Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][C:10]#[CH:11])([CH3:4])([CH3:3])[CH3:2].I[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][C:10]#[C:11][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(I)cc1
Reactant: C#CCCNC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC#Cc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
But-3-ynylcarbamic acid tert-butyl ester (3.66 g, 22 mmol) was added dropwise to an ice cooled, stirring, argon purged mixture of 4-iodobenzonitrile (4.5 g, 19.6 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.69 g, 0.98 mmol), copper (1) iodide (0.19 g, 0.98 mmol), triethylamine (11 mL, 78.4 mmol), and THF (24 mL). After stirring for 10 min, the ice bath was removed, and the reaction was allowed to stir for an additional 2 h. The reaction mixture was passed through a pad of silica gel with methylene chloride/ethyl acetate (5:1) as eluant. After evaporating the solvent, the crude product was chromatographed with methylene chloride/ethyl acetate (20:1) as eluant. Evaporation of the solvent, followed by placement under vacuum for 1 h, afforded the pure product 56 (5.2 g, 99%) as an oil. 1H NMR (300 MHz, CDCl3) δ 1.46 (s, 9H), 2.64 (t, 2H), 3.37 (m, 2H), 4.85 (br s, 1H), 7.47 (d, 2H), 7.58 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH2:15]([O:17]CC)[CH3:16].C(OC(=O)C)(=O)C>CCCCCC>[C:15]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1)(=[O:17])[CH3:16]
Reactant: CCOCC
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C=Cc1ccc(NC(C)=O)cc1

Procedure:
A sample of 50 g. of ethyl p-aminocinnamate is dissolved in 500 ml. of ethyl ether and a solution of 28 g. of acetic anhydride in 30 ml. of ether is added dropwise. When the addition is complete, the reaction is allowed to stir for another hour. The mixture is then diluted with hexane and filtered, providing ethyl p-acetamidocinnamate.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:7]=[CH:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([O-:3])=[O:2].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([S:17]([NH2:20])(=[O:18])=[O:19])[CH:7]=[CH:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([S:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:29])=[O:28])[CH2:13][CH2:12]1)([O-:3])=[O:2]
Reactant: NS(=O)(=O)c1ccc(NC2CCNCC2)c([N+](=O)[O-])c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccc(NC2CCN(S(=O)(=O)c3ccccc3)CC2)c([N+](=O)[O-])c1

Procedure:
A mixture of EXAMPLE 157B (84 mg), benzenesulfonyl chloride (46 mg), and triethylamine (101 mg) in CH2Cl2 (2 mL) was stirred for 1 hours. The product was chromatographed on silica gel with 25% ethyl acetate/hexanes.
Reaction SMILES: [CH:1]([C:4]1[O:8][N:7]=[C:6]([CH2:9][OH:10])[CH:5]=1)([CH3:3])[CH3:2].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.O>N1C=CC=CC=1>[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17]([O:10][CH2:9][C:6]2[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[O:8][N:7]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: CC(C)c1cc(CO)no1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCc2cc(C(C)C)on2)cc1
Reaction time: 5 h
Yield: 20.5 %

Procedure:
4.24 g of (5-i-propyl-isoxazol-3-yl)methanol was dissolved in 10 ml of pyridine, and 6.67 g of 4-toluenesulfonyl chloride was then added under ice-cooling. The mixture was stirred for 5 hours under ice-cooling. After water was added, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.82 g of (5-i-propyl-isoxazol-3-yl)methyl 4-toluenesulfonate.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].I[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[N:20][C:21]=2[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=[C:14]([C:6]3[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:9]=[CH:8][CH:7]=3)[C:22]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: CC(=O)c1cccc(B(O)O)c1
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: CCO
Solvent: COCCOC
Product: CC(=O)c1cccc(-c2nn(C(C)C)c3ncnc(N)c23)c1
Temperature: 80 °C
Yield: 18.2 %

