Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:19])=[C:4]([O:8][C:9](=[O:18])[NH:10][CH2:11][C@@H:12]2[CH2:17][C@@H:16]3[C@@H:14]([CH2:15]3)[NH:13]2)[CH:5]=[CH:6][CH:7]=1.ClC1C(F)=C(OC(=O)NC[C@@H]2C[C@@H]3[C@@H](C3)N2C(=O)NC2C3C(=CC=CC=3)N(C(=O)N)C=2)C=CC=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:87]([C:90]1[C:98]2[C:93](=[CH:94][CH:95]=[CH:96][CH:97]=2)[N:92]([CH2:99][C:100](O)=[O:101])[CH:91]=1)(=[O:89])[CH3:88]>C1COCC1>[Cl:1][C:2]1[C:3]([F:19])=[C:4]([O:8][C:9](=[O:18])[NH:10][CH2:11][C@@H:12]2[CH2:17][C@@H:16]3[C@@H:14]([CH2:15]3)[N:13]2[C:100](=[O:101])[CH2:99][N:92]2[C:93]3[C:98](=[CH:97][CH:96]=[CH:95][CH:94]=3)[C:90]([C:87](=[O:89])[CH3:88])=[CH:91]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cn(CC(=O)O)c2ccccc12
Reactant: O=C(NC[C@@H]1C[C@H]2C[C@H]2N1)Oc1cccc(Cl)c1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC(=O)n1cc(NC(=O)N2[C@H](CNC(=O)Oc3cccc(Cl)c3F)C[C@H]3C[C@H]32)c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)c1cn(CC(=O)N2[C@H](CNC(=O)Oc3cccc(Cl)c3F)C[C@H]3C[C@H]32)c2ccccc12
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a solution of [(1R,3S,5R)-1-(2-aza-bicyclo[3.1.0]hex-3-yl)methyl]-carbamic acid 3-chloro-2-fluoro-phenyl ester, trifluoroacetate (prepared as described in Example 115) (60.0 mg, 0.211 mmol) in THF (3 mL) was added HBTU (120 mg, 0.316 mmol), DIPEA (0.147 mL, 0.843 mmol) and (3-acetyl-indol-1-yl)-acetic acid (50 mg, 0.232 mmol). The reaction mixture was stirred at RT for 60 h. Volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, eluent: 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min) to give after lyophilization of the purified HPLC fractions the title compound. MS (LC/MS): 484.0 [M+H]+; tR (HPLC conditions k): 3.69 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1.Cl.CN(C)CCCN=C=NCC.O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(Br)cn1
Reaction time: 15 h
Yield: 58.5 %

Procedure:
In 100 ml of pyridine was dissolved 10.13 g of N-t-butoxycarbonylglycine and the solution was added with 5 g of 2-amino-5-bromopyridine, 13.85 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 7.06 g of 4-dimethylaminopyridine, individually at room temperature. Stirring was conducted for 15 hours at the same temperature. Water was added to the reaction mixture which was then extracted with ethyl acetate. The organic layer thus separated was washed with brine, dehydrated, filtered, and concentrated under vacuum to give 5.58 g of 2-(N-t-butoxycarbonylglycinylamino)-5-bromopyridine. This compound was dissolved, along with 5.82 g of (S)-[N-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide, in 70 ml of dimethylformamide and added with 4.9 ml of triethyl amine and 2.97 g of dichlorobistriphenylphosphine palladium (II) at room temperature. Reaction was performed at 100° C. for 4 hours with stirring. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dehydrated, filtered and concentrated under vacuum. Recrystallization of the concentrate provided 5.13 g of (S)-[N-3-(4-(2-(N-t-butoxycarbonylglycinylaminopyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl)methyl acetamide. This product was reacted with 1.65 ml of trimethylsilyl iodide in chloroform at room temperature for 30 min under a nitrogen atmosphere with stirring. Following the addition of chloroform, the organic layer thus separated was washed with brine, dehydrated, filtered, and concentrated in vacuo. The concentrate was purified through column chromatography to provide the title compound. 550 mg.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([C:15]2[CH:16]=[CH:17][C:12]([C:11]([F:22])([F:21])[F:10])=[CH:13][CH:14]=2)[N:3]=1
Reactant: Cc1cc(Cl)nc(Br)c1
Reactant: OB(O)c1ccc(C(F)(F)F)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: O
Solvent: COCCOC
Product: Cc1cc(Cl)nc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 55 °C
Yield: 67.4 %

