Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1(O)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[CH2:8][CH2:7]1)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[Cl-].[Cl-].[Ca+2]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[CH2:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)CC1(O)CCc2ccc(F)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CC1=CCc2ccc(F)cc21
Yield: 21.4 %

Procedure:
The crude (6-Fluoro-1-hydroxy-indan-1-yl)-acetic acid ethyl ester (Compound G in FIG. 7; 3.55 g), p-toluene sulfonic acid.H2O (PTSA; 5.67 g, 29.8 mmol), and CaCl2 (4.13 g, 37.2 mmol) in toluene (66 mL) were refluxed overnight. The solution was filtered and the solid residue washed with benzene. The combined organics were washed with water, NaHCO3, water, dried (MgSO4), filtered, and concentrated in vacuo. Purification using flash chromatography (13:1 hexane/EtOAc) afforded the title compound (Compound H in FIG. 7) as an orange solid (0.703 g). 1H NMR (CDCl3) δ 7.25 (m, 2H), 7.06 (m, 1H), 6.25 (d, J=2.3 Hz, 1H), 4.24 (q, J=7.0 Hz, 2H), 3.32 (s, 2H), 3.03 (s, 2H), 1.33 (t, J=7.1 Hz, 3H); ESI-CID 221 (M-H+).
Reaction SMILES: Cl[Sn]Cl.O.[Cl:5][C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[C:8]([Cl:15])[C:7]=1[CH3:16]>C(O)C>[Cl:5][C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]([Cl:15])[C:7]=1[CH3:16]
Reactant: Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Cc1c(Cl)ccc(N)c1Cl
Yield: 99.4 %

Procedure:
To a solution of SnCl2.H2O (140 g, 0.62 mol) in ethanol (350 mL) was added a solution of 2,6-dichloro-3-nitrotoluene (25 g, 0.12 mol) in ethanol (50 mL). The reaction mixture was refluxed for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (100 mL), pH was adjusted to approximately pH 12 with 1N NaOH solution and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over sodium sulfate, and concentrated to afford 2,6-dichloro-3-aminotoluene (21 g, 98%); NMR (CDCl3) 2.42 (s, 3), 6.62 (d, 1), 7.14 (d, 1) ppm.
Reaction SMILES: ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH:23]1([C:26]2[CH:31]=[C:30]([O:32][CH2:33][C:34]3[C:39]([F:40])=[CH:38][CH:37]=[CH:36][C:35]=3[F:41])[N:29]3[N:42]=[C:43]([CH3:48])[C:44]([C:45](O)=[O:46])=[C:28]3[CH:27]=2)[CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C.[C:58]([O:62][C:63](=[O:72])[NH:64][C:65]([CH3:71])([CH2:68][CH2:69][CH3:70])[CH2:66][NH2:67])([CH3:61])([CH3:60])[CH3:59]>O1CCCC1>[C:58]([O:62][C:63](=[O:72])[NH:64][C:65]([CH3:71])([CH2:68][CH2:69][CH3:70])[CH2:66][NH:67][C:45]([C:44]1[C:43]([CH3:48])=[N:42][N:29]2[C:30]([O:32][CH2:33][C:34]3[C:35]([F:41])=[CH:36][CH:37]=[CH:38][C:39]=3[F:40])=[CH:31][C:26]([CH:23]3[CH2:25][CH2:24]3)=[CH:27][C:28]=12)=[O:46])([CH3:61])([CH3:60])[CH3:59]
Reactant: Cc1nn2c(OCc3c(F)cccc3F)cc(C3CC3)cc2c1C(=O)O
Reactant: CCCC(C)(CN)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(C3CC3)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
76 mg (0.6 mmol) of 1-hydroxy-7-azabenzotriazole and 107 mg (0.6 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added to a solution of 167 mg (0.5 mmol) of 5-cyclopropyl-7-[(2,6-difluorobenzyl)oxy]-2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid (Example 149A), 244 μl (1.4 mmol) of N,N-diisopropylethylamine and 121 mg (0.6 mmol) of rac-(1-amino-2-methylpentan-2-yl)carbamic acid tert-butyl ester from Example 152A in 5 ml of tetrahydrofuran. The mixture was stirred at room temperature for 18 h and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase was removed and washed with water and saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The residue was purified by chromatography on silica gel (40 g silica gel cartridge, mobile phase: cyclohexane/ethyl acetate, gradient 0% to 100%). This gave 125 mg of the target compound (48% of theory).