Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[N:8][N:7]=[C:6]1[N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([NH:19]C(=O)OC(C)(C)C)[CH2:14]1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[NH2:19][C@@H:15]1[CH2:16][CH2:17][CH2:18][N:13]([C:6]2[N:5]([CH2:4][C:3]3[CH:2]=[CH:30][CH:29]=[C:28]([F:31])[CH:27]=3)[C:10](=[O:11])[C:9]([CH3:12])=[N:8][N:7]=2)[CH2:14]1
Reactant: Cc1nnc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2cc(F)ccc2Br)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nnc(N2CCC[C@@H](N)C2)n(Cc2cccc(F)c2)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (R)-tert-butyl 1-(4-(2-bromo-5-fluorobenzyl)-6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)piperidin-3-ylcarbamate (18, 30 mg) in dichloromethane (1 mL) was added TFA (0.5 mL), and the mixture was stirred at RT for 3 h. The mixture was carefully neutralized with NaHCO3 (aq, saturated), and extracted with CH2Cl2 (10 mL×3). The combined extracts were dried over Na2SO4 and concentrated to give the crude product. This was purified by column chromatography on silica gel, and eluted with 92:6:2 dichloromethane-methanol-ammonia to provide (R)-3-(3-aminopiperidin-1-yl)-4-(3-fluorobenzyl)-6-methyl-1,2,4-triazin-5(4H)-one (19). MS: m/z, 396 (100%, M+1), 398 (100%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>C1COCC1.[Cl-].[Na+].O>[C:30]([O:29][C:27](=[O:28])[CH2:26][C:2]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)C1Cc2ccccc2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1(CC(=O)OC(C)(C)C)Cc2ccccc2C1
Reaction time: 0.25 h

Procedure:
To a solution of ethyl indane-2-carboxylate (Schaaf et al., J. Med. Chem. 1983, 26, 328-334) (2.00 g, 10.5 mmol) in THF at −78° C. was added sodium bis(trimethylsilyl)amide (15.8 mL of a 1.0 M solution in THF, 15.8 mmol) dropwise, over 10 min. The mixture was stirred for 15 min, then tert-butyl bromoacetate (3.08 g, 15.8 mmol) was added dropwise, over 30 min. The resulting mixture was stirred for 30 min at −78° C., then poured into brine (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 90:10, to give the title compound. MS: m/z=368 (M+Na+CH3CN).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[C:11][CH2:12][CH2:13][OH:14])([O-:3])=[O:2].[CH3:15]I>C(#N)C.[Ag]=O>[CH3:15][O:14][CH2:13][CH2:12][C:11]#[C:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CI
Reactant: O=[N+]([O-])c1ccccc1C#CCCO
Agent: O=[Ag]
Solvent: CC#N
Product: COCCC#Cc1ccccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 70 h

Procedure:
A solution of 2.9 g of 4-(2-nitrophenyl)but-3-yn-1-ol in 750 ml of acetonitrile is admixed at room temperature with 17.5 g of silver oxide and 9.4 ml of methyl iodide and stirred at 50° C. over 70 hours. The reaction mixture is clarified by filtration and the filtrate is concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.34 (1:2 EtOAc-heptane); Rt=4.17.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:28][C:29]([CH3:34])([CH3:33])[CH2:30][CH:31]=O.[BH4-].[Na+]>CO>[CH3:28][C:29]([CH3:34])([CH3:33])[CH2:30][CH2:31][N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:16]2[N:15]=[CH:14][N:13]=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[C:17]=2[N+:18]([O-:20])=[O:19])[CH2:23][CH2:24]1
Reactant: CC(C)(C)CC=O
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)CCN1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Compound A2 (0.20 mmol, 80 mg), and 3,3-dimethyl-butyraldehyde (0.24 mmol, 30 μL) were dissolved in methanol (2 mL) and stirred for 5 minutes at room temperature. Then, added sodium borohydride (0.25 mmol, 8.7 mg) and stirred for 10 minutes at room temperature. The reaction mixture was quenched with saturated ammonium chloride solution (1 mL) followed by an extraction with dichloromethane. Removal of organic solvent in vacuo and purification by prep-LCMS provided Compound A7 as a yellow solid (12 mg, 13%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.17 (s, 1H), 8.36 (s, 1H), 7.90 (d, 2H), 7.78 (d, 2H), 5.71 (s broad, 1H), 3.51 (d, 2H), 3.08 (m, 2H), 2.97 (m, 5H), 2.38 (m, 2H), 2.14 (m, 2H), 1.60 (m, 2H), 0.85 (s, 9H). LCMS (ESI), m/z 478.3 (M+H+, 100%).
Reaction SMILES: [I-:1].[CH3:2][N+:3]1[C:8]2[CH:9]=[CH:10][S:11][C:7]=2[C:6](SC)=[N:5][C:4]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[I-].[CH3:21][C:22]1[S:23][C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[N+:26]=1[CH3:27].C(N(CC)CC)C>CN(C)C=O>[I-:1].[CH3:27][N+:26]1[C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[S:23][C:22]=1[CH:21]=[C:6]1[N:5]=[C:4]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:3]([CH3:2])[C:8]2[CH:9]=[CH:10][S:11][C:7]1=2
Reactant: Cc1sc2ccccc2[n+]1C
Reactant: CSc1nc(-c2ccccc2)[n+](C)c2ccsc12
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1C(c2ccccc2)=NC(=Cc2sc3ccccc3[n+]2C)c2sccc21
Temperature: 80 °C
Reaction time: 1 h

