Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:9]=[C:10]([CH2:16][CH3:17])[C:11](=[O:15])[NH:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[C:18](Cl)(=[O:20])[CH3:19]>>[CH2:16]([C:10]1[C:11](=[O:15])[NH:12][C:13]([CH3:14])=[C:8]([C:6]2[O:7][C:3]([CH2:2][NH:1][C:18](=[O:20])[CH3:19])=[CH:4][CH:5]=2)[CH:9]=1)[CH3:17]
Reactant: CCc1cc(-c2ccc(CN)o2)c(C)[nH]c1=O
Reactant: CC(=O)Cl
Product: CCc1cc(-c2ccc(CNC(C)=O)o2)c(C)[nH]c1=O

Procedure:
Example 269 is substantially repeated except for utilizing 5-(5-aminomethylfuran-2-yl)-3-ethyl-6-methyl-1H-pyridin-2-one and acetyl chloride to afford the title compound. MS: m/e=275 (M+H). 1H NMR (D6-DMSO, δ ppm): 11.64 (s, 1H); 8.30 (t, 1H, J=5.3 Hz); 7.45 (s, 1H); 6.39 (d, 1H, J=3.2 Hz); 6.30 (d, 1H, J=3.2 Hz); 4.26 (d, 2H, J=5.3 Hz); 2.40 (q, 2H, J=7.4 Hz); 2.32 (s, 3H); 1.84 (s, 3H); 1.10 (t, 3H, J=7.4 Hz).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[O:28][CH2:29][C:30]1[C:34]([CH2:35][OH:36])=[C:33]([CH:37]([CH3:39])[CH3:38])[O:32][N:31]=1.O[C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:56]=[C:55]3[C:50]([CH:51]=[C:52]([C:57]([O:59][CH3:60])=[O:58])[N:53]=[CH:54]3)=[CH:49][CH:48]=2)=[CH:43][CH:42]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[O:28][CH2:29][C:30]1[C:34]([CH2:35][O:36][C:41]2[CH:42]=[CH:43][C:44]([C:47]3[CH:56]=[C:55]4[C:50]([CH:51]=[C:52]([C:57]([O:59][CH3:60])=[O:58])[N:53]=[CH:54]4)=[CH:49][CH:48]=3)=[CH:45][CH:46]=2)=[C:33]([CH:37]([CH3:39])[CH3:38])[O:32][N:31]=1
Reactant: Cc1cccc(C)c1OCc1noc(C(C)C)c1CO
Reactant: COC(=O)c1cc2ccc(-c3ccc(O)cc3)cc2cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc2ccc(-c3ccc(OCc4c(COc5c(C)cccc5C)noc4C(C)C)cc3)cc2cn1
Temperature: 90 °C
Yield: 36.5 %

Procedure:
To a solution of triphenylphosphine (160 mg, 0.611 mmol), [3-{[(2,6-dimethylphenyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolyl]methanol (153 mg, 0.556 mmol) and methyl 7-(4-hydroxyphenyl)-3-isoquinolinecarboxylate (155 mg, 0.556 mmol) in dichloromethane (1.5 mL) was added diisopropyl azodicarboxylate (0.110 mL, 0.611 mmol) dropwise. The solution was heated in a microwave reactor at 90° C. for 10 minutes and then purified by chromatography (silica gel, 0-25% acetone in hexanes gradient elution) to afford methyl 7-[4-({[3-{[(2,6-dimethylphenyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-3-isoquinolinecarboxylate (109 mg, 37%). 1H-NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.64 (s, 1H), 8.50 (s, 1H), 8.29-8.20 (m, 2H), 7.86 (d, J=9 Hz, 2H), 7.19 (d, J=9 Hz, 2H), 7.00-6.90 (m, 3H), 5.09 (s, 2H), 4.90 (s, 2H), 3.91 (s, 3H), 3.41 (septet, J=7 Hz, 1H), 2.14 (s, 6H), 1.28 (d, J=7 Hz, 6H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].C[Si]([CH:12]=[N+:13]=[N-:14])(C)C.O>C1COCC1>[CH2:6]([O:5][C:1]([C:2]1[CH:3]=[CH:12][NH:13][N:14]=1)=[O:4])[CH3:7]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C#CC(=O)OCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc[nH]n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
A solution of ethyl propiolate (10.0 g, 0.10 mol) in THF (67 mL) was treated dropwise with (trimethylsilyl)diazomethane (51 mL, 0.10 mol) maintaining the temperature between 20-30° C. with ice bath cooling. The mixture was stirred at RT for 4 h then treated cautiously with water (250 mL) with cooling in an ice bath. The organics were evaporated in vacuo and the resulting precipitate was collected by filtration, washed with water and dried at RT in vacuo to give the title compound (13.5 g, 94%). LCMS (Method 3): Rt 2.22 min, m/z 141 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1.[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([NH:31][C:32]([CH:34]3[CH2:36][CH2:35]3)=[O:33])[CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1>>[CH:34]1([C:32]([NH:31][C:27]2[CH:26]=[C:25]([CH:22]3[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][CH2:16][NH:15][C:12]([C:9]4([C:3]5[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=5[Cl:1])[CH2:10][CH2:11]4)=[O:14])[CH2:24][CH2:23]3)[CH:30]=[CH:29][CH:28]=2)=[O:33])[CH2:35][CH2:36]1
Reactant: NCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1
Reactant: O=C(O)C1(c2ccc(Cl)cc2Cl)CC1
Product: O=C(Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4Cl)CC3)CC2)c1)C1CC1

