Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[C:14]([C:16]3[CH:17]=[C:18]([CH2:21]O)[S:19][CH:20]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:48]1[CH2:51][CH:50]([C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:49]1.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>ClCCl.O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:15]=[C:14]([C:16]3[CH:17]=[C:18]([CH2:21][N:48]4[CH2:51][CH:50]([C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH2:49]4)[S:19][CH:20]=3)[O:13][N:12]=2)=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(-c2cc(-c3csc(CO)c3)on2)cc1
Reactant: CCOC(=O)C1CNC1
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(Cc2cc(-c3cc(-c4ccc(CC(C)C)cc4)no3)cs2)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 82 %

Procedure:
A solution of {4-[3-(4-isobutylphenyl)isoxazol-5-yl]-2-thienyl}methanol (0.43 g, 1.4 mmol) that was obtained in Example 9 (9g), carbon tetrabromide (0.68 g, 2.1 mmol) and triphenylphosphine (0.54 g, 2.1 mmol) in dichloromethane (15 ml) was stirred at 0° C. for 5 minutes. Subsequently, to the reaction mixture were added successively ethyl 3-azetidinecarboxylate hydrochloride (0.34 mg, 2.1 mmol) and N,N-diisopropylethylamine (0.60 ml, 3.4 mmol) with stirring, and the resulting mixture was stirred at room temperature for 18 hours. After stirring, a saturated aqueous solution of sodium hydrogencarbonate (5 ml) was added to the reaction mixture to quench the reaction, and the resulting mixture was poured into water (50 ml) and extracted with dichloromethane. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:4 to 3:2) as the eluent to afford the title compound (0.48 g) in a yield of 82% as a white crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=S)=[CH:14][CH:13]=1)#[N:11]>>[N:1]1[C:2]2[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:5][C:19]=1[NH:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]#[N:11])=[CH:13][CH:14]=1
Reactant: NCc1ccccc1N
Reactant: N#Cc1ccc(N=C=S)cc1
Product: N#Cc1ccc(NC2=Nc3ccccc3CN2)cc1

Procedure:
The title compound (MS: m/e=249.0 [M+H+]) was prepared in analogy to example 1 from 2-aminobenzylamine and 4-cyanophenylisothiocyanate.
Reaction SMILES: COC([C:5]1([CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20])[C:9](=[O:10])[CH:8]=[CH:7][CH:6]1[CH2:11][C:12]([O:14][CH3:15])=[O:13])=O.[Cl-].[Na+]>CS(C)=O.O>[CH3:15][O:14][C:12]([CH2:11][CH:6]1[CH:5]([CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20])[C:9](=[O:10])[CH:8]=[CH:7]1)=[O:13]
Reactant: CC/C=C\CC1(C(=O)OC)C(=O)C=CC1CC(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC/C=C\CC1C(=O)C=CC1CC(=O)OC
Temperature: 175 °C
Yield: 91 %

Procedure:
A 360 mg quantity of 5-methoxycarbonyl-4-methoxycarbonylmethyl-5-(cis-2-pentenyl)-2-cyclopentenone is dissolved in 8 ml of dimethyl sulfoxide containing 23 mg of water. The solution is reacted in a sealed tube with addition of 20 mg of sodium chloride. After the solution has been heated at 175° C. for 4 hours, the product is cooled to room temperature and then extracted with ethyl ether. The ethereal layer is washed, dried and distilled for the removal of the solvent. Purification of the residue by a silica gel column affords a compound (1-a) and compound (1-b) (R2 =CH3 in each). Yield of compound (1-a): 62.5%. Yield of compound (1-b): 28.5%. Combined yield: 91%. B.p. 87°-91° C./2.5 mm Hg.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:20]=[CH:19][C:6]2[C:7](=[O:18])[C:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:9][O:10][C:5]=2[CH:4]=1.[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28](I)[CH:27]=1.[Cl-].[NH4+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:25]([C:26]1[CH:27]=[C:28]([C:3]2[CH:20]=[CH:19][C:6]3[C:7](=[O:18])[C:8]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:9][O:10][C:5]=3[CH:4]=2)[CH:29]=[CH:30][CH:31]=1)([O:24][CH3:23])=[O:33]
Reactant: C[Sn](C)(C)c1ccc2c(=O)c(Cc3ccccc3)coc2c1
Reactant: COC(=O)c1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2ccc3c(=O)c(Cc4ccccc4)coc3c2)c1
Temperature: 25 °C
Yield: 100.4 %

