Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:30]=[CH:29][CH:28]=[CH:27][C:3]=1[C:4]([NH:6][C@H:7]([C:9]1[N:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11](=[O:20])[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[CH3:8])=[O:5].CN(C=O)C.[NH:36]1[CH:40]=[C:39](B(O)O)[CH:38]=[N:37]1.C([O-])([O-])=O.[Na+].[Na+]>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.CCO>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[C:11](=[O:20])[N:10]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]([C@@H:7]([NH:6][C:4](=[O:5])[C:3]1[CH:27]=[CH:28][CH:29]=[N:30][C:2]=1[C:39]1[CH:40]=[N:36][NH:37][CH:38]=1)[CH3:8])=[CH:18]2
Reactant: OB(O)c1cn[nH]c1
Reactant: C[C@H](NC(=O)c1cccnc1Br)c1cc2cccc(Cl)c2c(=O)n1-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: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1cccnc1-c1cn[nH]c1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-2-bromo-N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl) nicotinamide (52) (125 mg, 0.26 mmol) in a 1:1 mixture of DMF and EtOH (9 mL), 1H-pyrazole-4-boronic acid (37 mg, 0.34 mmol), tetrakis(triphenylphosphine)palladium (0) (21 mg, 0.018 mmol) and aqueous Na2CO3 solution (1.0 M, 0.78 mL, 0.78 mmol) were added sequentially. The resulting mixture was stirred at 85° C. for 16 h. The mixture was allowed to cool to RT and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by prep-TLC plate (10% MeOH-DCM) to afford the product (S)—N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)-2-(1H-pyrazol-4-yl)nicotinamide (compound 58). ESI-MS m/z: 471.0 [M+H]+.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1.N([O-])=O.[Na+].[BrH:21]>O1CCOCC1.O.[Cu]Br>[Br:21][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Br
Reactant: N#Cc1ccccc1-c1cc(N)ccc1F
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccccc1-c1cc(Br)ccc1F
Temperature: 3 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A solution of 5′-amino-2′-fluorobiphenyl-2-carbonitrile (7.85 g, 37 mmol) in 1,4-dioxane (25 ml) was treated with 48% hydrobromic acid (125 ml) and the resulting suspension stirred and cooled to 3° C. (internal temperature). A solution of sodium nitrite in water (5 ml) was then added dropwise over 20 min keeping the internal temperature <5° C. Stirring at <5° C. was continued for 2 h before pouring the reaction into a cooled (5° C.) solution of freshly purified copper(I) bromide (6.37 g, 44 mmol) in 48% hydrobromic acid (50 ml). The resulting purple reaction mixture was stirred at 5° C. for 10 min then warmed to 50° C. for 20 min. The reaction was diluted with ice-cold water (500 ml) and extracted with ethyl acetate (2×250 ml). The organics were combined, washed with 5% aqueous sodium sulfite, saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by chromatography on silica eluting with isohexane (containing 1% methanol) on a gradient of ethyl acetate (2-10%) afforded a colourless oil which crystallised on standing to give 5′-bromo-2′-fluorobiphenyl-2-carbonitrile as a white solid (6.5 g, 64%): δH (400 MHz, CDCl3) 7.09-7.14 (1H, m), 7.45-7.57 (4H, m), 7.66 (1H, td, J 8 and 2), 7.77 (1H, dd, J 8 and 2).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][C:8](Cl)=[N:9]2)=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1.Cl.O1CCOCC1>C(O)(C)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][C:8]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([S:20]([NH:23][CH2:24][CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)(=[O:22])=[O:21])=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)NCCCN2CCCC2)cc1
Reactant: Clc1ncc2ccc(Br)cc2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: O=S(=O)(NCCCN1CCCC1)c1ccc(Nc2ncc3ccc(Br)cc3n2)cc1
Temperature: 120 °C

Procedure:
To a 0.1M suspension of 7-bromo-2-chloroquinazoline in isopropanol was added 4-amino-N-(3-(pyrrolidin-1-yl)propyl)benzenesulfonamide (1.1 eq), followed by the addition of 4.0M HCl in dioxane (1.1 eq). The reaction mixture was heated to 120° C. in an oil bath for 1 h. LCMS showed that reaction was complete under the condition. Ethyl acetate was added to the reaction flask and the mixture was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. Desired product was a yellow color solid. ES/MS m/z 490/492 (MH+).
