Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[C:29]([F:35])=[CH:28][C:27]=4[O:36][CH3:37])=[CH:24][CH:23]=[C:22](Cl)[N:21]=3)[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:42](B(O)O)([CH3:44])=[CH2:43]>C1COCC1.C(=O)([O-])[O-].[K+].[K+]>[F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[C:29]([F:35])=[CH:28][C:27]=4[O:36][CH3:37])=[CH:24][CH:23]=[C:22]([C:42]([CH3:44])=[CH2:43])[N:21]=3)[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(Cl)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: C=C(C)B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)c1ccc(-c2cc(C(C)C)c(F)cc2OC)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Temperature: 25 °C

Procedure:
A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[6-chloro-3-(4-fluoro-5-isopropyl-2-methoxyphenyl)pyridin-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (EXAMPLE 18) (43 mg, 0.071 mmol) and isopropenyl boronic acid (Molander, G. A.; et. al. J. Am. Chem. Soc. 2003, 125, 11148-11149) (122 mg, 1.42 mmol) in THF (3 mL) and 1N aqueous potassium carbonate (3 mL). 1,1-Bis(di-t-Bu-phosphino)ferrocene palladium dichloride (4.6 mg, 0.0071 mmol) was heated at 80° C. for 4 h in a sealed tube. The mixture was cooled to room temperature and filtered through Celite. The filtrate was diluted with water and extracted with EtOAc (3×). The combined organic extracts were washed with brine (1×), dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si, hexanes/EtOAc) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-(4-fluoro-5-isopropyl-2-methoxyphenyl)-6-isopropenylpyridin-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. LCMS calc.=611.2; found=611.2 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers) δ 7.88 (s, 1H); 7.75 (s, 2H); 7.51 (s, 2H); 7.04 (br, s, 0.5H); 6.99 (br, s, 0.5H); 6.71 (s, 0.5H); 6.69 (s, 0.5H); 5.98 (s, 1H); 5.68 (br, s, 0.5H); 5.66 (br, s, 0.5H); 5.37 (m, 1H); 5.00-4.74 (m, 1H); 4.56-4.20 (m, 1H); 4.20-3.90 (m, 1H); 3.77 (s, 3H); 3.25-3.18 (m, 1H); 2.28 (s, 3H); 1.32-1.22 (m, 6H); 0.74 (br, s, 1.5H); 0.64 (br, s, 1.5H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2OC=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)O1.Cl[C:22]1[C:31]([N:32]([CH3:36])[CH:33]([CH3:35])[CH3:34])=[N:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:37]([O:39][CH3:40])=[O:38])[CH:28]=2)[N:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[O:49]1CCOC[CH2:50]1>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>[CH3:36][N:32]([CH:33]([CH3:35])[CH3:34])[C:31]1[C:22]([C:50]2[O:49][C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:13][CH:9]=2)=[N:23][C:24]2[C:29]([N:30]=1)=[CH:28][C:27]([C:37]([O:39][CH3:40])=[O:38])=[CH:26][CH:25]=2
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: CC1(C)OB(c2cc(-c3ccccc3)co2)OC1(C)C
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc(-c4ccccc4)o3)c(N(C)C(C)C)nc2c1
Temperature: 95 °C
Reaction time: 1 h

Procedure:
To a solution of 4,4,5,5-tetramethyl-2-(4-phenylfuran-2-yl)-1,3,2-dioxaborolane (200 mg, crude) in dioxane (5.5 mL) and water (3 drops) was added methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (72 mg, 0.25 mmol), K3PO4 (156 mg, 0.73 mmol) and Pd(PPh3)4 (14 mg, 0.01 mmol) with stirring for 1 h at 95° C. in an oil bath which was maintained under an inert atmosphere of nitrogen. The reaction mixture was concentrated under reduced pressure to give the residue, which was purified by silica gel column chromatography eluting with 2% ethyl acetate in petroleum ether to afford methyl 3-[methyl(propan-2-yl)amino]-2-(5-phenylfuran-2-yl)quinoxaline-6-carboxylate as a light yellow solid (50 mg).
Reaction SMILES: [CH:1]([N:4]([CH2:12][CH2:13][NH:14]S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].C1(S)C=CC=CC=1>C(#N)C.O>[NH2:14][CH2:13][CH2:12][N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)N(CCNS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CC(C)N(CCN)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.8 %