Procedure:
To a degassed solution of 2-bromo-6-chloro-4-methyl-pyridine (900 mg, 4.37 mmol), 4-trifluoromethylbenzeneboronic acid (830 mg, 4.37 mmol), 2N Na2CO3 (4 mL) in DME (40 mL) was added tetrakis(triphenylphosphine)palladium (320 mg, 0.3 mmol) under argon. The mixture was heated to 55° C. for 5 h, cooled to room temperature, diluted with water, and extracted with methylene chloride (3×). The organic solution was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (10-25% methylene chloride in heptane) to give the product as an off white solid (800 mg, 68%). 1H NMR (300 MHz, CDCl3) δ 8.09 (d, J=7.91 Hz, 2H), 7.71 (d, J=8.29 Hz, 2H), 7.49 (s, 1H), 7.16 (s, 1H), 2.43 (s, 3H). MS m/e 272.1 (M+H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:9]=[O:10])C.[CH3:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>O>[CH:9]([C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:12]([CH3:11])[CH2:13][CH2:14]2)=[O:10]
Reactant: CN(C)C=O
Reactant: CN1CCc2ccccc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CN1CCc2cc(C=O)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62 %

Procedure:
Phosphorus oxychloride (1.23 g., 0.0080 mole) was slowly added dropwise to 5 ml. of DMF which was cooled in an ice bath. The solution was stirred for 5 minutes and to it there was added dropwise a solution of 1-methylindoline (1.0 g., 0.0075 mole) in 2 ml. of DMF. The resulting mixture was stirred in the ice bath for 5 minutes, then at room temperature for 1 hour and finally at 80° C. for 2 hours. The reaction mixture was cooled to room temperature, slowly poured into water with stirring and extracted with ethyl ether. The crude oil was chromatographed on silica gel with 80/20 (v/v) CH2Cl2 /EtOAc to yield 0.745 g. (62% yield) of 5-formyl-1-methylindoline as a yellow solid, m.p. 39°-41° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(P(CCCC)CCCC)CCC.[CH2:35](O)[CH2:36][CH2:37][OH:38].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[CH:5]=[C:6]([CH:7]=1)[O:8][CH2:35][CH2:36][CH2:37][OH:38]
Reactant: OCCCO
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a solution of 5-methyl-3-(2-nitrophenylsulfonyloxy)phenol (1.1 g, 4.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (1.22 g, 6.0 mmol) and 1,3-propanediol (1.52 g, 20 mmol) in anhydrous tetrahydrofuran (40 mL) was added 1,1'-(azodicarbonyl)dipiperidine (1.51 g, 6.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (60 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (5% ethyl acetate in dichloromethane) to give the title compound as a pale yellow oil (1.05 g, 71%). 1H-NMR (300 MHz, CDCl3) δ 7.99 (d, J=7.7 Hz, 1H), 7.84 (m, 2H), 7.70 (m, 1H), 6.65 (s, 1H), 6.61 (s, 1H), 6.58 (s, 1H), 4.03 (t, J=6.0 Hz, 2H), 3.82 (t, J=5.9 Hz, 2H), 2.27 (s, 3H), 2.00 (t, J=6.0 Hz, 2H), 1.67 (br s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[Cl:31])[CH3:2].[CH3:33][O:34][CH2:35][C:36]#[CH:37]>C(N(CC)CC)C.CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:17]=[C:16]([C:37]#[C:36][CH2:35][O:34][CH3:33])[CH:15]=2)=[CH:9][C:8]=1[Cl:31])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCCCN3CCOCC3)c2)cc1Cl
Reactant: C#CCOC
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc(Sc2cc(C#CCOC)cc(OCCCN3CCOCC3)c2)cc1Cl