Reaction SMILES: Cl[Si](C)(C)C.C[OH:7].[C:8]([O:12][C:13]([N:15]1[CH2:19][C@@H:18]([C:20]#N)[CH2:17][C@H:16]1[C:22](=[O:33])[NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[F:32])=[O:14])([CH3:11])([CH3:10])[CH3:9].[C:34](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:35]>C(Cl)Cl>[CH3:34][O:35][C:20]([C@H:18]1[CH2:17][C@@H:16]([C:22](=[O:33])[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=2[F:32])[N:15]([C:13]([O:12][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:14])[CH2:19]1)=[O:7]
Reactant: CO
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C#N)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@@H](C(=O)NCc2cccc(Cl)c2F)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Chlorotrimethylsilane (5.66 mL, 44.8 mmol) was added dropwise to dry MeOH (7.6 mL) at 0° C. followed by a solution of (2S,4S)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester (900 mg, 2.36 mmol) in dry CH2Cl2 (6.7 mL) and the resulting mixture was stirred at RT for 5 h. The mixture was cooled to 0° C., quenched with a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (×3). To the organic extracts was added di-tert-butyl dicarbonate (514 mg, 2.36 mmol) at RT and the resulting solution was stirred overnight. The reaction mixture was concentrated in vacuo and the crude material purified by flash column chromatography (c-hexane to c-hexane/EtOAc 1:1) to give the expected compound. tR (HPLC conditions a): 3.50 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(N(CC)CC)C>ClCCl>[CH2:24]([O:23][C:21]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)/[C:6](=[CH:12]/[C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)/[C:7]1=[O:11])=[O:22])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1C(=O)/C(=C\c2ccc(Cl)cc2)c2ccc(Cl)cc21
Yield: 73.3 %

Procedure:
In a manner similar to the method described in example 4b, E/Z-6-chloro-3-(4-chloro-benzylidene)-1,3-dihydro-indol-2-one (3.3 g, 11.3 mmol) was reacted with ethyl chloroformate (1.62 mL, 17.0 mmol) and triethylamine (3.16 mL, 22.6 mmol) in dichloromethane to give E/Z-6-chloro-3-(4-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester as a yellow solid (Yield 3.0 g, 73%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:7]=[CH:6][N:5]([CH2:8]O)[N:4]=1.S(Cl)([Cl:14])=O>ClCCl>[Cl:14][CH2:8][N:5]1[CH:6]=[N:7][C:3]([C:2]([F:11])([F:10])[F:1])=[N:4]1
Reactant: O=S(Cl)Cl
Reactant: OCn1cnc(C(F)(F)F)n1
Solvent: ClCCl