Procedure:
To a stirred solution of the compound of step F (7.0 g, 17.5 mmole) in dimethylformamide (DMF) (35 mL) was added Pd(PPh3)2Cl2 (490 mg, 0.7 mmole), 3 crystals of BHT and methyl-3-iodobenzoate (5.0 g, 19.1 mmole). The mixture was stirred at reflux for 1.5 hours, cooled to room temperature and poured into 150 mL of saturated aqueous ammonium chloride solution. The mixture was extracted with 3×150 mL of diethyl ether, and the combined extract was washed with 2×100 mL of water, and then brine. The solution was dried over sodium sulfate, filtered and evaporated in vacuo to afford a yellow oil. Chromatography over silica gel (4:1 hexane:ether elution) afforded 6.51 g of the title compound as a viscous oil.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:12]=[C:13]([C:22](O)=[O:23])[CH:14]=[C:15]2[C:19]([CH3:20])=[C:18]([CH3:21])[NH:17][C:16]=12.O.O[N:27]1[C:31]2C=[CH:33][CH:34]=[CH:35][C:30]=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.N1CCCCC1>ClCCl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:12]=[C:13]([C:22]([N:27]2[CH2:33][CH2:34][CH2:35][CH2:30][CH2:31]2)=[O:23])[CH:14]=[C:15]2[C:19]([CH3:20])=[C:18]([CH3:21])[NH:17][C:16]=12
Reactant: Cc1[nH]c2c(N3CCc4ccccc4C3)nc(C(=O)O)cc2c1C
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCNCC1
Product: Cc1[nH]c2c(N3CCc4ccccc4C3)nc(C(=O)N3CCCCC3)cc2c1C
Yield: 46 %

Procedure:
A solution of 7-(3,4-dihydro-1H-isoquinolin-2-yl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid (450 mg, 1.4 mmol) prepared in Step 1, 1-hydroxybenzotriazole hydrate (284 mg, 2.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (401 mg, 2.1 mmol), diisopropylethylamine (730 μl, 4.2 mmol), and piperidine (270 μl, 2.1 mmol) in dichloromethane (5 ml) was stirred overnight at room temperature and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/1, v/v) to give 250 mg of the titled compound as a white solid. (Yield: 50%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([CH3:36])=[C:18]([CH2:20][CH2:21][O:22][C:23]3[CH:35]=[CH:34][C:26]([O:27][C:28]([CH3:33])([CH3:32])[C:29]([OH:31])=[O:30])=[CH:25][CH:24]=3)[N:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].O1CCCC1.CO.C(Cl)Cl>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([CH3:36])=[C:18]([CH2:20][CH2:21][O:22][C:23]3[CH:35]=[CH:34][C:26]([O:27][C:28]([CH3:32])([CH3:33])[C:29]([OH:31])=[O:30])=[CH:25][CH:24]=3)[N:19]=2)=[CH:11][CH:10]=1
Reactant: Cc1oc(-c2ccc(OCc3ccccc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: Cc1oc(-c2ccc(O)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
A mixture of 2-(4-{2-[2-(4-benzyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid (0.238 g, 0.490 mmol) and 5% palladium on carbon (0.10 g) in tetrahydrofuran (10 mL) and methanol (10 mL) was purged successively with nitrogen then hydrogen, and then stirred under a hydrogen balloon at room temperature for 18 h. The reaction mixture was filtered through hyflo and solvent was removed from the filtrate in vacuo to give an oil which was dissolved in CH2Cl2 and dried (MgSO4). The solvent was removed in vacuo to give a crude oil which was purified by flash chromatography (9/1 CH2Cl2/MeOH) to afford 0.072 g (37%) 2-(4-{2-[2-(4-hydroxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid. 1H NMR (500 MHz, DMSO-d6) δ 10.08 (bs, 1H), 7.70 (d, 2H, J=8.60 Hz), 6.84-6.72 (m, 6H), 4.08 (t, 2H, J=6.65 Hz), 2.83 (t, 2H, J=6.65 Hz), 2.28 (s, 3H), 1.33 (s, 6H); MS (ES+) Calc'd for C22H23NO6: Found m/e 398 (M+1, 100%)
Reaction SMILES: [C:1]([CH:4]([C:14](=O)[CH3:15])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6])(=O)[CH3:2].O.[NH2:18][NH2:19].O>C(O)(=O)C>[CH3:2][C:1]1[C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])=[C:14]([CH3:15])[NH:19][N:18]=1
Reactant: NN
Reactant: CC(=O)C(C(C)=O)C(=O)Nc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1n[nH]c(C)c1C(=O)Nc1ccccc1
Yield: 88 %