Procedure:
The compound (34.21 g, 82.60 mmol) obtained in step A was dissolved in acetonitrile (300 ml), cesium carbonate (52.38 g, 161 mmol) and benzenethiol (12 ml, 117 mmol) were added and the mixture was stirred at room temperature for one day. The reaction mixture was diluted with water, and the aqueous layer was extracted with dichloromethane. The obtained organic layer was dried over potassium carbonate, the insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was dissolved in toluene, and the mixture was extracted with 1N aqueous hydrogensulfate potassium solution. An aqueous sodium hydroxide solution was added to the aqueous layer to give a strong alkaline solution, and the suspending oil was extracted. The aqueous layer was extracted with dichloromethane, mixed with oil and dichloromethane solution, and the mixture was dried over sodium sulfate. The insoluble material was filtered off and the solution was concentrated under reduced pressure to give the title compound as a pale-yellow oil (15.0 g, yield 79%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]#[CH:15])(=O)=O)=CC=1.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17].O1CCOCC1>C(OCC)C>[CH2:16]([N:18]([CH2:19][CH3:20])[CH2:12][CH2:13][C:14]#[CH:15])[CH3:17]
Reactant: CCNCC
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Solvent: C1COCCO1
Solvent: CCOCC
Product: C#CCCN(CC)CC
Temperature: 80 °C
Yield: 64.2 %

Procedure:
Prepared using methodology described by Olomucki, M., et al. Ann. Chim. 1960, 5, 845. A stirred mixture of but-3-ynyl 4-methylbenzenesulfonate (21.2 g, 94.5 mmol), diethylamine (6.91 g, 94.5 mmol), and p-dioxane (100 mL) was heated to 80° C. under N2 for 6 hours. After cooling to room temperature, the suspension was diluted with diethyl ether (100 mL) and filtered. The solids were washed with diethyl ether (50 mL). The filtrate was concentrated to a brown oil. The crude was co-distilled (55-65° C.) with p-dioxane under a mild vacuum (10-50 torr). The product was obtained as an oil (7.6 g, 27%), in a 42:58 mixture with p-dioxane based on 1H NMR. 1H NMR (400 MHz, CDCl3) δ 2.70 (t, J=8 Hz, 2H), 2.55 (q, J=7 Hz, 4H), 2.32 (m, 2H), 1.97 (t, J=3 Hz, 1H), 1.04 (t, J=7 Hz, 6H).
Reaction SMILES: [C:1]1([P:7](=[O:12])([CH:10]=[CH2:11])[CH:8]=[CH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[CH2:13]([N:20]1[CH2:11][CH2:10][P:7](=[O:12])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=CP(=O)(C=C)c1ccccc1
Reactant: NCc1ccccc1
Solvent: O
Product: O=P1(c2ccccc2)CCN(Cc2ccccc2)CC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Phenyl(divinyl)phosphine oxide (1.47 g, 8.25 mmol) and benzylamine (901 μL, 8.25 mmol) were combined in water (20 mL) and stirred at 90° C. for 1 h. A second portion of benzylamine (901 mL, 8.25 mmol) was added, and the reaction was stirred at 90° C. for an additional 1 h. The solution was cooled and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried (MgSO4), and evaporated. The crude residue was purified by flash chromatography (0-10% MeOH/CH2Cl2) to afford the desired product as a colorless solid. 1H NMR (CDCl3, 600 MHz) δ 7.79-7.73 (m, 2H), 7.55-7.46 (m, 3H), 7.35-7.30 (m, 4H), 7.27-7.23 (m, 1H), 3.63 (m, 2H), 3.04-2.89 (m, 4H), 2.21-2.14 (m, 2H), 2.08-1.99 (m, 2H). MS: cal'd 286 (MH+), exp 286 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[CH:14]=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C@H:26]([NH2:28])[CH3:27]>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C@H:26]([NH:28][CH2:14][C:13]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:2]([CH3:1])[CH:3]=[CH:4]4)[CH:12]=2)[CH3:27])[CH:29]=[CH:30][CH:31]=1
Reactant: COc1cccc([C@@H](C)N)c1
Reactant: COc1ccc(C=O)cc1-c1ccc2c(ccn2C)c1
Product: COc1cccc([C@@H](C)NCc2ccc(OC)c(-c3ccc4c(ccn4C)c3)c2)c1

