Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:36]=[CH:35][C:8]([CH2:9][C:10]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=2)(C(OCC=C)=O)[C:11]([O:13]CC=C)=[O:12])=[CH:7][CH:6]=1)=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C(O)=O>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH:10]([CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:30]=2)[C:11]([OH:13])=[O:12])=[CH:35][CH:36]=1)=[O:4]
Reactant: C=CCOC(=O)C(CCc1ccc(C(=O)OC)cc1)(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O=CO
Product: COC(=O)c1ccc(CCC(Cc2ccc(C(=O)OC)cc2)C(=O)O)cc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A solution of 40 g (80.9 mmol) of diallyl 2-[4-(methoxycarbonyl)benzyl]-2-{2-[4-(methoxycarbonyl)phenyl]ethyl}malonate, 1.49 g (5.67 mmol) of triphenylphosphine and 363 mg of palladium acetate in 500 ml of dioxane is mixed at room temperature with a solution of 37.2 ml (267 mmol) of triethylamine and 7.6 ml (202 mmol) of formic acid in 100 ml of dioxane. The reaction mixture is then stirred at 110° C. overnight. After conversion is complete, the reaction solution is cooled, and the solvent is removed in vacuo. The resulting residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1). 20.98 g (56.6 mmol, 70% of theory) of a colourless solid are obtained.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[N:10][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])=[N:12][C:13](Cl)=[C:8]2[C:7]([CH3:22])=[N:6]1)[CH2:2][CH2:3][CH3:4].[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>COOCCOOC>[CH2:1]([N:5]1[C:9]2=[N:10][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])=[N:12][C:13]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[C:8]2[C:7]([CH3:22])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1nc(C)c2c(Cl)nc(-c3ccccc3F)nc21
Reactant: Nc1ccncc1
Agent: COOCCOOC
Product: CCCCn1nc(C)c2c(Nc3ccncc3)nc(-c3ccccc3F)nc21
Yield: 113.1 %

Procedure:
1-Butyl-4-chloro-6-(2-fluoro-phenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (100 mg, 0.31 mmole) and 4-aminopyridine (58 mg, 0.626 mmole) were combined in ethyleneglycol dimethoxy ether and heated to reflux for 4 hours. Cooled reaction mixture and isolated product by filtration, washed with minimum cold solvent and dried to give 132 mg product. 50 mg of this material was subjected to HPLC purification on reversed phase C18 column, eluting with gradient of water/acetonitrile/0.1% trifluoroacetic acid).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]4[C:24](=[O:25])[CH2:23][S:22][C:21]4=[O:26])=[CH:13][CH:12]=[CH:11][N:10]3[CH:27]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:28](=O)[CH2:29][CH2:30][CH3:31].N1CCCCC1>C(O)C>[CH:28](=[C:23]1[S:22][C:21](=[O:26])[N:20]([CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:14]2[C:9]3[N:10]([CH:27]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH:11]=[CH:12][CH:13]=2)[C:24]1=[O:25])[CH2:29][CH2:30][CH3:31]
Reactant: O=C1CSC(=O)N1CCCCOc1cccn2cc(-c3ccccc3)nc12
Reactant: CCCC=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCC=C1SC(=O)N(CCCCOc2cccn3cc(-c4ccccc4)nc23)C1=O

