Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[N:30]([CH:33]([CH3:35])[CH3:34])=[C:31]=[O:32]>C(Cl)Cl>[CH:33]([NH:30][C:31]([N:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=1)=[O:32])([CH3:35])[CH3:34]
Reactant: CC(C)N=C=O
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)NC(=O)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (70 mg, 0.252 mmol, example 9 (step 3) and DIEA (44 μL, 0.252 mmol) in DCM (1.6 mL) was added 2-isocyanatopropane (25 μL, 0.252 mmol). The resulting mixture was reacted under the same conditions as described for example 10 to give the title compound as a white solid. MS (ESI, positive ion) m/z: 363 (M+H).
Reaction SMILES: [Mg:1].[CH3:2][C:3]1[CH:4]=[N:5][C:6]([CH2:12][S+:13]([O-:25])[C:14]2[NH:15][C:16]3[CH:17]=[CH:18][C:19]([O:23][CH3:24])=[CH:20][C:21]=3[N:22]=2)=[C:7]([CH3:11])[C:8]=1[O:9][CH3:10]>O>[CH3:2][C:3]1[CH:4]=[N:5][C:6]([CH2:12][S+:13]([O-:25])[C:14]2[N-:15][C:16]3[CH:17]=[CH:18][C:19]([O:23][CH3:24])=[CH:20][C:21]=3[N:22]=2)=[C:7]([CH3:11])[C:8]=1[O:9][CH3:10].[CH3:2][C:3]1[CH:4]=[N:5][C:6]([CH2:12][S+:13]([O-:25])[C:14]2[N-:15][C:16]3[CH:17]=[CH:18][C:19]([O:23][CH3:24])=[CH:20][C:21]=3[N:22]=2)=[C:7]([CH3:11])[C:8]=1[O:9][CH3:10].[Mg+2:1]
Reactant: [Mg]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Solvent: O
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Product: [Mg+2]

Procedure:
One specific variant of this aspect of the invention involves dissolving magnesium at a temperature of 30° C. to 60° C. in a straight or branched lower alkanol (one to four carbons) solvent, adding haloalkane (one to three carbons) solvent, cooling to 0° C. to 15° C., adding esomeprazole base in a straight or branched lower alkanol solvent to generate a reaction mass, decomposing the reaction mass by pouring the mass into water and stirring for one to two hours, filtering out the resulting solid by conventional methods, suspending the solid obtained by filtering in a solvent such as acetone and stirring for one to two hours, filtering out the solid from the suspension by conventional methods (to remove excess magnesium), dissolving the solid resulting from the filtering in a straight or branched lower alkanol solvent and filtering the solution a straight or branched lower alkanol solvent, distilling off the solvent from the filtrate under reduced pressure, suspending the resulting solid in a solvent such as ethyl acetate (to crystallize solid), then either filtering by conventional methods; or adding esomeprazole magnesium in the form of an amorphous solid as seeding material and cooling to a temperature of 0° C. to 20° C. and then filtering by conventional methods, and drying the resulting solid at a temperature of 3° C. to 100° C., preferably 60° C., to obtain a hydrate of esomeprazole magnesium in the form of an amorphous solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:3][CH2:2]1.[Br:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:27])=[C:22]([CH:26]=1)[C:23](Cl)=[O:24].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:27])=[C:22]([CH:26]=1)[C:23]([C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][CH2:3][N:4]([C:11](=[O:16])[C:12]([F:15])([F:13])[F:14])[C:5]=2[CH:10]=1)=[O:24]
Reactant: O=C(Cl)c1cc(Br)ccc1Cl
Reactant: O=C(N1CCOc2ccccc21)C(F)(F)F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)N(C(=O)C(F)(F)F)CCO2)c1cc(Br)ccc1Cl
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To a stirred solution of 1-(2,3-dihydro-benzo[1,4]oxazin-4-yl)-2,2,2-trifluoro-ethanone (6.5 g, 28.1 mmol) in dichloromethane (45 mL) was added 5-bromo-2-chlorobenzoyl chloride (8.54 g, 33.7 mmol) in dichloromethane (35 mL) and AlCl3 (5.61 g, 42.2 mmol) at 0° C. After 2 h, the reaction mixture was brought to room temperature and stirred overnight. The reaction was quenched by pouring over crushed ice and extracted with dichloromethane (2×50 mL). The organic layer was washed with aq. NaHCO3 (30 mL), H2O (20 mL), and the solvent evaporated to get the crude product which was purified by silica gel column chromatography to give 1-[6-(5-bromo-2-chloro-benzoyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-2,2,2-trifluoro-ethanone (10.0 g).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1>C(O)C>[C:1]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:15][CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(CC(=O)O)cc1
Solvent: CCO
Product: O=C(O)Cc1ccc(NC(=O)c2ccccc2)cc1
Yield: 52 %

