Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:49]=[CH:48][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:37]=[C:38]([CH2:42][C:43]([O:45]CC)=[O:44])[CH:39]=[CH:40][CH:41]=4)[O:33][C:34]=3[CH3:35])=[C:26]([O:50][CH3:51])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:7]([O:6][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:49]=[CH:48][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:37]=[C:38]([CH2:42][C:43]([OH:45])=[O:44])[CH:39]=[CH:40][CH:41]=4)[O:33][C:34]=3[CH3:35])=[C:26]([O:50][CH3:51])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:15]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)Cc1cccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/P(=O)(OCC)OCC)cc3OC)c(C)o2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccc(CC(=O)O)c3)oc2C)c(OC)c1)OCC
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a mixture of ethyl {3-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (1.87 g), tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (5 mL), and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture were added 1N hydrochloric acid (5 mL) and water, and the precipitated crystals were collected by filtration to give {3-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid as colorless crystals (1.67 g, yield 93%). Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 174-175° C.
Reaction SMILES: O=[C:2]([C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[F:17])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].COC(OC)[N:21]([CH3:23])C.Cl.[C:27]1([NH:33]N)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)C.CCOC(C)=O>[C:27]1([N:33]2[C:2]([C:9]3[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=3[F:17])=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:23]=[N:21]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)cc1F
Reactant: NNc1ccccc1
Reactant: COC(OC)N(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ccccc2)c1-c1cc(F)c(F)cc1F

Procedure:
A solution of ethyl 3-oxo-3-(2,4,5-trifluorophenyl)propanoate (0.326 g, 1.32 mmol) and N,N-dimethyformamide dimethyl acetal in ethanol (5 mL) was heated in a 90° C. oil bath for 3 hours. Upon removal of the volatiles, the residue was dissolved in EtOH (3 mL) and phenylhydrazine hydrochloride salt (191 mg, 1.324 mmol) was added. The mixture was then heated at reflux for 6 hours. The reaction was cooled and diluted with EtOAc and the organic layer was washed with NaHCO3 and brine. The organic phase was dried with Na2SO4, filtered and concentrated to afford the title compound as oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.C[Sn](C)C.C[Sn](C)C.Br[C:25]1[N:30]=[C:29]([C:31]2[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=2[C:33]#[N:34])[CH:28]=[CH:27][CH:26]=1>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:12]([F:15])([F:14])[C:6]1[N:7]=[C:8]2[C:3]([C:2]([C:25]3[N:30]=[C:29]([C:31]4[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=4[C:33]#[N:34])[CH:28]=[CH:27][CH:26]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: N#Cc1ccccc1-c1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Sn](C)C
Solvent: COCCOC
Product: N#Cc1ccccc1-c1cccc(-c2ccnc3nc(C(F)(F)F)ccc23)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 5-Chloro-2-trifluoromethyl[1,8]naphthyridine (200 mg, 0.86 mmol) and hexamethylditin (178 μL, 282 mg, 0.86 mmol) in DME (5 mL) was degassed via three “freeze-thaw” cycles. Tetrakis(triphenylphosphine)palladium(0) (49.7 mg, 0.043 mmol) was added, and the mixture was degassed as before, then was heated under nitrogen at 80° C. overnight. 2-(6-Bromopyridin-2-yl)benzonitrile (126 mg, 0.48 mmol) was added and the mixture was degassed as before, then more tetrakis(triphenylphosphine)palladium(0) (49.7 mg, 0.043 mmol) was added, the mixture was degassed again, then was stirred at 80° C. under nitrogen overnight. Water (25 mL) and dichloromethane (15 mL) were added to the cooled mixture, and the aqueous layer was washed with more dichloromethane (2×15 mL). The combined organic layers were washed with saturated sodium chloride solution (1×25 mL) then were dried over magnesium sulfate and concentrated in vacuo. The residual material was purified by flash chromatography on silica gel, eluting with 10% to 40% ethyl acetate in dichloromethane, affording 2-[6-(7-trifluoromethyl[1,8]naphthyridin-4-yl)pyridin-2-yl]benzonitrile as a colourless solid, which was recrystallised from ethyl acetate/isohexane (44 mg, 24%). δH (400 MHz, CDCl3) 7.52-7.60 (1H, td, J 7.6 and 1.2), 7.71-7.77 (2H, m), 7.82 7.92 (5H, m), 8.12 (1H, t, J 7.8), 9.11 (1H, d, J 8.6), 9.35 (1H, d, J 4.3). m/z (ES+) 377 [MH]+.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[C:10]([C:12](O)([CH3:14])[CH3:13])[N:11]=1)=[O:5].C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)=[C:10]([C:12]([CH3:14])=[CH2:13])[N:11]=1)=[O:5]
Reactant: CC(C)(O)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: C=C(C)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
Into a solution of Compound 68 (22 mg, 0.05 mmol) in 5 mL of toluene was added dropwise of 0.2 mL of TFA. The mixture was heated to reflux for 30 minutes. After cooled down to room temperature, the reaction was concentrated. The residue was purified by column chromatography on silica gel (10-20% EtOAc in hexanes) to give Compound 68a (20 mg, 95%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:13]N1C(=O)CCC1=O>C(#N)C>[Br:13][C:7]1[CH:8]=[C:9]([CH:10]([CH3:12])[CH3:11])[C:2]([OH:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: CC(C)c1cccc(C=O)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)c1cc(Br)cc(C=O)c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 106.4 %

