Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH:10]([C@@H:13]1[CH2:17][O:16][C:15](=[O:18])[N:14]1[C:19]1[CH:20]=[C:21]([CH:25]2[C:34]([CH3:36])([CH3:35])[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:37](O)=[O:38])[CH:31]=3)[NH:26]2)[CH:22]=[CH:23][CH:24]=1)([CH3:12])[CH3:11].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH:10]([C@@H:13]1[CH2:17][O:16][C:15](=[O:18])[N:14]1[C:19]1[CH:20]=[C:21]([CH:25]2[C:34]([CH3:36])([CH3:35])[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:37]([NH:9][S:6]([CH:3]4[CH2:5][CH2:4]4)(=[O:8])=[O:7])=[O:38])[CH:31]=3)[NH:26]2)[CH:22]=[CH:23][CH:24]=1)([CH3:12])[CH3:11]
Reactant: CC(C)[C@@H]1COC(=O)N1c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[C@@H]1COC(=O)N1c1cccc(C2Nc3ccc(C(=O)NS(=O)(=O)C4CC4)cc3CC2(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
To a suspension of 60% sodium hydride (290 mg, 7.3 mmol) in N,N-dimethylformamide (2.5 mL) was added cyclopropanesulfonamide (895 mg, 7.4 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-[3-((R)-4-isopropyl-2-oxo-oxazolidin-3-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (300 mg, 0.74 mmol) and 1,1′-carbonyldiimidazole (300 mg, 1.84 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid {2-[3-((R)4-isopropyl-2-oxo-oxazolidin-3-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-amide (75 mg, 20%) as a white solid: LC/MS m/e calcd for C27H33N3O5S (M+H)+: 512.65, observed: 512.1.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)(=[O:4])=[O:3].[H-].[Na+].[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]([CH2:32][CH:33]([CH3:35])[CH3:34])[S:22]([C:25]2[C:26](Cl)=[N:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])=[CH:17][CH:16]=1.C([O-])(O)=O.[Na+]>C1COCC1.O>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]([CH2:32][CH:33]([CH3:35])[CH3:34])[S:22]([C:25]2[CH:26]=[N:27][C:28]([O:11][CH:8]3[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][CH2:9]3)=[CH:29][CH:30]=2)(=[O:24])=[O:23])=[CH:19][CH:20]=1
Reactant: CS(=O)(=O)N1CCC(O)CC1
Reactant: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1cccnc1Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(OC2CCN(S(C)(=O)=O)CC2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.3 %

Procedure:
To a solution of 1-methanesulfonyl-piperidin-4-ol (86 mg, 482 μmol) in anhydrous THF (5 mL) at room temperature was added NaH (60% dispersion in mineral oil, 21 mg, 526 μmol) and the reaction was stirred at room temperature for 15 minutes. Chloro-pyridine-3-sulfonic acid (4-fluoro-phenyl)-isobutyl-amide (150 mg, 439 μmol) was added and the reaction stirred at room temperature for 45 minutes then heated at 80° C. for 2 hours. Water and saturated NaHCO3 were added and then extracted with EtOAc, washed with brine, dried with Na2SO4 then concentrated and purified by silica gel column chromatography (0-25% EtOAc in cyclohexane) to give the title compound (137 mg). 1H NMR (400 MHz, DMSO): δ 8.30 (dd, J=2.6, 0.67 Hz, 1H), 7.75 (dd, J=8.8, 2.60 Hz, 1H), 7.19-7.20 (m, 4H), 6.97 (dd, J=8.8, 0.7 Hz, 1H), 5.23-5.25 (m, 1H), 3.39 (d, J=8.8 Hz, 4H), 3.13 (ddd, J=12.2, 8.56, 3.46 Hz, 2H), 2.91 (s, 3H), 2.04-2.09 (m, 2H), 1.78-1.80 (m, 2H), 1.44 (dd, J=13.6, 6.9 Hz, 1H), 0.85 (d, J=6.6 Hz, 6H). LCMS (m/z, Method B) ES+ 485.9 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C>[CH2:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(CC(=O)c2ccc(O)cc2)cc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CC(=O)c2ccc(OCc3ccccc3)cc2)cc1
Reaction time: 2 h
Yield: 30.1 %