Procedure:
The foregoing diacetyl acetanilide (2.2 g) in glacial acetic acid (30 ml) was treated with hydrazine hydrate (1.5 g) and the mixture boiled under reflux for 30 min. The mixture was then poured into water and the product collected and crystallised from ethanol. 3,5-dimethyl-N-phenyl-4-pyrazolecarboxamide (1.9 g, 86%) was obtained as colourless plates, m.p. 244-5° C (Found: C, 66.8 H, 6.0 N, 19.3 C12H13N3O requires C, 66.9; H, 6.1; N, 19.5%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:54]([NH:57][C:58]1[S:59][C:60]([S:64](Cl)(=[O:66])=[O:65])=[C:61]([CH3:63])[N:62]=1)(=[O:56])[CH3:55]>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:64]([C:60]1[S:59][C:58]([NH:57][C:54](=[O:56])[CH3:55])=[N:62][C:61]=1[CH3:63])(=[O:65])=[O:66])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(C)=O)nc1C)O[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Yield: 13.2 %

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(3R,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (94 mg) was reacted with 2-acetylamino-4-methyl thiazole-5-sulfonyl chloride (64 mg) according to General Procedure E to obtain (S)-2-({(3R,8S)-7-(2-acetylamino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (16 mg). This was hydrolyzed according to General Procedure B to give the title compound (11 mg). LCMS: (m/z) 955. 1H NMR (400 MHz, DMSO-d6): 7.80-7.75 (m, 4H), 7.71 (d, 1H), 7.66-7.64 (m, 3H), 7.54 (d, 2H), 7.45 (d, 1H), 7.32 (d, 2H), 7.10 (d, 1H), 7.04-7.02 (m, 2H), 6.72 (s, 1H), 6.63 (s, 1H), 5.57-5.56 (m, 2H), 5.53-5.52 (m, 1H), 5.14 (s, 2H) 5.02-4.99 (m, 1H), 4.55-4.53 (m, 1H), 4.35-4.29 (m, 1H), 4.27-4.20 (m, 3H), 3.94-3.89 (m, 1H), 3.74-3.70 (m, 2H), 2.95-2.92 (m, 1H), 2.48 (s, 3H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:47][O:48][C:49]([C:51]1[C:59]2[N:58]=[C:57]([NH2:60])[NH:56][C:55]=2[C:54]([F:61])=[C:53]([O:62][CH3:63])[C:52]=1[F:64])=[O:50]>CN(C=O)C>[CH3:47][O:48][C:49]([C:51]1[C:59]2[NH:58][C:57]([NH:60][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])=[N:56][C:55]=2[C:54]([F:61])=[C:53]([O:62][CH3:63])[C:52]=1[F:64])=[O:50]
Reactant: COC(=O)c1c(F)c(OC)c(F)c2[nH]c(N)nc12
Reactant: O=C(O)c1cc2ccccc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1c(F)c(OC)c(F)c2nc(NC(=O)c3cc4ccccc4cn3)[nH]c12
Yield: 48.7 %