Procedure:
A solution of 3-Acetylphenylboronic acid (23 mg, 0.14 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.13 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA55 (7 mg, 18% yield). ESI-MS (M+H)+ m/z calcd 296.1, found 296.1.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.CC(O)=O.C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=3)[CH2:8][CH2:9]2)[CH2:16][CH2:15]1
Reactant: CN1CCC(=O)CC1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CN1CCC(N2CCc3ccc([N+](=O)[O-])cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Nitroindoline (5 g) was dissolved in 200 mL of dichloroethane. N-Methyl-4-piperidone (5 g) was added to the mixture, followed by NaHB(OAc)3 (12 g) and 1 mL of glacial AcOH. The mixture was stirred at RT overnight. A saturated NaHCO3 (200 mL) solution was added to the reaction mixture and stirred for 1 h. The resulting mixture was separated by separation funnel. The organic layer was extracted once with saturated NaHCO3 solution and once with brine. The resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 2:1 EtOAc:MeOH to afford orange oil. MS: 262 (M+1). Calc'd. for C14H19N3O2—261.3.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8](=[S:11])SC)(=[O:3])[CH3:2].O.[NH2:13][NH2:14]>C(O)C>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8](=[S:11])[NH:13][NH2:14])(=[O:3])[CH3:2]
Reactant: CSC(=S)NCCNC(C)=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(=O)NCCNC(=S)NN
Temperature: 4 °C

Procedure:
A solution of methyl N-(2-acetamidoethyl)-dithiocarbamate (57.7 g) and hydrazine hydrate (14.6 cc) in absolute ethanol (300 cc) is heated under reflux for 2 hours. The mixture is then cooled to 4° C. and is filtered, and the insoluble matter is dried at 30° C. under 0.05 mm Hg. 4-(2-Acetamidoethyl)-thiosemicarbazide (39.5 g) is obtained in the form of white crystals (instantaneous m.p. [Kofler]=171° C.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11](=[O:30])[N:10]2[C:31]([O:33]C2C=CC([N+]([O-])=O)=CC=2)=O)=[CH:5][CH:4]=1)#[N:2].[CH3:43][NH:44][CH3:45]>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)[C:11](=[O:30])[N:10]2[C:31]([N:44]([CH3:45])[CH3:43])=[O:33])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Reactant: CNC
Solvent: CC#N
Product: CN(C)C(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A mixture of 4-nitrophenyl 4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazoline-3(4H)-carboxylate (intermediate 37, 51 mg, 8 μmol) and dimethylamine (2.0 M in tetrahydrofuran, 220 μL, 440 μmol) in acetonitrile (1.5 mL) is stirred at room temperature for 30 h and purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 14 mg; ESI mass spectrum [M+H]+=483; Retention time HPLC: 1.03 min (Z018_S04).
Reaction SMILES: [OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]([N:26]2[CH2:31][CH2:30][C@:29]([CH2:38][C:39](O)([CH3:41])[CH3:40])([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:28][C:27]2=[O:43])[CH3:25])=[CH:20][CH:19]=1>O1CCCC1.C1(C)C=CC=CC=1>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([C@@H:24]([N:26]2[CH2:31][CH2:30][C@@:29]([CH2:38][C:39]([CH3:41])=[CH2:40])([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[O:28][C:27]2=[O:43])[CH3:25])=[CH:22][CH:23]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=C(C)C[C@@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
(Methoxycarbonylsulfamoyl)triethylammonium hydroxide (1.38 g) was added to 3-[(S)-1-(4-bromo-phenyl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one (2.0 g) dissolved in tetrahydrofuran (30 mL) and toluene (15 mL). The resulting solution was stirred at room temperature for 0.5 h and at 75° C. for 1 h. After cooling to room temperature, the solution was concentrated and ethyl acetate was added to the residue. The resulting mixture was washed with aqueous NaHCO3 solution and brine and dried (MgSO4). The title compound was obtained after removal of the solvent. Yield: 1.9 g (quantitative). Mass spectrum (ESI+): m/z=414/416 (Br) [M+H]+
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[CH:14]=[C:13](Cl)[C:12]2[C:7](=[CH:8][C:9]([C:16]3[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][CH:11]=2)[N:6]=1.O>C1COCC1>[Cl:4][C:5]1[CH:14]=[C:13]([O:2][CH3:1])[C:12]2[C:7](=[CH:8][C:9]([C:16]3[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][CH:11]=2)[N:6]=1
Reactant: C[O-]
Reactant: FC(F)(F)c1cccnc1-c1ccc2c(Cl)cc(Cl)nc2c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cl)nc2cc(-c3ncccc3C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add sodium methoxide (4M, 1.1 mmol) to a solution of 2,4-dichloro-7-(3-trifluoromethyl-pyridin-2-yl)-quinoline (1.0 mmol) in THF (10 mL). Stir at room temperature for 1 hour, add water (15 mL) and extract with ethyl acetate. Wash the combined organic extracts with brine, dry (MgSO4) and evaporate. Purify the mixture of 2-chloro-4-methoxy-7-[3-(trifluoromethyl)pyridin-2-yl]quinoline and 4-chloro-2-methoxy-7-[3-(trifluoromethyl)pyridin-2-yl]quinoline by flash chromatography (elute with 1:2 hexane:ether) to give the title compound.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=[C:2]1[C:11](=[N:15][O:16][CH3:17])[C:12]([OH:14])=O.[NH2:18][CH:19]1[C:36](=[O:37])[N:21]2[C:22]([C:33]([OH:35])=[O:34])=[C:23]([CH2:26][S:27][C:28]3[S:29][CH:30]=[N:31][N:32]=3)[CH2:24][S:25][C@H:20]12>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=[C:2]1[C:11](=[N:15][O:16][CH3:17])[C:12]([NH:18][CH:19]1[C:36](=[O:37])[N:21]2[C:22]([C:33]([OH:35])=[O:34])=[C:23]([CH2:26][S:27][C:28]3[S:29][CH:30]=[N:31][N:32]=3)[CH2:24][S:25][C@H:20]12)=[O:14]
Reactant: CON=C(C(=O)O)C1=CSc2ccccc2O1
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)C1=CSc2ccccc2O1