Procedure:
200 mg (0.50 mmol) 1-Methyl-4-methylsulfanyl-2-phenyl-thieno(3,2-d)pyrimidin-1-ium iodide and 145 mg (0.50 mmol) 2,3-dimethyl-benzothiazol-3-ium iodide were dissolved in 2.0 ml dimethylformamide and 202 mg (0.28 ml, 2.00 mmol) triethylamine were added. The green solution was stirred for 1 h at 80° C., filtrated and the residue was washed with methanol. The crude product was purified further by HPLC.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([SH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:24]=[C:23](F)[CH:22]=[CH:21][C:18]=1[CH:19]=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:23]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[C:17]([Cl:16])[CH:24]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Sc1cccc(OCc2ccccc2)c1
Reactant: O=Cc1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl
Temperature: 0 °C

Procedure:
3-Benzyloxybenzenethiol (13) (75.0 g, 347 mmol) and 2-chloro-4-fluorobenzaldehyde (55.0 g, 347 mmol) were dissolved in dimethylformamide (DMF) (350 mL) while the solution was being stirred. The solution was then placed in a water bath at 30° C. and potassium carbonate (62.3 g, 451 mmol) and dimethylformamide (25 mL) were added. This mixture was stirred for 30 min at an internal temperature of 40 to 42° C. Tap water (125 mL) was then added and the mixture was cooled in ice water. To the cooled mixture, additional tap water (625 mL) was added dropwise for crystallization. The mixture was stirred for 30 min and the resulting crystals were collected by filtration and washed with 10% aqueous 2-propanol (188 mL). The moist crystals were dissolved in ethyl acetate (750 mL) and the solution was washed twice with tap water (375 mL×2). The organic layer was concentrated under reduced pressure and acetone (900 mL) was added to the resulting residue. Purified water (386 mL) was then added dropwise at an internal temperature of 23° C. The mixture was stirred for 30 min and the resulting crystals were collected by filtration and washed with 50% aqueous acetone (400 mL). The washed crystals were air-dried overnight. Subsequently, the product was dried by blowing an air stream at 45° C. for 1 hour. This gave 4-(3-benzyloxyphenylthio)-2-chlorobenzaldehyde (1) as a colorless prism crystals (115 g, 94%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[CH3:12])[CH2:7]Br)([O-:3])=[O:2].[H-].[Na+].[F:15][C:16]([F:25])([F:24])[CH2:17][CH2:18][CH:19]([C:22]#[N:23])[C:20]#[N:21]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[CH3:12])[CH2:7][C:19]([CH2:18][CH2:17][C:16]([F:15])([F:24])[F:25])([C:20]#[N:21])[C:22]#[N:23])([O-:3])=[O:2]
Reactant: Cc1ccc(CBr)cc1[N+](=O)[O-]
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CC(C#N)(C#N)CCC(F)(F)F)cc1[N+](=O)[O-]
Yield: 32.1 %

