Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[C:14](#[N:16])C.ClS(N=C=O)(=O)=O.CN(C)C=O>CCOC(C)=O.C(OCC)(=O)C.CCCCCC>[C:14]([C:9]1[N:8]([NH:7][C:6](=[O:13])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:12]=[CH:11][CH:10]=1)#[N:16]
Reactant: CC#N
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Agent: O=C=NS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)Nn1cccc1C#N
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A 2 L, 3-neck RB was fitted w/stir bar, N2 inlet, rubber septum low-temp. thermometer and ice/acetone cooling bath. Pyrrol-1-yl-carbamic acid tert-butyl ester (99.0 g, 0.543 mol) was added to the reactor, dissolved w/anhydrous acetonitrile (700 mL) and the stirred solution was cooled to 0° C. Chlorosulfonyl isocyanate (49.7 mL, 0.57 mol) was added dropwise via syringe (maintaining an internal temp. below 5° C.); after ˜20 minutes a suspension was observed. After 45 minutes N,N-dimethylformamide (anhydrous, 100 mL) was added dropwise via addition funnel (keeping internal temp. below 5° C.) and the reaction mixture became a solution. Stirring @ 0° C. was continued for 45 minutes, then the reaction was allowed to warm to RT; monitoring by TLC (silica gel, 1:3 ethyl acetate/hexane, UV, ninydrin stain) of a quenched sample indicated that the reaction had progressed to completion. The mixture was poured onto ice (˜2 L) and stirred with addition of EtOAc (2 L). The layers were separated and the organic layer was dried over magnesium sulfate. The dried solution was filtered through a pad of 30/40 Magnesol and the filtrate was concentrated to dryness in vacuo, then the residue was dissolved in a minimum volume of dichloromethane and chromatographed on a plug of silica gel, eluting with ethyl acetate/hexane, 0-50% ethyl acetate. The clean, product-containing fractions were combined and concentrated to dryness in vacuo, to afford the desired product as a white solid, 69.8 g (62%). A somewhat impure fraction provided additional material, 16.8 g (15%), bringing the total recovery to 86.6 g, (77%). 1H-NMR (CD3OD): 0.01 (dd, 1H, J=3.0, 1.6 Hz), 6.82 (dd, 1H, J=4.4, 1.7 Hz), 6.19 (dd, 1H, J=4.2, 2.9 Hz), 4.88 (s, 1H, H2O+NH—), 1.50 (br s, 9H, HN—BOC); MS: LC/MS (+esi), m/z=207.9 [M+H]
Reaction SMILES: [C:1]([O:7][C@@H:8]1[C@@H:13]([O:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[C@H:12]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C@@H:11]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[O:10][C@H:9]1[O:36][C:37]1[C:45]2[C:40](=[N:41][CH:42]=[CH:43][C:44]=2[CH2:46][CH2:47][C:48]2[CH:53]=[CH:52][C:51]([O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])=[CH:50][CH:49]=2)[NH:39][N:38]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:68]([CH3:70])[CH3:69]>CC(C)=O>[CH:68]([N:39]1[C:40]2=[N:41][CH:42]=[CH:43][C:44]([CH2:46][CH2:47][C:48]3[CH:49]=[CH:50][C:51]([O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])=[CH:52][CH:53]=3)=[C:45]2[C:37]([O:36][C@@H:9]2[O:10][C@H:11]([CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:33])([CH3:34])[CH3:32])[C@@H:12]([O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[C@H:13]([O:14][C:15](=[O:20])[C:16]([CH3:17])([CH3:19])[CH3:18])[C@H:8]2[O:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5])=[N:38]1)([CH3:70])[CH3:69]
Reactant: CC(C)I
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccc(OC(=O)C(C)(C)C)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)n1nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c2c(CCc3ccc(OC(=O)C(C)(C)C)cc3)ccnc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-4-[2-(4-pivaloyloxyphenyl)ethyl]-1H-pyrazolo-[3,4-b]pyridine (84 mg) in acetone (1.5 mL) were added cesium carbonate (0.11 g) and 2-iodopropane (0.03 mL), and the mixture was stirred at room temperature for 2days. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1−2/1) to give 1-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-4-[2-(4-pivaloyloxyphenyl)ethyl]-1H-pyrazolo[3,4-b]pyridine (61 mg). This material was dissolved in methanol (2 mL). To the solution was added sodium methoxide (28% methanol solution, 0.04 mL), and the mixture was stirred at 60° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (26 mg).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[NH2:11][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:21]=1[Cl:22])=[CH:19][CH:18]=[CH:17][CH:16]=2>O1CCCC1>[Cl:22][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[NH:11][CH:5]=[O:7]
Reactant: Nc1cnc2ccccc2c1Cl
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CNc1cnc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 83 %