Procedure:
To a 0° C. solution of 1-(4-hydroxyphenyl)-2-(4-methoxyphenyl)ethanone (3.0 g, 0.01 mol) in acetonitrile (60 mL) under an inert atmosphere was added potassium carbonate (3.4 g, 0.02 mol) followed by benzyl chloride (1.8 mL, 0.014 mol). The reaction mixture was brought to 80° C. and stirred for 2 h. The reaction was quenched with cold water, filtered and the filtrate was extracted with DCM (2×100 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford 1-(4-(benzyloxy)phenyl)-2-(4-methoxyphenyl)ethanone (1.0 g, 24%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][NH:10][CH:11]([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][C:17]1=[O:26].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(#N)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][N:10]([C:16]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][C:17]1=[O:26])[CH:11]([CH3:12])[CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)NCCNC(=O)OC(C)(C)C
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)N(CCNC(=O)OC(C)(C)C)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
A mixture of (2-Isopropylamino-ethyl)-carbamic acid tert-butyl ester (100 mg, 0.5 mmol), rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (185 mg, 0.5 mmol) and K2CO3 (138 mg, 1 mmol) in DCM (1 mL) and acetonitrile (2 mL) was stirred at room temperature overnight. The mixture was concentrated and purified by column chromatography to give 180 mg rac-(2-{[6-Chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-isopropyl-amino}-ethyl)-carbamic acid tert-butyl ester. MS: [M+H]+=492
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][NH2:14]>>[CH3:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:14][CH3:13])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: CN
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Product: CNCc1ccc(S(C)(=O)=O)cc1

Procedure:
(4-Methanesulfonyl-benzyl)-methyl-amine was synthesized starting from 1-bromomethyl-4-methanesulfonylbenzene and methylamine in a manner known to the skilled worker.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]1[CH:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH3:28])[CH:22]=2)[CH:17]=[CH:16][N:15]=1.N1C=CC=CC=1.Cl[C:36]([C:38]1[CH:39]=[C:40]([CH:49]=[CH:50][CH:51]=1)[CH2:41][S:42][CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])=[O:37]>O1CCCC1>[CH3:28][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:3]3[CH:4]=[C:5]([N:8]4[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]4)[CH:6]=[CH:7][C:2]=3[NH:1][C:36]([C:38]3[CH:39]=[C:40]([CH:49]=[CH:50][CH:51]=3)[CH2:41][S:42][CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])=[O:37])[CH:19]=2)[CH:26]=[CH:25][C:24]=1[CH3:27]
Reactant: COC(=O)CCSCc1cccc(C(=O)Cl)c1
Reactant: Cc1ccc(Nc2ccnc(-c3cc(N4CCCCC4)ccc3N)c2)cc1C
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(Nc3ccc(C)c(C)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Into a 50-mL 3-necked round bottom flask, was placed a solution of 2-(2-amino-5-(piperidin-1-yl)phenyl)-N-(3,4-dimethylphenyl)pyridin-4-amine (270 mg, 0.72 mmol, 1.00 equiv) in tetrahydrofuran (10 mL), pyridine (170 mg, 2.15 mmol, 2.97 equiv), and methyl 3-(3-(chlorocarbonyl)benzylthio)propanoate (197.6 mg, 0.72 mmol, 1.00 equiv). The resulting solution was stirred for 1.5 h at room temperature. This reaction was used directly in next step without workup.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])(OCC)=O)C.[CH2:20]([C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[C:24]([O:36]COC)=[C:25]([O:34][CH3:35])[CH:26]=[C:27]2[CH:32]=O)[CH3:21].O>CN(C)C=O>[CH2:20]([C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[C:24]([OH:36])=[C:25]([O:34][CH3:35])[CH:26]=[C:27]2/[CH:32]=[CH:11]/[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:13])[CH3:21]
Reactant: CCc1cccc2c(C=O)cc(OC)c(OCOC)c12
Reactant: CCOP(=O)(CC(=O)N1CCCCC1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cccc2c(/C=C/C(=O)N3CCCCC3)cc(OC)c(O)c12
Reaction time: 0.17 h
Yield: 111.1 %