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:26]([O:62][CH3:63])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:60][CH3:61])[C@@H:36]([CH3:59])[C:37](=[O:58])[NH:38][C@H:39]([C:47]1[O:48][C:49]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[N:50][N:51]=1)[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12].O=[CH:69][CH2:70][CH2:71][C:72]([OH:74])=[O:73].C([BH3-])#N.[Na+].O1CCOCC1>O1CCOCC1.O>[C:72]([CH2:71][CH2:70][CH2:69][N:9]([CH3:8])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:26]([O:62][CH3:63])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:60][CH3:61])[C@@H:36]([CH3:59])[C:37](=[O:58])[NH:38][C@H:39]([C:47]1[O:48][C:49]([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)=[N:50][N:51]=1)[CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:12])[CH3:13])([OH:74])=[O:73]
Reactant: O=CCCC(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C

Procedure:
22.4 mg (24 μmol) of N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetate were dissolved in 1.4 ml of dioxane/water and, analogously to the preparation of Intermediate 61, reacted with 15% aqueous solution of 4-oxobutanoic acid in the presence of sodium cyanoborohydride. After lyophilization from dioxane, 8.2 mg (38% of theory) of the title compound were obtained in the form of a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)[CH:5]=[CH:4][N:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CS(C)=O>[CH3:18][C:17]1[O:16][N:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]=1[C:10]1[O:9][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:7]=2)=[N:12][N:11]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccnc(Cl)c2)o1
Reactant: C1COCCN1
Solvent: CS(C)=O
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccnc(N3CCOCC3)c2)o1
Temperature: 170 °C
Reaction time: 18 h
Yield: 72.3 %

Procedure:
To a solution of 2-chloro-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine (200 mg, 0.59 mmol) in DMSO (2 mL) was added morpholine (257 μL, 2.95 mmol) and stirred for 18 h under an argon atmosphere at 170° C. After cooling to ambient temperature the resulting dark brown solution was extracted with ethyl acetate (20 mL) and aqueous sodium carbonate (saturated, 20 mL). The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers were washed with water (20 mL) and brine (20 mL). Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20) afforded the title compound (166 mg, 72%) as a white solid. MS: m/e=390.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][CH:15]([S:18](Cl)(=[O:20])=[O:19])[CH2:14][CH2:13]1.[NH3:22].C1COCC1>>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][CH:15]([S:18]([NH2:22])(=[O:20])=[O:19])[CH2:14][CH2:13]1
Reactant: N
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(S(=O)(=O)Cl)CC1
Solvent: C1CCOC1
Product: NS(=O)(=O)C1CCC(N2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A mixture of 4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-sulfonyl chloride (5 g, 15.2 mmol) in NH3/THF (150 mL) was stirred at room temperature overnight. The mixture was concentrated in vacuo. The residue was dissolved into about 100 mL of hot water and the solid was filtered under hot condition. The filtrate was concentrated in vacuo to give 4-(1,3-dioxoisoindolin-2-yl)cyclohexane-1-sulfonamide (3 g, 64%) as an off-white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:28][C:9]2[N:10]=[CH:11][N:12]=[C:13]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[O:22][C@@H:23]3[CH2:27][CH2:26][O:25][CH2:24]3)[C:8]=2[C:7]=1[CH3:29])=[O:5])C.[OH-].[Na+]>CO>[F:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:13]2[C:8]3[C:7]([CH3:29])=[C:6]([C:4]([OH:5])=[O:3])[S:28][C:9]=3[N:10]=[CH:11][N:12]=2)=[C:16]([O:22][C@@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[CH:17]=1