Procedure:
Acetic anhydride (16 mL, 170 mmol) was cooled to 0° C., and formic acid (7.2 mL of 97% pure material, 190 mmol) was added over a period of ten minutes. The solution was stirred for 2.5 hours at room temperature and then added to a stirred solution of 3-amino-4-chloroquinoline (10.0 g, 56.0 mmol) in tetrahydrofuran (THF) (100 mL). The reaction was stirred for one hour at room temperature and then concentrated under reduced pressure. Methanol (50 mL) was added to the residue, stirred for 30 minutes, and removed under reduced pressure. The residue was then stirred with dichloromethane (150 mL) and saturated aqueous sodium bicarbonate (50 mL) for three days. A solid was present and was isolated by filtration and dried under high vacuum. The filtrate was concentrated under reduced pressure, and the residue was dissolved in methanol (400 mL). The solution was dried over potassium carbonate, filtered, and concentrated under reduced pressure. The residue was combined with the solid isolated by filtration to provide 9.6 g of 4-chloroquinolin-3-ylformamide as a brown solid.
Reaction SMILES: Cl[Si](C)(C)C.[O:6]=[C:7]1[N:12]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:11]2=[N:10][C:9]2[CH2:20][CH2:21][S:22][C:8]1=2.ClN1C(=O)CCC1=O>N1C=CC=CC=1>[O:6]=[C:7]1[N:12]2[CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=[CH:16][C:11]2=[N:10][C:9]2[CH:20]=[CH:21][S:22][C:8]1=2
Reactant: O=C(O)c1ccc2nc3c(c(=O)n2c1)SCC3
Agent: C[Si](C)(C)Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Product: O=C(O)c1ccc2nc3ccsc3c(=O)n2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Chlorotrimethylsilane (2.35 ml, 0.018 mol) is added to a cooled (ice bath) solution of 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylic acid (4.5 g., 0.018 mol) in pyridine (35 ml) under nitrogen. The mixture is stirred at ice bath temperature for 1 hour and then allowed to warm at room temperature. N-chlorosuccinimide (2.44 g, 0.018 mol) is added and the mixture is heated at 95° C. for 20 minutes. The mixture is cooled, diluted with ice water (5 ml) and stirred for 15 minutes. The precipitate is filtered, washed with boiling acetone and dried to give the product (3.5 g.) mp 335° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH3:18])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:19]([O:21][C:22]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)=[O:23])[CH3:20].C(OCC)(=O)C>CCCCCC>[CH2:19]([O:21][C:22](=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([N:14]2[C:13]([C:12]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[N:9][O:10][C:11]=3[CH3:18])=[CH:17][N:16]=[CH:15]2)[CH:29]=1)[CH3:20]
Reactant: Cc1onc(-c2cccc(F)c2)c1-c1c[nH]cn1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1cccc(-n2cncc2-c2c(-c3cccc(F)c3)noc2C)c1
Yield: 32 %

Procedure:
As described for Example 3, 3-(3-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (2.43 g, 10 mmol) was converted, using of 3-ethoxycarbonylphenylboronic acid instead of 4-fluorophenylboronic acid, through chromatography (SiO2, ethyl acetate: hexane=20:10) to the title compound (1.26 mg, 32%) which was obtained as a light yellow solid. MS: m/e=392.1 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=O)[CH2:2]1.[C:11]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:13]C)=[O:12]>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:15][C:11]([OH:13])=[O:12]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1COc2ccccc21
Solvent: Cc1ccccc1
Product: O=C(O)Cc1cc2ccccc2o1
Yield: 94.6 %