Product: FC(F)(F)c1ncn(CCl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.52 g of 3-(trifluoromethyl)-1H-1,2,4-triazole 1-ylmethanol was dissolved to 50 ml of dichloromethane, and 2.7 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure to obtain 1.36 g of 1-(chloromethyl)-3-(trifluoromethyl)-1H-1,2,4-triazole.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)(=[O:27])=[O:26])[CH:20]=[CH:21][C:22]=2[F:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][Zn]C>>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:36])[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)(=[O:27])=[O:26])[CH:20]=[CH:21][C:22]=2[F:23])[N:10]=1)([CH3:16])[CH3:15]
Reactant: C[Zn]C
Reactant: CC(C)(C)c1nc(-c2c(F)ccc(NS(=O)(=O)c3cccc(F)c3)c2F)c(-c2ccnc(Cl)n2)s1
Product: Cc1nccc(-c2sc(C(C)(C)C)nc2-c2c(F)ccc(NS(=O)(=O)c3cccc(F)c3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 25 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-3-fluorobenzenesulfonamide (100 mg, 0.186 mmol) and dimethylzinc (0.186 mL, 0.371 mmol), the title compound was obtained as an off white solid (90 mg, 94% yield). MS (ESI): 519.1 [M+H]+.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.FC(F)(F)C(O)=O.[NH2:15][C:16]1[N:21]=[CH:20][N:19]=[C:18]2[N:22]([CH:26]([C:28]3[C:29](OCC)=[C:30]([CH:37]4[CH2:40][N:39]([C:41]([CH3:46])([CH3:45])[C:42]([OH:44])=O)[CH2:38]4)[C:31]([C:35]#[N:36])=[C:32]([Cl:34])[CH:33]=3)[CH3:27])[N:23]=[C:24]([CH3:25])[C:17]=12.N.C(O)C.C([N:56](CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[NH2:15][C:16]1[N:21]=[CH:20][N:19]=[C:18]2[N:22]([CH:26]([C:28]3[C:29]([O:5][CH2:3][CH3:2])=[C:30]([CH:37]4[CH2:38][N:39]([C:41]([CH3:45])([CH3:46])[C:42]([NH2:56])=[O:44])[CH2:40]4)[C:31]([C:35]#[N:36])=[C:32]([Cl:34])[CH:33]=3)[CH3:27])[N:23]=[C:24]([CH3:25])[C:17]=12
Reactant: CCN(CC)CC
Reactant: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C(C)(C)C(=O)O)C1
Reactant: O=C(O)C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C#N)c1C1CN(C(C)(C)C(N)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
A solution of 2-(3-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-6-cyano-2-ethoxyphenyl}azetidin-1-yl)-2-methylpropanoic acid bis(trifluoroacetate) (0.05 g, 0.069 mmol, chiral intermediate from Example 237, Step 1) and 2.0 M ammonia in ethanol (0.17 mL, 0.34 mmol) in N,N-dimethylformamide (1 mL) was treated with triethylamine (0.048 mL, 0.35 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.046 g, 0.10 mmol) and stirred at room temperature for 1 h. The reaction mixture was quenched with a few drops of water, diluted with methanol, and purified by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (25 mg, 73%). The product was isolated as a single enantiomer. 1H NMR (400 MHz, DMSO-d6) S 8.11 (s, 1H), 7.51 (s, 1H), 7.23 (s, 1H), 6.98 (s, 1H), 6.23 (q, J=7.0 Hz, 1H), 4.09-3.96 (m, 1H), 3.84-3.61 (m, 4H), 3.39-3.34 (m, 1H), 3.32-3.28 (m, 1H), 2.54 (s, 3H), 1.71 (d, J=7.0 Hz, 3H), 1.31 (t, J=6.9 Hz, 3H), 1.02 (s, 6H). LCMS for C24H30ClN8O2 (M+H)+: m/z=497.2; Found: 497.3.
