Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]1([C:15]2([CH3:22])[O:21][CH:16]2[C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)([CH3:22])[CH:16]([OH:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:3]=1
Reactant: COC(=O)C1OC1(C)c1ccccc1
Reactant: Oc1ccc(Br)cc1
Product: COC(=O)C(O)C(C)(Oc1ccc(Br)cc1)c1ccccc1
Yield: 19.7 %

Procedure:
51.9 g (0.3 mol) of 4-bromophenol and 19.2 g (0.1 mol) of methyl 3-phenyl-2,3-epoxybutyrate are stirred at 100° C. for 8 hours and at room temperature for 12 hour. After removal of the excess phenol by distillation, the residue is purified by flash chromatography (silica gel, n-hexane/ethyl acetate 9:1) to result in 7.2 g of a white solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[F:13][C:14]([F:28])([F:27])[C:15]([N:17]=[C:18]([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[O:16]>ClCCl>[F:13][C:14]([F:27])([F:28])[C:15]1[O:16][C:6]([C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=2)=[N:7][C:18]([C:23]([F:25])([F:26])[F:24])([C:19]([F:20])([F:22])[F:21])[N:17]=1
Reactant: N#Cc1cccc(C(F)(F)F)c1
Reactant: O=C(N=C(C(F)(F)F)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)C1=NC(C(F)(F)F)(C(F)(F)F)N=C(c2cccc(C(F)(F)F)c2)O1
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.8 %

Procedure:
3-Trifluoromethylbenzonitrile (5.8 g, 3.39 mmol) and 2,2,2-trifluoro-N-{2,2,2-trifluoro-1-(trifluoromethyl) ethylidene}acetamide (1.8 g, 6.90 mmol) were dissolved in dichloromethane (3 mL) and stirred in a sealed vial at room temperature for three days. The solvent and excess reagent were distilled off to give a colorless oil that was chromatographed on silica gel using 5 percent ethyl acetate/hexanes as eluent. The desired product was present as an oil (0.92 g, 63 percent yield) in the first eluted fraction. EIMS (m/z): 432 (M+), 413 (M−F), 363 (M-CF3).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].[CH3:8][C:9]1([CH3:36])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:19](O)=[O:20])[CH:16]=2)[NH:11][CH:10]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29]([CH3:35])([C:31](=[O:34])[NH:32][CH3:33])[CH3:30])[CH:23]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:1][S:2]([NH:5][C:19]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:22]1[CH:23]=[C:24]([NH:28][C:29]([CH3:35])([CH3:30])[C:31]([NH:32][CH3:33])=[O:34])[CH:25]=[CH:26][CH:27]=1)[C:9]([CH3:36])([CH3:8])[CH2:18]2)=[O:20])(=[O:4])=[O:3]
Reactant: CS(N)(=O)=O
Reactant: CNC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)C(C)(C)Nc1cccc(C2Nc3ccc(C(=O)NS(C)(=O)=O)cc3CC2(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
To a suspension of methanesulfonamide (85 mg, 0.89 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (36 mg, 0.89 mmol). The resulting mixture was stirred at 25° C. for 1 h. A solution of 3,3-dimethyl-2-[3-(1-methyl-1-methylcarbamoyl-ethylamino)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (50 mg, 0.127 mmol) and 1,1′-carbonyldiimidazole (41 mg, 0.253 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at 70° C. for 1 h. Then the above suspension of methanesulfonamide 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 2-[3-(6-methanesulfonylaminocarbonyl-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2,N-dimethyl-propionamide (15 mg, 25%) as a white solid: LC/MS m/e calcd for C24H32N4O4S (M+H)+: 473.61, observed: 473.1.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[F:17])[C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CO.C1COCC1>[NH2:1][C:2]1[C:3]([CH2:4][OH:5])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[F:17])[CH:7]=[CH:8][N:9]=1
Reactant: Nc1nccc(-c2ccc(Cl)cc2F)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nccc(-c2ccc(Cl)cc2F)c1CO