Procedure:
A mixture of 71.1 g of 3-benzofuranone [D. C. Schroeder, P. O. Corcoran, C. A. Holden, and M. C. Mulligan, J. Org. Chem., 27, 586 (1962)], 210 g of carbomethoxymethylenetriphenylphosphorane and 300 ml of toluene was heated under reflux for 8 hours. The solvent was removed and the residue stirred with ether and filtered. The filtrate was concentrated and the residue heated under reflux with 300 ml of methanol and 300 ml of 15% sodium hydroxide solution for 2 hours. The cooled mixture was diluted with water and extracted several times with methylene chloride. Acidification of the water layer and extraction with methylene chloride gave 88.3 g of crude 3-benzofuranacetic acid. The product was dissolved in 500 ml of tetrahydrofuran, and 50 g of borane-methyl sulfide complex added. After stirring at room temperature overnight, the excess reagent was destroyed by slow addition of 100 ml of conc. hydrochloric acid. The mixture was made basic and extracted several times with methylene chloride and the product shortpath distilled (bath temperature) 110°, 1 micron pressure) to give 65.8 g (76%) of 3-benzofuranethanol. NMR spectrum (in CDCl3): τ2.3-3.0 (m, 5); 6.2 (t, J=6 Hz, 2) 7.1 (t, J=6 Hz, 2) and 7.3 (s, 1).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[CH2:7][C:8]([OH:10])=[O:9])=[O:4].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+].Cl.[CH3:29][O:30][C:31](=[O:41])[C@H:32]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH2:33]>C(O)(=O)C>[CH3:29][O:30][C:31](=[O:41])[C@H:32]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH:33][C:11](=[O:13])[C@H:6]([CH2:7][C:8](=[O:9])[OH:10])[NH:5][C:3](=[O:4])[C:2]([F:1])([F:15])[F:14]
Reactant: O=C(O)C[C@H](NC(=O)C(F)(F)F)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)C(F)(F)F
Reaction time: 6 h
Yield: 79 %

Procedure:
In 63.3 g of acetic acid, 22.9 g (0.1 mole) of N-trifluoroacetyl-L-aspartic acid was suspended and 10.2 g (0.1 mole) of acetic anhydride was added. The mixture was warmed to 55°-60° C. and stirred for 6 hours at the same temperature. After finishing the reaction, the resulting mixture was cooled to 15°-20° C. and then 9.2 g (0.11 mole) of sodium acetate and 20.5 g (0.095 mole) of L-phenylalanine methyl ester hydrochloride were successively added at the same temperature. The reaction was carried out for 2 hours with stirring at the same temperature. Precipitated crystals were filtered, washed and dried. Crystals of N-trifluoroacetyl-α-L-aspartyl-L-phenylalanine methyl ester were obtained in the yield of 29.3 g (79.0% yield on L-phenylalanine methyl ester hydrochloride). The crystals thus obtained were analyzed by high performance liquid chromatography to find α-isomer alone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:11]#[N:12])[CH2:10][CH2:9]1.[OH2:13].Cl.[NH2:15]O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:11](=[NH:15])[NH:12][OH:13])[CH2:9][CH2:10]1
Reactant: O
Reactant: N#CC1(c2ccccc2Br)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: N=C(NO)C1(c2ccccc2Br)CC1
Temperature: 25 °C
Yield: 36 %

Procedure:
To a solution of 1-(2-bromophenyl)cyclopropanecarbonitrile (19.6 g, 0.1 mole) in ethanol (100 ml), there was added water (100 ml) and then added hydroxylamine hydrochloride (14.0 g, 0.2 mole) and finally added sodium carbonate (11.0 g, 0.1 mole). The reaction mixture was refluxed for 16 hrs. The reaction mixture was cooled to room temperature and water (100 ml) was added. A white precipitate formed and was filtered to give 9.39 g of product (36% yield; M.P. 164°-167° C.).
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].C(N(CC)CC)C.[Br:20][CH2:21][C:22](Br)=[O:23]>C(Cl)Cl>[Br:20][CH2:21][C:22]([O:3][C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([O:11][CH3:12])=[O:10])=[O:23]
Reactant: COC(=O)[C@H](O)c1ccccc1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](OC(=O)CBr)c1ccccc1
Temperature: -78 °C
Reaction time: 5 h
Yield: 84 %