Procedure:
Prepared analogously to Example 4a) from benzoylchloride and 4-aminobenzene acetic acid in a yield of 52% of theory. Colourless crystals, Mp. 207-208° C. (ethanol).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[C:46]([C:50]1[CH:51]=[C:52]([CH:54]=[CH:55][CH:56]=1)[NH2:53])([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C>[C:46]([C:50]1[CH:51]=[C:52]([NH:53][C:12]([C:3]2[C:2](=[O:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][CH:4]=2)=[O:14])[CH:54]=[CH:55][CH:56]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: O=C(O)c1c[nH]c2ccccc2c1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cccc(NC(=O)c2c[nH]c3ccccc3c2=O)c1
Temperature: 60 °C

Procedure:
A flask charged with 4-oxo-1H-quinoline-3-carboxylic acid (38 mg, 0.20 mmol), HBTU (76 mg, 0.20 mmol), Et3N (61 mg, 84 μL, 0.60 mmol) and DMF (2 mL) was heated at 60° C. for 15 minutes. To the reaction mixture was then added 3-tert-butylaniline (29.98 mg, 0.2009 mmol) and the reaction mixture was stirred at 60° C. for an additional 30 minutes. The reaction mixture was cooled to room temperature, filtered and purified via reverse phase HPLC using 10 to 99% CH3CN in H2O to obtain N-(3-tert-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ 12.94 (s, 1H), 12.45 (s, 1H), 8.89 (s, 1H), 8.34 (dd, J=1.1, 8.2 Hz, 1H), 7.84-7.80 (m, 1H), 7.76-7.71 (m, 2H), 7.62-7.53 (m, 2H), 7.29 (t, J=7.9 Hz, 1H), 7.15-7.12 (m, 1H), 1.31 (s, 9H). LC/MS: m/z 321.5 (M+H)+ at 1.8 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=C(Br)[CH:12]=1)[CH3:9].[CH2:21]([Li])CCC.CCCCCC.[Cl-].[NH4+].[CH3:34][C:35]([CH3:37])=[O:36]>O1CCCC1>[CH3:1][C:2]([CH3:19])([CH3:20])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:12]=[C:34]([C:35]([OH:36])([CH3:21])[CH3:37])[CH:14]=[C:15]([CH3:17])[CH:16]=1)[CH3:9]
Reactant: [Li]CCCC
Reactant: Cc1cc(Br)cc(CN(C)C/C=C/C#CC(C)(C)C)c1
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(CN(C)C/C=C/C#CC(C)(C)C)cc(C(C)(C)O)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 53.8 %

Procedure:
Compound 16 (2.24 g; 6.70 mmol) was dissolved in tetrahydrofuran (25 ml), and the solution was cooled to −78° C. under nitrogen atmosphere. n-butyl lithium in n-hexane (1.56 M: 4.3 ml; 6.70 mmol) was added dropwise to the resultant mixture, and stirred for 15 minutes. Acetone (3 ml) was added dropwise to the mixture, and brought to room temperature over 3 hours, followed by stirring for 1 hour at room temperature. Reaction was stopped by dropwise addition of saturated aqueous ammonium chloride solution, followed by extraction with diethyl ether (50 ml). The organic layer was washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 1.13 g of the target compound (yield: 53.8%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH3:58])[CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:31][N:24]([CH2:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:8]2[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:5]3[CH:4]=[CH:3][C:2]([C:50]4[CH:51]=[CH:46][CH:47]=[C:48]([O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57][CH3:58])[CH:49]=4)=[CH:32][C:6]=3[CH:7]=2)=[O:15])=[CH:18][CH:19]=1)[CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCCOCCOc1cccc(OB([O-])[O-])c1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCOCCOc1cccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) was added toluene/ethanol/water (20/1/1, 13.9 ml) and then were added 3-(propoxyethoxy)phenyl borate (155 mg) and potassium carbonate (176 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was refluxed for 16 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=5/2) and recrystallized from ethanol to give N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-[3-(2-propoxyethoxy)phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 110) (154 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH:24]([C:28]1[CH:32]=[C:31]([NH:33][C:34]([N:36]2[CH2:42][CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[O:35])[O:30][N:29]=1)([CH2:26][CH3:27])[CH3:25]>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[CH:24]([C:28]1[CH:32]=[C:31]([NH:33][C:34]([N:36]2[CH2:42][CH2:41][CH2:40][N:39]([C:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[O:9])[CH2:38][CH2:37]2)=[O:35])[O:30][N:29]=1)([CH2:26][CH3:27])[CH3:25]
Reactant: O=C(O)C1CCOCC1
Reactant: CCC(C)c1cc(NC(=O)N2CCCNCC2)on1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: CCC(C)c1cc(NC(=O)N2CCCN(C(=O)C3CCOCC3)CC2)on1
Reaction time: 8 h
Yield: 36 %