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a stirred solution of 2-amino-4-(4-chloro-2-fluorophenyl)nicotinaldehyde (50 mg, 0.199 mmol) in MeOH (2 mL) and THF (5 mL) was added sodium borohydride (9.06 mg, 0.239 mmol) then the solution was stirred for 1 h. The volatile organics were removed under reduced pressure and the residue was quenched by addition of saturated aqueous ammonium chloride solution (10 mL). The reaction mixture was extracted with CH2Cl2 (2×10 mL). The combined organic extracts were washed with brine (1×10 mL), dried over sodium sulfate and concentrated under reduced pressure to yield (2-amino-4-(4-chloro-2-fluorophenyl)pyridin-3-yl)methanol (50 mg, 0.198 mmol, 21% yield for two steps). LCMS (ESI) m/e 253 [(M+H)+, calcd for C12H11ClFN2O 253.0]; LC/MS retention time (Method C): tR=1.48 min.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:23]1([NH-:29])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[H][H]>CO.[Pd]>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:23]1([NH-:29])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: [H][H]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: [Pd]
Agent: [NH-]N1CCOCC1
Solvent: CO
Product: N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
A solution of 5.5 g of Z-(L)-Phe-morpholin-4-ylamide in 150 ml of methanol is converted into the title compound by hydrogenolysis with the calculated amount of hydrogen for 1 hour at room temperature in the presence of 1.5 g of 10% Pd/C. The catalyst is filtered off and the reaction mixture is concentrated, and after dilution with ethyl acetate the resulting solution is washed with a saturated sodium hydrogen carbonate solution, dried over sodium sulfate and concentrated under reduced pressure. After column chromatography (analogously to Example 1 g)) the title compound is obtained in pure form. TLC Rf (D)=0.3.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[CH:29]=[CH:28][C:17]([O:18][C:19]2[N:27]=[CH:26][CH:25]=[CH:24]C=2C(O)=O)=[CH:16][CH:15]=1.CN(C=O)C>C(Cl)Cl>[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[CH:29]=[CH:28][C:17]([O:18][C:19]2[N:27]=[CH:26][CH:25]=[CH:24][C:1]=2[C:2]([Cl:4])=[O:3])=[CH:16][CH:15]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccnc1Oc1ccc(Nc2ccccn2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccnc1Oc1ccc(Nc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 2M solution of oxaloyl chloride (3.86 mL, 7.71 mmol) was added slowly to a suspension of 2-(4-(pyridin-2-ylamino)phenoxy)nicotinic acid (1580 mg, 5.14 mmol) in CH2Cl2 (20 mL). DMF (0.040 mL, 0.514 mmol) was added drop wise and the mixture was stirred at RT for 2 h. The mixture was concentrated under reduced pressure to deliver a yellow solid. The solid was suspended in CH2Cl2 (5 ml) and filtered to deliver 2-(4-(pyridin-2-ylamino)phenoxy)nicotinoyl chloride as a yellow solid that was taken on without further purification.
Reaction SMILES: [F:1][C:2]1([F:38])[CH2:3][CH2:4][N:5]([C:24]([C:26]2[S:30][C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:28][C:27]=2[CH3:37])=[O:25])[C:6]2[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=2/[C:8]/1=[CH:9]/[C:10]([N:12]1[CH2:17][CH2:16][C:15](=[N:18][OH:19])[CH2:14][CH2:13]1)=[O:11].[C:39](OC(=O)C)(=[O:41])[CH3:40]>N1C=CC=CC=1>[F:38][C:2]1([F:1])[CH2:3][CH2:4][N:5]([C:24]([C:26]2[S:30][C:29]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[N:28][C:27]=2[CH3:37])=[O:25])[C:6]2[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=2/[C:8]/1=[CH:9]/[C:10]([N:12]1[CH2:13][CH2:14][C:15](=[N:18][O:19][C:39](=[O:41])[CH3:40])[CH2:16][CH2:17]1)=[O:11]
Reactant: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)N2CCC(=NO)CC2)c2ccccc21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)ON=C1CCN(C(=O)/C=C2/c3ccccc3N(C(=O)c3sc(-c4ccccc4)nc3C)CCC2(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 51 mg of (Z)-4,4-difluoro-5-{2-[4-(hydroxyimino)piperidino]-2-oxoethylidene}-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepine in a mixture of 800 μl of acetic anhydride and 800 μl of pyridine was stirred at room temperature for eight hours. The solvent was evaporated, the residue was dissolved in ethyl acetate, and the solution was washed with 1N hydrochloric acid and a saturated aqueous solution of NaCl. After drying over anhydrous magnesium sulfate, the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (eluting with chloroform) to give 36 mg of (Z)-4,4-difluoro-5-{2-[4-(acetoxyimino)piperidino]-2-oxoethylidene}-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepine as a colorless solid.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[O:17]CC1C=CC=CC=1)=[O:7])[CH2:2][CH2:3][CH3:4]>CO>[CH2:1]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[OH:17])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1cc2cccc(OCc3ccccc3)c2[nH]1