Procedure:
To a stirred solution of DCM, (R)-methyl mandelate (1.48 g, 8.92 mmol), and triethylamine (2.02 g, 20.0 mmol), in DCM (30 ml) under a nitrogen atmosphere at −78° C. was added dropwise bromoacetyl bromide (3.03 g, 15.0 mmol). After stirring at −78° C. for 5 h, the reaction mixture was allowed warm up to −20° C. and quenched by addition of water (20 mL). The organic phase was washed with distilled water (3×20 mL), saturated ammonium chloride (3×20 mL), saturated sodium bicarbonate (3×20 mL) and brine (2×20 mL). The organic phase was then dried over magnesium sulfate, filtered and solvents removed via rotary evaporation to yield a crude product in 84% yield (2.13 g, 7.42 mmol). Column chromatography was performed on the crude product (mobile phase: DCM:Hexane, 50:50) to give a pale yellow liquid at RT in 73% yield (1.85 g, 6.45 mmol).
Reaction SMILES: [CH:1]([CH:3]1[CH2:7][CH2:6][N:5]([C:8](OC(C)(C)C)=O)[CH2:4]1)=[O:2].FC(F)(F)C(O)=O.BrC[C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH:1]([CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)[CH2:4]1)=[O:2]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(CN2CCC(C=O)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-Butyl 3-formylpyrrolidine-1-carboxylate (4.75 g, 23.84 mmol) was dissolved in dichloromethane (DCM) (20 mL). Trifluoroacetic acid (15 mL, 195 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. After concentrating acetonitrile (100 mL) was added followed by methyl 4-(bromomethyl)benzoate (6.55 g, 28.6 mmol) and potassium carbonate (16.47 g, 119 mmol). The reaction was heated to reflux for 16 hours. The mixture was filtered and concentrated. Dichloromethane (75 ml) was added and the solution was washed with water, dried over MgSO4, filtered and concentrated. The residue was purified via silica gel chromotography (0% to 100% EtOAc:Hex; 50 g-HP— silica gel column). Obtained 2.00 g 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.99-2.23 (m, 2H), 2.46-2.57 (m, 1H), 2.60-2.79 (m, 2H), 2.88-2.99 (m, 2H), 3.68 (d, J=4.29 Hz, 2H), 3.92 (s, 3H), 7.40 (d, J=8.59 Hz, 2H), 7.93-8.09 (m, 2H), 9.66 (d, J=2.02 Hz, 1H);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[C:43]([C:46]1[S:50][C:49]([NH2:51])=[N:48][C:47]=1[CH3:52])(=[O:45])[CH3:44]>C(Cl)(Cl)Cl.O>[C:43]([C:46]1[S:50][C:49]([NH:51][C:35]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][C:18]=2[F:23])=[O:41])=[N:48][C:47]=1[CH3:52])(=[O:45])[CH3:44]
Reactant: CC(=O)c1sc(N)nc1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nc(C)c(C(C)=O)s4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (30 mg) was dissolved in chloroform (3 ml) to prepare a solution. Triethylamine (0.3 ml) and a solution of triphosgene (27 mg) in chloroform (0.2 ml) were then added thereto, and the mixture was stirred at room temperature for 30 min. Next, a solution of 5-acetyl-2-amino-4-methylthiazole (64 mg) in chloroform (0.6 ml) was added thereto, and the mixture was further stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The extract was washed with saturated brine and was dried over anhydrous sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give 6 mg of the title compound.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.Br[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14].CO>C(O)C.C(Cl)(Cl)Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]2[S:8][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:9]=2)[CH:3]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)c1cccnc1
Solvent: CO
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1csc(-c2cccnc2)n1
Temperature: 70 °C
Yield: 71.4 %

Procedure:
A solution containing thionicotinamide (30 g, 217.1 mmol) in ethanol (540 mL) was treated with ethyl bromopyruvate (30.3 mL, 241.4 mmol), heated at 70° C. for 3 hours, cooled to 25° C., concentrated and partitioned between chloroform and saturated NaHCO3. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with chloroform and then with 15% methanol in chloroform containing 1% ammonium hydroxide to give the product (36.3 g, 71% yield).
Reaction SMILES: O=C1N(CC(OC(C)(C)C)=O)C2C=CC=CC=2N1.C([O:23][C:24](=[O:47])[CH2:25][N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[N:28]([C:35]2[CH:45]=[CH:44][C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:37][CH:36]=2)[C:27]1=[O:46])(C)(C)C>>[CH2:42]([O:41][C:39]([C:38]1[CH:37]=[CH:36][C:35]([N:28]2[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[N:26]([CH2:25][C:24]([OH:47])=[O:23])[C:27]2=[O:46])=[CH:45][CH:44]=1)=[O:40])[CH3:43]
Reactant: CCOC(=O)c1ccc(-n2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)cc1
Agent: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Product: CCOC(=O)c1ccc(-n2c(=O)n(CC(=O)O)c3ccccc32)cc1