Procedure:
Using 0.23 g of 3-nitro-4-methylbenzyl bromide, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.10 g of 2-(3-nitro-4-methylbenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (30)).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:16]=[C:17]([Cl:28])[C:18]([S:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])C.C1COCC1.O[Li].O>O>[CH2:21]([S:20][C:18]1[C:17]([Cl:28])=[CH:16][C:14]2[NH:15][C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]3)=[N:12][C:13]=2[CH:19]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(SCc4ccccc4)c(Cl)cc3[nH]2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnn(-c2nc3cc(SCc4ccccc4)c(Cl)cc3[nH]2)c1
Temperature: 23 °C
Reaction time: 18 h
Yield: 98.5 %

Procedure:
To a mixture of 1-(5-benzylsulfanyl-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.115 g, 0.256 mmol), THF (4.8 mL), and water (1.2 mL) was added LiOH.H2O (0.107 g, 2.56 mmol). The mixture was stirred for 18 h at 23° C. The solvent was evaporated, water (3 mL) was added and the mixture acidified to pH 3 with 1M HCl. The resulting white precipitate was filtered and dried to yield the titled compound (97.0 mg, 99%). MS (ESI/CI): mass calcd. for C18H13ClN4O2S, 384.0; m/z found, 385.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 8.86 (s, 1H), 8.29 (s, 1H), 7.67 (s, 1H), 7.53 (s, 1H), 7.39 (d, J=7.4 Hz, 2H), 7.31 (t, J=7.4 Hz, 2H), 7.25 (t, J=7.1 Hz, 1H), 4.29 (s, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[O:17])=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH:2]=1.O.[CH3:19][N:20](C)[C:21]1C=CC(B(O)O)=CN=1>>[CH3:19][N:20]([CH3:21])[C:6]1[N:1]=[CH:2][C:3]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[O:17])=[CH:13][CH:14]=3)[NH:9][N:8]=2)=[CH:4][CH:5]=1
Reactant: O=Cc1ccc2c(-c3cccnc3)n[nH]c2c1
Reactant: CN(C)c1ccc(B(O)O)cn1
Solvent: O
Product: CN(C)c1ccc(-c2n[nH]c3cc(C=O)ccc23)cn1

Procedure:
According to the procedure for the synthesis of 3-(pyridin-3-yl)-1H-indazole-6-carbaldehyde, except substituting 2-(dimethylamino)pyridine-5-boronic acid hydrate (41 mg, 0.22 mmol), the title compound was prepared as a yellow powder (14 mg, 29%). 1H NMR (400 MHz, d6-DMSO) δ ppm 10.13 (s, 1H), 8.72 (d, J=2.4 Hz, 1H), 8.17-8.16 (m, 2H), 8.09 (dd, J=8.4, 2.1 Hz, 1H), 7.62 (d, J=8.9 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 3.09 (s, 6H); MS ESI 267.0 (100) [M+H]+, calcd for [C15H14N4O+H]+ 267.12.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[C:31]([NH:35][CH3:36])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([N:35]([CH3:36])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:21][CH:22]=3)=[CH:13][C:11]=2[CH:12]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1
Reactant: CNC(C)(C)C
Product: CN(CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1)C(C)(C)C