Procedure:
The title compound was prepared from 3-(1-methylindol-5-yl)-4-methoxybenzaldehyde and (R)-3-methoxy-α-methylbenzylamine according to general procedure C.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[OH2:7].[Br:8][C:9]1[O:13][C:12]([CH:14]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:15][NH:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:18])=[CH:11][CH:10]=1>CO>[C:26]1([S:25]([CH:14]([C:12]2[O:13][C:9]([Br:8])=[CH:10][CH:11]=2)[CH2:15][NH:16][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[O:18])=[O:7])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O
Reactant: O=C(NCC(Sc1ccccc1)c1ccc(Br)o1)c1ccccn1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Product: O=C(NCC(c1ccc(Br)o1)S(=O)c1ccccc1)c1ccccn1
Reaction time: 4.5 h

Procedure:
Sodium periodate (57 mg, 0.2677 mmol) in a small amount of water was added to pyridine-2-carboxylic acid [2-(5-bromofuran-2-yl)-2-phenylsulfanylethyl]-amide (90 mg, 0.2231 mmol) in methanol (13 ml). After refluxing for 4 h another 57 mg (0.2677 mmol) of sodium periodate was added and refluxing was continued for 4.5 h. Water (30 ml) was added and the product was extracted into EtOAc. The organic phase was washed with water, dried with Na2SO4 and evaporated. The crude product was used as such in the next step.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].B(OB=O)=O.[Cl:13][C:14]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:15]=1[CH:16]=O.C(OC)(OC)OC.C(N)CCC.Cl>C(OCC)(=O)C>[Cl:13][C:14]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:15]=1[CH:16]=[CH:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5]
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1ccc(O)cc1Cl
Agent: Cl
Agent: O=BOB=O
Solvent: COC(OC)OC
Solvent: CCOC(C)=O
Solvent: CCCCN
Product: CC(=O)CC(=O)C=Cc1ccc(O)cc1Cl
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 15.4 %

Procedure:
Ethyl acetate (0.8 mL), 2,4-pentanedione (1.03 mL, 10.0 mmol) and boron trioxide (0.63 g, 9.1 mmol) was placed in a 200 mL reaction vessel with a reflux condenser. To the stirring mixture at 85° C. was added dropwise a solution of 2-chloro-4-hydroxybenzaldehyde (238 mg, 1.52 mmol) and trimethyl orthoformate (0.17 mL, 1.5 mmol) in 3.0 mL of ethyl acetate. After the reaction mixture was stirred for 30 min at 95° C., n-butylamine (0.80 mL, 7.6 mmol) was added dropwise with additional stirring for 2 h. The reaction mixture was cooled to 50° C. before addition of 3N HCl (3.5 mL). After being stirred at 50° C. for 30 min, the mixture was filtered to remove solids. The filtrate was diluted with ethyl acetate, washed with brine twice, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=85/15 to 75/25) followed by recrystallization (hexane/ethyl acetate) to obtain the title compound as a yellow crystal (56 mg, 12%).
Reaction SMILES: Cl[CH2:2][S:3][CH3:4].[C:5]1([C:11]2[NH:16][C:15](=[S:17])[NH:14][C:13](=[O:18])[C:12]=2[CH3:19])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:4][S:3][CH2:2][N:16]1[C:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[C:12]([CH3:19])[C:13](=[O:18])[NH:14][C:15]1=[S:17]
Reactant: Cc1c(-c2ccccc2)[nH]c(=S)[nH]c1=O
Reactant: CSCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSCn1c(-c2ccccc2)c(C)c(=O)[nH]c1=S
Yield: 8.1 %

