Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH2:7])[N:3]=1.[C:8]1([CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([NH:7][C:15](=[O:16])[CH:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: Cc1nc(N)no1
Product: Cc1nc(NC(=O)C(c2ccccc2)c2ccccc2)no1

Procedure:
The title compound, white solid, m.p. 153° C. and MS: m/e=293 (M+) was prepared in accordance with the general method of example 44a from 5-methyl-[1,2,4]oxadiazol-3-ylamine (EP 413545) and 2,2-diphenylacetic acid chloride.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[C:10](B(O)O)[CH:9]=[N:8][C:7]=12)[CH3:2].O1CCOCC1.[C:21]([O:25][C@@H:26]([C:32]1[C:47]([CH3:48])=[CH:46][C:35]2[N:36]=[C:37]([C:39]3[CH:44]=[CH:43][N:42]=[C:41](Cl)[CH:40]=3)[S:38][C:34]=2[C:33]=1[C:49]1[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=1)[C:27]([O:29][CH2:30][CH3:31])=[O:28])([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([O:25][C@@H:26]([C:32]1[C:47]([CH3:48])=[CH:46][C:35]2[N:36]=[C:37]([C:39]3[CH:44]=[CH:43][N:42]=[C:41]([C:10]4[CH:9]=[N:8][C:7]5[N:6]([N:5]=[CH:4][C:3]=5[CH2:1][CH3:2])[CH:11]=4)[CH:40]=3)[S:38][C:34]=2[C:33]=1[C:49]1[CH:50]=[CH:51][C:52]([Cl:55])=[CH:53][CH:54]=1)[C:27]([O:29][CH2:30][CH3:31])=[O:28])([CH3:22])([CH3:23])[CH3:24]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Reactant: CCc1cnn2cc(B(O)O)cnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4cnc5c(CC)cnn5c4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a mixture of the above crude 3-ethylpyrazolo[1,5-a]pyrimidin-6-ylboronic acid in dioxane (˜0.18M, 0.68 mL, 0.123 mmol) was added (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (50 mg, 0.0944 mmol), Pd(PPh3)4 (11 mg, 0.0094 mmol) and 2M potassium carbonate (0.19 mL, 0.378 mmol) was heated in a microwave at 110° C. for 1 h. Reaction mixture was stored overnight at rt, diluted with ethyl acetate and washed with brine, dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 40% EtOAc/Hex) to give product. LCMS-ESI+: calc'd for C35H35ClN5O3S: 640.2 (M+H+); Found: 640.3 (M+H+).
Reaction SMILES: [CH2:1]([C@@:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:39]>C(Cl)Cl>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@@:4]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)([CH2:1][CH:2]3[CH2:3][O:39]3)[O:9][C:8]2=[O:10])[CH3:12])=[CH:18][CH:17]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CC2CO2)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To a solution of (R)-6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (900 mg, 2.0 mmol) in dry CH2Cl2 (30 mL) was added dropwise 3-chlorobenzoperoxoic acid (690 mg, 4.0 mmol) by portion at 0° C. Then the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was quenched by 10% Na2SO3 solution. The organic phase was dried over Na2SO4, filtered and concentrated to afford the residue, which was purified by TLC to give (6S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(oxiran-2-ylmethyl)-1,3-oxazinan-2-one (470 mg, 50%). 1H NMR (CDCl3): 1.54 (m, 3H), 1.71 (m, 3H), 2.01 (m, 1H), 2.15 (m, 3H), 2.48 (m, 2H), 2.67 (m, 1H), 3.00 (m, 1H), 5.67 (m, 1H), 6.84 (m, 4H), 7.02 (m, 2H), 7.21 (m, 4H), 7.31 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(N(CC)CC)C.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:10]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C#CCCCCCCCCCC
Reactant: O=Cc1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC#Cc1cccc(C=O)c1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
To a solution of 3-bromobenzaldehyde (26.5 g) and (25.0 g) 1-dodecyne in triethylamine (105 ml) was added bis(triphenylphosphine)palladium(II)chloride (1.73 g) followed by copper(1) iodide (0.24 g). The resultant mixture was stirred in the dark at 55° C. for 7 hrs, under nitrogen. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to yield 37.7 g 3-(1-dodecynyl)benzaldehyde. The filtrate was an oil.
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[C:16]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:17]3[CH2:23][NH:22][CH2:21][CH2:20][C:18]=3[N:19]=2)=[CH:10][CH:9]=1)=[O:6])[CH3:3].CN(C)C=O.C(N(CC)C(C)C)(C)C.[CH:45]1([S:48](Cl)(=[O:50])=[O:49])[CH2:47][CH2:46]1>>[CH:45]1([S:48]([N:22]2[CH2:21][CH2:20][C:18]3[N:19]=[C:14]([C:11]4[CH:12]=[CH:13][C:8]([NH:7][C:5]([NH:4][CH2:2][CH3:3])=[O:6])=[CH:9][CH:10]=4)[N:15]=[C:16]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:17]=3[CH2:23]2)(=[O:50])=[O:49])[CH2:47][CH2:46]1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNCC3)cc1
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(S(=O)(=O)C2CC2)CC3)cc1
Reaction time: 2 h