Procedure:
2-(1,4-Benzoxathiin-2-yl)-2-methoxyiminoacetic acid (syn isomer, 0.85 g.) was allowed to react with 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.09 g.) in a similar manner to that of Example 1 to give the captioned compound (1.50 g.), yellow powder, mp. 157° to 161° C. (dec.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[Br:12][C:13]1[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=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>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)=[CH:15][CH:14]=1
Reactant: Brc1ccc(I)cc1
Reactant: N#Cc1cccc(B(O)O)c1
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: CN(C)C=O
Product: N#Cc1cccc(-c2ccc(Br)cc2)c1
Temperature: 75 °C
Yield: 39.5 %

Procedure:
To a magnetically stirring solution of 3-cyanophenyl boronic acid (0.62 g, 4.24 mmol) and 1-bromo-4-iodobenzene (1.0 g, 3.53 mmol) in anhydrous DMF (7.0 mL), under argon at room temperature, was added 2M sodium carbonate solution (7.0 mL) followed by Pd(PPh3)4 (0.21 g, 0.18 mmol). The resulting mixture was heated to 75° C. overnight. The resulting dark reaction mixture was cooled to room temperature filtered to remove the solids and the resultant filtrate was poured into water (50 mL) and extracted with EtOAc (2×25 mL). The organics were washed with water (50 mL) and brine (50 mL) then dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography (5% EtOAc in Hexanes) to yield the intermediate bromide as a white solid (0.36 g, 33%). 1H NMR (CDCl3): δ 1H NMR (CDCl3) δ: 7.43 (d, J=7.4 Hz, 2H), 7.53-7.67 (m, 4H), 7.76-7.84 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=O.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:43][C:44]1[C:48]2[CH2:49][NH:50][CH2:51][CH2:52][C:47]=2[S:46][C:45]=1[C:53]([O:55][CH2:56][CH3:57])=[O:54]>CN(C)C=O>[CH3:43][C:44]1[C:48]2[CH2:49][N:50]([C:7]([C:3]3[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=3)=[O:9])[CH2:51][CH2:52][C:47]=2[S:46][C:45]=1[C:53]([O:55][CH2:56][CH3:57])=[O:54]
Reactant: Cn1cccc1C(=O)O
Reactant: CCOC(=O)c1sc2c(c1C)CNCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc2c(c1C)CN(C(=O)c1cccn1C)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-methylpyrrole-2-carboxylic acid (12.5 mg, 0.1 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.048 g, 0.11 mmol) and N,N-diisopropylethylamine (52.2 μL, 0.3 mmol) in N,N-dimethylformamide (1 mL, 12.9 mmol) was stirred at room temperature for 15 minutes. A solution of ethyl 3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (22.5 mg, 0.1 mmol) in N,N-dimethylformamide (1 mL) was then added and the reaction was further stirred at room temperature overnight. The solution was evaporated to dryness and the residue obtained was partitioned between DCM (2 mL) and half-saturated aqueous sodium bicarbonate solution (2 mL). Upon separation of the layers, the aqueous layer was extracted with additional DCM (2 mL) and the combined organic layers were concentrated to dryness.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[CH3:21][O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH2:25].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(OCC)(=O)C>[CH3:21][O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH:25][C:17](=[O:19])[C@H:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.6 %