Reaction SMILES: [NH2:1][CH:2]([C:8]#[N:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:10]([O-])([O-])OCC.[NH2:16][C:17]1[S:18][CH:19]=[N:20][N:21]=1>>[NH2:9][C:8]1[N:16]([C:17]2[S:18][CH:19]=[N:20][N:21]=2)[CH:10]=[N:1][C:2]=1[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(N)C#N
Reactant: CCOC([O-])[O-]
Reactant: Nc1nncs1
Product: CCOC(=O)c1ncn(-c2nncs2)c1N

Procedure:
The desired compound was synthesized following the procedures described in Reference Example 7 by using ethyl α-aminocyanoacetate, ethyl orthoformate and 2-amino-1,3,4-thiadiazole as raw materials. m.p.: 181° to 183° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[N:15]([CH:16]=2)[CH:14]=[CH:13][S:12]3)=[CH:5][CH:4]=1.[CH2:17]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:28]([C:30]2[C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=[CH:32][N:31]=2)=O)=[C:20]1[CH3:39])[CH3:18].C(OC(=O)C)(=O)C.[OH-].[NH4+]>O>[CH2:17]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:28]2([C:16]3[N:15]4[C:11]([S:12][CH:13]=[CH:14]4)=[N:10][C:9]=3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:30]3=[N:31][CH:32]=[CH:33][CH:34]=[C:35]3[C:36](=[O:37])[O:38]2)=[C:20]1[CH3:39])[CH3:18]
Reactant: COc1ccc(-c2cn3ccsc3n2)cc1
Reactant: CCn1c(C)c(C(=O)c2ncccc2C(=O)O)c2ccccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCn1c(C)c(C2(c3c(-c4ccc(OC)cc4)nc4sccn34)OC(=O)c3cccnc32)c2ccccc21
Reaction time: 1 h
Yield: 123.6 %

Procedure:
A mixture of 0.92 gram of 6-p-methoxy phenylimidazo[2,1-b]thiazole, 0.69 gram of (1-ethyl-2-methylindol-3-yl)(3-carboxypyridin-2-yl)ketone and 20 ml. of acetic anhydride was stirred 2.5 hours at 50° C. The reaction solution was poured into 250 ml. of water and adjusted to pH 9.8 with ammonium hydroxide. After one hour stirring the solid material was filtered and washed with water to give 1.44 grams (95%) of desired product, mp. 115°-118° C. The infrared spectrum showed a strong 1770 cm-1 lactone carbonyl peak. A solution of the product on silica gel produced a purple color.
Reaction SMILES: [SH:1][C:2]([C@H:5]1[O:10][C:8](=[O:9])[C@@H:7]([CH2:11][SH:12])[CH2:6]1)([CH3:4])[CH3:3].[Cl-].[NH4+]>C(Cl)Cl.C(N(CC)CC)C.C(Cl)(=O)C>[C:8]([S:1][C:2]([C@H:5]1[O:10][C:8](=[O:9])[C@@H:7]([CH2:11][S:12][C:5](=[O:10])[CH3:2])[CH2:6]1)([CH3:4])[CH3:3])(=[O:9])[CH3:7]
Reactant: CC(C)(S)[C@@H]1C[C@H](CS)C(=O)O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)SC[C@H]1C[C@@H](C(C)(C)SC(C)=O)OC1=O
Reaction time: 0.5 h
Yield: 185.3 %

Procedure:
To a stirred solution of cis-4-(1-mercapto-1-methylethyl)-2-mercaptomethyl-4-butanolide (compound No.9-3, 0.102 g) in methylene chloride (3 ml), triethylamine (0.20 ml) and acetyl chloride (0.10 ml) were added and stirred for 30 minutes under nitrogen atmosphere and ice-cooling. The mixture was poured into saturated aqueous ammonium chloride solution (30 ml) and extracted with ether. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue was purified by silica gel column chromatography to give 0.133 g (93%) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31].[CH3:40][O:41][C:42]([C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1)=[O:43].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:40][O:41][C:42]([C:44]1[CH:49]=[CH:48][C:47]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][C@@H:9]3[CH2:13][CH2:12][N:11]([N:14]4[CH2:19][CH2:18][CH:17]([O:20][Si:21]([CH:25]([CH3:27])[CH3:26])([CH:28]([CH3:30])[CH3:29])[CH:22]([CH3:23])[CH3:24])[CH2:16][CH2:15]4)[C:10]3=[O:31])=[C:2]([Cl:1])[CH:3]=2)=[CH:46][CH:45]=1)=[O:43]