Procedure:
Example 117 was prepared from 1-(2,4-dichlorophenyl)cyclopropanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}cyclopropanecarboxamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.00–7.82 (br, 1H), 7.52–7.04 (m, 6H), 6.86 (d, 1H, J=7.2 Hz), 5.92–5.73 (br, 1H), 3.35–3.12 (m, 4H), 2.74–2.58 (m, 2H), 2.58–2.42 (m, 1H), 2.40–2.20 (m, 2H), 2.01–1.61 (m, 7H), 1.15–0.90 (m, 6H), 0.89–0.71 (m, 2H); ESMS m/e: 514.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:21][C:22]#[N:23]>>[Cl:1][C:2]1[C:11](/[CH:12]=[C:21](/[C:20]2[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:18]([O:17][CH3:16])[CH:19]=2)\[C:22]#[N:23])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1
Reactant: COc1ccc(CC#N)cc1OC
Reactant: COc1ccc2nc(Cl)c(C=O)cc2c1
Product: COc1ccc2nc(Cl)c(/C=C(\C#N)c3ccc(OC)c(OC)c3)cc2c1
Yield: 91.3 %

Procedure:
2-Chloro-6-methoxy-3-quinolinecarboxaldehyde (500 mg) was condensed with 3,4-dimethoxybenzyl cyanide (400 mg) through Method A (production step 2), to thereby yield the target product (yield: 784 mg, 91%).
Reaction SMILES: Br[C:2]1[C:3]([O:13][CH3:14])=[N:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]=[CH:8][C:7]2=[O:12].C([O-])=O.[NH4+]>CO.[Pd]>[CH3:14][O:13][C:3]1[CH:2]=[C:11]2[C:6]([C:7](=[O:12])[CH:8]=[CH:9][NH:10]2)=[CH:5][N:4]=1
Reactant: COc1ncc2c(=O)cc[nH]c2c1Br
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1cc2[nH]ccc(=O)c2cn1
Temperature: 25 °C

Procedure:
8-Bromo-7-methoxy-1H-[1,6]naphthyridin-4-one (12 g, 33.5 mmol) was dissolved in anhydrous methanol (240 mL) and 10% Dry Pd/C (2.4 g) was added carefully in portions. This was followed by portionwise addition of ammonium formate (24 g) which caused an exotherm. The reaction mixture was heated to reflux for 1 h. The reaction mixture was cooled to room temperature, filtered through Celite, and washed with hot methanol. The filtrate was concentrated and the residue purified by column chromatography on silica gel (230-400 mesh) eluting with ethyl acetate-methanol.
Reaction SMILES: [CH2:1]([C:3]1[CH:26]=[CH:25][C:6]2[CH:7]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[NH:21][CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2].[CH2:27]([O:29][C:30]([C:32]1[O:33][C:34]([CH2:37]Br)=[CH:35][CH:36]=1)=[O:31])[CH3:28]>>[CH2:1]([C:3]1[CH:26]=[CH:25][C:6]2[CH:7]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[N:21]([CH2:37][C:34]4[O:33][C:32]([C:30]([O:29][CH2:27][CH3:28])=[O:31])=[CH:36][CH:35]=4)[CH:22]=3)[C:8]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Reactant: CCOC(=O)c1ccc(CBr)o1
Product: CCOC(=O)c1ccc(Cn2cc(C3c4ccc(C)cc4C=Cc4cc(CC)ccc43)c(=O)[nH]c2=O)o1