Procedure:
To a solution of 1.91 g (5.0 mmol) of 3-[4-(2-phenylimidazo[1,2-a]pyridin-8-yloxy)butyl]thiazolidine-2,4-dione and 0.45 ml (5.0 mmol) of n-butyraldehyde in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=2/1) to yield 1.70 g (78.0%, yellow foamy substance) of the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=NC1CCCCC1)=NC1CCCCC1.N1(O)C2C=CC=CC=2N=N1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:10]([O:12][C@@H:47]1[CH:48]2[CH2:51][CH2:52][N:45]([CH2:50][CH2:49]2)[CH2:46]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(Cl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 44.4 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)acetic acid (I46) (2.17 g, 7.58 mmol) in dry THF (70 ml), were added N,N′-methanediylidenedicyclohexanamine (1.88 g, 9.10 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (1.23 g, 9.10 mmol), and (R)-quinuclidin-3-ol (1.16 g, 9.10 mmol). The reaction was stirred at RT for 15 hours, and the solvent was evaporated. The residue was taken up with DCM, the insoluble solid was filtered off, and the organic solution was washed twice with aq. Na2CO3 and then brine, dried over Na2SO4 and evaporated. The crude was purified by flash chromatography (EtOAc/MeOH=8/2 to 85/15) to obtain (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)acetate (1.33 g; 44% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Li]CCCC.[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19].O>O1CCCC1>[F:8][C:4]1[CH:3]=[C:2]([CH:18]([C:17]2[CH:20]=[CH:21][CH:22]=[C:15]([F:14])[CH:16]=2)[OH:19])[CH:7]=[CH:6][CH:5]=1
Reactant: Fc1cccc(Br)c1
Reactant: O=Cc1cccc(F)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OC(c1cccc(F)c1)c1cccc(F)c1
Reaction time: 0.33 h
Yield: 80.3 %

Procedure:
To a solution of 1-bromo-3-fluorobenzene (10.0 g, 57.1 mmol) in tetrahydrofuran (100 mL) was added n-BuLi (1.6M, 35.7 mL, 62.8 mmol) at −78° C. and the mixture was stirred at that temperature for 20 minutes. To the mixture was added 3-fluorobenzaldehyde (7.80 g, 62.8 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. To this mixture was added water and the product was extracted with ethyl acetate. The extract was washed with water, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide 10.1 g of bis(3-fluorophenyl]methanol. To a solution of this compound (6.60 g, 3.0 mmol) in diisopropylether (50 mL) was added phosphorus tribromide (5.41 g, 20.0 mmol) with ice-cooling and the mixture was stirred at that temperature for 1 hour. This reaction mixture was diluted with water and extracted with diisopropylether. The organic layer was washed with water and saturated with aqueous sodium hydrogen carbonate solution, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide 5.61 g of the title compound. Yield 53%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[O:16][CH2:15][C:14]3[CH:17]=[C:18]([CH2:21][OH:22])[CH:19]=[CH:20][C:13]=3[CH2:12][O:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[S:32](Cl)([CH3:35])(=[O:34])=[O:33].C(=O)(O)[O-].[Na+]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[O:16][CH2:15][C:14]3[CH:17]=[C:18]([CH2:21][O:22][S:32]([CH3:35])(=[O:34])=[O:33])[CH:19]=[CH:20][C:13]=3[CH2:12][O:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc(C2OCc3ccc(CO)cc3CO2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc2c(c1)COC(c1ccc([N+](=O)[O-])cc1)OC2
Yield: 15.8 %

Procedure:
3 g (10 mmol) of [7-(4-nitrophenyl)-(5H,9H)-6,8-dioxabenzocyclohepten-2-yl]methanol in 50 ml of dichloromethane are introduced into a flask. 1.54 g (12 mmol) of diisopropylethylamine are added and 1.37 g (12 mmol) of mesyl chloride in solution in 10 ml of dichloromethane are added dropwise at −5° C. After 1 hour 30 minutes of reaction at −5° C., 20 ml of a 5% sodium bicarbonate solution are added, the phases are separated by decantation and the organic phase is washed with water. It is dried over sodium sulfate and the solvent is evaporated off. The crude product is purified by silica gel chromatography (heptane/ethyl acetate: 3/2) to give 0.6 g of methanesulfonic acid [7-(4-nitrophenyl)-(5H,9H)-6,8-dioxabenzocyclohepten-2-yl]methyl ester.
Reaction SMILES: C(OC([N:8]1[C:17]2=[CH:18][N:19]([C@@H:21]3[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[C@@H:27]([O:28][C:29](=[O:32])[CH2:30][CH3:31])[C@H:22]3[O:23][C:24](=[O:26])[CH3:25])[N:20]=[C:15]3[C:16]2=[C:10]([C:11](=[O:40])[NH:12][N:13]=[CH:14]3)[C:9]1=[O:41])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:31][CH2:30][C:29]([O:28][C@@H:27]1[C@@H:33]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[O:34][C@@H:21]([N:19]2[CH:18]=[C:17]3[NH:8][C:9](=[O:41])[C:10]4[C:11](=[O:40])[NH:12][N:13]=[CH:14][C:15]([C:16]=43)=[N:20]2)[C@@H:22]1[O:23][C:24](=[O:26])[CH3:25])=[O:32]
Reactant: CCC(=O)O[C@H]1[C@@H](OC(C)=O)[C@H](n2cc3c4c(cn[nH]c(=O)c4c(=O)n3C(=O)OC(C)(C)C)n2)O[C@@H]1COC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)O[C@H]1[C@@H](OC(C)=O)[C@H](n2cc3[nH]c(=O)c4c(=O)[nH]ncc(n2)c34)O[C@@H]1COC(C)=O