Procedure:
N-Cbz-L-leucine (Chemical Dynamics) (1.32 g, 4.97 mmol), L-leucine methyl ester hydrochloride (Aldrich) (0.99 g, 5.47 mmol), 1-hydroxybenzotriazole (0.14 g, 1.0 mmol) and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (1.05 g, 5.47 mmol) were combined, dissolved in 25 mL of DMF and stirred at room temperature for 15 h. The solution was diluted with ethyl acetate (250 mL) and washed successively with water, 0.1 N HCl, saturated aqueous NaHCO3 and saturated brine, then dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on 230-400 mesh silica gel, eluting with 1:3 ethyl acetate hexanes, to give the title compound as a white solid (1.28 g, 66%). 1H NMR (400 MHz, CDCl3) δ7.37-7.32 (m, 5H), 6.28 (d, 1H), 5.28 (m, 3H), 4.6-4.58 (m, 1H), 4.20 (m, 1H), 3.74 (s, 3H), 1.69-1.54 (m, 6H), 0.96-0.92 (m, 12H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[S:11][C:12]4[C:17]([N:18]=3)=[CH:16][CH:15]=[C:14]([C:19]3([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:21][CH2:20]3)[N:13]=4)=[CH:9][C:4]=2[N:3]=[CH:2]1.CN1CCCN2C1=NCCC2.[C:39]([O:43][CH2:44][CH3:45])(=[O:42])[CH:40]=[CH2:41]>C(#N)C>[C:22]1([C:19]2([C:14]3[N:13]=[C:12]4[S:11][C:10]([C:8]5[CH:7]=[CH:6][C:5]6[N:1]([CH2:41][CH2:40][C:39]([O:43][CH2:44][CH3:45])=[O:42])[CH:2]=[N:3][C:4]=6[CH:9]=5)=[N:18][C:17]4=[CH:16][CH:15]=3)[CH2:20][CH2:21]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C=CC(=O)OCC
Reactant: c1ccc(C2(c3ccc4nc(-c5ccc6[nH]cnc6c5)sc4n3)CC2)cc1
Agent: CN1CCCN2CCCN=C12
Solvent: CC#N
Product: CCOC(=O)CCn1cnc2cc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2-(1H-benzo[d]imidazol-5-yl)-5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine (100 mg, 0.271 mmol) was added acetonitrile (2.7 mL) before 7-methyl-1,5,7-triazabicyclo(4.4.0)dec-5-ene (1.949 μL, 0.014 mmol) and ethyl acrylate (36.2 μL, 0.326 mmol) were added and stirred at ambient temperature for 2 h to give a 2:1 mixture of regioisomers. Ethyl 3-(5-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-1H-benzo[d]imidazol-1-yl)propanoate was obtained after regioisomer separation via SFC (Column: ChiralPak AD-H; Mobile Phase: 50:50 liquid CO2/isopropanol with 0.2% isopropylamine). MS (ESI) m/z: Calculated: 468.2; Observed: 469.2 (M++H).
Reaction SMILES: CC([Si](C)(C)O[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([C:23]([OH:30])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[CH:9]=1)(C)C.CN(C=O)C.S(Cl)([Cl:40])=O>C(Cl)Cl>[Cl:40][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([C:23]([OH:30])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C(O)(C(C)C)C(C)C)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CCl)cc2C(O)(C(C)C)C(C)C)c1
Reaction time: 1.5 h
Yield: 109.6 %

