacuo. The resulted oil was extracted with ethyl acetate (50 ml) and water (30 ml). The organic layer was washed with water (30 ml×4), brine (30 ml) and dried over magnesium sulfate. The solvent was removed in vacuo and the resulted oil was slurried with ether for 2 hours. The suspension was filtered to give 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionic acid as a white solid (720 mg, 85%). 1HNMR (CDCl3): 0.35-0.39 (m, 2H), 0.64-0.68 (m, 2H), 1.15-1.36 (m, 1H), 2.27 (s, 3H), 3.24 (dd, J=5.8, 17 Hz, 1H), 3.82 (dd, J=10, 17 Hz, 1H), 3.88 (d, J=8.3 Hz, 2H), 5.70 (dd, J=5.8, 10 Hz, 1H), 6.59 (t, JH-F=75 Hz, 1H), 7.06-7.14 (m, 3H), 7.48 (d, J=7.3 Hz, 1H), 7.65 (t, J=7.5 Hz, 1H), 8.76 (d, J=8.3 Hz, 1H), 9.47 (s, 1H).
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-])=[O:18])=[C:10]([C:14]([O-:16])=O)[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[NH2:23][CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.Cl>>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:13][C:12]2=[CH:11][C:10]3[C:14](=[O:16])[N:23]([CH2:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[C:17](=[O:18])[C:9]=3[CH:8]=[C:7]2[CH2:6]1)[CH2:21][CH3:22]
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Reactant: NCc1ccncc1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccncc1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with 4-aminomethylpyridine (0.14 mL, 1.4 mmol). Purification using silica gel, eluting with 3:1 CH2Cl2 /acetone, afforded an oil that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 117 as a white solid (m.p. 283-284° C.).
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37][NH2:38])=[CH:6][CH:5]=1.[CH3:40][O:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[S:48](Cl)(=[O:50])=[O:49]>>[CH:23]([N:15]1[C:16]2[C:21](=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:13]([CH2:12][CH2:11][NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:39])=[O:2])=[CH:5][CH:6]=2)=[C:14]1[CH2:36][CH2:37][NH:38][S:48]([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[O:41][CH3:40])(=[O:50])=[O:49])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC(=O)c1ccc(NCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: COc1ccccc1S(=O)(=O)Cl
Product: COc1ccccc1S(=O)(=O)NCCc1c(CCNc2ccc(C(=O)O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Yield: 85 %

Procedure:
The intermediate from example 143 step 12 was treated with 2-methoxy-benzenesulfonyl chloride according to the procedure in Example 87 step 2 to generate the desired product in 85% yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:38])=[C:11]([CH2:13][O:14][C:15]3[CH:35]=[CH:34][C:18]([CH2:19][O:20][C:21]4[C:25]([CH:26]=[O:27])=[CH:24][N:23]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:22]=4)=[CH:17][C:16]=3[O:36][CH3:37])[N:12]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:40][C:41]([O:43][CH3:44])=[O:42].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:26]([C:25]1[C:21]([O:20][CH2:19][C:18]2[CH:34]=[CH:35][C:15]([O:14][CH2:13][C:11]3[N:12]=[C:8]([C:4]4[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=4)[O:1][CH2:40][C:41]([O:43][CH3:44])=[O:42])[O:9][C:10]=3[CH3:38])=[C:16]([O:36][CH3:37])[CH:17]=2)=[N:22][N:23]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=1)=[O:27]
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2cccc(O)c2)oc1C
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
A mixture of 3-[(4-{[2-(3-hydroxyphenyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.80 g), methyl bromoacetate (0.37 g), potassium carbonate (0.33 g) and N,N-dimethylformamide (30 mL) was stirred at 90° C. for 1 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl (3-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenoxy)acetate as colorless crystals (0.38 g, yield 41%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 107-109° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][C:11](=O)[C:12](F)(F)F)=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.C(OC([NH:24][C@H:25]1[CH2:30][CH2:29][C@H](COS(C(F)(F)F)(=O)=O)[CH2:27][CH2:26]1)=O)(C)(C)C>>[NH2:24][CH:25]1[CH2:30][CH2:29][CH:12]([CH2:11][NH:10][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[C:5]([O:8][CH3:9])[N:4]=2)[CH2:27][CH2:26]1
Reactant: COc1ccc(Cl)c(NC(=O)C(F)(F)F)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](COS(=O)(=O)C(F)(F)F)CC1
Product: COc1ccc(Cl)c(NCC2CCC(N)CC2)n1