Procedure:
0.15 g of 60% sodium hydride was suspended in 20 ml of N,N-dimethylformamide, to which 1.15 g of N-(diethoxyphosphoryl)acetylpiperidine was gradually added at room temperature. After stirring for 10 minutes, a solution of 800 mg of 5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthalenecarbaldehyde in N,N-dimethylformamide (10 ml) was gradually added. After stirring for 20 minutes, water was added, followed by extraction with ethyl acetate. The combined extracts were washed with water and dried over anhydrous magnesium sulfate. After removal of the solvent, the resultant residue was purified by silica gel column chromatography (30% ethyl acetate/hexane) to obtain 1.1 g of the titled compound as pale yellow crystals.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@H:15]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23](=[O:37])[NH:24][CH2:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32]([NH2:36])=[N:31][CH:30]=[CH:29]2)=[O:17])(C)(C)C>ClCCl>[NH2:36][C:32]1[C:33]2[C:28](=[CH:27][C:26]([CH2:25][NH:24][C:23]([C@@H:19]3[CH2:20][CH2:21][CH2:22][N:18]3[C:16](=[O:17])[C@H:15]([NH2:14])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:37])=[CH:35][CH:34]=2)[CH:29]=[CH:30][N:31]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccc2cc(CNC(=O)[C@@H]3CCCN3C(=O)[C@H](N)c3ccccc3)ccc12
Reaction time: 2 h
Yield: 62.4 %

Procedure:
Trifluoroacetic acid (3.0 mL) was added to 150 mg of (2-{2(S)-[(1-amino-isoquinolin-6-ylmethyl)-carbamoyl]-pyrrolidin-1-yl}-2-oxo-1(R)-phenyl-ethyl)-carbamic acid tert-butyl ester (prepared according to the procedures described in example 110) in 3.0 mL dichloromethane. Stirring was continued for 2 h at ambient temperature. The solvent was removed i.vac, the residue was dissolved in methanol and applied to a reversed-phase chromatography column (lenght 100 mm, diameter 14 mm; Merck Lichroprep RP-18, 15-25μ). Elution was started with 25 mL of methanol/water containing 0.3% acetic acid (10:90), then a linear gradient to pure methanol over a period of 75 mL was applied followed by 50 mL of pure methanol. Fractions of 5 mL each were sampled, The solvent was removed to give 75 mg (62%) of the title compound. MS: 404.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([N:10]1[C:14]([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)=[CH:13][C:12]([CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)=[N:11]1)([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl.C(=O)([O-])O.[Na+]>[C:6]([N:10]1[C:14]([NH:15][C:16](=[O:29])[C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][N:26]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:25][CH2:24]3)=[CH:21][CH:22]=2)=[CH:13][C:12]([CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)=[N:11]1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc(CCc2cc(NC(=O)c3ccc(N4CCNCC4)cc3)n(C(C)(C)C)n2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(CCc2cc(NC(=O)c3ccc(N4CCN(S(C)(=O)=O)CC4)cc3)n(C(C)(C)C)n2)c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
Methanesulphonyl chloride (0.042 mL, 0.55 mmol) was added at 0° C. to a solution of N-(1-tert-butyl-3-(3-methoxyphenethyl)-1H-pyrazol-5-yl)-4-(piperazin-1-yl)benzamide (0.231 g, 0.5 mmol) and N,N-diethylethanamine (0.077 mL, 0.55 mmol) in DCM (4 mL). The resulting solution was stirred at 20° C. for 1 h. The reaction mixture was diluted with saturated sodium hydrogen carbonate (10 ml) filtered and the solid washed with DCM (2×10 ml). The organic layers were combined and washed with water (20 ml) and saturated brine (20 ml). The organics were dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by silica column chromatography, eluting with a gradient of 0-5% MeOH in DCM. Pure fractions were evaporated to dryness to afford N-(1-tert-butyl-3-(3-methoxyphenethyl)-1H-pyrazol-5-yl)-4-(4-(methylsulfonyl)piperazin-1-yl)benzamide (0.255 g, 94%) as a white solid. MS: m/z=540 (MH+).
Reaction SMILES: C1(S([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][CH3:20])[C:13]=3[C:12](I)=[CH:11]2)(=O)=O)C=CC=CC=1.C(OC(=O)[N:28]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[Cl:45])[C:29]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[C:31]([F:37])[N:30]=1)(C)(C)C>>[Cl:45][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[CH2:38][NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:12]2[C:13]3[C:18]([O:19][CH3:20])=[N:17][CH:16]=[N:15][C:14]=3[NH:10][CH:11]=2)=[C:31]([F:37])[N:30]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1Cl)c1ccc(C=O)c(F)n1
Reactant: COc1ncnc2c1c(I)cn2S(=O)(=O)c1ccccc1
Product: COc1ncnc2[nH]cc(Cc3ccc(NCc4ccccc4Cl)nc3F)c12