Procedure:
(S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)phenyl)urea hydrochloride (0.1000 g, 0.2310 mmol) in dry N,N-Dimethylformamide (1.60 mL, 20.7 mmol) was added N,N-Diisopropylethylamine (0.161 mL, 0.924 mmol) followed by Cyclopropanesulfonyl chloride (0.0354 mL, 0.347 mmol). The reaction mixture was stirred for 2 hours. The reaction mixture was purified by HPLC. 1H NMR (500 MHz, DMSO) δ 8.69 (s, 1H), 8.19 (d, J=8.8, 2H), 7.49 (d, J=8.8, 2H), 6.18 (t, J=5.6, 1H), 4.31 (q, J=15.1, 2H), 3.89 (dd, J=12.2, 9.2, 2H), 3.75-3.52 (m, 5H), 3.44 (d, J=5.0, 2H), 3.19-3.05 (m, 2H), 2.99 (d, J=3.7, 2H), 2.75-2.66 (m, 1H), 1.24 (d, J=6.6, 3H), 1.06 (t, J=7.2, 3H), 0.93 (dt, J=13.8, 5.5, 4H). LC/MS-m/z+501.2 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[NH:19]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@H:20]([C:27](O)=[O:28])[CH2:21][O:22][C:23]([CH3:26])([CH3:25])[CH3:24].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[NH:19]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C@H:20]([C:27]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:28])[CH2:21][O:22][C:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](COC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
8.90 g of H-Asn-Leu-OMe and 11.0 g of Z-Ser(tBu)-OH are dissolved in 100 ml of freshly distilled dimethylformamide. The solution is cooled to 0°C and 3.90 g of N-hydroxysuccinimide followed by 8.70 g of dicyclohexylcarbodiimide are added. After 30 minutes standing at 0°C and 18 hours at 25°C the precipitated dicyclohexylurea is filtered off and the filtrate is poured into 800 ml of ice water. The crystalline precipitate which hereupon separates out is dried in vacuo at 40°C and then recrystallised from methanol-water. The Z-Ser(tBu)-Asn-Leu-OMe which is hereupon obtained in an analytically pure form melts at melting point 202° - 205°C; [α]D20 =-18° (c = 1.05 in glacial acetic acid).
Reaction SMILES: [F:1][C:2]([F:27])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].Br([O-])(=O)=[O:29].[Na+].S(=O)(=O)(O)[O-].[Na+].O>C(#N)C>[F:27][C:2]([F:1])([O:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:29])=[O:24])=[CH:25][CH:26]=3)=[N:15]2)=[CH:12][CH:13]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Reactant: [O-][Br+2]([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Yield: 95.1 %