Procedure:
This compound is prepared from N-(3-chloro-6-methoxypyridin-2-yl)-2,2,2-trifluoroacetamide (Int. BB step 1) and trans-trifluoro-methanesulfonic acid 4-tert-butoxycarbonylamino-cyclohexylmethyl ester (Int. B step 1) analogously to Intermediate B step 2 and 3; 1H NMR (d6-DMSO, 400 MHz) δ 7.86 (3H, br), 7.42 (1H, d), 6.48 (1H, t), 5.91 (1H, d), 3.77 (3H, s), 3.21 (2H, t), 2.92 (1H, m), 1.94 (2H, m), 1.78 (2H, m), 1.59 (1H, m), 1.28 (2H, m), 1.01 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:17]3[C:12](=[C:13]([OH:18])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]2[CH2:19][CH3:20])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26]>>[CH3:28][O:27][C:25](=[O:26])[CH2:24][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH:11]=[C:10]([CH2:19][CH3:20])[N:9]2[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: CCc1cc2c(O)cccc2n1Cc1cccc(Cl)c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCc1cc2c(OCC(=O)OC)cccc2n1Cc1cccc(Cl)c1
Yield: 64.9 %

Procedure:
Using the procedure described in Example 1, Part E, 1-[(3-chlorophenyl)methyl]-2-ethyl-4-hydroxy-1H-indole (512 mg, 1.8 mmol) was treated with 72 mg (1.8 mmol) of 60% NaH/mineral oil and then 0.17 mL (1.8 mmol) of methyl bromoacetate. The product was purified by chromatography over silica gel eluting with 20% EtOAc/hexane, to give 418 mg (65% yield) of [[1-[(3-chlorophenyl)methyl]-2-ethyl-1H-indol-4-yl]oxy]acetic acid methyl ester, mp, 85-90° C.
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:20]=[C:19]([C:21](=[O:36])[CH2:22][N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[CH:18]=[C:17]2[C:12]=1[CH2:13][N:14]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=1)[C:15](=[O:45])[N:16]2[C:37]1[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][C:38]=1[Cl:44]>C(Cl)Cl>[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:20]=[C:19]([C:21]([OH:36])([CH3:1])[CH2:22][N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[CH:18]=[C:17]2[C:12]=1[CH2:13][N:14]([CH2:46][C:47]1[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=1)[C:15](=[O:45])[N:16]2[C:37]1[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][C:38]=1[Cl:44]
Reactant: C[Mg]Br
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(C(=O)CN4CCN(C(=O)OC(C)(C)C)CC4)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Solvent: ClCCl
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(C(C)(O)CN4CCN(C(=O)OC(C)(C)C)CC4)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methylmagnesium bromide (68 μL, 1.4M) in CH2Cl2 (0.2 mL) at 0° C. was added tert-butyl 4-{2-[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]-2-oxoethyl}piperazine-1-carboxylate (EXAMPLE ABA4, Step A) (35.6 mg, 0.047 mmol) dissolved in CH2Cl2 (0.3 mL) slowly. The reaction mixture was stirred for 2 h while warming up to rt. It was quenched with saturated aqueous solution of NH4Cl, and extracted with CH2Cl2. The combined organic layers were washed with brine and dried over Na2SO4. After removal of the solvent, the crude product was purified by preparative thin layer chromatography eluting with 1:3 acetone:hexane to obtain the title compound. Mass spectrum (ESI): 765.2 (M+1).