Procedure:
The product from Step 7 in DCM is cooled to 0° C., and TFA is added to the vigorously stirred mixture. The mixture is allowed to stir until product is sufficiently deboc'd as determined by TLC. The crude material is concentrated in vacuo and purified by flash chromatography to give the target compound.
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH2:20])=[S:19])=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21](I)[CH3:22].C(=O)(O)[O-].[Na+]>C(#N)C>[C:1]([NH:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][C:18](=[NH:20])[S:19][CH2:21][CH3:22])=[CH:15][CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: NC(=S)Nc1ccc(CNC(=O)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCSC(=N)Nc1ccc(CNC(=O)c2ccccc2)cc1
Yield: 88 %

Procedure:
To a mixture of N-benzoyl-4-thioureidobenzylamine (139.1 mg) and acetonitrile (10 ml), ethyl iodide (0.5 ml) was added and heated under reflux for 3 h. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform:methanol=20:1) to give 134.8 mg of the titled compound (yield, 88%).
Reaction SMILES: [NH2:1][C:2](C(Cl)(Cl)Cl)=[C:3]([C:19]#[N:20])[C:4]([NH:6][C:7]1[N:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([CH3:12])=[N:10][CH:11]=1)=O.[OH2:25].[NH2:26][NH2:27]>CN1C(=O)CCC1>[NH2:20][C:19]1[C:3]([C:4]([NH:6][C:7]2[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]([CH3:12])=[N:10][CH:11]=2)=[O:25])=[C:2]([NH2:1])[NH:27][N:26]=1
Reactant: NN
Reactant: Cc1ncc(NC(=O)C(C#N)=C(N)C(Cl)(Cl)Cl)n1-c1ccccc1
Reactant: O
Solvent: CN1CCCC1=O
Product: Cc1ncc(NC(=O)c2c(N)n[nH]c2N)n1-c1ccccc1
Temperature: 85 °C

Procedure:
To a solution of 3-amino-4,4,4-trichloro-2-cyano-N-(2-methyl-3-phenyl-imidazol-4-yl)but-2-enamide (150 mg, 0.39 mmol) in NMP (1.5 mL) was added hydrazine hydrate (0.032 mL, 1.02 mmol) and the mixture heated to 85° C. for 3 h. The reaction was allowed to cool to RT and concentrated in vacuo to give 3,5-diamino-N-(2-methyl-1-phenyl-1H-imidazol-5-yl)-1H-pyrazole-4-carboxamide as an orange oil. (116 mg, 100%). MS (ES+) 298.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:30]I>C(Cl)Cl.N1C=CN=C1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][I:30])=[CH:4][CH:3]=1
Reactant: II
Reactant: OCCc1ccc(Br)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Brc1ccc(CCI)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
A solution of 2-(4-bromophenyl)ethanol (20.0 g, 100 mol) in CH2Cl2 (10 mL) was added dropwise to a solution of imidazole (22.4 mg, 0.33 mmol), PPh3 (33.3 g, 127 mmol), and I2 (32.5 g, 130 mmol) in CH2Cl2 (50 mL) at 0° C., and the reaction was warmed to room temperature and stirred overnight. The reaction mixture was washed with saturated aqueous sodium thiosulfate (2×50 mL), brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude, which was purified by flash chromatography (silica gel/PE) to yield 1-bromo-4-(2-iodoethyl)benzene (9.2, 22.7 g, 73%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 3.13 (t, J=7.6 Hz, 2H), 3.32 (t, J=7.6 Hz, 2H), 7.07 (d, J=8.0 Hz, 2H), 7.44 (d, J=8.2 Hz, 2H).
Reaction SMILES: [N+](=[CH2:3])=[N-].[O:4]([CH2:11][C:12](Cl)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[ClH:15]>C(OCC)C>[Cl:15][CH2:3][C:12]([CH2:11][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:13]
Reactant: O=C(Cl)COc1ccccc1
Reactant: Cl
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: O=C(CCl)COc1ccccc1
Reaction time: 8 h