Procedure:
A solution of 4-[1-(4-pentafluoroethyloxy-phenyl)-1H-[1,2,4]triazol-3-yl]-benzaldehyde (1.7 g, 4.4 mmol), sodium bromate (2.1 g, 13.9 mmol) and sodium bisulfate (0.53 g, 4.5 mmol) in 50 mL of acetonitrile was heated to reflux for 5 h, during which time a voluminous precipitate formed. The solution was then cooled and poured into 100 mL of water, filtered, and dried to furnish 1.67 g of the acid as a white solid. 1H NMR (300 MHz, CDCl3) δ 10.1 (s, 1H), 8.65 (s, 1H), 8.40 (d, J=8.4 Hz, 2H), 8.0 (d, J=8.4 Hz, 2H), 7.85 (d, J=9 Hz, 2H), 7.45 (d, J=9 Hz, 2H); ESIMS 399.2 (M+H+); mp 225° C.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:15][C@@H:16]([C:27]([OH:29])=[O:28])[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1>>[C:27]([C@H:16]([NH:15][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)([OH:29])=[O:28]
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O=C(O)c1cc2ccccc2nc1Cl
Product: O=C(O)c1cc2ccccc2nc1N[C@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2-chloroquinoline-3-carboxylic acid is reacted with D-tryptophan to provide the title compound in moderate yield as yellow needles (recrystallization from isopropanol).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]([OH:19])(=[O:18])[C:12]([CH2:14][C:15]([OH:17])=[O:16])=[CH2:13].S(=O)(=O)(O)O>O>[N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][C:2]=1[S:1][CH2:13][CH:12]([C:11]([OH:19])=[O:18])[CH2:14][C:15]([OH:17])=[O:16]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: C=C(CC(=O)O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CC(CSc1nc2ccccc2[nH]1)C(=O)O
Yield: 105.5 %

Procedure:
47.4 g of 2-mercaptobenzimidazole and 40.7 g of itaconic acid, mixed in finely powdered form, are introduced into 150 ml of 70% aqueous sulfuric acid in the course of 1 hour. The temperature is kept at 40° to 43°, with stirring. The mixture is then allowed to react completely at the above temperature over a period of 11/2 hours and the reaction mixture is diluted with water and ice to about 2 liters. The product is precipitated by addition of 30% aqueous sodium hydroxide solution to pH 4 and filtered off. After washing with water and drying in vacuo at about 30°, 92.5 g of 3-(benzimidazol-2-ylthio)-propane-1,2-dicarboxylic acid are obtained in the form of a dihydrate of melting point 113° (decomposition), corresponding to 97% of theory.
Reaction SMILES: [CH2:1](I)I.[O:4]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:21]>CCOCC>[CH:12]12[CH2:1][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:4][C:5](=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2
Reactant: ICI
Reactant: O=C1CCCCCC=CCCCCCCCCO1
Solvent: CCOCC
Product: O=C1CCCCCCC2CC2CCCCCCCO1
Reaction time: 4 h

Procedure:
To a dry 500 ml multi-neck round bottom flask fitted with an air stirrer, nitrogen inlet condenser and an addition funnel 8 g of ZnCu, 26 g of CH2I2, 100 ml of Et2O and 2 crystals of 12, were added and stirred. 12 g of oxacycloheptadec-8-en-2-one were added to the mixture and the mixture was heated to reflux. In 4 hours, first sample was taken at 35° C. The mixture was left to age overnight. Next morning, the mixture was quenched with saturated NH4Cl, aqueous layer separated and the organic layer washed with NaHCO3. The organic layer was then dried over anhydrous MgSO4. The gas chromatography test indicated that 8.1% of the starting alkene lactone converted to the cyclopropanated lactone.
Reaction SMILES: C[O:2][P:3]([O:6][CH3:7])[O:4][CH3:5].Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]>>[CH2:12]([O:11][C:9]([P:3](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COP(OC)OC
Reactant: O=C(Cl)OCc1ccccc1
Product: COP(=O)(OC)C(=O)OCc1ccccc1

Procedure:
From 50 ml (0.4 mole) of trimethylphosphite and 56.9 g (0.3 mole) of benzyl chloroformate (Sigma 90-95%) (100° C., 2 hours). Yield 73 g (90%). Bp0.02 135°-6° C. nD25 1,4997.
Reaction SMILES: Cl[S:2]([CH2:5][C:6]([O:8][CH3:9])=[O:7])(=[O:4])=[O:3].[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([O:20][C:21]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:22]=2[NH2:23])[N:13]=1.N1C=CC=CC=1>ClCCl>[CH3:19][O:18][C:16]1[CH:17]=[C:12]([O:11][CH3:10])[N:13]=[C:14]([O:20][C:21]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:22]=2[NH:23][S:2]([CH2:5][C:6]([O:8][CH3:9])=[O:7])(=[O:4])=[O:3])[N:15]=1
Reactant: COc1cc(OC)nc(Oc2cccc(F)c2N)n1
Reactant: COC(=O)CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CS(=O)(=O)Nc1c(F)cccc1Oc1nc(OC)cc(OC)n1
Reaction time: 8 h