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3ccc(OS(=O)(=O)C(F)(F)F)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Reactant: COC(=O)c1ccc(B(O)O)cc1
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: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(C[C@@H]3CCN(N4CCC(O[Si](C(C)C)(C(C)C)C(C)C)CC4)C3=O)c(Cl)c2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
Bring a mixture of trifluoro-methanesulfonic acid 3-Chloro-4-[(R)-2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-phenyl ester (0.83 g, 1.35 mmol), 4-methoxycarbonylphenylboronic acid (0.29 g, 1.62 mmol), sodium carbonate (0.43 g, 4.06 mmol) in THF (20 mL) and water (6 mL) to 60° C. To the mixture at 60° C., add Pd(PPh3)4 (0.08 g, 0.07 mmol). Raise the reaction temperature to 80° C. and stir for 1 hour. Cool the reaction, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer with Na2SO4, remove the solvent in vacuo, and purify on silica gel column with 0% to 50% ethyl acetate in hexanes gradient to afford 0.76 g (93%) of the titled product. MS (m/z): 599 (M+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]3[C:19]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[CH:28][C:27]=1[CH:36]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:12][C:13]3[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH2:36][C:27]5[CH:28]=[N:29][C:30]6[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=6)[N:26]=5)[CH2:22][CH2:21]4)=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2nc3cccc(N4CCNCC4)c3s2)cc1
Reactant: O=Cc1cnc2ccccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)c1ccc(-c2nc3cccc(N4CCN(Cc5cnc6ccccc6n5)CC4)c3s2)cc1
Temperature: 25 °C
Yield: 55 %

Procedure:
The piperazine template (0.075 g, 0.213 mmol) of Example 24 was dissolved in 1,2-dichloroethane (3 mL) and treated with quinoxaline-2-carbaldehyde (0.044 g, 0.277 mmol) and glacial acetic acid (2 drops). Sodium triacetoxyborohydride (0.090 g, 0.426 mmol) was added, and the mixture was stirred at room temperature until the reaction was complete by LCMS analysis. The solvent was removed under reduced pressure, and the resulting residue was purified by RP-HPLC to yield the free base (0.0578 g, 55% yield). MS (ESI) m/z 494.
Reaction SMILES: CC1N=C(N2C(=O)N(CC3C=CC(C(F)(F)F)=CC=3)N=C2)SC=1C(O)=O.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45](O)=[O:46])=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:30][CH:29]=1.Cl.[O:51]1[CH:55]=[CH:54][N:53]=[C:52]1[CH2:56][NH2:57]>>[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[C:37](=[O:38])[N:36]([C:39]3[S:40][C:41]([C:45]([NH:57][CH2:56][C:52]4[O:51][CH:55]=[CH:54][N:53]=4)=[O:46])=[C:42]([CH3:44])[N:43]=3)[CH:35]=[N:34]2)=[CH:30][CH:29]=1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: NCc1ncco1
Agent: Cc1nc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)sc1C(=O)O
Agent: Cl
Product: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)NCc1ncco1
Yield: 57 %

Procedure:
Following the procedure as described in Example 21, making variations as required to replace 4-methyl-2-(5-oxo-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylic acid with 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with oxazol-2-ylmethanamine hydrochloride, the title compound was obtained as a white solid in 57% yield: mp 152-153° C. (ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ 8.26 (s, 1H), 7.65 (s, 1H 7.41-7.32 (m, 2H), 7.09 (s, 1H), 7.07-6.98 (m, 2H), 6.54 (t, J=5.2 Hz, 1 H), 4.98 (s, 2H), 4.73 (d, J=5.2 Hz, 2H), 2.67 (s, 3H); MS (ES+) m/z 415.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][N:6]1[C:10]2=[N:11][C:12]([CH3:22])=[C:13]([C@H:16]([OH:21])[C:17]([O:19][CH3:20])=[O:18])[C:14]([I:15])=[C:9]2[CH:8]=[CH:7]1.C(O[C:31]([CH3:34])([CH3:33])[CH3:32])(=O)C.Cl(O)(=O)(=O)=O>>[C:31]([O:21][C@@H:16]([C:13]1[C:14]([I:15])=[C:9]2[CH:8]=[CH:7][N:6]([CH2:5][C:4]3[CH:23]=[CH:24][C:25]([F:26])=[C:2]([F:1])[CH:3]=3)[C:10]2=[N:11][C:12]=1[CH3:22])[C:17]([O:19][CH3:20])=[O:18])([CH3:34])([CH3:33])[CH3:32]