Procedure:
2-hydroxy-3-isopropylbenzaldehyde (20.19 g) was dissolved in acetonitrile (160 mL), and N-bromosuccinimide (17.80 g) was added to the solution at 0° C., and then the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (25.88 g) as a yellow oily substance.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([CH:30]([CH3:32])[CH3:31])[CH2:13][NH:14][C:15]([CH2:17][CH2:18][NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:16].C(N(CC)CC)C>ClCCl>[CH2:22]([O:21][C:20](=[O:29])[NH:19][CH2:18][CH2:17][C:15](=[O:16])[NH:14][CH2:13][C:12](=[O:11])[CH:30]([CH3:32])[CH3:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)C(O)CNC(=O)CCNC(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)CNC(=O)CCNC(=O)OCc1ccccc1
Temperature: -70 °C
Reaction time: 0.1 h

Procedure:
10.81 ml (126.08 mmol) oxalyl chloride are placed in 300 ml dichloromethane, cooled to −70° C. 11.94 ml (168.11 mmol) dimethylsulphoxide are slowly added dropwise. The mixture is stirred for 0.1 hours, then 32.40 g (105.07 mmol) benzyl [2-(2-hydroxy-3-methyl-butylcarbamoyl)-ethyl]-carbamate in 70 ml dichloromethane are added. The mixture is stirred for 1 hour, then 62.48 ml (450.72 mmol) triethylamine are added dropwise. The reaction mixture is stirred for 1.5 hours at −70° C., then slowly allowed to come up to ambient temperature. It is diluted with dichloromethane and washed with 1 molar hydrochloric acid, saturated sodium carbonate solution, water and saturated sodium chloride solution. The organic phase is dried and evaporated to dryness.
Reaction SMILES: C(O[C:4](=[O:23])[CH:5]=[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH3:7])C>C1C(Cl)=CC=C(Cl)C=1.CCCCC>[CH2:16]([O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:6]([CH3:7])[CH:5]=[C:4]2[OH:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)C=C(C)Nc1ccc(OCc2ccccc2)cc1
Solvent: CCCCC
Solvent: Clc1ccc(Cl)cc1
Product: Cc1cc(O)c2cc(OCc3ccccc3)ccc2n1