Procedure:
Methyl (chlorosulfonyl)acetate (13.0 g) in dichloromethane (20 ml) was aaded dropwise with stirring and cooling to 2-(4,6-dimethoxypyrimidin-2-yloxy)-6-fluoroaniline (20 g) and pyridine (6.3 g) in dichloromethane (120 ml). After stirring for 2 hours, the mixture was allowed to stand at room temperature overnight. Washing with dilute hydrochloric acid and water, dryiny over magnesium sulfate, and running down, gave an oil which was triturated with ether. The resulting off-white solid was separated by filtration to qive 20.4 of the desired product, mp 111°-114° C.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C[Al](C)C.C[O:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[N:21]([CH3:31])[N:22]=[N:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:14][CH:13]=1>O1CCOCC1>[CH:1]([NH:4][C:11](=[O:10])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[N:21]([CH3:31])[N:22]=[N:23][C:24]=2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[N:14][CH:13]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)nnn2C)nc1
Agent: C[Al](C)C
Solvent: C1COCCO1
Product: CC(C)NC(=O)c1ccc(OCc2c(-c3ccccc3)nnn2C)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a solution of isopropylamine (95 μL, 1.11 mmol) in dioxane (5.5 mL) was added dropwise trimethylaluminium (2 M in heptane, 600 μL, 1.11 mmol). The resulting solution was stirred at room temperature for 1 h, then a solution of 6-(3-methyl-5-phenyl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid methyl ester (90 mg, 0.28 mmol) in dioxane (2.8 mL) was added and the reaction mixture was stirred at 90° C. for 5 h. After cooling to room temperature the mixture was poured into a Na—K-tartrate solution extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated to afford the title compound (83 mg, 85%) as a white solid. MS: m/e=352.3 [M+H]+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:30]=[CH:29][C:12]([O:13][C:14]3[N:18]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:17]4[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=4[N:15]=3)=[CH:11][CH:10]=2)O1.Br[C:33]1[C:37]2=[N:38][CH:39]=[CH:40][CH:41]=[C:36]2[N:35]([CH2:42][CH3:43])[N:34]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:42]([N:35]1[C:36]2[C:37](=[N:38][CH:39]=[CH:40][CH:41]=2)[C:33]([C:9]2[CH:30]=[CH:29][C:12]([O:13][C:14]3[N:18]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:17]4[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=4[N:15]=3)=[CH:11][CH:10]=2)=[N:34]1)[CH3:43]
Reactant: CCn1nc(Br)c2ncccc21
Reactant: CCOC(=O)Cn1c(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)Cn1c(Oc2ccc(-c3nn(CC)c4cccnc34)cc2)nc2ccccc21
Yield: 18.6 %

Procedure:
A mixture of ethyl {2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-1H-benzimidazol-1-yl}acetate (540 mg), 3-bromo-1-ethyl-1H-pyrazolo[4,3-b]pyridine (289 mg), Pd(PPh3)4 (44.3 mg), Na2CO3 (474 mg) in DME (10 mL) and water (2 ml) was refluxed overnight under Ar atmosphere. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (105 mg).
Reaction SMILES: C(C1C=CC(C2C3C(=CC=C(C#C[C:21]4[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=4)C=3)SC(C)(C)C=2)=CC=1)C.[OH-].[Na+].Cl>C1COCC1.CCO>[C:25]([OH:27])(=[O:26])[C:24]1[CH:30]=[CH:31][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(CC)cc2)=CC(C)(C)S3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-[[4-(4-ethylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]ethynyl]-benzoate (940.0 mg. 2.08 mmol) in 10.0 mL THF and 5.0 mL EtOH was added NaOH (416.0 mg, 10.4 mmol, 5.2 mL of a 2M aqueous solution). The resulting solution was stirred overnight at room temperature. The reaction was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure. The residual solid was recrystallized from CH3CN to give 786.0 mg (89%) of 4-[[4-(4-ethylphenyl)-2,2-dimethyl-2H)-thiochromen-6-yl]-ethynyl]-benzoic acid as a colorless solid. 1H NMR (300 MHz, d5 acetone) δ: 8.01 (2H, d, J=8.3 Hz), 7.60 (2H, d, J=8.5 Hz), 7.42 (2H, m), 7.29 (2H, m), 7.22 (3H, m), 5.94 (1H, s), 2.69 (2H, 1, J=7.7 Hz), 1.47 (6H, s), 1.25 (3H, t, J=7.7 Hz). This compound is hereinafter designated as AGN 194310.
Reaction SMILES: [C:1]1([S:7]([O:10][C:11]2[C:20]([Br:21])=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([CH:22]=[O:23])=[N:18]3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24](Br)[CH:25]=[CH2:26]>C1COCC1.[NH4+].[Cl-]>[C:1]1([S:7]([O:10][C:11]2[C:20]([Br:21])=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([CH:22]([OH:23])[CH2:26][CH:25]=[CH2:24])=[N:18]3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc2ccc(OS(=O)(=O)c3ccccc3)c(Br)c2n1
Reactant: C=CCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCC(O)c1ccc2ccc(OS(=O)(=O)c3ccccc3)c(Br)c2n1
Yield: 96.5 %