Procedure:
{4-[3-Bromo-5-(3-morpholin-4-yl-propoxy)-phenylsulfanyl]-2-chloro-phenoxy}-acetic acid ethyl ester (0.2 g; 0.37 mmol), 3-methoxy-propyne (0.10 g; 1.47 mmol), bis(triphenylphosphine) palladium (II) chloride (21 mg; 0.029 mmol) and copper iodide (4.2 mg; 0.022 mmol) were dissolved in a mixture of triethylamine (2 mL) and DMF (2 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 150° C. for 1 h. The reaction mixture was evaporated to dryness and extracted with ethyl acetate from a aqueous 5% citric acid solution. The crude product was dried, evaporated to dryness and purified by preparative HPLC (method B). Yield: 160 mg. HPLC-MS: m/z: 534.1 (M+); Rt: 1.79 min.
Reaction SMILES: C(OC(=O)C)(=O)C.I([O-])(=O)(=O)=O.[Na+].[I:14]I.S(=O)(=O)(O)O.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1>C(O)(=O)C>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][C:24]=1[I:14]
Reactant: II
Reactant: Cc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc(Br)cc1I
Yield: 197.9 %

Procedure:
2-Methyl-5-bromo-iodobenzene was synthesized according to the method described by Lulinski, P., Skulski, L., Bull. Chem. Soc. Jpn. 2000 73:951-956. To a mixture of acetic acid (100 ml) and acetic anhydride (50 ml), cooled in an ice bath, was added sodium periodate (15.4 g, 72 mmol) and iodine (12.2 g, 48 mmol). While stirring vigorously, concentrated sulfuric acid (21 ml) was added slowly followed by 4-bromotoluene (23.1 g, 135 mmol). After stirring for 2 hours, the ice bath was removed and the mixture was protected from light. After stirring for 16 hours, the mixture was poured into a mixture of 10% aqueous sodium sulfite solution (250 ml) and ice (250 g), and extracted with dichloromethane (3×100 ml). The combined extracts were washed with water (100 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residual oil was purified by distillation (87-92° C., 1 mm) to provide 2-methyl-5-bromo-iodobenzene (28.2 g, 70% yield) as colorless oil. 1H NMR (DMSO-d6) δ 7.99 (s, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 2.33 (s, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8](OS(C(F)(F)F)(=O)=O)=[N:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2.[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[C:8]1[C:7]([N:3]2[CH2:4][CH2:5][CH2:6][C@@H:2]2[CH3:1])=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=2)[N:9]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCC[C@@H]3C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3F)c(N3CCC[C@@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a solution of (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate (150 mg, 0.36 mmol) in dioxane (5 mL) was added 2,4-difluorophenylboronic acid (113 mg, 0.72 mmol), K3PO4 (152 mg, 0.72 mmol), Pd(PPh3)4 (20 mg, 0.02 mmol) and water (3 drops). The resulting solution was stirred for 1 hour at 90° C. and then concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (5% ethyl acetate in petroleum ether) to afford (S)-methyl 2-(2,4-difluorophenyl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate as a yellow solid (115 mg, 84%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].C(O)(=O)C.[CH:22]([C:25]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[C:26]=1[NH2:27])([CH3:24])[CH3:23]>C(O)C>[CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=[N:27][C:26]2[C:28]([CH:32]([CH3:33])[CH3:34])=[CH:29][CH:30]=[CH:31][C:25]=2[CH:22]([CH3:24])[CH3:23])[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: CC1=C(C)C(c2ccccc2C=O)C(C)=C1C
Solvent: CCO
Solvent: CC(=O)O
Product: CC1=C(C)C(c2ccccc2C=Nc2c(C(C)C)cccc2C(C)C)C(C)=C1C
Temperature: 25 °C
Yield: 99.8 %