Procedure:
3-(4-Benzyloxyphenylamino)but-2-enoic acid ethyl ester (3.1 g; see step (i) above) in dichlorobenzene (12 mL) was heated in a microwave at 220° C. for 45 minutes. The reaction mixture was diluted with pentane and the resulting precipitate was filtered, washed with pentane and dried to give 6-benzyloxy-4-hydroxy-2-methyl-quinoline.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([C:9]([CH3:11])=[O:10])=[C:4]([CH3:12])[CH:3]=1.[N+:13]([C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22](=O)[CH3:23])=[CH:18][CH:17]=1)([O-:15])=[O:14].N1CCCC1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:23][C:22]1([CH2:21][O:20][C:19]2[CH:25]=[CH:26][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=2)[CH2:11][C:9](=[O:10])[C:5]2[C:6](=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=2[CH3:12])[O:8]1
Reactant: CC(=O)COc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)c1c(C)cc(C)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: C1CCNC1
Solvent: O
Product: Cc1cc(C)c2c(c1)OC(C)(COc1ccc([N+](=O)[O-])cc1)CC2=O
Yield: 30.6 %

Procedure:
A procedure similar to that described in Preparation 1 was repeated, except that 10 g of 2-hydroxy-4,6-dimethylacetophenone, 12 g of 4-nitrophenoxyacetone, 6 ml of pyrrolidine, 3 g of p-toluenesulfonic acid monohydrate and 200 ml of benzene were reacted, to afford 6.36 g of the title compound, colored a pale yellow and melting at 86°-88.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[N:6]=[C:5]2[C:24]([OH:26])=O.Cl.[CH3:28][O:29][C:30]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[C:36]2[C:31]=1[CH2:32][CH2:33][NH:34][CH2:35]2>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[N:6]=[C:5]2[C:24]([N:34]1[CH2:33][CH2:32][C:31]2[C:36](=[CH:37][C:38]([O:40][CH3:41])=[CH:39][C:30]=2[O:29][CH3:28])[CH2:35]1)=[O:26]
Reactant: COc1cc2c(c(OC)c1)CCNC2
Reactant: COc1cc(-c2nc(C(=O)O)c3cc(F)ccc3n2)cc(OC)c1OC
Agent: Cl
Product: COc1cc2c(c(OC)c1)CCN(C(=O)c1nc(-c3cc(OC)c(OC)c(OC)c3)nc3ccc(F)cc13)C2
Yield: 34.3 %

Procedure:
Reaction of 6-fluoro-2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 5,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 106 (34.3% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.84 and 2.99 (2t, 2H), 3.48 (s, 1H), 3.53 and 4.03 (2t, 2H), 3.69-3.3.81 (m, 6H), 3.86-3.92 (m, 8H), 4.31 and 4.77 (2s, 2H), 6.35-6.50 (m, 2H), 7.66-7.85 (m, 3H), 8.02-8.05 (m, 1H), 8.23-8.28 (m, 1H); MS (ESI) m/z 534 ([M+H]+).
Reaction SMILES: [H-].[Na+].CCO.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:35])[C:14]([NH:16][C:17]2[N:22]=[C:21]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:20]=[C:19]([O:29][CH2:30][C:31](F)(F)F)[N:18]=2)=[O:15])=[CH:9][CH:8]=1.C(O)(=O)C>CN(C=O)C>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:35])[C:14]([NH:16][C:17]2[N:18]=[C:19]([O:29][CH2:30][CH3:31])[CH:20]=[C:21]([O:23][CH2:24][C:25]([F:27])([F:26])[F:28])[N:22]=2)=[O:15])=[CH:9][CH:8]=1
Reactant: CN(C(=O)Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1)c1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOc1cc(OCC(F)(F)F)nc(NC(=O)N(C)c2ccc(Br)cc2)n1
Temperature: 60 °C
Yield: 20.7 %