Reactant: CCOC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCOC3)c2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCOC3)c12

Procedure:
4-{4-Fluoro-2-[(R)-(tetrahydro-furan-3-yl)oxy]-phenylamino}-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (150 mg) was dissolved in methanol (5 ml) and NaOH (1M; 1.9 ml) was added. The reaction was stirred over the weekend. The organic solvent was evaporated and the residue was neutralised with HCl. The resultant precipitate was filtered and dried.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([F:22])=[C:12]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.Cl[C:25]1[N:26]=[N:27][CH:28]=[CH:29][CH:30]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][CH2:9][C:10]1[C:11]([F:22])=[C:12]([N:16]2[CH2:21][CH2:20][N:19]([C:25]3[N:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: Clc1cccnn1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N2CCNCC2)c1F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(N2CCN(c3cccnn3)CC2)c1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazine (400 mg) was suspended in toluene (8 ml), and 3-chloropyridazine hydrochloride (242 mg), Pd2(dba)3(56 mg), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (51 mg), and sodium tert-butoxide (308 mg) were added thereto, followed by stirring at 100° C. overnight. The reaction mixture was cooled to room temperature, and filtered by the addition of CHCl3 and Celite, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (EtOAc:hexane=70:30 to 100:0), and then purified by basic silica gel column chromatography (EtOAc/hexane) to obtain 3-{4-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperazin-1-yl}pyridazine (325 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[CH3:13][C:14]([CH3:18])([CH3:17])[CH:15]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCl>[CH3:13][C:14]([CH3:18])([CH3:17])[CH2:15][NH:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: CC(C)(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(NCC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
4-Methoxy-2-nitroaniline (10 g, 59.5 mmol, 1.0 equiv.) and trimethyl-acetaldehyde (9.73 g, 113 mmol, 1.9 equiv.) were dissolved in anhydrous dichloromethane (100 ml). The resulting solution was then treated with acetic acid (18.72 ml, 327 mmol, 5.5 equiv.), followed by sodium triacetoxyborohydride (30.3 g, 143 mmol, 2.4 equiv.). The mixture was stirred at room temperature. When LCMS showed completion of the reaction, the mixture was treated with saturated aqueous NaHCO3, then extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated to give the crude N-(2,2-dimethylpropyl)-4-methoxy-2-nitroaniline (1-3), which was used without purification. LRMS m/z (M+H) 239.0 found, 238.1 required.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([O:8][CH3:9])[CH:4]=1.[CH2:10]([O:12][P:13]([O:17]CC)[O:14][CH2:15][CH3:16])[CH3:11].ClCC1C=CON=1>>[CH3:9][O:8][C:5]1[CH:4]=[C:3]([CH2:2][P:13]([O:14][CH2:15][CH3:16])(=[O:17])[O:12][CH2:10][CH3:11])[O:7][N:6]=1
Reactant: COc1cc(CCl)on1
Reactant: CCOP(OCC)OCC
Agent: ClCc1ccon1
Product: CCOP(=O)(Cc1cc(OC)no1)OCC
Yield: 56.1 %

Procedure:
3.8 g 5-chloromethyl-3-methoxy-isoxazole and 6.0 g of triethylphosphite were stirred at 150° C. until complete conversion of the chloromethyl isoxazole (2-8 h). Kugelrohr destillation gave 3.6 g of diethyl (3-methoxy-isoxazol-5-yl)-methane phosphonate. Bp. 160°-165° C./0.3 mm Hg.