Procedure:
To 4 ml of dimethylformamide, 0.17 ml (2.0 mmol) of chloromethylmethylsulfide, 0.47 g (2.0 mmol) of 6-phenylthiothymine, 0.56 ml (2.0 mmol) of triethylamine were added and allowed to react for 22 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was adsorbed on a silica gel column and eluted with chloroform. The eluate was concentrated and crystallized from ethyl acetate to obtain 45 mg of the target compound (Yield: 8%).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:3]=1.[K].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][CH2:32][S:33]([NH2:36])(=[O:35])=[O:34].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[Cl:17][C:6]1[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:3]=[C:2]([NH:36][S:33]([CH2:32][CH2:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)(=[O:35])=[O:34])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1Cl
Reactant: NS(=O)(=O)CCc1ccccn1
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)CCc1ccccn1
Reaction time: 96 h
Yield: 38 %

Procedure:
A solution of 4,6-dichloro-5-(2-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (1.75 g, Referential Example 7) and 2-pyridin-2-yl-ethanesulfonic acid amide potassium salt (1.13 g) in DMSO (30 ml) was stirred at rt for 24 h. Triethylamine (657 mg) was added and stirring was continued for another 96 h before the mixture was diluted with ethyl acetate (150 ml) and washed 4% aq. citric acid and water. The aqueous phase was extracted three more times with EA. The organic phase was dried over MgSO4 and evaporated. The crude product was purified by column chromatography on silica gel eluting with EA containing 0–10% methanol to give 2-pyridin-2-yl-ethanesulfonic acid [6-chloro-5-(2-methoxyphenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide (950 mg) as a brown powder. LC-MS: tR=3.63 min, [M+1]+=498.31, [M−1]−=496.10.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=3)[NH2:14])[CH:9]=2)[NH:4][CH:3]=1.C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP([CH2:39][CH2:40][CH3:41])(=O)O1)CC.[C:43](OCC)(=[O:45])[CH3:44]>C(#N)C>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:14][C:43](=[O:45])[C:44]#[C:39][CH2:40][CH3:41])[CH:15]=[CH:16][CH:17]=3)[CH:9]=2)[NH:4][CH:3]=1
Reactant: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Reactant: Cc1c[nH]c2ncc(-c3cccc(N)c3)cc12
Reactant: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC#CC(=O)Nc1cccc(-c2cnc3[nH]cc(C)c3c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 24 (25 mg, 0.112 mmol) and 59 (9.86 mg, 0.112 mmol) in acetonitrile (4 mL) was added triethylamine (22.6 mg, 0.224 mmol). T3P (71.1 mg, 0.224 mmol) was added to the reaction mixture. The reaction was stirred overnight at rt, then diluted with ethyl acetate (25 mL). The organic layer was washed with water (25 mL) followed by brine solution (25 mL). The organic layer was dried over sodium sulphate, filtered and concentrated to get the crude, which was purified through flash chromatography by using 100-200 mesh silica gel. The compound was eluted at 2% methanol in chloroform as pale yellow colour solid compound 64. MS-ES+303.9; 1H NMR (400 MHz, DMSO-D6) 64: 11.37 (s, 1H), 10.65 (s, 1H), 8.41 (d, 1H), 8.06 (d, 1H), 7.90 (bs, 1H), 7.59 (d, 1H), 7.40 (m, 2H), 7.28 (bs, 1H), 2.42 (m, 2H), 2.30 (bs, 3H), 1.17 (t, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([CH2:15][C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C@@H:11]1[OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH2:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([CH2:15][C:16]([O:18][CH3:20])=[O:17])[CH:13]=[CH:12][C@@H:11]1[OH:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C[C@H]1C=C[C@H](O)[C@@H]1COCc1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)C[C@H]1C=C[C@H](O)[C@@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 100.2 %