Procedure:
The subtitle compound was prepared from the product of step (vi) (0.6 g) and 5-bromomethyl-2-furancarboxylic acid ethyl ester (J. Chem. Soc. Perkin Trans. 1, 1981, 1125, Bull. Chem. Soc. Jpn. 1987, 60, 1807)(0.47 g) according to the method of example 1 step (iv). Purification was by chromatography eluting with 50% ethyl acetate in isohexane. Yield 0.19 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([O:24][CH:25]2[CH2:28][O:27][CH2:26]2)[N:18]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([O:24][CH:25]3[CH2:26][O:27][CH2:28]3)[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: Cc1cc(OC2COC2)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(Nc2nc(C)cc(OC3COC3)n2)ccc1-n1cnc(C)c1
Yield: 27 %

Procedure:
Prepared in analogy to example 81b) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 2-chloro-4-methyl-6-(oxetan-3-yloxy)-pyrimidine, using potassium carbonate as a base. The title compound was isolated in a yield of 27%. MS ISP (m/e): 368.1 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=9.62 (s broad, 1H), 7.67 (d, 2H), 7.41 (dxd, 1H), 7.26 (d, 1H), 7.04 (s, 1H), 6.28 (s, 1H), 5.65 (m, 1H), 4.90 (t, 2H), 4.58 (m, 2H), 3.81 (s, 3H), 2.31 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]3)=[C:20]([O:30][CH3:31])[CH:19]=2)[N:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:28]=[C:27]([CH3:29])[N:26]=[CH:25]4)=[C:20]([O:30][CH3:31])[CH:19]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: Oc1ccc(Cl)cc1
Product: COc1cc(Nc2nc(C)cc(Oc3ccc(Cl)cc3)n2)ccc1-n1cnc(C)c1
Yield: 73 %

Procedure:
The title compound was prepared in analogous manners as described in example 9) from 4-chlorophenol and (4-chloro-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. It was obtained in 73% yield as a pale-brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11](O)=O)=[CH:5][CH:4]=1)#[N:2].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:21](=[O:31])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH3:29])=[C:24]([NH2:30])[CH:23]=1>ClCCl.CO>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:21]([C:22]1[CH:27]=[CH:26][C:25]2[N:28]([CH3:29])[C:11]([CH2:10][NH:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)=[N:30][C:24]=2[CH:23]=1)=[O:31]
Reactant: CCOC(=O)CCN(C(=O)c1ccc(NC)c(N)c1)c1ccccn1
Reactant: N#Cc1ccc(NCC(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccn1
Yield: 61 %

Procedure:
Prepared analogously to Example 25c from N-(4-cyanophenyl)glycine and 3-amino-4-methylaminobenzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide. Yield: 61% of theory; Rf value: 0.62 (silica gel; dichloromethane/methanol=19:1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[CH:2]1.C(=O)=O.CC(C)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>C1COCC1>[CH2:35]([O:34][C:32]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[CH:2]1)=[O:33])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=C(O)Cc1cn(C(=O)OCc2ccccc2)c2ccccc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Indole-3-acetic acid (13 g, 74 mmol) was taken up in 130 mL anhydrous THF in a flame-dried, 2-necked 1 L round-bottomed flask, under an inert atmosphere, and cooled to −78° C. (dry ice/acetone bath). A 1.0 M THF solution of LHMDS (163 mL, 0.163 mol) was added via syringe over 30 minutes, and the reaction mixture allowed to stir for an additional 30 minutes at −78° C. once the addition was complete. Next, benzyl chloroformate (11.7 mL, 13.9 g, 81.6 mmol) was added dropwise via syringe. Stirring was then continued for 1 hour. To work up the reaction mixture, it was quenched with 2 M HCl, and partitioned between 2 M HCl and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate, and the combined organic layers washed with brine, dried over anhydrous MgSO4, filtered, and evaporated to give a white solid with a pinkish tinge (22.49 g, 98% yield): 1H NMR (400 MHz, DMSO-d6) δ 3.71 (s, 2H) 5.47 (s, 2H) 7.27 (t, J=7.2 Hz, 1H) 7.32-7.47 (m, 4H) 7.54 (d, J=6.8 Hz, 2H) 7.58 (d, J=7.6 Hz, 1H) 7.68 (s, 1H) 8.08 (d, J=8.1 Hz, 1H) 12.43 (s, 1H); HRMS (ESI+) calcd for C18H16NO4 (MH+) 310.1074. found 310.1080.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([NH2:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[C:14]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([C:26](=O)[CH2:27][C:28](OCC)=[O:29])=[CH:23][CH:24]=2)[CH:19]=[N:18]1)(=[O:16])[CH3:15].CC1C=CC(S(O)(=O)=O)=CC=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:14]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([C:26]3[NH:13][C:11]4[N:10]([N:9]=[C:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[N:12]=4)[C:28](=[O:29])[CH:27]=3)=[CH:23][CH:24]=2)[CH:19]=[N:18]1)(=[O:16])[CH3:15]
Reactant: Nc1nc(-c2ccc(F)cc2)n[nH]1
Reactant: CCOC(=O)CC(=O)c1ccc2c(cnn2C(C)=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(=O)n1ncc2cc(-c3cc(=O)n4nc(-c5ccc(F)cc5)nc4[nH]3)ccc21
Temperature: 170 °C
Reaction time: 5 h