Solvent: CO
Product: CCCCOC(=O)c1cc2cccc(O)c2[nH]1
Yield: 76.5 %

Procedure:
Under the conditions of Example 14(C), a solution of 5.8 g of 7-benzyloxyindole-2-carboxylic acid n-butyl ester in 200 ml of methanol is hydrogenated and worked up, thus obtaining 3.2 g of 7-hydroxyindole-2-carboxylic acid n-butyl ester, mp 150°-151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=4[F:26])[CH2:14][CH2:13]3)[N:10]=2)[CH:7]=1.[OH-].[Na+].C([OH:33])(C)(C)C>OO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:25]=[CH:24][C:21]([C:22]([NH2:23])=[O:33])=[CH:20][C:19]=4[F:26])[CH2:14][CH2:13]3)[N:10]=2)[CH:7]=1
Reactant: CC(C)(C)O
Reactant: N#Cc1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)c(F)c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)c(F)c1
Temperature: 90 °C

Procedure:
A mixture of 4-[4-[(6-chloroimidazo[1,2-a]pyridin-2-yl)methyl]-1-piperazinyl]-3-fluorobenzonitrile (Example 38; 0.298 g), pulverized NaOH (0.159 g), tert-butanol (3 mL), and 5 drops of 30% hydrogen peroxide in water is heated at 90° C. for 5.5 h. The mixture is then concentrated under reduced pressure and the resulting solids are slurried in water, collected by filtration, and washed and dried under reduced pressure. The solids are then crystallized from dichloromethane/methanol to give 0.180 g of material, which is chromatographed on silica gel using methanol/dichloromethane (4/96). After combining and concentrating the appropriate fractions, the residue is crystallized from ethyl acetate/dichloromethane/methanol to give 0.084 g of the title compound; mp 253-255° C.; MS m/z 387, 389; IR (mineral oil) 1435, 1620, 1678, 1225, 1505 cm-1 ; 1H NMR (CDCl3 +CD3OD) δ2.77, 3.38, 3.80, 6.94, 7.19, 7.53, 7.62, 8.23.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:34].[Na+].OP([O-])(O)=O.[Na+]>C(#N)C.O.C(O)(C)(C)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:34])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[CH:17][CH:18]=1
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(OCCN4CCOCC4)cc3)cc12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(C)(C)O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCN4CCOCC4)cc3)cc12
Reaction time: 0.03 h
Yield: 22 %

Procedure:
To a solution of 6-chloro-5-{4-[2-(morpholin-4-yl)ethoxy]phenyl}-1H-indole-3-carbaldehyde (130 mg, 0.34 mmol) in acetonitrile (4 mL) was added tert-butanol (4 mL), water (4 mL) and 2-methyl-2-butene (2.76 mL). After stirred for 2 min, sodium chlorite (680 mg, 10.15 mmol) and sodium phosphate monobasic (1.59 mg, 10.19 mmol) were added to the reaction mixture. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with sodium sulfite and the mixture was concentrated in vacuo to give a residue, which was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (2×15 mL), dried over Na2SO4 and concentrated in vacuo to give a residue, which was purified by prep-HPLC to give 6-chloro-5-{4-[2-(morpholin-4-yl)ethoxy]phenyl}-1H-indole-3-carboxylic acid (30 mg, 22%) as a yellow solid. MS (ES+) 401.1 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 8.28 (s, 1H), 8.02 (s, 1H), 7.98 (s, 1H) 7.57 (s, 1H), 7.39 (d, 2H), 7.04 (d, 2H), 4.31 (m, 2H), 3.83 (m, 4H), 3.17 (m, 2H), 2.96 (m, 4H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:6]=1[NH2:7].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CC(N(C)C)=O>[O:18]1[CH2:19][CH2:20][N:15]([CH2:2][CH2:3][O:4][C:5]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:6]=2[NH2:7])[CH2:16][CH2:17]1