Procedure:
To a solution of 23.6 g of (1S,2S,3S)-2-benzyloxymethyl-3-carboxymethyl-4-cyclopenten-1-ol [the compound described in J. Am. Chem. Soc., 93, 1492 (1971)] in 200 ml of acetone, 27.6 g of potassium carbonate and 11.36 g of methyl iodide were added. The mixture was stirred for 50 min at room temperature, and then refluxed for 2 hrs. After reacting, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (2:1) as eluent to give 24.9 g of the title compound having the following physical characteristics, in a 99% yield.
Reaction SMILES: C([O:8][C:9]([CH:11]1[C:18](=[O:19])[N:17]2[CH:13]([CH2:14][CH2:15][C:16]2=[O:20])[CH2:12]1)=[O:10])C1C=CC=CC=1.[H][H]>O1CCOCC1.[Pd]>[O:19]=[C:18]1[N:17]2[CH:13]([CH2:14][CH2:15][C:16]2=[O:20])[CH2:12][CH:11]1[C:9]([OH:10])=[O:8]
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)C1CC2CCC(=O)N2C1=O
Agent: [Pd]
Solvent: C1COCCO1
Product: O=C(O)C1CC2CCC(=O)N2C1=O

Procedure:
A solution of hexahydro-3,5-dioxo-1H-pyrrolizine-2-carboxylic acid benzyl ester 25.90.1 g, yy mole) in dioxane (200 ml) is treated with hydrogen gas in the presence of 20% Pd/C catalyst for eight hours. The mixture is filtered and concentrated at reduced pressure (below 25° C.) to yield pure hexahydro-3,5-dioxo-1H-pyrrolizine-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(COC)OC.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>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.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(Cl)ccc1I
Reactant: OB(O)c1ccccc1
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: O
Solvent: COCCOC
Product: CCOC(=O)c1cc(Cl)ccc1-c1ccccc1
Yield: 90.7 %

Procedure:
A degassed mixture of ethyl 5-chloro-2-iodobenzoate (0.621 g, 2.00 mmol), Pd(PPh3)4 (0.116 mg, 0.1 mmol), dimethoxyethane (20 mL), phenylboronic acid (0.268 g, 2.2 mmol), K2CO3 (0.829 g, 6.0 mmol), and water (5 mL) was heated under reflux for 6 h. Solvent was removed under reduced pressure. The residue was diluted with sat. NH4Cl (15 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were dried (MgSO4) and concentrated. The crude product was purified by chromatography to afford ethyl 5-chloro-2-phenylbenzoate (0.473 g, 91%) as colorless oil. MS (ESI) m/z: 261.0 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[N:9]=[C:10]([NH:13][C:14]2[CH:19]=[C:18]([S:20][C:21]3[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=3)[CH:17]=[CH:16][N:15]=2)[S:11][CH:12]=1.Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>CN(C=O)C.O>[CH3:7][C:8]1[N:9]=[C:10]([NH:13][C:14]2[CH:19]=[C:18]([S:20][C:21]3[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=3)[O:27][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:17]=[CH:16][N:15]=2)[S:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1csc(Nc2cc(Sc3cccc(O)c3)ccn2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1csc(Nc2cc(Sc3cccc(OCC(=O)OC(C)(C)C)c3)ccn2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A mixture of potassium carbonate (1.08 g, 7.82 mmol), 3-(2-(4-methylthiazol-2-ylamino)pyridin-4-ylthio)phenol (0.274 g, 0.869 mmol), and tert-butyl 2-bromoacetate (0.169 g, 0.869 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature overnight, then diluted with water and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was purified using prepacked silica gel column chromatography with 15-20% ethyl acetate to afford the desired product (0.224 g, 58.8% yield) as light yellow solid. 1H NMR (CDCl3) δ 8.08 (d, 1H), 7.33 (t, 1H), 7.15 (m, 1H), 7.04 (t, 1H), 6.98 (m, 1H), 6.57 (dd, 1H), 6.49 (dd, 1H), 6.33 (d, 1H), 4.50 (s, 2H, 2.22 (d, 3H), 1.46 (s, 9H); Mass spectrum (esi) m/z=430 (100)(M+H).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25](O)=[O:26])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:32][CH2:31][CH2:30]1>>[F:1][C:2]1[N:7]=[C:6]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([N:29]4[CH2:32][CH2:31][CH2:30]4)=[O:26])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3cccc(F)n3)nc2c1
Reactant: C1CNC1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(-c3cccc(F)n3)nc2c1
Yield: 72.7 %