Procedure:
Essentially following the procedures described for Intermediate 7, but using ethyl 4-[3-(2-tert-butoxy-2-oxoethyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]benzoate from Step D in place of tert-butyl (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate, the title compound was prepared. MS: m/z=341 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[Li].C[Si]([N-][Si](C)(C)C)(C)C>C1(C)C=CC=CC=1>[CH2:25]([O:24][C:22]([C:19]1([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=2)[CH2:20][CH2:21][N:16]([C:14]([O:13][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:15])[CH2:17][CH2:18]1)=[O:23])[CH3:26]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Fc1ccc(Br)nc1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(c2ccc(F)cn2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 87 h

Procedure:
Under an inert atmosphere a 250 mL three necked round bottom flask (flame dried) with a magnetic stirring bar was charged with 4 g (22.7 mmol) 2-bromo-5-fluoropyridine, 11.7 g (45 mmol) ethyl 1-tert.-butyloxycarbonylpiperidine-4-carboxylate, 416 mg (0.04 mmol) tris(dibenzylideneacetone)palladium(0), 0.91 mL tri-tert-butylphosphine (1M in toluene) and 60 ml toluene. To the dark red solution, 50 mL lithium-bis-(trimethylsilyl)-amid (1M in hexane) was added dropwise during 1 h at 18 to 23° C. The dark brown reaction solution was stirred for 87 h at room temperature. The reaction was quenched with saturated aqueous NH4Cl-solution. The aqueous layer was separated and extracted once with 200 mL ethyl acetate. The organic layers were washed once with 150 mL brine, dried over Na2SO4, filtered off and concentrated under vacuum. The residue was purified on silica eluting with a gradient formed from heptane and TBME to yield after evaporation of the product fractions 4 g (50%) of the title compound as yellow viscous oil. MS ISP (m/e): 253.3 (M-Boc)/353.2 [(M+H)+].
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[C:15]([CH3:21])[N:14]=1.[CH2:22]([Sn:26](Cl)([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH3:25]>C1COCC1>[CH3:12][C:13]1[N:20]2[C:16]([S:17][C:18]([Sn:26]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:19]2)=[C:15]([CH3:21])[N:14]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1nc(C)n2ccsc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cn2c(C)nc(C)c2s1
Temperature: -30 °C
Reaction time: 1.33 h

Procedure:
To 50 ml of anhydrous THF cooled to −65° C. under the atmosphere of argon was added 10.9 ml of a 1.63 N n-butyl lithium/n-hexane solution, and a solution of 2.564 g of 5,7-dimethylimidazo[5,1-b]thiazole in 17 ml of anhydrous THF was further added dropwise at −64-−60° C. over a period of 15 minutes. The reaction mixture was then stirred at the same temperature for 80 minutes. After 5.0 ml of tri-n-butylstannyl chloride was added dropwise to the mixture at a temperature of −63-−58° C. over a period of 10 minutes, it was warmed to −30° C., and further stirred for 110 minutes. The reaction mixture was diluted with 100 ml of semi-saturated aqueous saline, extracted with 150 ml of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The oil thus obtained was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1-−1:2) to give the title compound as a light orange oil in a yield of 6.164 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23](O)=[O:24])=[C:16]2[CH:15]=1.CCN=C=NCCCN(C)C.[C:37]([S:41]([NH2:44])(=[O:43])=[O:42])([CH3:40])([CH3:39])[CH3:38]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:37]([S:41]([NH:44][C:23]([C:22]1[CH:21]=[N:20][N:17]2[CH:18]=[CH:19][C:14]([N:10]3[CH2:11][CH2:12][CH2:13][C@@H:9]3[C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])=[CH:15][C:16]=12)=[O:24])(=[O:43])=[O:42])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)S(N)(=O)=O
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)S(=O)(=O)NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Reaction time: 2 h

Procedure:
To a stirred solution of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (170 mg, 0.49 mmol) in dry DCM (10 mL) was added EDCI (288 mg, 1.5 mmol) followed by DMAP (0.18 g, 1.4 mmol) and stirring was continued at 25° C. for 2 h. To the reaction mixture was added tert-butyl sulfonamide (67 mg, 0.49 mmol) and the stirring was continued at 25° C. for 72 h. Reaction mixture was diluted with DCM (50 mL) and the organic layer was washed with saturated aqueous KHSO4 solution followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude, which was purified by combiflash chromatography followed by re-crystallization from EtOH to afford (R)—N-(tert-butylsulfonyl)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide as white solid. MS (ESI): m/z 463.2 (M+H).