Procedure:
To a suspension of NaH (320 mg, 8.0 mmol, 60% dispersion in mineral oil) in anhydrous DMF (5 mL) under an N2 atmosphere was added anhydrous EtOH (583 μL, 10 mmol). To this solution was added a solution of N-(4-bromophenyl)-N′-[4,6-bis(2,2,2-trifluoroethoxy)pyrimidin-2-yl]-N-methylurea (1.0 g, 2.0 mmol), prepared in a manner similar to 7, in anhydrous DMF (3 mL). The resulting solution was heated (ca. 60° C.) for 2 h, the heat was removed and the solution cooled to room temperature. The solution was diluted with EtOAc (100 mL) and extracted with 2 N HCl (2×50 mL). The organics were dried over MgSO4, filtered and concentrated to afford a brown oil. The brown oil was eluted through a plug of silica using a mixture of hexane and EtOAc and the resulting organic solution concentrated to afford a yellow oil. The yellow oil was further purified by reverse phase chromatography (HPLC grade acetonitrile and water, both with 0.1% acetic acid) to afford 103 as a yellow tacky oil (186 mg, 41% yield): 1H NMR (CDCl3) δ 7.64 (d, 2H, J=8.8 Hz), 7.24 (d, 2H, J=8.8 Hz), 6.84 (s, 1H), 4.81-4.72 (q, 2H, J=8.5 Hz), 4.33-4.26 (q, 2H J=7.1 Hz), 1.39-1.37 (t, 3H, J=7.1 Hz); ESI/MS 449, 451 (M+H), 447, 449 (M−H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:14])[CH:3]=1.C=O.[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1CCCC[CH2:25]1>C(O)(=O)C.C(O)C>[OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:5][C:4](=[O:14])[C:3]=1[CH2:25][S:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=c1cc(O)cc(-c2ccccc2)o1
Reactant: Sc1ccccc1
Reactant: C1CCNCC1
Agent: C=O
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1oc(-c2ccccc2)cc(O)c1CSc1ccccc1

Procedure:
The title compound was prepared by Method C using 4-hydroxy-6-phenyl-2H-pyran-2-one (1.00 g, 5.31 mmol), ethanol (10 mL), paraformaldehyde (0.175 g, 5.80 mmol), thiophenol (1.40 mL, 13.8 mmol), piperdine (0.5 mL), acetic acid (0.5 mL). m.p. dec. 211° C.; 1H NMR (400 MHz, DMSO-d6) δ3.98 (s, 2 H), 6.73 (s, 1 H), 7.17 (m, 1 H), 7.30 (m, 2 H), 7.37 (m, 2 H), 7.54 (m, 3 H), 7.77 (m, 2 H), 12.05 (bs, 1 H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=5)[N:21]([CH3:29])[N:20]=4)[N:17]=3)[N:12](COCC[Si](C)(C)C)[CH:11]=2)=[O:9])[CH2:3]1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[OH:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=5)[N:21]([CH3:29])[N:20]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:3]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@H]2CC[C@@H](O)C2)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)N[C@H]4CC[C@@H](O)C4)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (cis-3-hydroxy-cyclopentyl)-amide (49 mg, 0.093 mmol) was dissolved in dichloromethane (0.5 ml) and trifluoroacetic acid (0.3 ml, 3.8 mmol) was added. The orange reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (0.5 ml) and ethylenediamine (0.4 ml, 5.7 mmol) was added. The light yellow solution was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting precipitate was filtered, washed with hot water and ethyl acetate and dried under high vacuum to provide 29 mg (75%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (cis-3-hydroxy-cyclopentyl)-amide as an off-white powder. MS: (M+H)+=395; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.42 (br. s., 1H), 9.11 (s, 1H), 8.59 (dd, J=9.1, 5.3 Hz, 1H), 8.42 (s, 1H), 8.20 (d, J=8.3 Hz, 1H), 7.68 (dd, J=9.6, 2.1 Hz, 1H), 7.24 (td, J=9.2, 2.1 Hz, 1H), 4.78 (br. s., 1H), 4.36-4.52 (m, 1H), 4.22 (br. s., 1H), 4.15 (s, 3H), 2.30 (ddd, J=13.7, 8.2, 5.7 Hz, 1H), 2.04-2.19 (m, 1H), 1.67-1.86 (m, 3H), 1.49-1.63 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[C:16]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[C:11]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:10]=2[O:33][CH3:34])=[O:7])=[CH:4][C:3]=1[F:37].O.[F:39][C:40]([F:44])([F:43])[CH:41]=O.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.O.CCOC(C)=O>[CH2:22]([O:21][C:16]1[C:15]([C:13]2[CH:12]=[C:11]([C:29]([CH3:31])([CH3:32])[CH3:30])[C:10]([O:33][CH3:34])=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:35]=[CH:36][C:2]([NH:1][CH2:41][C:40]([F:44])([F:43])[F:39])=[C:3]([F:37])[CH:4]=3)[CH:14]=2)=[CH:20][CH:19]=[CH:18][N:17]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=CC(F)(F)F
Reactant: COc1c(NC(=O)c2ccc(N)c(F)c2)cc(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(NC(=O)c2ccc(NCC(F)(F)F)c(F)c2)cc(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38.1 %