Procedure:
To a solution of 3-(4-fluorophenyl)-1H-1,2,4-triazol-5-amine (120 mg, 0.67 mmol) in diphenyl ether (2 ml) was added ethyl 3-(1-acetyl-1H-indazol-5-yl)-3-oxopropanoate (650 mg, 2.36 mmol) and TsOH (5.76 mg, 0.03 mmol), and the resulting mixture was stirred for 5 h at 170° C. The reaction was then quenched by the addition of ethyl ether (8 ml). The solids were collected by filtration to afford 5-(1-acetyl-1H-indazol-5-yl)-2-(4-fluorophenyl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a light yellow crude solid (100 mg, crude).
Reaction SMILES: BrC1C=C(C=CC=1)[CH2:5][N:6]([C@@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)[C:7]([C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[C:21]([OH:23])=[O:22])=[O:8].[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[C:42]1[CH:43]=[C:44](B(O)O)[CH:45]=[CH:46][CH:47]=1>>[C@@H:24]1([N:6]([CH2:5][C:44]2[CH:45]=[CH:46][CH:47]=[C:42]([C:38]3[S:37][CH:41]=[CH:40][CH:39]=3)[CH:43]=2)[C:7]([C:9]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=2[C:21]([OH:23])=[O:22])=[O:8])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: OB(O)c1cccc(-c2cccs2)c1
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(Br)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O
Product: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(-c3cccs3)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O

Procedure:
The product from Example 15B (165 mg, 0.3 mmol) and 3-(2-thienyl)phenylboronic acid were processed as described in Example 85 to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:38])([CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[C@H:10]([S:12][C@@H:13]1[CH2:18][O:17][C@@H:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[F:31])[O:15][CH2:14]1)[CH3:11].[H-].[Na+].[CH2:41]([O:44][P:45]([O:51][CH2:52][C:53]1[C:61]([O:62][CH3:63])=[CH:60][CH:59]=[CH:58][C:54]=1[C:55](Cl)=[O:56])([O:47][CH2:48][CH:49]=[CH2:50])=[O:46])[CH:42]=[CH2:43]>O1CCCC1>[CH2:48]([O:47][P:45]([O:51][CH2:52][C:53]1[C:61]([O:62][CH3:63])=[CH:60][CH:59]=[CH:58][C:54]=1[C:55]([O:38][C@:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1)[C@H:10]([S:12][C@@H:13]1[CH2:18][O:17][C@@H:16](/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=2[F:31])[O:15][CH2:14]1)[CH3:11])=[O:56])([O:44][CH2:41][CH:42]=[CH2:43])=[O:46])[CH:49]=[CH2:50]
Reactant: C=CCOP(=O)(OCC=C)OCc1c(OC)cccc1C(=O)Cl
Reactant: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOP(=O)(OCC=C)OCc1c(OC)cccc1C(=O)O[C@@](Cn1cncn1)(c1ccc(F)cc1F)[C@@H](C)S[C@H]1CO[C@H](/C=C/C=C/c2ccc(C#N)cc2F)OC1
Yield: 49 %

Procedure:
According to a similar procedure to that described in Example 1-(12), 4-[(1E,3E)-4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-1,3-butadienyl]-3-fluorobenzonitrile (542.6 mg, 1.00 mmol) described in Reference example 1, sodium hydride (55% dispersion in mineral oil; 52.4 mg, 1.20 mmol), and the crude 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-methoxybenzoyl chloride were reacted in tetrahydrofuran (7 ml), and the reaction mixture was worked up to afford, after extraction, the title compound as a crude oil. The crude oil was subjected to chromatography on a silica gel (30 g) column (eluent; ethyl acetate:hexane=2:1˜4:1) to afford the title compound (425.5 mg, 49% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([CH3:15])[N:7](S(N(C)C)(=O)=O)[CH:8]=1.Cl>O1CCOCC1>[CH3:15][C:6]1[NH:7][CH:8]=[C:4]([CH2:3][CH2:2][OH:1])[N:5]=1
Reactant: Cc1nc(CCO)cn1S(=O)(=O)N(C)C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(CCO)c[nH]1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(2-hydroxyethyl)-N,N,2-trimethyl-1H-imidazole-1-sulfonamide (compound 282.2, 1 g, 4.29 mmol) in 1,4-dioxane (30 mL) was added HCl (6 M, 30 mL). The reaction mixture was stirred for 4 h at 85° C., then concentrated under reduced pressure. The pH of the solution was adjusted to 7-8 with NaHCO3 (sat.). The resulting mixture was concentrated under reduced pressure to afford 3 g (crude) of the title compound as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].[CH:14]([O:17][CH2:18][CH2:19][CH2:20][NH2:21])([CH3:16])[CH3:15]>>[CH:14]([O:17][CH2:18][CH2:19][CH2:20][NH:21][C:11]([C:8]1[CH:7]=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:10][N:9]=1)=[O:13])([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Reactant: CC(C)OCCCN
Product: CC(C)OCCCNC(=O)c1ccc(C(=O)O)cn1