Procedure:
The product from Example 23D and tert-butyl(methyl)amine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.83 (m, 1H), 7.74 (d, J=8.1, 2H), 7.55 (m, 2H), 7.51 (d, J=8.1 Hz, 2H), 6.81 (s, 1H), 3.3-3.8 (m, 12H), 2.93 (s, 3H), 1.48 (s, 9H); MS (DCI) m/z 421 (M+H)+;
Reaction SMILES: [F:1][C:2]1[C:3]([N:20]2[C:25](=[O:26])[CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[N:22]([CH3:31])[C:21]2=[O:32])=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[C:6]([N+:8]([O-])=O)[CH:7]=1.O>C(O)(=O)C.[Fe]>[F:1][C:2]1[C:3]([N:20]2[C:25](=[O:26])[CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[N:22]([CH3:31])[C:21]2=[O:32])=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2[N+](=O)[O-])c1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2N)c1
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A solution of 4.17 g of 5-fluoro-2-(3-methoxyphenoxy)-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene in 10 ml of acetic acid was added dropwise over 20 minutes to a mixture of 4.5 g of iron powder, 10 ml of acetic acid and 1 ml of water. After the addition, the mixture was stirred for 2 hours, filtered through celite and diluted with ethyl acetate. The resultant was washed with water 2 times, the organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 3.67 g of 5-fluoro-2-(3-methoxyphenoxy)-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]aniline.
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[O:21]1[CH2:23][CH:22]1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.O>CN(C=O)C>[CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:23][CH:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[OH:21])[C:7]3[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CN1CCc2[nH]c3ccc(C(F)(F)F)cc3c2C1
Reactant: c1cc(C2CO2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCc2c(c3cc(C(F)(F)F)ccc3n2CC(O)c2ccncc2)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-methyl-8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.0 g, 3.937 mmol) in DMF (10 mL) was added sodium hydride (472 mg, 11.81 mmol) in portions at RT. After stirring at RT for 15 min, the suspension was allowed to cool to 0° C. and 4-(oxiran-2-yl)pyridine (762 mg, 6.299 mmol) was added dropwise into the reaction mixture, which was stirred at RT overnight. The reaction mixture was poured into ice-cooled water and extracted with EtOAc (3×50 mL). The organic layer was washed with water (2×50 mL), dried over anhydrous sodium sulfate and concentrated. The solid obtained was re-crystallized in DCM-diethyl ether to yield 2-(2-methyl-8-(trifluoromethyl)-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(pyridin-4-yl)ethanol. 1H NMR (CDCl3, freebase) δ (ppm): 8.59 (d, 2H), 7.4 (s, 1H), 7.39 (d, 1H), 7.3 (d, 1H), 7.19 (d, 2H), 4.68 (m, 1H), 4.1 (m, 2H), 3.4 (dd, 2H), 2.82 (m, 1H), 2.74 (bs, 2H), 2.6 (m, 1H), 2.4 (s, 3H). Separation by chiral HPLC provides enantiomers 6a and 6b.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5]([CH2:7]Cl)=O.[C:10]([NH:13][C:14]([NH2:16])=[S:15])(=[O:12])[CH3:11]>>[C:10]([NH:13][C:14]1[S:15][CH:7]=[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:9])[N:16]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)NC(N)=S
Reactant: COC(=O)CC(=O)CCl
Product: COC(=O)Cc1csc(NC(C)=O)n1
Reaction time: 23 h

Procedure:
Methyl-4-chloroacetoacetate (11.54ml), N-acetylthiourea (11.8g) and 4A molecular sieves (10g) were stirred in dry, distilled dimethylformamide (DMF) (50ml) at 50° C., for 23h. After this time the reaction appeared complete by t.1.c. The mixture was cooled and filtered through a dicalite pad. The residue was washed with DMF and tetrahydrofuran and the resultant filtrates diluted with water. This solution was washed five times with ethyl acetate; the organic washes were combined, dried, filtered and evaporated to give a yellow oil. This was triturated under water whereupon a white precipitate formed. This was cooled to complete and the resultant solid filtered off, washed with cold water and dried to give the desired product (14.63g) as a white crystalline solid, m.p. 122°-123° C. (from ethyl acetate-hexane); υ max (nujol) 3175 (w), 1740, 1655, 1560 and 1543cm-1 ; δ[(CD3)2SO, 60MHz]2.1 (3H, s). 3.6 (3H. s). 3.7 (2 H. s). and 6.9 (1H. s). (Found: C, 44.9; H, 4.7; N, 13.4; S, 15.3. C8H10N2O3S requires: C, 44.9; H, 4.7; N, 13.1; S, 15.0%). The mother liquors were concentrated to low volume and cooled to yield a second crop of the desired material (2.54g) which was slightly less pure by NMR.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=C)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[BH4-].[Na+].C[OH:25]>>[OH:25][CH2:12][CH:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: CO
Reactant: C=CC(NC(=O)OC(C)(C)C)C1CCC2(CC1)OCCO2
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)NC(CO)C1CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 250 mL round bottom flask was charged with tert-butyl (1-(1,4-dioxaspiro[4.5]decan-8-yl)allyl)carbamate (5.3 g, 17.8 mmol), prepared in the previous step, and methanol (198 mL). The mixture was cooled to −78° C. and ozone was bubbled through the solution at a rate of 3 L/min for 1 hour. The mixture turned pale blue in color after 30 minutes. After 1 hour air was bubbled through the solution for 30 minutes until the blue color disappeared. Sodium borohydride (2.7 g, 71.3 mmol) was added to the mixture in 4 portions. The mixture was gradually warmed to room temperature. After 6 h at room temperature the mixture quenched with saturated aqueous ammonium chloride. After dilution with water and extraction with ethyl acetate, the organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give the product as a clear oil.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][C:34]([NH2:36])=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[NH2:36][C:34](=[O:35])[CH2:33][NH:32][C:3](=[O:5])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:24])([F:25])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:10][CH:11]=1
Reactant: NCC(N)=O
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: NC(=O)CNC(=O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 41.4 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-IX, 30 mg, 0.070 mmol), 2-aminoacetamide (7.73 mg, 0.104 mmol), HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (28.1 mg, 0.278 mmol) were added to DMF (1 mL). It was stirred for 1 h and then was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.5 min) to provide (R/S)-N-(2-amino-2-oxoethyl)-2-hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (18 mg, 0.029 mmol, 42.2% yield): LCMS=488.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.16 (2 H, d, J=7.48 Hz), 7.58-7.87 (7 H, m), 5.20 (1 H, s), 3.81-4.13 (2 H, m); HPLC peak RT=8.0 min (Method A).
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][NH:19][C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[C:35]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:40]=[CH:39][C:38]([C:41](Cl)=[O:42])=[CH:37][CH:36]=1>>[CH2:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][N:19]([C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)[C:41]([C:38]3[CH:39]=[CH:40][C:35]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)=[CH:36][CH:37]=3)=[O:42])=[CH:16][CH:15]=2)=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: Cl
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)c3ccc(-c4ccccc4)cc3)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1