Procedure:
To a stirred solution of 69.19B (0.050 g, 0.1 mmol) in DCM (2.00 mL) at 23° C. was added DMF (0.0008 mL) followed by thionyl chloride (0.01 mL, 0.2 mmol). The reaction was then stirred for 1.5 hours and then concentrated in vacuo. The product was purified on silica gel (0-10% EtOAc in hexanes) to yield 69.19C as a colorless oil (0.04 g, 100% yield).
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]#[C:12][CH2:13][CH2:14]O)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.C(N(CC)CC)C.[B-](F)(F)(F)[F:30].CCN([S+](F)F)CC.C([O-])(O)=O.[Na+]>ClCCl>[F:1][C:2]1[C:10]([C:11]#[C:12][CH2:13][CH2:14][F:30])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1
Reactant: OCCC#Cc1ccc2c(cnn2C2CCCCO2)c1F
Reactant: F[B-](F)(F)F
Agent: CCN(CC)[S+](F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: FCCC#Cc1ccc2c(cnn2C2CCCCO2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
To a solution of 4-(4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn-1-ol (3.4 g, 11.8 mmol; Intermediate 29, Step 1) in dry dichloromethane (100 mL), was added triethylamine.3HF (7.6 g, 47.2 mmol). XtalFluor-E (8.0 g, 34.9 mmol) was then added. The resulting solution was stirred at room temperature for 30 minutes. Upon completion, the reaction solution was neutralized by slow addition of saturated NaHCO3 (30 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜20% EtOAc in petroleum ether), and then re-crystallized from petroleum ether to afford the title compound (1.3 g). 1H NMR (300 MHz, DMSO-d6): δ 8.27 (s, 1H), 7.58 (d, 1H), 7.44 (dd, 1H), 5.89 (dd, 1H), 4.60 (dt, 2H), 3.91-3.85 (m, 1H), 3.80-3.69 (m, 1H), 2.93 (dt, 2H), 2.46-2.28 (m, 1H), 2.06-1.95 (m, 2H), 1.78-1.67 (m, 1H), 1.60-1.52 (m, 2H); LCMS: 291 (M+H)+.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[Br:10][C:11]1[O:19][C:18]2[CH:17]=[CH:16][N:15]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][N:24]=[CH:23]4)[C:14](=[O:29])[C:13]=2[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CS(C)=O>[Br:10][C:11]1[O:19][C:18]2[CH:17]=[CH:16][N:15]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[N:25]([CH2:3][CH2:4][N:5]3[CH2:9][CH2:8][CH2:7][CH2:6]3)[N:24]=[CH:23]4)[C:14](=[O:29])[C:13]=2[CH:12]=1
Reactant: O=c1c2cc(Br)oc2ccn1-c1ccc2[nH]ncc2c1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=c1c2cc(Br)oc2ccn1-c1ccc2c(cnn2CCN2CCCC2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 46.4 %

Procedure:
1-(2-Chloroethyl)pyrrolidine hydrochloride (213 mg, 1.25 mmol) was added to a suspension of 2-bromo-5-(1H-indazol-5-yl)furo[3,2-c]pyridin-4(5H)-one (187 mg, 0.570 mmol) and Cs2CO3 (1.11 g, 3.42 mmol) in anhydrous DMSO (3 mL) and the resulting suspension was stirred at 25° C. for 14 h. H2O (10 mL) was added and the aqueous suspension was filtered. The solid was dried under reduced pressure. Flash chromatography on silica gel [4.75:4.75:0.5 MTBE/CH2Cl2/(9:1 EtOH/NH4OH)] afforded the title compound (113 mg, 47%) as a light yellow powder with data matching those reported in Example 9.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[Cs+].[Cs+].[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(N(C)C)=O.O>[CH3:11][O:10][C:6]1[C:3]([C:4]#[N:5])=[C:2]([O:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:9]=[CH:8][CH:7]=1
Reactant: COc1ccnc(Cl)c1C#N
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccnc(Oc2ccccc2)c1C#N
Temperature: 75 °C
Yield: 70.4 %

Procedure:
A solution of 2-chloro-4-methoxynicotinonitrile (1.02 g) in dimethylacetamide (30 mL) was treated with cesium carbonate (2.96 g) followed by phenol (0.683 g) at room temperature. The mixture was heated to 75° C. overnight. The mixture was cooled to room temperature, diluted with water (100 mL) and the precipitated solids collected by filtration, to provide the title compound (0.964 g) with the following physical data.