Procedure:
step 3—To a solution of 318 (201 mg, 0.402 mmol) in TFA (4 mL) at RT was added trifluoroacetaldehyde hydrate (98 mg, 0.845 mmol) and H2O (2 drops). The reaction mixture was stirred at RT for 5 min, and then sodium cyanoborohydride (33 mg, 0.523 mmol) was added. Gas evolution was briefly observed. The reaction mixture was stirred at RT for 4.5 h, then diluted with H2O and EtOAc and carefully poured into sat'd NaHCO3. The layers were separated, and the organic phase was subsequently twice washed sequentially with sat'd. NaHCO3, H2O and brine. The organic layer was dried (MgSO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography, eluting with an EtOAc/hexane gradient (0% to 30% EtOAc) to afford 89 mg (38%) of N-[5-(2-benzyloxy-pyridin-3-yl)-3-tert-butyl-2-methoxy-phenyl]-3-fluoro-4-(2,2,2-trifluoro-ethylamino)-benzamide (320) as a foamy, light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:27](=O)[CH3:28].[C:30](O[BH3-])(=O)[CH3:31].[Na+]>CO.C(O)(=O)C.C(=O)([O-])O.[Na+]>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[NH:11][C:9]1[N:8]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:7]2[C:2]([N:1]([CH2:27][CH3:28])[CH2:30][CH3:31])=[CH:3][CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: [BH3-]OC(C)=O
Reactant: CC=O
Reactant: CCOC(=O)CCn1c(Nc2ccc(Cl)cc2Cl)nc2cccc(N)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CCn1c(Nc2ccc(Cl)cc2Cl)nc2cccc(N(CC)CC)c21
Yield: 104.2 %

Procedure:
To a solution of ethyl 3-{7-amino-2-[(2,4-dichlorophenyl)amino]-1H-benzimidazol-1-yl}propanoate (Reference Example 27; 214 mg, 0.544 mmol) in methanol (5.5 mL) and acetic acid (0.110 mL) was added acetaldehyde (0.204 mL, 3.27 mmol) at 0° C. The resultant mixture was stirred at 0° C. for 30 min. To the reaction mixture was added sodium acetoxyborohydride (692 mg, 3.27 mmol) at 0° C. After the resultant mixture was stirred at room temperature for 12 hr, the mixture was diluted with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on NH-silica gel eluting with ethyl acetate to give the title compound as a solid (255 mg, 0.567 mmol, quant).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]([NH:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]1)=O)([CH3:4])([CH3:3])[CH3:2].[H-].COCCO[Al+]OCCOC.[Na+].[H-].C1(C)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:9][NH:11][CH2:12][CH:13]1[CH2:14][CH2:15][N:16]([CH:19]([CH3:20])[CH3:21])[CH2:17][CH2:18]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)N1CCC(CNC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccccc2)CC1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)N1CCC(CNC[C@H](NC(=O)OC(C)(C)C)c2ccccc2)CC1
Temperature: 0 °C