Procedure:
The product was prepared in the same manner as described in example 3 using 5-(2-(6-fluoropyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (60 mg, 157 μmol) and azetidine (27.0 mg, 472 μmol) as starting materials. The reaction affords 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid [2-(6-fluoropyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (48 mg, 72.6%) as white solid. mp: 263.9° C., MS: m/z=421.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][O:6][B:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17](O)=O)=[CH:10][CH:9]=2)[O:4][CH2:3]1.BrC1C=CC(CCCC[C:32]([OH:34])=[O:33])=CC=1.CC1(C)COB(B2OCC(C)(C)CO2)OC1>>[CH3:1][C:2]1([CH3:20])[CH2:7][O:6][B:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:32]([OH:34])=[O:33])=[CH:10][CH:9]=2)[O:4][CH2:3]1
Reactant: CC1(C)COB(c2ccc(CCCC(=O)O)cc2)OC1
Reactant: O=C(O)CCCCc1ccc(Br)cc1
Agent: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Product: CC1(C)COB(c2ccc(CCCCC(=O)O)cc2)OC1
Yield: 71 %

Procedure:
Using a procedure analogous to that used to prepare 2A, 5-(4-bromophenyl)pentanoic acid (537 mg, 2.09 mmol) was reacted with 5,5,5′,5′-Tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to afford 5A (429 mg, 71%) as a white solid. 1H NMR (400 MHz, tetrahydrofuran-d8) δ 0.99 (s, 6H), 1.55-1.70 (m, 4H), 2.24 (t, J=7.5 Hz, 2H), 2.61 (t, J=7.0 Hz, 2H), 3.73 (s, 4H), 7.12 (d, J=7.9 Hz, 2H), 7.65 (d, J=7.9 Hz, 2H).
Reaction SMILES: O=C1N=C2C=CC=CC2=[N:3]1.[H][H].Cl[C:14]1[CH:21]=[CH:20][C:17]([CH2:18][OH:19])=[CH:16][C:15]=1[N+:22]([O-:24])=[O:23].C(O)C1C=CC=CC=1>>[NH2:3][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][OH:19])=[CH:16][C:15]=1[N+:22]([O-:24])=[O:23]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(CO)ccc1Cl
Reactant: O=C1N=c2ccccc2=N1
Solvent: OCc1ccccc1
Product: Nc1ccc(CO)cc1[N+](=O)[O-]

Procedure:
The required keto benzimidazole reactants in which R4 is hydrogen can be prepared from 4-chloro-3-nitrobenzyl alcohol. The benzyl alcohol is ammoniated to give 4-amino-3-nitrobenzyl alcohol which is hydrogenated catalytically to yield 4-hydroxymethyl-o-phenylenediamine. The phenylenediamine is reacted with cyanogen bromide by the methods known to the benzimidazole art to provide 2-amino-5(6)-hydroxymethylbenzimidazole. The hydroxymethyl group of the benzimidazole compound can be oxidized with Jones reagent (a solution of chromic acid and sulfuric acid in water) to provide the corresponding 5(6)-formyl benzimidazole.