Reaction SMILES: [Cl-].[Li+].N1C=CC=CC=1.O.C([CH:15]1[CH2:20][C:19](C(OCC)=O)([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH2:17][C:16]1=[O:31])(OCC)=O>CS(C)=O.C(OCC)(=O)C>[C:21]([CH:19]1[CH2:20][CH2:15][C:16](=[O:31])[CH2:17][CH2:18]1)([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C1CC(C(=O)OCC)(C(=O)OCC)CCC1=O
Agent: [Cl-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1CCC(=O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To 540 ml of dimethyl sulfoxide were added 21.9 g of lithium chloride, 13.9 ml of pyridine and 9.3 ml of water, and the resulting mixture was gently heated under reflux. While refluxing the mixture, 100 ml of a solution of 54.0 g of 2,4,4-tricarbethoxy-cyclohexanone in dimethyl sulfoxide was dropwise added thereto over one hour. After a reaction at the same temperature as above for 2 hours, the mixture was cooled and poured into a mixture of ice water and ethyl acetate, and the organic layer was separated. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by distillation under reduced pressure gave 13.5 g of 4-carbethoxycyclohexanone as a light yellow oily product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][C:10]3[CH:14]=[C:15]([S:18]([N:21](CC4C=CC(OC)=CC=4)[C:22]4[S:23][CH:24]=[CH:25][N:26]=4)(=[O:20])=[O:19])[CH:16]=[CH:17][C:9]2=3)=[C:4]([C:36]#[N:37])[CH:3]=1.[F:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:36]([C:4]1[CH:3]=[C:2]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[F:38])[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15]([S:18]([NH:21][C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:19])=[O:20])[CH:16]=[CH:17][C:9]1=2)#[N:37]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc(Br)cc2C#N)cc1
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: N#Cc1cc(-c2ccccc2F)ccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
A solution of PdCl2(dppf)-CH2Cl2 adduct (0.017 g, 0.021 mmol), 4-(4-bromo-2-cyanophenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.124 g, 0.208 mmol), (2-fluorophenyl)boronic acid (0.032 g, 0.228 mmol, Aldrich) and potassium phosphate (0.220 g, 1.038 mmol) in dioxane (0.553 ml)/water (0.277 ml) was heated to 90° C. for 1 h until completion. The reaction was cooled to RT and then diluted with DCM and washed with water. The organics were dried via phase separator (Radleys Discovery Technologies) and concentrated in vacuo. The material was taken up in a mixture of DCM and methanol, and further purified using a 2-g SCX column (product eluted with methanol wash). After concentration, DCM (1.0 mL) and TFA (0.5 mL) were added and stirred at RT for 3 h until complete deprotection. The reaction was concentrated in vacuo and purified via silica-gel chromatography, eluting with 0-100% ethyl acetate in heptanes to yield, after concentration, 4-(3-cyano-2′-fluoro-[1,1′-biphenyl]-4-yl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.082 g, 0.166 mmol, 80% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.79-3.86 (m, 2 H) 4.32-4.40 (m, 2 H) 6.64 (d, J=8.51 Hz, 1 H) 6.80 (d, J=4.50 Hz, 1 H) 7.17-7.21 (m, 1 H) 7.21-7.24 (m, 2 H) 7.31-7.40 (m, 2 H) 7.45-7.53 (m, 1 H) 7.60-7.68 (m, 2 H) 7.95 (dt, J=8.56, 1.83 Hz, 1 H) 8.11 (s, 1 H) 12.62 (br. S., 1 H). m/z (ESI) 493.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7](OS(C(F)(F)F)(=O)=O)=[CH:6][CH:5]=[C:4]([F:16])[C:3]=1[C:17]1[N:22]=[C:21]([C:23]([O:25]C)=[O:24])[CH:20]=[CH:19][CH:18]=1.[CH2:27]([Zn]CC)[CH3:28]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH2:27]([C:7]1[C:2]([F:1])=[C:3]([C:17]2[N:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[CH:19][CH:18]=2)[C:4]([F:16])=[CH:5][CH:6]=1)[CH3:28]
Reactant: COC(=O)c1cccc(-c2c(F)ccc(OS(=O)(=O)C(F)(F)F)c2F)n1
Reactant: CC[Zn]CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCc1ccc(F)c(-c2cccc(C(=O)O)n2)c1F
Temperature: 70 °C

Procedure:
To a solution of methyl 6-(2,6-difluoro-3-(trifluoromethylsulfonyloxy)-phenyl)picolinate (1.0 equiv.) in toluene (0.15M) was added Pd(dppf)Cl2-DCM (0.1 equiv.) followed by diethyl zinc (3.0 equiv.). The solution turned from orange to bright yellow. The reaction was heated to 70° C. for 2 hours at which time, LC/MS analysis indicated a mixture of 1:3:1 ratio of hydrolyzed product, desired product and unknown by-product. The reaction was cooled to room temperature, diluted with ethyl acetate and washed with 1N NaOH (2×). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to provide a brown oil. The oil was redissolved in THF and treated with 1N NaOH for one hour. The reaction was then diluted with ethyl acetate and washed with 1N NaOH (2×). The basic washings were combined, acidified with concentrated HCl and extracted with ethyl acetate (3×). The organic phase was dried with magnesium sulfate, filtered, and concentrated in vacuo to provide 6-(3-ethyl-2,6-difluorophenyl)picolinic acid as a light brown oil in >99% yield. LC/MS=264.1 (M+H), Rt=0.88 min.