Procedure:
The title compound was synthesized in two steps. The first as described for Intermediate example I-97, starting from 5-(methoxycarbonyl)pyridine-2-carboxylic acid and 3-isopropoxypropylamine, and the second as described for Intermediate example I-98, starting from the product received in the first step which was first purified by column chromatography using a gradient of ethyl acetate in heptane. Total yield (two steps) 22%; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.06 (d, 1 H), 8.99 (t, 1 H), 8.43 (dd, 1 H), 8.13 (dd, 1 H), 3.48-3.56 (m, 1 H), 3.34-3.45 (m, 4 H, obscured by H2O), 1.70-1.80 (m, 2 H), 1.09 (d, 6 H); MS (APPI/APCI) m/z 267[M+H+].
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH:16]([B-](F)(F)F)=[CH2:17].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[F:13][C:12]([F:15])([F:14])[O:11][C:4]1[CH:3]=[C:2]([CH:16]=[CH2:17])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(Br)cc1OC(F)(F)F
Reactant: C=C[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C=Cc1ccc(C(=O)O)c(OC(F)(F)F)c1
Temperature: 80 °C
Yield: 46.9 %

Procedure:
To a stirred solution of 4-bromo-2-(trifluoromethoxy)benzoic acid (1 g, 3.67 mmol) in DMSO (20 mL) was added potassium vinyltrifluoroborate (1.47 g, 11.02 mmol) and potassium carbonate (1.52 g, 11.02 mmol). The reaction mixture was degassed with argon for 30 min Bistriphenylphosphine(diphenylphosphinoferrocene)palladium dichloride (0.13 g, 0.18 mmol) was added and the reaction mixture was heated to 80° C. for 1 h. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (2×50 mL), washed with brine, and dried over Na2SO4. Concentration under reduced pressure furnished the crude compound which was purified by flash column chromatography to afford the product as pale yellow gummy material (0.4 g, 47%): 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J=8.1 Hz, 1H), 7.44 (d, J=1.8 Hz, 1H), 7.35 (s, 1H), 6.78 (dd, J=17.4.1, 11.1 Hz, 1H), 5.92 (d, J=17.4 Hz, 1H), 5.51 (d, J=10.8 Hz, 1H); ESIMS m/z 232.97 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([CH2:25][NH2:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([CH2:25][NH:26][S:34]([CH3:33])(=[O:36])=[O:35])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CN)ccc2c1=O
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CNS(C)(=O)=O)ccc2c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.3 %

Procedure:
To a solution of crude tert-butyl[6-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.16 g) (Example 285) in tetrahydrofuran (2 mL) was added methanesulfonyl chloride (0.028 mL, 0.36 mmol) and triethylamine (0.050 mL, 0.36 mmol), and the mixture was stirred at room temperature for 4 h. The reaction mixture was washed with water (4 mL) and concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1 (v/v)) to give tert-butyl(2-isobutyl-6-{[(methylsulfonyl)amino]methyl}-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.13 g, 84%) as a pale yellow oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:53]([O:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([NH2:68])[CH:63]=2)=[CH:58][CH:57]=1)[CH3:54]>CN(C=O)C>[CH2:53]([O:55][C:56]1[CH:57]=[CH:58][C:59]([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([NH:68][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:63]=2)=[CH:60][CH:61]=1)[CH3:54]
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Reactant: CCOc1ccc(-c2cccc(N)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC(F)(F)F)c4oc3=O)c2)cc1
Temperature: 25 °C
Yield: 54.8 %

Procedure:
DIEA (0.014 mL, 0.077 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.019 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-ethoxy-biphenyl-3-ylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.018 g of product in 55% yield: LCMS (ESI) m/z 470 (MH+).