Reactant: COC(=O)[C@@H](O)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1I
Reactant: CC(=O)OC(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
To a solution of (S)-methyl 2-(1-(3,4-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-hydroxyacetate (660 mg, 1.328 mmol) in tert-butyl acetate (15 mL, 111 mmol) was added dropwise in ˜5 min perchloric acid (0.456 mL, 5.31 mmol) (70% reagent) and the mixture was stirred at RT for 1 h. The mixture was carefully quenched with saturated NaHCO3/water and extracted with EtOAc. The organic phase dried (Na2SO4), concentrated, and purified by column chromatography to provide (S)-methyl 2-(tert-butoxy)-2-(1-(3,4-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate (551 mg, 1.032 mmol, 78% yield) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.27 (s, 9 H), 2.74 (s, 3 H), 3.70 (s, 3 H), 5.40 (d, J=2.15 Hz, 2 H), 5.76 (s, 1 H), 6.36 (d, J=3.51 Hz, 1 H), 6.92-7.17 (m, 4 H); LCMS (m/z) ES+=529 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[C:14]([C:21]#[N:22])[CH:13]=2)[O:9][N:8]=1.O.O.[Sn](Cl)Cl.ClCCl>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([C:21]#[N:22])[CH:15]=[C:16]([NH2:18])[CH:17]=2)[O:9][N:8]=1
Reactant: N#Cc1cc(-c2nc(-c3ccccn3)no2)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: N#Cc1cc(N)cc(-c2nc(-c3ccccn3)no2)c1
Yield: 10.6 %

Procedure:
3-(2-Pyridyl)-5-(3-cyano-5-nitrophenyl)-1,2,4-oxadiazole (30 mg, 0.10 mmol) and tin(II) chloride dihydrate (115 mg, 0.51 mmol) in ethanol (1 mL) were sealed in a glass vial and then heated at 78 oC for 2 hours. The reaction was cooled and dichloromethane was added to the reaction mixture. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel chromatography of the residue using hexanes:ethyl acetate:dichloromethane 1:3:4 followed by recrystallization using methanol afforded 2.8 mg (10%) of 3-(2-Pyridyl)-5-(3-amino-5-cyanophenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.85 (d, 1H), 8.22 (d, 1H), 7.91 (m, 2H), 7.78 (s, 1H), 7.48 (m, 1H), 7.11 (s, 1H), 4.17 (bs, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([F:36])[CH:30]=1.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:35][C:32]3[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][C:31]=3[F:36])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: Oc1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
A mixture of the crude 7-benzyloxy-4-chloro-6-methoxyquinazoline, potassium carbonate (50 g, 362 mmol) and 4-chloro-2-fluorophenol (8.8 ml, 83 mmol) in DMF (500 ml) was stirred at 100° C. for 5 hours then allowed to cool to ambient temperature overnight. The reaction mixture was poured into water (2 l) and was stirred at ambient temperature for a few minutes. The crude solid was collected by filtration washing with water. The resultant solid was dissolved in dichloromethane and filtered through diatomaceous earth. The filtrate was treated with decolourising charcoal, boiled for a few minutes then filtered through diatomaceous earth. The filtrate was filtered through phase separating paper and then evaporated under vacuum to give a solid residue which was triturated with ether, filtered and dried to give 7-benzyloxy-4-(4-chloro-2-fluorophenoxy)-6-methoxyquinazoline (23.2 g, 76%).