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]([NH:13][C@H:14]1[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:22]([O:28][C:29](=[O:31])[CH3:30])[C@@H:21]([CH2:32][O:33][C:34](=[O:36])[CH3:35])[O:20][C@@H:15]1OC(=O)C)(=[O:12])[CH3:11].[CH2:37]([SH:46])[CH:38]=[CH:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)(Cl)Cl>[C:10]([NH:13][C@H:14]1[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:22]([O:28][C:29](=[O:31])[CH3:30])[C@@H:21]([CH2:32][O:33][C:34](=[O:36])[CH3:35])[O:20][C@@H:15]1[S:46][CH2:37][CH:38]=[CH:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:12])[CH3:11]
Reactant: SCC=Cc1ccccc1
Reactant: CC(=O)N[C@@H]1[C@@H](OC(C)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: FB(F)F
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CC(=O)N[C@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@@H]1SCC=Cc1ccccc1
Reaction time: 48 h
Yield: 52.2 %

Procedure:
Boron trifluoride etherate (200 μl, 1.3 mmol) is added to a solution of 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-α-D-mannopyranose (389 mg) and cinnamyl mercaptan (150 mg) in chloroform (10 ml), and the solution is kept under nitrogen for 2 days. Another portion of boron trifluoride etherate (200 μl) is added and the solution is kept under nitrogen for another 2 days. Chloroform (15 ml) is added and the solution is washed with aqueous sodium hydrogencarbonate and water, dried, and evaporated in vacuo to a residue, which is purified by preparative chromatography (EtOAc--CHCl3, 10:90, v/v, as a developing phase) to give the title compound (250 mg, 52%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.[CH3:21][C:22]1[NH:23][C:24](=[S:28])[S:25][C:26]=1[CH3:27]>>[CH3:21][C:22]1[N:23]([CH2:3][C:4]2[N:8]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]3=[N:6][C:5]=2[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:24](=[S:28])[S:25][C:26]=1[CH3:27]
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CCl)cc1
Reactant: Cc1[nH]c(=S)sc1C
Agent: Cl
Product: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2c(C)c(C)sc2=S)cc1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 92 from 3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and 4,5-dimethylthiazole-2(3H)-thione. m/e+ 380 for C21H22N3S2 [M+H]+; 1H-NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.65 (d, J=8.0 Hz, 2H), 7.55 (d, J=8.8 Hz, 1H), 7.26 (d, J=8.0 Hz, 2H), 7.08 (dd, J=1.4, 9.1 Hz, 1H), 4.83 (s, 2H), 2.39 (s, 3H), 2.35 (s, 3H), 2.29 (s, 3H), 2.28 (s, 3H) ppm; 13C-NMR (100 MHz, CDCl3, δ) 156.250, 149.085, 145.149, 144.391, 137.642, 131.159, 129.347, 128.748, 128.217, 127.929, 122.090, 121.794, 116.828, 113.612, 30.301, 21.308, 18.449, 14.688, 11.374 ppm.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[C:10]([C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1[CH3:22])[C:15](OC)=[O:16])#N.[OH2:23].Cl>C(Cl)Cl>[OH:16][CH2:15][C:14]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:12]([CH:13]=1)[CH:10]=[O:23]
Reactant: O
Reactant: COC(=O)c1ccc(C)c(C#N)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(CO)cc1C=O
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a stirring solution of 27 mL of DIBAL-H (1.5 M solution in toluene) in 10 mL of CH2Cl2 at −78° C. was added 1.32 g (7.54 mmol) of methyl 3-cyano-4-methylbenzoate in 35 mL of CH2Cl2 dropwise over a period of 30 min. After stirring for about 40 min. at −78° C., the solution was allowed to warm to r.t. After 75 min., the solution was cooled to −78° C. and 10 mL of H2O and 16 mL of 1N HCl were added. The cold bath was removed, and the mixture was allowed to warm to r.t. Concentrated HCl (5-6 mL) was added and stirring was continued for 1.5 h. Chloroform was added, the layers were separated, and the organic layer was washed with 20 mL of brine. The combined aqueous layers were extracted with chloroform (4×). The combined extracts were dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (50% EtOAc/hexanes) provided the 800 mg of 5-(hydroxymethyl)-2-methylbenzaldehyde as a yellow oil with some impurity.