Procedure:
4-Tetrahydropyran-carboxylic acid (66 mg; 0.50 mmol; 1.1 equiv.), HOBt (81 mg; 0.6 mmol; 1.4 equiv.) and EDC (115 mg; 0.6 mmol; 1.4 equiv.) were combined in 2 mL anhydrous DMF. After 15 minutes [1,4]Diazepane-1-carboxylic acid (3-sec-butyl-isoxazol-5-yl)-amide from above (117 mg; 0.44 mmol; 1.0 equiv.) was added, followed by 2 mg of DMAP (catalytic). The mixture was left stirring overnight. Water was added to the reaction mixture and it was extracted with EtOAc. The organic layer was washed with water once then saturated aqueous NaHCO3 solution, saturated aqueous NH4Cl solution, then brine. The organics were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 2.5% MeOH/DCM mixtures as eluent, then switched to 10% MeOH/DCM. Solvents were removed from the enriched fractions and 61 mg of 4-(Tetrahydro-pyran-4-carbonyl)-[1,4]diazepane-1-carboxylic acid (3-sec-butyl-isoxazol-5-yl)-amide was obtained (36% yield) as a light yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([OH:19])[CH2:16][CH:15]2[C:20](=[O:29])[N:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH2:28])[CH3:22])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])C.[Li+].[OH-].Cl>CN(C=O)C>[CH2:23]([N:21]([CH3:22])[C:20]([CH:15]1[CH2:16][CH:17]([OH:19])[CH2:18][CH:14]1[C:12]([NH:11][C:6]1([C:4]([OH:5])=[O:3])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:13])=[O:29])[CH2:24][CH2:25][CH2:26][CH:27]=[CH2:28]
Reactant: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C=CCCCCN(C)C(=O)C1CC(O)CC1C(=O)NC1(C(=O)O)CC1C=C
Temperature: 40 °C
Yield: 89.5 %

Procedure:
Compound 6 (493 mg, 1.21 mmol) was dissolved in DMF (1 ml) and transferred to a 20 ml microwave reaction vessel. Then, aqueous LiOH (2 M, 10.5 ml) and a stirbar were added. The reaction vessel was sealed and the immiscible slurry was shaken vigorously before insertion in the microwave cavity. The reaction was irradiated for 30 min to 130° C. The reaction mixture was cooled to 40° C. and the clear solution acidified to pH 2 with aqueous HCl (1 M, 24 ml) and extracted 3 times with ethyl acetate (20 ml). The pooled organic layers were washed with brine, dried (MgSO4) and filtered. The solvent was evaporated in vacuo to afford compound 7 (410 mg, 90%). LC/MS (Method A): tR=2.46 min, >95%, m/z (ESI+)=379 (MH+).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]([C:6]2[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=2[S:15]([CH3:18])(=[O:17])=[O:16])[C:9](O)=[O:10])=[N:2]1.C1C=CC=CC=1.S(Cl)([Cl:28])=O>N1C=CC=CC=1>[O:1]1[CH2:5][CH2:4][C:3]([C:6]2[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=2[S:15]([CH3:18])(=[O:17])=[O:16])[C:9]([Cl:28])=[O:10])=[N:2]1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1C1=NOCC1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: Cc1c(C(=O)Cl)ccc(S(C)(=O)=O)c1C1=NOCC1