Procedure:
0.4 g (2.0 mmol) of isoquinoline-3-carboxylic acid and 800 mg (2.1 mmol) HBTU were dissolved in 3.0 mL of DMF and 0.6 mL of DIEA and treated with 0.35 g (1.5 mmol) of 2-amino-5,7-difluoro-6-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester as described in general procedure A to produce 0.3 g (0.73 mmol, 49%) of 5,7-difluoro-2-[(isoquinoline-3-carbonyl)-amino]-6-methoxy-3H-benzoimidazole-4-carboxylic acid methyl ester. LCMS: 413 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.Cl[C:37]1[CH:38]=[CH:39][C:40]2[O:52][CH2:51][N:43]3[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:49]=4[CH:50]=[C:42]3[C:41]=2[N:53]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:23])=[O:24])[C:18]([C:37]4[CH:38]=[CH:39][C:40]5[O:52][CH2:51][N:43]6[C:44]7[CH:45]=[CH:46][CH:47]=[CH:48][C:49]=7[CH:50]=[C:42]6[C:41]=5[N:53]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:6][CH:7]=1
Reactant: Clc1ccc2c(n1)-c1cc3ccccc3n1CO2
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5ccccc5n3CO4)cc12
Temperature: 110 °C
Yield: 46.1 %

Procedure:
To a degassed solution of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (502 mg, 1.0 mmol), 2-chloro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole (256 mg, 1.0 mmol) and K3PO4 (636 mg, 3.0 mmol) in dioxane:H2O (1.5 mL:0.4 mL) was added Pd2(dba)3 (91 mg, 0.1 mmol) and X-Phos (91 mg, 0.2 mmol) under N2. The mixture was heated to 110° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc and filtered. The filtrate was washed with H2O, brine, dried over Na2SO4. After being concentrated in vacuo, the resulting resulting residue was purified using prep-HPLC to provide the desired product of Compound 1 (275 mg, yield: 46.1%). 1H-NMR (CDCl3, 400 MHz) δ 7.88˜7.94 (m, 3H), 7.61˜7.63 (m, 2H), 7.40 (s, 2H), 7.09˜7.28 (m, 6H), 5.94 (s, 2H), 5.86 (d, J=4.4 Hz, 1H), 3.29 (s, 3H), 2.92 (d, J=4.8 Hz, 3H), 2.65 (s, 3H). MS (M+H)+: 597.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12](=[O:14])[CH3:13])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.C(C1C2C(=CC=C(OC(F)(F)F)C=2)N([CH2:32][C:33]([OH:35])=[O:34])C=1)(=O)C>>[C:12]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:9]([CH2:32][C:33]([OH:35])=[O:34])[CH:8]=1)(=[O:14])[CH3:13]
Reactant: COc1ccc2c(C(C)=O)c[nH]c2c1
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Product: COc1ccc2c(C(C)=O)cn(CC(=O)O)c2c1

Procedure:
was prepared from 1-(6-methoxy-1H-indol-3-yl)-ethanone [99532-52-2] in a similar manner as described in step B and C of Scheme A13 for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid. Brown solid. MS: 248 [M+H]+, 517 [2M+Na]+; tR (HPLC conditions k): 2.30 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C:13](C(O)=O)([C:18]([OH:20])=[O:19])[CH2:12]3)=[O:8])=[CH:5][CH:4]=1>Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][CH:13]([C:18]([OH:20])=[O:19])[CH2:12]3)=[O:8])=[CH:24][CH:25]=1
Reactant: COc1ccc(C(=O)c2ccc3c(c2)CC(C(=O)O)(C(=O)O)C3)cc1
Agent: Cl
Product: COc1ccc(C(=O)c2ccc3c(c2)CC(C(=O)O)C3)cc1