Procedure:
To a solution of N-[(R)-2-[(1-isopropylpiperidin-4-yl-methyl) amino]-1-phenyl-2-oxoethyl]carbamic acid tert-butyl ester (1.0 g, 2.6 mmol) in 15 mL of THF was added 65 wt % sodium bis(2-methoxyethoxy)aluminum hydride in toluene (2.4 mL, 7.7 mmol). The reaction mixture was heated at reflux for 3 h after which time the mixture was cooled to 0° C. and the reaction was quenched by the slow addition of a saturated solution of Rochelle's salt. The product was extracted into EtOAc; and the combined extracts were dried over sodium sulfate, filtered, and concentrated to afford, after purification (SiO2: 0 to 30% isopropylamine in 1:1 hexane:EtOAc), 0.9 g (94%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3]OS(C(F)(F)F)(=O)=O.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C(C)=CC=CC=1>[CH2:14]([NH:21][CH2:3][C:2]([F:13])([F:12])[F:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1C
Product: FC(F)(F)CNCc1ccccc1

Procedure:
2.2 g (9.4 mmol) 2,2,2-trifluoroethyltrifluoromethanesulphonate were added to 2.0 g (18.7 mmol) benzylamine in 50 mL xylene and the reaction mixture was refluxed overnight. After cooling the precipitate formed was suction filtered, washed with DIPE and the filtrate was evaporated down using the rotary evaporator. The residue was purified by flash chromatography. The product fractions were combined and evaporated down i.vac.
Reaction SMILES: [OH:1][C:2]1[C@@:6]([CH3:13])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:5][C:4](=[O:14])[CH:3]=1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=2)[NH:26][CH:25]=1>>[CH3:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=2)[NH:26][C:25]=1[CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]1[C:4](=[O:14])[NH:5][C@:6]([CH3:13])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]=1[OH:1]
Reactant: C[C@]1(c2ccccc2)NC(=O)C=C1O
Reactant: Cc1ccc2[nH]cc(C)c2c1
Reactant: O=Cc1ccccc1
Product: Cc1ccc2[nH]c(C(C3=C(O)[C@@](C)(c4ccccc4)NC3=O)c3ccccc3)c(C)c2c1

Procedure:
Using general procedure D, (R)-4-hydroxy-5-methyl-5-phenyl-1,5-dihydro-pyrrol-2-one (prepared according to Lit. 11, see also Lit. 19) was reacted with benzaldehyde and 3,5-dimethyl-1H-indole (Lit. 21) to give the title compound as a yellow foam. MS: 423.3 ([M+H]+).
Reaction SMILES: [CH:1]1([NH:8][C:9]2[N:14]3[N:15]=[C:16]([NH2:18])[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:19]1[CH2:24][CH2:23][CH:22]([C:25](Cl)=[O:26])[CH2:21][CH2:20]1>>[CH:1]1([NH:8][C:9]2[N:14]3[N:15]=[C:16]([NH:18][C:25]([CH:22]4[CH2:23][CH2:24][O:19][CH2:20][CH2:21]4)=[O:26])[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(Cl)C1CCOCC1
Reactant: Nc1nc2cccc(NC3CCCCCC3)n2n1
Product: O=C(Nc1nc2cccc(NC3CCCCCC3)n2n1)C1CCOCC1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from N5-cycloheptyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine ((A10), 50 mg; 0.20 mmol; 1.0 eq.) and tetrahydro-2H-pyran-4-carbonyl chloride (45 mg; 0.30 mmol; 1.5 eq.) as a white solid (33 mg, 46%). HPLC, Rt: 3.02 min. (purity 96.9%). LC/MS, M+(ESI): 358.0, M−(ESI): 356.0.