Procedure:
A mixture of compound 16 (448 mg, 1.14 mmol), In powder (150 mg, 1.31 mmol) and allyl bromide (160 μL, 1.87 mmol) were stirred in a mixture of 10 mL THF and 10 mL aq. NH4Cl for 3 hours. THF was removed in vacuo, and residue was extracted with EtOAc and then dried over anhydrous Na2SO4. Solvent was removed in vacuo, and the residue was purified by SiO2 column chromatography (hexanes/EtOAc=2/1) to yield 17 as a colorless oil (478 mg, 1.10 mmol, 96% yield). 1H NMR (500 MHz, CDCl3) δ 8.13 (d, 1H, J=8.0 Hz), 7.96−7.93 (m, 2H), 7.76 (d, 1H, J=9.0 Hz), 7.68 (t, 1H, J=8.5 Hz), 7.54−7.50 (m, 3H), 7.42 (d, 1H, J=8.5 Hz), 5.89−5.80 (m, 1H), 5.11−5.03 (m, 2H), 4.97 (s, 2H), 2.73−2.69 (m, 1H), 2.54−2.48 (m, 1H). 13C NMR (500 MHz, CDCl3) δ 163.40, 148.17, 144.08, 137.34, 135.61, 134.86, 133.88, 129.40, 128.67, 128.01, 126.84, 122.47, 119.53, 118.22, 118.12, 72.24, 42.34. MS-ESI (m/z): [M+H]+ calculated for C19H17BrNO4S, 434.01 (79Br) and 436.00 (81Br); found 434.11 (79Br) and 436.10 (81Br).
Reaction SMILES: [F:1][C:2]([F:15])([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]=1)[C:3]([O:5]CC)=[O:4].[OH-].[Na+:17]>CO.C1COCC1>[F:15][C:2]([F:1])([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][N:9]=1)[C:3]([O-:5])=[O:4].[Na+:17]
Reactant: CCOC(=O)C(F)(F)c1ccc(F)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C([O-])C(F)(F)c1ccc(F)cn1
Reaction time: 0.17 h
Yield: 100.9 %

Procedure:
To ethyl 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate (560 mg, 2.55 mmol) in 1:1 MeOH/THF (10 mL) at rt was added 1 M NaOH (2.8 mL, 2.8 mmol). The solution was stirred for 10 min and then concentrated to dryness to afford sodium 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate (548 mg, quantitative). 1H NMR (300 MHz, DMSO-d6) δ 7.66 (dd, 1H), 7.79 (dt, 2H), 8.54 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([OH:23])=[CH:18][C:17]=3[CH3:24])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>N1C=CC=CC=1>[CH3:22][C:21]1[CH:20]=[C:19]([O:23][S:33]([CH3:32])(=[O:35])=[O:34])[CH:18]=[C:17]([CH3:24])[C:16]=1[C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][O:8][C:6]2[CH:5]=[CH:4][C:3]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:2]([F:1])[CH:7]=2)[CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(O)cc3C)c2)cc1F
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(OS(C)(=O)=O)cc3C)c2)cc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.9 %

Procedure:
To an ice-cooled solution of ethyl 3-{2-fluoro-4-[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy]phenyl}propanoate (310 mg, 0.736 mmol) in pyridine (8 mL) was added dropwise methanesulfonyl chloride (168 mg, 1.47 mmol). The mixture was stirred at room temperature for 2 days. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-1/1) to give the title compound (320 mg, yield 87%) as a colorless oil.