Procedure:
To 2.75 g of 3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoic acid were added 30 ml of benzene, then 1.7 ml of thionyl chloride and a drop of pyridine to heat at reflux for 3 hours. The reaction solution was cooled down. The solvent was distilled out under reduced pressure to give 2.90 g of 3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoyl chloride. Separately 0.93 g of 1-ethyl-5-hydroxypyrazole hydrochloride was dissolved in 20 ml of chloroform, and 1.60 g of triethylamine was added, while cooling with ice. Into the obtained solution was added dropwise 10 ml of a chloroform solution containing 1.90 g of 3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoyl chloride to stir at room temperature for 30 minutes, and 0.76 g of triethylamine and 0.16 g of acetone cyanohydrin were added to further stir overnight. The reaction solution was washed with dilute hydrochloric acid, then with a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled out under reduced pressure. Methanol was added to the residue. The obtained crystals were separated by filtration to give 1.59 g of the title compound as white crystals. m.p. 183~184.5° C.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[S:26][N:25]=[C:24]([CH3:27])[CH:23]=3)[C:19]3[C:28](=[O:38])[N:29](C(OC(C)(C)C)=O)[CH2:30][C:18]=3[C:17]=2[F:39])[CH2:13][CH2:12][O:11][CH2:10]1)=O)(C)(C)C.[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>C(Cl)Cl>[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41].[NH2:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[S:26][N:25]=[C:24]([CH3:27])[CH:23]=3)[C:19]3[C:28](=[O:38])[NH:29][CH2:30][C:18]=3[C:17]=2[F:39])[CH2:13][CH2:12][O:11][CH2:10]1
Reactant: Cc1cc(-c2nc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)N(C(=O)OC(C)(C)C)C3)sn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2nc(N[C@@H]3CCOC[C@@H]3N)c(F)c3c2C(=O)NC3)sn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-7-fluoro-4-(3-methylisothiazol-5-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (5.5 mg, 9.7 μmol) in DCM (2.0 mL) was added TFA (2.0 mL, 26.0 mmol). The reaction mixture was stirred at RT for 1 h, and concentrated in vacuo. The resulting crude material was reconstituted in DMF and purified via preparative HPLC eluting with water (0.05% TFA) and ACN (55-80% gradient, 0.035% TFA). The collected fractions were combined and the ACN was removed via rotary evaporation. The resulting aq solution was neutralized with saturated aq NaHCO3, washed with EtOAc (2×50 mL), dried over anhydrous Na2SO4, filtered, and the organic phase stripped to dryness via rotary evaporation. The residue was recrystallized from THF/hexane to give a TFA salt of the title compound. [M+H] calc'd for C16H18FN5O2S, 364. found, 364.
Reaction SMILES: [Li][N:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1)[C:3]([C:5]([O-:7])=O)=[O:4].N[CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[C:31]([C:38]([F:41])([F:40])[F:39])[CH:30]=2)[CH2:24][CH2:23]1.CC[N:44]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[N:2]([CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[C:31]([C:38]([F:39])([F:40])[F:41])[CH:30]=2)[CH2:24][CH2:23]1)[C:3](=[O:4])[C:5]([NH2:44])=[O:7]
Reactant: NCCOC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reactant: [Li]N(C(=O)C(=O)[O-])c1ccc2ccccc2c1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)C(=O)N(CCOC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.2 %