Procedure:
To a stirred solution of diazomethane (ca 6 g=0.141 mmol) in ethyl ether (400 ml) was added over 2 hours at 1°-3° phenoxyacetyl chloride (11.95 g=0.07 mole) dissolved in ethyl ether (50 ml). The mixture was stirred at the same temperature for two more hours and was allowed to stand overnight at room temperature. Then 5.5 N hydrochloric acid (25 ml, 0.137 moles) was added with stirring over 110 min. at 16°-20°. After the mixture was stirred for an additional 4 hours, the layers were separated and the ether layer was washed with three 80 ml portions of water and dried over anhydrous sodium sulfate. Removal of the solvent gave the crude product as a yellow oil, 13 g (100%); ir (film, cm-1) 1740, 1595, 1495, 1240; nmr (DCCl3, ppm) 7.40-6.70 (m, 5H), 4.60 (s, 2H), 4.25 (s, 2H). This product was used without purification to prepare phenoxyacetylmethyltriphenylphosphonium chloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:18][C:17](=[O:19])[C:16]4[CH:20]=[C:21](I)[CH:22]=[C:23]([CH3:24])[C:15]=4[N:14]=3)=[CH:11][C:10]([C:26]([F:29])([F:28])[F:27])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cu][C:31]#[N:32]>O1CCCC1.C(OCC)(=O)C.[Cu]I.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>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:18][C:17](=[O:19])[C:16]4[CH:20]=[C:21]([C:31]#[N:32])[CH:22]=[C:23]([CH3:24])[C:15]=4[N:14]=3)=[CH:11][C:10]([C:26]([F:29])([F:28])[F:27])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(I)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: N#C[Cu]
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reaction time: 1 h

Procedure:
To a solution of 2-[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-6-iodo-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the benzoxazinone product of Step D) (500 mg, 0.94 mmol) in tetrahydrofuran (10 mL) was added copper(I) iodide (180 mg, 0.094 mmol), tetrakis(triphenyphosphine)palladium(0) (5.4 mg, 0.047 mmol) and copper(I) cyanide (420 mg, 4.7 mmol) sequentially at room temperature. After heating the reaction mixture at reflux overnight, additional copper(I) cyanide (420 mg, 4.7 mmol), copper(I) iodide (107 mg, 0.56 mmol) and tetrakis(triphenylphosphine)palladium(0) (325 mg, 0.28 mmol) were added and the reflux was continued for 1 hour. The reaction mixture turned black in color, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The reaction mixture was then diluted with ethyl acetate (20 mL) and filtered through Celite®, followed by washing three times with 10% aqueous sodium bicarbonate solution and once with brine. The organic extract was dried (MgSO4) and concentrated under reduced pressure to afford 410 mg of the title compound as a crude yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:25])[C@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[C:12]([CH:20]2[S:24][CH2:23][CH2:22][S:21]2)[CH:11]=1)[NH:5][C:6](=[O:8])[CH3:7].O.[OH-].[Li+].Cl>C1COCC1.O>[S:21]1[CH2:22][CH2:23][S:24][CH:20]1[C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[CH2:16][C:17]([OH:19])=[O:18])[CH2:9][C@@H:4]([C:3]([OH:25])=[O:2])[NH:5][C:6](=[O:8])[CH3:7]
Reactant: COC(=O)[C@H](Cc1ccc(CC(=O)O)c(C2SCCS2)c1)NC(C)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](Cc1ccc(CC(=O)O)c(C2SCCS2)c1)C(=O)O
Reaction time: 0.75 h