Procedure:
77.5 g (0.228 mole) of the crude acid obtained in (d) and 1070 cm3 of concentrated hydrochloric acid are placed in a 2 liter reaction vessel equipped with a stirrer and cooler. The mixture is heated to reflux for 15 hours. After cooling, the reaction mixture is extracted with diethyl ether, the extract dried over anhydrous sodium sulphate, filtered, and the filtrate concentrated. A doughy solid is obtained which, after recrystallization from ethyl acetate, melts at 149°-151° C. (capillary tube). If difficulty is experienced in purifying the acid by recrystallization, the methyl ester of the acid may first be formed, for example, and purified by distillation (boiling point at 0.67 torr=218° C.) and then hydrolyzed with aqueous alcoholic potash using a known method. The acid obtained is thus more easily able to be purified.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[O:46]([C:53]1[S:57][C:56]([CH2:58][NH2:59])=[CH:55][CH:54]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C)C=O.[Cl-].[Na+].O>[NH2:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:59][CH2:58][C:56]1[S:57][C:53]([O:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[CH:54][CH:55]=1)=[O:6]
Reactant: NCc1ccc(Oc2ccccc2)s1
Reactant: Nc1nc(Cl)ccc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
2-Amino-6-chloro-nicotinic acid described in Preparation Example A-1 (400 mg, 2.31 mmol) was dissolved in N,N-dimethylformamide (10 mL), triethylamine (0.78 mL, 5.6 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.23 g, 2.8 mmol) and C-(5-phenoxy-thiophen-2-yl)-methylamine described in Preparation Example 26 (572 mg, 2.8 mmol) were added, and the solution was stirred for 13 hours 30 minutes at room temperature. After the reaction was completed, the reaction solution was poured into brine, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then concentrated, the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1), and the title compound (380 mg, 1.05 mmol, 46%) was obtained.
Reaction SMILES: [I:1][C:2]1[C:7](CC(O)=O)=[C:6]([I:12])[C:5](CC(O)=O)=[C:4]([I:17])[C:3]=1[C:18]1[CH:23]=[CH:22][C:21]([C:24](O)=[O:25])=[C:20]([N+:27]([O-:29])=[O:28])[CH:19]=1.[C:30]([O:33][CH:34]1[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:53])[CH3:52])[C@@H:42]([O:43][C:44](=[O:46])[CH3:45])[C@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:35]1[NH2:36])(=[O:32])[CH3:31].Cl.CN(C)CCCN=C=NCC>>[N+:27]([C:20]1[CH:19]=[C:18]([C:3]2[C:2]([I:1])=[C:7]([C:30]([OH:33])=[O:32])[C:6]([I:12])=[C:5]([C:39]([OH:41])=[O:38])[C:4]=2[I:17])[CH:23]=[CH:22][C:21]=1[C:24]([C:34]1([O:48][C@H:47]([CH2:49][O:50][C:51](=[O:53])[CH3:52])[C@@H:42]([O:43][C:44](=[O:46])[CH3:45])[C@H:37]([O:38][C:39](=[O:41])[CH3:40])[C@H:35]1[NH2:36])[O:33][C:30](=[O:32])[CH3:31])=[O:25])([O-:29])=[O:28]
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(O)Cc1c(I)c(CC(=O)O)c(I)c(-c2ccc(C(=O)O)c([N+](=O)[O-])c2)c1I
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CC(=O)OC[C@H]1OC(OC(C)=O)(C(=O)c2ccc(-c3c(I)c(C(=O)O)c(I)c(C(=O)O)c3I)cc2[N+](=O)[O-])[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
2′,4′,6′-triiodo-3′,5′-bis(carboxymethyl)-3-nitrobiphenyl-4-carboxylic acid (18) is coupled with 1,3,4,6-tetra-O-acetyl-D-glucosamine in the presence of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride and N-hydrosuccinamide to yield 2-nitro-4-[3′,5′-bis(carboxy)-2′,4′,6′-triiodophenyl]-benzoyl-1,3,4,6-tetra-O-acetyl-D-glucosamine. The protecting acetyl groups on the glucosamine moiety are removed by reaction with sodium hydroxide in methanol to yield 2-nitro-4-[3′,5′-bis(carboxy)-2′,4′,6′-triiodophenyl]-benzoyl-D-glucosamine (19).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][O:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)[CH:5]=[C:4]([CH2:14][O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[N:30]1[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]1)[NH2:26].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH:11]1([CH2:10][O:9][CH2:8][C:6]2[CH:5]=[C:4]([CH2:14][O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[N:3]=[C:2]([NH:26][C:25]3[CH:27]=[CH:28][C:29]([N:30]4[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]4)=[C:23]([O:22][CH3:21])[CH:24]=3)[N:7]=2)[CH2:13][CH2:12]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: FC(F)(F)COCc1cc(COCC2CC2)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(COCC3CC3)cc(COCC(F)(F)F)n2)ccc1-n1cnc(C)c1
Temperature: 120 °C