Procedure:
To a solution of lithio[(naphthalen-2-yl)carbamoyl]formate (172 mg, 0.78 mmol, 1.5 eq) in N,N-dimethylformamide (15 ml) was added N-[4-(2-aminoethoxy)cyclohexyl]-4-nitro-3-(trifluoromethyl) aniline (180 mg, 0.52 mmol), EDAC.HCl (149 mg, 0.78 mmol, 1.5 eq), HOBt (105 mg, 0.78 mmol, 1.5 eq) and triethylamine (157 mg, 1.55 mmol, 3 eq). The resulting solution was stirred for 24 hours at room temperature. The solution was diluted with ethyl acetate (200 ml), washed with water (3×100 ml), and then washed with saturated aqueous sodium chloride (100 ml). The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude material was purified by silica gel chromatography using 1% methanol in dichloromethane to elute. The product-containing fractions were combined and concentrated under vacuum to afford N-(naphthalen-2-yl)-N-[2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethyl]ethanediamide as a yellow solid (48.6 mg, 17%). (ES, m/z) [M+H]+ 545.25; 1H NMR (300 MHz, CDCl3): δ 9.45 (s, 1H), 8.33 (d, J=2.1 Hz, 1H), 8.02 (d, J=9.0 Hz, 1H), 7.80-7.98 (m, 4H), 7.60 (dd, J=2.1 Hz, 8.7 Hz, 1H), 7.40-7.55 (m, 2H), 6.85 (d, J=2.4 Hz, 1H), 6.63 (dd, J=2.4 Hz, 9.0 Hz, 1H), 4.47 (d, J=7.5 Hz, 1H), 3.55-3.70 (m, 4H), 3.30-3.45 (m, 2H), 2.08-2.22 (m, 4H), 1.40-1.53 (m, 2H), 1.20-1.37 (m, 2H).
Reaction SMILES: C(OC(=O)[N:7]([C:17]1[CH:22]=[CH:21][C:20]([CH:23](O)[C:24]2[C:32]3[C:27](=[N:28][CH:29]=[C:30]([CH3:33])[CH:31]=3)[N:26]([Si](C(C)C)(C(C)C)C(C)C)[CH:25]=2)=[C:19]([F:45])[N:18]=1)CC1C=CC(OC)=CC=1)(C)(C)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[F:45][C:19]1[N:18]=[C:17]([NH2:7])[CH:22]=[CH:21][C:20]=1[CH2:23][C:24]1[C:32]2[C:27](=[N:28][CH:29]=[C:30]([CH3:33])[CH:31]=2)[NH:26][CH:25]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(O)c3cn([Si](C(C)C)(C(C)C)C(C)C)c4ncc(C)cc34)c(F)n2)cc1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc2[nH]cc(Cc3ccc(N)nc3F)c2c1
Temperature: 50 °C
Yield: 62.6 %

Procedure:
To {6-fluoro-5-[hydroxy-(5-methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin-2-yl}-(4-methoxy-benzyl)-carbamic acid tert-butyl ester (48, 21 g, 32.4 mmol) in 500 mL of acetonitrile, triethylsilane (51.7 mL, 324 mmol) and trifluoroacetic acid (24.93 mL, 324 mmol) are added. The reaction is stirred at 50° C. for several hours, then concentrated under vacuum, and the residue is taken up in 250 mL of dichloromethane and 250 mL of trifluoroacetic acid is added. The mixture is stirred at reflux for several hours, then concentrated under vacuum. The residue is taken up in ethyl acetate and poured into aqueous potassium carbonate. The organic layer is separated, concentrated under vacuum and purified by silica gel column chromatography, eluting with 0-5% methanol in dichloromethane. Appropriate fractions are combined and the solvents removed under vacuum to provide the desired compound (49, 5.2 g, 20.29 mmol, 62.7% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[NH:13])[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Br[CH2:20][C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23].CC(O)=O>CC(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:20]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:13]=[C:9]2[CH2:10][CH2:11][CH3:12])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCCC(=N)Nc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CCCc1nc(C(=O)OCC)cn1-c1ccc(Cl)cc1
Temperature: 85 °C
Reaction time: 72 h
Yield: 24.6 %

Procedure:
To a solution of N-(4-chlorophenyl)butyrimidamide (compound 3, 3.5 g, 17.80 mmol), NaHCO3 (3.14 g, 37.38 mmol) in i-PrOH was added ethyl bromopyruvate (compound 4, 4.7 mL, 37.38 mmol) under N2. The reaction mixture was stirred at 85° C. for 72 hrs, then added AcOH (15 mL). After 4 hrs, the mixture was concentrated under reduced pressure. The residue was diluted with H2O, and extracted with CH2Cl2. The organic layer was washed with saturated NaHCO3 and 1N-HCl solution, then dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (Biotage Isolera™ FLASH Purification System was used for normal phase column chromatography with EtOAc and hexane) to provide the title compound (1.28 g, 25%) as a brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:11]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#CCc1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1cccc(OCc2ccccc2)c1
Temperature: 90 °C
Yield: 86.6 %

Procedure:
3-Hydroxyphenylacetonitrile (834 mg, 6.26 mmol) was dissolved in DMF (10 ml), and to this solution were successively added benzyl bromide (0.82 ml, 6.89 mmol, 1.1 eq) and anhydrous potassium carbonate (1.30 g, 9.40 mmol, 1.5 eq). The mixture was stirred under heating at 90° C. for 1.5 hours. This reaction mixture was cooled to room temperature, and water (20 ml) was added. The mixture was extracted twice with ethyl acetate (40 ml). The organic layers were combined, washed with saturated brine (80 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane/ethyl acetate=1/1) to give (3-benzyloxyphenyl)acetonitrile (1.21 g, 86.8%).