Procedure:
The titled compound was prepared following the procedure J using 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one hydrochloride and biphenyl-4-carbonyl chloride as a pale yellow oil (43%). 1H NMR (CDCl3, 300 MHz) δ 7.72 (brs, 1H), 7.53-7.27 (m, 15H), 7.17 (d, J=8.3 Hz, 2H), 6.98 (brd, J=8.7 Hz, 1H), 6.73 (d, J=8.7 Hz, 1H), 5.15 (s, 2H), 2.63 (t, J=7.5 Hz, 2H), 1.67 (s, 6H), 1.61 (m, 2H), 1.37 (m, 2H), 0.94 (t, J=7.2 Hz, 3H). HPLC, Rt: 6.07 min (Purity: 99.8%).
Reaction SMILES: CCN(C(C)C)C(C)C.[I:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][C:16](=[O:21])[C:15]([C:22]([OH:24])=O)=[CH:14]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12>CN(C=O)C>[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH:64][C:22]([C:15]3[C:16](=[O:21])[O:17][C:18]4[C:13]([CH:14]=3)=[CH:12][C:11]([I:10])=[CH:20][CH:19]=4)=[O:24])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12
Reactant: O=C(O)c1cc2cc(I)ccc2oc1=O
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
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: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2cc(I)ccc2oc1=O
Temperature: 25 °C
Yield: 33.8 %

Procedure:
DIEA (30.3 μL, 0.17 mmol) was added to 6-iodo-3-carboxy-coumarin (50.0 mg, 0.16 mmol) and HATU (66.2 g, 0.17 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (33.1 mg, 0.16 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 27.4 mg of product in 34% yield: LCMS (ESI) m/z 508 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15]C)[CH:10]=3)[O:8][C:4]=2[CH:3]=1.B(Br)(Br)Br.O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=3)[O:8][C:4]=2[CH:3]=1
Reactant: COc1cccc(-c2nc3ccc(Br)cc3o2)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: Oc1cccc(-c2nc3ccc(Br)cc3o2)c1
Temperature: 65 °C
Reaction time: 9 h
Yield: 88.7 %

Procedure:
To a solution of 6-bromo-2-(3-methoxyphenyl)benzoxazole (Compound of Example 242) (19.45 g) in chloroform (800 ml) was added dropwise boron tribromide (100.05 g) at 0° C., and the mixture was stirred at room temperature for 4 hours and 65° C. for 9 hours. The reaction mixture was poured into water, and the mixture was stirred at room temperature for 30 minutes and extracted with chloroform-tetrahydrofuran (4:1, v/v). The organic layer was washed with water and dried over MgSO4, and the solvent was distilled off under reduced pressure. The resulting crystals were collected by filtration to obtain 3-(6-bromobenzoxazol-2-yl)phenol (16.46 g, 89%).