Procedure:
(2-Chloro-benzyl)-[6-fluoro-5-(4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-amine P-0090 was prepared in three steps from 7-benzenesulfonyl-5-iodo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine 42 and (2-chloro-benzyl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester 19 as shown in Scheme 9.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.Cl.CCN(C(C)C)C(C)C.[C:42]([Cl:45])(=[O:44])[CH3:43]>CN1C(=O)CCC1>[C:42]([N:25]1[CH2:26][CH2:27][CH:22]([C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:8]3[CH:7]=[C:6]([NH:5][CH2:4][C:3]4[CH:28]=[CH:29][CH:30]=[CH:31][C:2]=4[F:1])[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:21][CH:20]=2)[CH2:23][CH2:24]1)(=[O:44])[CH3:43].[ClH:45]
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1ccccc1F
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCC(c2ccc(Nc3cc(NCc4ccccc4F)c(C(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Compound 4-(2-fluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 106) HCl salt (100 mg, 0.2 mmol) was stirred in 5 mL NMP. To the solution were added DIEA (0.18 mL, 1.0 mmol) and acetyl chloride (0.022 mL, 0.3 mmol). The mixture was stirred at RT for 15 min and quenched with Me2NH. The mixture was concentrated in vacuo and subjected to reverse phase prep HPLC to isolate the title compound as HCl salt. UV=259 nm. M+H found for C26H28FN5O2: 462.5. NMR (CD3OD): 8.12 (1H, s), 7.37 (1H, m), 7.34 (2H, d, J=8.4 Hz), 7.28 (1H, m), 7.18 (1H, m), 7.15-7.10 (3H, m), 5.88 (1H, s), 4.69 (1H, m), 4.51 (2H, s), 4.06 (1H, m), 3.24 (1H, m), 2.89 (1H, m), 2.73 (1H, m), 2.15 (3H, s), 1.92 (2H, m), 1.66 (2H, m) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1.Cl.[CH3:13][NH:14][O:15][CH3:16].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C=O)C.ON1C2N=CC=CC=2N=N1>[CH3:13][N:14]([O:15][CH3:16])[C:7]([C:6]1[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=1)=[O:9]
Reactant: CNOC
Reactant: COc1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N(C)OC)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.6 %

Procedure:
A mixture of 6-methoxynicotinic acid (0.784 g) in DMF (10 ml) was stirred with N,O-dimethylhydroxylamine hydrochloride (0.5 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.16 g) and 1-hydroxy-7-azabenzotriazole (50 mg). Triethylamine (1.67 ml) was added and the reaction mixture was stirred at room temperature for 18 h. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was separated using a hydrophobic filter tube and the solvent was evaporated to give the title compound as a colourless oil (0.86 g).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:29]=1)[C:18]1[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([O:20][C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[C:23]#[N:24])=[CH:9][CH:10]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.C1COCC1.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=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>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:29]=1)[C:18]1[CH:17]=[C:16]([C:32]3[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=3)[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([O:20][C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[C:23]#[N:24])=[CH:9][CH:10]=1
Reactant: OB(O)c1cccnc1
Reactant: N#Cc1ccccc1Oc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(Br)ccc1O2
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: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1Oc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Temperature: 100 °C

Procedure:
A vial was charged with (R)-2-(2-amino-2′-bromo-5H-spiro[oxazole-4,9′-xanthene]-7′-yloxy)benzonitrile (75 mg, 0.167 mmol), pyridin-3-ylboronic acid (51.4 mg, 0.418 mmol), tetrakis(triphenylphosphine)palladium(0) (9.67 mg, 8.37 μmol), THF (837 μL), and potassium carbonate (418 μL, 0.837 mmol) (as a 2.0 M aq. solution). The vial was sealed and heated to 100° C. in a shaker overnight. The mixture was diluted with EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc (2×). The combined organic extracts were evaporated, and the residue was chromatographed on a 25-g SNAP column, eluting with 0-80% of a 90:10:1 mix of DCM/MeOH/NH4OH in DCM to give (S)-2-(2-amino-2′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yloxy)benzonitrile as a pale-yellow solid.
Reaction SMILES: [CH2:1]([N:9]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]1=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:16]([NH2:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(N(CC)CC)C>C(#N)C>[CH2:1]([N:9]1[C:10](=[O:15])[CH2:11][CH:12]([NH:24][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:13]1=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN1C(=O)C=CC1=O
Reactant: CCCCCCCCN
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCNC1CC(=O)N(CCCCCCCC)C1=O