Procedure:
2-Chloro-4-((cyclopropylmethoxy)methyl)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (approximately 50% pure, 33 mg, 0.11 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (26 mg, 0.13 mmol), palladium (II) acetate (4 mg, 0.02 mmol), 2-(dicyclohexylphosphino)-biphenyl (6 mg, 0.02 mmol) cesium carbonate (69 mg, 0.21 mmol) and dioxane (2 mL) were mixed in a vial. The vial was capped, evacuated and flushed with nitrogen. The mixture was heated by microwave irradiation at 120° C. for 1.5 h. The mixture was filtered through a pad of silica, the pad was washed with 10% methanol in ethyl acetate. The solvents were evaporated and the residue was purified by preparative HPLC to give the title compound as a dry film, 15 mg (28%).
Reaction SMILES: [CH:1]1([CH:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[C:14]([C:30]([F:33])([F:32])[F:31])=[C:15]4[C:20](=[CH:21][CH:22]=3)[CH:19]=[C:18]([C@:23]3([CH3:29])[CH2:27][O:26]C(=O)[NH:24]3)[CH:17]=[CH:16]4)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].O>>[NH2:24][C@@:23]([C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([O:12][C@H:9]3[CH2:10][CH2:11][C@H:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:7][CH2:8]3)[C:14]=2[C:30]([F:32])([F:33])[F:31])[CH:19]=1)([CH3:29])[CH2:27][OH:26]
Reactant: C[C@@]1(c2ccc3c(C(F)(F)F)c(OC4CCC(C5CCCC5)CC4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: C[C@](N)(CO)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C4CCCC4)CC3)ccc2c1

Procedure:
The compound was prepared in a manner similar as to that described above (R)-4-[6-(4-Cyclopentyl-cyclohexyloxy)-5-trifluoromethyl-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (15 mg, 0.000032 mol), (0.14 g, 0.0030 mol), 4.2 M lithium hydroxide, monohydrate in water (0.13 mL, 0.00055 mol) to give 12 mg of the desired product as a white solid (81%). ESI-MS: 419 (M-16)+. 1H NMR (400 MHz, MeOD) δ=8.64-8.50 (m, 1 H), 8.17-7.98 (m, 2 H), 7.98-7.87 (m, 1 H), 7.73-7.62 (m, 1 H), 7.50-7.40 (m, 1 H), 4.84-4.76 (m, 2 H), 3.80-3.58 (m, 2 H), 2.12-1.96 (m, 2 H), 1.85-1.42 (m, 18 H), 1.21-1.05 (m, 2 H).