Reactant: C1COCCN1
Reactant: Nc1c(OCCCl)cccc1[N+](=O)[O-]
Solvent: CC(=O)N(C)C
Product: Nc1c(OCCN2CCOCC2)cccc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
2-(2-Chloroethoxy)-6-nitroaniline (1.9 g, 4.63 mmol), morpholine (0.5 mL) was dissolved in 5 mL of DMA. The mixture was heated at 110° C. in a pressure bottle overnight, and then cooled to room temperature. The reaction mixture was separated between ethyl acetate and water, the combined organic layers were washed with water, brine, dried, and concentrated to get 1.3 g of 2-(2-Morpholinoethoxy)-6-nitroaniline, which was used without any further purification. 1H-NMR (400 MHz, CDCl3): δ 7.78 (d, 1H), 6.95 (d, 1H), 6.72 (b, 2H), 6.61 (dd, 1H), 4.16 (t, 2H), 3.75 (t, 2H), 2.82 (m, 2H), 2.58 (m, 4H), 2.10 (m, 2H). MS (EI): 263 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH3:31][N:32]([CH2:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)[CH3:33].C([O-])([O-])=O.[Na+].[Na+]>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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:38]2[CH:39]=[CH:40][C:35]([CH2:34][N:32]([CH3:33])[CH3:31])=[CH:36][CH:37]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CN(C)Cc1ccc(B(O)O)cc1
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
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: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2ccc(CN(C)C)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 53.8 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (0.2 g, 0.42 mmol) and (4-((dimethylamino)methyl)phenyl)boronic acid (0.15 g, 0.505 mmol) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (0.16 g, 1.51 mmol) was added and the solution purged with argon for 15 min. Pd (PPh3)4 (0.048 g, 0.042 mmol) was the added and the reaction mixture again purged with argon for 10 min. The reaction mixture was heated at 100° C. for 2 h. The reaction mixture was then diluted with water and extracted with 10% MeOH/DCM. The combined extracts were dried over Na2SO4 and the solvent removed under reduced pressure to afford the crude product which was purified by column chromatography over silica gel to afford the title compound (0.120 g, 53.8%). LCMS: 531.30 (M+1)+; HPLC: 94.88% (@254 nm) (Rt; 3.949; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.19 (t, 1H, J=4.4 Hz), 7.61 (d, 2H, J=8 Hz), 7.39-7.41 (m, 3H), 7.23 (s, 1H), 5.86 (s, 1H), 4.28 (d, 2H, J=4.8 Hz), 3.62-3.84 (m, 4H), 3.22-3.38 (m, 2H), 3.02-3.06 (m, 3H), 2.30 (bs, 6H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.64-1.67 (m, 2H), 1.51-1.53 (m, 2H), 0.83 (t, 3H, J=6.8 Hz).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](Cl)=[N:10][CH:9]=[N:8][C:7]=2[C:6]([C:14]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:24]=[CH:23]3)([OH:19])[C:15]([F:18])([F:17])[F:16])=[CH:5]1)[CH:2]=[CH2:3].FC(F)(F)C(O)=[O:39].C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[CH2:1]([N:4]1[C:12]2[C:11](=[O:39])[NH:10][CH:9]=[N:8][C:7]=2[C:6]([C:14]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:24]=[CH:23]3)([OH:19])[C:15]([F:18])([F:17])[F:16])=[CH:5]1)[CH:2]=[CH2:3]
Reactant: O=C(O)C(F)(F)F
Reactant: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ncnc(Cl)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2nc[nH]c(=O)c21
Temperature: 80 °C
Yield: 53 %

Procedure:
To a solution of 1-(5-allyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanol (250 mg, 0.5 mmol) in 3 mL of dioxane was added 2 mL of water followed by 2 mL of trifluoroacetic acid. The mixture was warmed at 80° C. for 1.5 hours, cooled to room temperature and made basic with saturated sodium bicarbonate, diluted with water, and extracted with EtOAc. The combined organic layers were dried, filtered, and evaporated. The residue was purified by flash chromatography eluting with MeOH—CH2Cl2 (0-2% gradient) to provide 129 mg (53%) of the title compound as a white solid. MS m/z 484.33 (MH+).