Procedure:
To a solution of 2-(2,3,4,5-tetramethylcyclopentadienyl)benzaldehyde (10.0 mmol) in ethanol (30.0 mL) were added dropwise acetic acid (1.0 mmol) and 2,6-diisopropylaniline (10.5 mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature. After disappearance of the aldehyde was confirmed by gas chromatography, the solvent was distilled off under reduced pressure to give N-[2-(2,3,4,5-tetramethylcyclopentadienyl)phenylmethylene]-N-(2,6-diisopropylphenyl)amine (3.85 g, yield 100%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[CH:35]=[C:34]([CH3:36])[NH:33][C:32]=2[CH:37]=O)=[O:30])[CH:25]=[CH:24][N:23]=[N:22]1>C(O)C.N1CCCCC1>[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[CH:35]=[C:34]([CH3:36])[NH:33][C:32]=2[CH:37]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=3)[NH:13][C:12]2=[O:18])=[O:30])[CH:25]=[CH:24][N:23]=[N:22]1
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCn2ccnn2)c(C=C2C(=O)Nc3cccc(-c4cccc(C(F)(F)F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.9 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3 carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (61.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (93.6 mg, 74%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>C1COCC1>[CH2:5]([O:4][C:2]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(O)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of benzyl chloroformate (14 ml) in THF (30 ml) was added dropwise over 40 minutes to an ice-cold solution of 4-aminophenol (11 g) in THF (500 ml), the temperature of the reaction mixture being maintained at 0°-5° C. On completion of the addition, the reaction mixture was stirred at ambient temperature for 2 hours and the precipitated solid was collected and crystallised from a mixture of ethyl acetate and hexane to give 4-benzyloxycarbonylaminophenol (11.3 g) as a white solid: m.p. 153°-154° C.; Elemental Analysis: calculated for C14H13NO3 : C, 69.1%; H, 5.4%; N, 5.8%; found: C, 69.3%; H, 5.3%; N, 5.8%.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]45[CH2:25][CH2:24][C:21]([CH2:26][C:27]([O:29]C)=[O:28])([CH2:22][CH2:23]4)[CH2:20][CH2:19]5)=[CH:14][CH:13]=3)[C:8]([CH3:32])([CH3:31])[O:7][C:6]=2[N:5]=[CH:4][N:3]=1.[OH-].[Na+]>CO.C1COCC1>[NH2:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([C:18]45[CH2:23][CH2:22][C:21]([CH2:26][C:27]([OH:29])=[O:28])([CH2:20][CH2:19]4)[CH2:24][CH2:25]5)=[CH:16][CH:17]=3)[C:8]([CH3:32])([CH3:31])[O:7][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: COC(=O)CC12CCC(c3ccc(C4=Nc5c(N)ncnc5OC4(C)C)cc3)(CC1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)Oc2ncnc(N)c2N=C1c1ccc(C23CCC(CC(=O)O)(CC2)CC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl {4-[4-(4-amino-7,7-dimethyl-7H-pyrimido[4,5-b][1,4]oxazin-6-yl)phenyl]bicyclo[2.2.2]oct-1-yl}acetate (122 mg, 0.28 mmol) in MeOH (10 mL) and THF (5 mL) was added 2M NaOH (0.7 mL). The reaction mixture was stirred at ambient temperature overnight then further 2M NaOH (0.7 mL) was added and the reaction mixture heated to 50° C. for 5 hrs. The mixture was allowed to cool, the solvent was removed under reduced pressure and the residue was acidified to pH 2 with 2M HCl and the suspension filtered and dried. The product was purified on a basic reverse phase preparative HPLC system loading in NMP (˜2 mL), water (˜2 mL) and 1-2 drops of 0.88 ammonia, and eluting with 13-40% water (+1% NH3)-MeCN, to provide the title compound as a solid, 40 mg (0.0952 mmol, 34%).
Reaction SMILES: [C:1]1([C:7]2([C:13]#[N:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:15]1[CH2:24][CH:16]1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1>[OH:15][CH:16]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:24][N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:13]#[N:14])[CH2:12][CH2:11]1
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: c1ccc(CC2CO2)cc1
Solvent: C1COCCO1
Product: N#CC1(c2ccccc2)CCN(CC(O)Cc2ccccc2)CC1