Procedure:
To 3-(1,3-dithiolan-2-yl)-4(carboxymethyl)-N-acetyl-L-phenylalanine methyl ester (0.22 g, 0.57 mmol) in THF (10 mL) at 0° C. was added lithium hydroxide monohydrate (0.025 g, 0.60 mmol, 1 mL water). The mixture was stirred for 45 min, diluted with water, made acidic with 1 N HCl, and extracted with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and concentrated to a glassy solid which was homogeneous by RP HPLC (0.18 g, 86%). MS [M−H]− 368.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]([OH:11])=O.[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:16]=[C:17]([CH:21]([NH2:23])[CH3:22])[CH:18]=[CH:19][CH:20]=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]([NH:23][CH:21]([C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][C:13]([F:12])([F:24])[F:25])[CH:16]=1)[CH3:22])=[O:11]
Reactant: O=C(O)C=Cc1ccccn1
Reactant: CC(N)c1cccc(OC(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(NC(=O)C=Cc1ccccn1)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3-(pyridin-2-yl)acrylic acid, Preparation 16 (50 mg) in CH2Cl2 (2 mL) at room temperature were added (±)-1-(3-trifluoromethoxy phenyl)ethylamine, Preparation 15 (76 mg), EDC hydrochloride (129 mg), DMAP (41 mg), and triethylamine (0.2 mL), and the resulting solution was stirred at room temperature for 12 hours. The crude product was purified by silica gel chromatography eluting with ethyl acetate to provide the title compound as the racemate (96 mg). This racemate was separated by HPLC using AD column eluting with hexanes/ethanol (9:1) to give the title compound as an enantiomer of undetermined chirality.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[CH:13]([CH3:17])[C:14]([OH:16])=O)/[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.O>FC(F)(F)S(O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH:8]=[C:9]([C:10]([OH:12])=[O:11])[C:13]([CH3:17])=[C:14]2[OH:16]
Reactant: CC(C(=O)O)/C(=C\c1ccc(F)cc1)C(=O)O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Product: Cc1c(C(=O)O)cc2ccc(F)cc2c1O
Yield: 100 %

Procedure:
A solution of 2-[1-(4-fluoro-phenyl)-meth-(E)-ylidene]-3-methyl succinic acid (28 g, 119 mmol) in trifluoromethanesulfonic acid (140 mL) was stirred at room temperature for 16 h. The resulting mixture was carefully poured into ice cooled water with continuous stirring to obtain a solid precipitate, which was filtered, washed with water and dried in vacuo to yield 6-fluoro-4-hydroxy-3-methyl-naphthalene-2-carboxylic acid (28g, >100% crude) as yellow solid. This crude product was used in the next step without further purification. MS cald. for C12H8FO3 [(M−H)+]: 219, obsd. 218.9.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[N:19]=[C:20]([C:23]6[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=6)[CH:21]=[N:22][C:17]5=[N:16][N:15]=4)[CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].Cl>C1COCC1.CO.O.O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3([C:14]4[N:18]5[N:19]=[C:20]([C:23]6[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=6)[CH:21]=[N:22][C:17]5=[N:16][N:15]=4)[CH2:12][CH2:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Yield: 73.5 %