Procedure:
A mixture of N-octyl maleimide (0.01 M) prepared as described in Example 10 above, octylamine (0.01 M), triethylamine [catalytic, 0.1 equivalent] in acetonitrile (25 ml) was stirred for 24 hours at room temperature. Acetonitrile was removed under vacuum to leave a residual liquid product which was flash chromatographed (25% ethyl acetate in petroleum ether) to yield a white solid as the desired product.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1.[H-].[Na+].CI.[C:38](=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:38][O:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1
Reactant: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1[C@@H]1CCCC[C@H]1O
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CO[C@@H]1CCCC[C@H]1n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(±)-2-(trans-2-Hydroxycyclohexyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 508, 73 mg, 0.17 mmol) was dissolved in degassed N,N-dimethylformamide (3 mL), cooled to 0° C. and treated with sodium hydride (10 mg, 0.25 mmol, 1.5 equiv). After stirring for 15 minutes, the mixture was warmed to ambient temperature, stirred for 15 minutes and cooled to 0° C. The mixture was treated with methyl iodide (0.026 mL, 0.41 mmol, 2.5 equiv) and stirred at 0° C. for 1 hour. The mixture was treated with sodium bicarbonate (1.5 mL, aqueous saturated) and then poured into sodium bicarbonate (25 mL, aqueous saturated). The aqueous layer was extracted with ethyl acetate (2×100 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The mixture was purified by silica gel gradient chromatography (100:0 to 90:10; dichloromethane:methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.40-8.37 (1H, m), 7.89 (1H, d, J=2.4 Hz), 7.72-7.68 (3H, m), 7.46-7.42 (2H, m), 7.40-736 (1H, m), 7.28 (2H, d, J=8.9 Hz), 6.46 (1H, m), 5.44 (2H, s), 4.39 (1H, td, J=10.2, 5.5 Hz), 3.83-3.77 (1H, m), 3.22 (3H, s), 2.27-2.23 (1H, m), 2.04-1.93 (2H, m), 1.86-1.77 (2H, m), 1.48-1.34 (4H, m) ppm; high resolution mass spectrometry (ES+) m/z 454.2250 [(M+H)+; calculated for C27H28N5O2: 454.2238].
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:31])[CH2:12][S:13][CH:14]2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16](=[O:21])[N:15]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:6][CH:5]=1.[Cl:33]C1C=CC(N)=NC=1>>[Cl:33][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:31])[CH2:12][S:13][CH:14]2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16](=[O:21])[N:15]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:6][CH:5]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: COC(=O)c1ccc(NC(=O)CSC2C(C)=C(C)C(=O)N2Cc2ccc(OC)cc2)nc1
Product: COc1ccc(CN2C(=O)C(C)=C(C)C2SCC(=O)Nc2ccc(Cl)cn2)cc1

Procedure:
The product from Example 1, Part C and 5-chloropyridin-2-ylamine were reacted as described in Example 5. After evaporation of the reaction solvent the residue was partitioned between water and EtOAc, and the organic phase was washed with EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered, and evaporated. The title compound was obtained by silica gel chromatography. 1H NMR (300 MHz, CDCl3) δ 8.47 (br s, 1H), 8.22 (d, J=2 Hz, 1H), 8.12 (d, J=9 Hz, 1H), 7.66 (dd, J=9 Hz, 2 Hz, 1H), 7.21 (d, J=9 Hz, 2H), 6.83 (d, J=9 Hz, 2H), 5.07 (d, J=15 Hz, 1H), 4.62 (s, 1H), 4.13 (d, J=15 Hz, 1H), 3.77 (s, 3H), 2.91 (s, 2H), 1.94 (s, 3H), 1.84 (s, 3H). MS: m/z (MH+) 432.