Procedure:
A mixture of 4-phenyl-piperidine-4-carbonitrile (6.3 g, 34 mmol) and (2.3-epoxypropyl)benzene (5.0 g, 37 mmol) in dioxane was refluxed for seven days. The solvent was evaporated and the residue was shaken between dilute sodium hydroxide and diethyl ether. The ether extract was dried over potassium carbonate, filtered and the product was converted to the hydrochloride as described in Example 5. Recrystallization from a mixture of ethanol and acetonitrile gave 10.0 g with m.p. 246-249° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=1.[C:11](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(Br)cc1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Br)ccc1C#N
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.1 %

Procedure:
To a solution of 4-bromo-2-hydroxybenzonitrile (2 g, 10 mmol) in DMF (15 mL) and was added iodomethanel (2.87 g, 20.2 mmol) and potassium carbonate (2.79 g, 20.2 mmol) at room temperature. The mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate (10 mL*3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 4-bromo-2-methoxybenzonitrile (2.08 g) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J=8.0 Hz, 1H), 7.10 (dd, J=8.4, 1.6 Hz, 1H), 7.06 (d, J=1.6 Hz, 1H), 3.87 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH3:19])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.F[C:21](F)(F)C(OC(=O)C(F)(F)F)=O.CI>CO>[F:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:6]2[CH:7]=[C:2]([NH:1][CH3:21])[C:3]([C:16]([O:18][CH3:19])=[O:17])=[N:4][CH:5]=2)=[CH:14][CH:13]=1
Reactant: COC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CO
Solvent: CI
Product: CNc1cc(Cc2ccc(F)cc2)cnc1C(=O)OC

Procedure:
This compound was prepared from methyl 3-amino-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate as described in Example 89, Steps 9-10 by reacting with trifluoroacetic anhydride, followed by alkylation with methyl iodide and subsequent deprotection upon heating in the presence of MeOH.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:36][CH3:37])=[C:19]([CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([C:31]([O:33]CC)=[O:32])[CH2:27][CH2:26]4)[CH:20]=[CH:21][CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:36][CH3:37])=[C:19]([CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][CH:28]([C:31]([OH:33])=[O:32])[CH2:29][CH2:30]4)[CH:20]=[CH:21][CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)C1CCN(CCc2cccc(-c3cnc(-c4ccc(OC(C)C)c(Cl)c4)s3)c2CC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCc1c(CCN2CCC(C(=O)O)CC2)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.8 %

Procedure:
To a solution of ethyl 1-{2-[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-4-piperidinecarboxylate (D89) (120 mg) in isopropanol (40 mL) and water (10 mL) stirred under nitrogen at room temperature was added a solution of NaOH (17.7 mg) in water in one charge. The reaction mixture was stirred at room temperature overnight. Isopropanol was removed in vacuo. The residue was dissolved in water and acidified with 1N HCl to pH=5. The solvent was removed in vacuo, the residue was dissolved in THF, and filtered. The filtrate was purified by Mass Directed AutoPrep to give 1-{2-[3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]ethyl}-4-piperidinecarboxylic acid (E40) (18 mg) as a TFA salt (white solid). δH (DMSO-d6, 400 MHz): 1.11 (3H, t), 1.34 (6H, d), 1.76 (2H, m), 2.11 (2H, m), 2.71 (2H, m), 3.07 (4H, m), 3.27 (2H, m), 3.53 (1H, m), 3.67 (2H, m), 4.80 (1H, m), 7.33 (4H, m), 7.82 (1H, s), 7.87 (1H, dd), 7.99 (1H, d), 9.29 (1H, br s), 12.59 (1H, br s). δF (DMSO-d6, 376 MHz): −73.5. MS (ES): C28H33ClN2O3S requires 512. found 513.1 (M+H+).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][NH:27][CH2:26]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][N:27]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:26]2
Reactant: Clc1ccc2c(c1)CNC2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Nc1c(F)c(N2Cc3ccc(Cl)cc3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 69.6 %

Procedure:
268 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 154 mg of 5- chloroisoindoline, 274 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 270 mg of the target compound.