Procedure:
Methyl 4-[3-(1-quinolin-6-ylcyclopropyl) [1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoate (300 mg, 0.7 mmol) was dissolved in 6 ml of THF-MeOH—H2O (3:1:1). To the solution was added a solution of 2.0 M of lithium hydroxide in water (710 μL) with stirring under N2 atmosphere. The mixture was stirred at RT for 1 h, and then neutralized with aqueous HCl solution (1.0 M, 1.420 mL). The white precipitate formed was collected by filtration, and dried in-vacuo to give the desired product (210 mg, 72%). Analytical LCMS: m/z 409.0 (M+H).
Reaction SMILES: [CH2:1]([OH:5])[C@@H:2]([OH:4])[CH3:3].[H-].[Na+].[CH2:8]([N:12]1[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[S:14]/[C:13]/1=[N:21]\[C:22](=[O:34])[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1F)[CH2:9][CH2:10][CH3:11]>C1COCC1.C([O-])(O)=O.[Na+]>[CH2:8]([N:12]1[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[S:14]/[C:13]/1=[N:21]\[C:22](=[O:34])[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[O:5][CH2:1][C@@H:2]([OH:4])[CH3:3])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)sc2ccncc21
Reactant: C[C@H](O)CO
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2OC[C@H](C)O)sc2ccncc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 18.2 %

Procedure:
(S)-propane-1,2-diol (52 mg, 0.68 mmol) in THF (1 mL) was treated with NaH (60% dispersion; 27 mg, 0.68 mmol) at room temperature for 20 minutes. The mixture was cooled to 0° C. and a solution of Example 18B (90 mg, 0.23 mmol) in THF (1 mL) was added. The mixture was allowed to warm to room temperature, and stirred for 4 hours. The mixture was diluted with saturated aqueous NaHCO3 (20 mL) and extracted with ethyl acetate (2×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford 19 mg (19%) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 1.04 (t, J=7.48 Hz, 3H) 1.28 (d, J=6.41 Hz, 3H) 1.47-1.59 (m, 2H) 1.88-1.98 (m, 2H) 3.87 (t, J=8.85 Hz, 1H) 4.21-4.31 (m, 1H) 4.35 (dd, J=9.15, 2.75 Hz, 1H) 4.51-4.59 (m, 2H) 7.12 (d, J=8.85 Hz, 1H) 7.72 (dd, J=8.54, 2.14 Hz, 2H) 8.51 (d, J=1.83 Hz, 2H) 8.75 (s, 1H); MS (DCI/NH3) m/z 454 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([NH2:15])[CH2:10]2)[C:5]([F:16])=[CH:4][N:3]=1.[C:17]([O:21][C:22]([N:24]=[C:25]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])N1C=CC=N1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:34]([O:33][C:32]([NH:31][C:25](=[N:24][C:22](=[O:23])[O:21][C:17]([CH3:20])([CH3:19])[CH3:18])[NH:15][C@@H:11]1[CH2:12][CH2:13][CH2:14][C@H:9]([NH:8][C:6]2[C:5]([F:16])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:10]1)=[O:38])([CH3:37])([CH3:36])[CH3:35]
Reactant: N[C@@H]1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N[C@@H]1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (1S,3R)—N1-(2-chloro-5-fluoro-pyrimidin-4-yl)cyclohexane-1,3-diamine, 70a, (0.122 g, 0.500 mmol) in CH2Cl2 (10 mL) was added tert-butyl N—(N-tert-butoxycarbonyl-C-pyrazol-1-yl-carbonimidoyl)carbamate (0.155 g, 0.500 mmol). The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated in vacuo and used without further purification: 1H NMR (300 MHz, CDCl3) δ 11.51 (s, 3H), 8.29 (d, J=8.3 Hz, 3H), 7.88 (d, J=2.8 Hz, 3H), 5.01 (d, J=7.4 Hz, 3H), 4.28-4.18 (m, 4H), 2.48 (d, J=11.7 Hz, 3H), 2.12 (d, J=9.4 Hz, 3H), 1.87 (dd, J=10.3, 3.5 Hz, 3H), 1.52 (s, 24H), 1.50 (s, 25H), 1.24-1.10 (m, 8H); LCMS RT=3.97 (M+H) 487.12.