Reaction SMILES: [OH-:1].[K+].[Cl:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([O:12][CH3:13])=[C:6]([Cl:14])[C:5]=1[C:15]1[C:24]2[N:23]=[C:22]([N:25]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH3:26])[CH:21]=[N:20][C:19]=2[C:18]([C:32]#N)=[CH:17][CH:16]=1.[OH2:34]>C(O)CO.CCOCC.O>[Cl:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([O:12][CH3:13])=[C:6]([Cl:14])[C:5]=1[C:15]1[C:24]2[N:23]=[C:22]([N:25]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH3:26])[CH:21]=[N:20][C:19]=2[C:18]([C:32]([OH:34])=[O:1])=[CH:17][CH:16]=1
Reactant: [OH-]
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C#N)c3ncc(N(C)CCN(C)C)nc23)c1Cl
Reactant: O
Agent: [K+]
Solvent: OCCO
Solvent: CCOCC
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncc(N(C)CCN(C)C)nc23)c1Cl
Temperature: 150 °C
Reaction time: 48 h

Procedure:
A solution of KOH (268 mg, 4.79 mmol, 10 equiv) in H2O (2 mL) was added to 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-[(2-dimethylamino-ethyl)-methyl-amino]-quinoxaline-5-carbonitrile (Step 85.2) (220 mg, 0.48 mmol) in ethylene glycol (2 mL). The reaction mixture was stirred at 150° C. for 48 h, allowed to cool to rt, diluted with Et2O/H2O, and extracted with Et2O. The aqueous phase was acidified to pH 5 by addition of 6 N HCl. Vacuum filtration of the resulting suspension afforded 450 mg of the title compound as an impure yellow solid, which was used without further purification: ESI-MS: 479.0/480.9 [M+H]+; tR=3.75 min (System 1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O-:9])=[O:8].[K+].[Br:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](=[O:19])[CH2:17]Br)=[CH:14][CH:13]=1.C1CC2OCCOCCOC3C(OCCOCCOC2CC1)CCCC3>C(#N)C>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:17][C:16]([C:15]1[CH:20]=[CH:21][C:12]([Br:11])=[CH:13][CH:14]=1)=[O:19])=[O:8]
Reactant: O=C([O-])CCCCCO
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: C1CCC2OCCOCCOC3CCCCC3OCCOCCOC2C1
Agent: [K+]
Solvent: CC#N
Product: O=C(CCCCCO)OCC(=O)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
A mixture of 8.5 g. (50 mmoles) of potassium 6-hydroxycaproate, 13.9 g. (50 mmoles) of p-bromophenacyl bromide, 0.75 g. (2 mmoles) of dicyclohexyl-18 -crown-6 in 500 ml. of acetonitrile is refluxed with stirring for 1 hour and stirred at room temperature overnight. The mixture is filtered and the filtrate evaporated to dryness in vacuo. The residual solid is recrystallized from benzene-hexane mixture affording 14.1 g. of p-bromophenacyl 6-hydroxycarproate, m.p. 79°-81° C.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[Cl:15][C:16]1[C:21]([NH2:22])=[CH:20][C:19]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[CH:18][CH:17]=1.[OH-].[Na+]>CN(C)C(=O)C>[F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4]([NH:22][C:21]1[C:16]([Cl:15])=[CH:17][CH:18]=[C:19]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:20]=1)=[O:5]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Nc1cc(S(=O)(=O)c2ccccc2)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CC(O)(C(=O)Nc1cc(S(=O)(=O)c2ccccc2)ccc1Cl)C(F)(F)F
Temperature: -20 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
To a solution containing 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (2.00 g) in N,N-dimethylacetamide (40 mL) cooled to -20° C. was added thionyl chloride (1.50 g) and the mixture was stirred for 1.0 hour. 6-chloro-3-phenylsulfonylaniline (2.42 g) was added in one portion and mixture was stirred for 48 hours at room temperature. The reaction mixture was poured into aqueous sodium hydroxide (1.0 N, 250 mL) and extracted with ethyl acetate. The combined ethyl acetate extracts were washed (aqueous sodium hydroxide, brine) and evaporated. Chromatography, with hexane:ethyl acetate as the eluent (4:1 then 2:1) yielded the title compound as a white solid (1.25 g); mp: 79-80° C.; NMR (250 MHz): 1.61 (s,3), 7.69 (m,3), 7.82 (m,2), 7.94 (d,1, J=9), 7.98 (m,2), 8.52 (s,1), 9.93 (s,1); MS: m/z=408(M+1). Analysis for C16H13ClF3NO4S: Calculated: C, 47.11; H, 3.19; N, 3.44; Found: C, 47.10; H, 3.28; N, 3.38.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[C:10]([N:16]2[CH2:28][CH2:27][C:19]3([CH2:23][N:22]([C:24](=[O:26])[CH3:25])[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)[C:9]=1[Cl:29])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:24]([N:22]1[CH2:21][CH2:20][C:19]2([CH2:18][CH2:17][N:16]([C:10]3[CH:11]=[C:12]([CH:13]=[C:8]([NH2:7])[C:9]=3[Cl:29])[C:14]#[N:15])[CH2:28][CH2:27]2)[CH2:23]1)(=[O:26])[CH3:25]
Reactant: CC(=O)N1CCC2(CCN(c3cc(C#N)cc(NC(=O)OC(C)(C)C)c3Cl)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1CCC2(CCN(c3cc(C#N)cc(N)c3Cl)CC2)C1
Yield: 91 %

Procedure:
tert-butyl(3-(2-acetyl-2,8-diazaspiro[4.5]decan-8-yl)-2-chloro-5-cyanophenyl)carbamate (100 mg, 0.231 mmol) in DCM (2 mL) was treated with TFA (0.338 mL, 4.39 mmol) at room temperature for 2 h. Solvent was evaporated and the residue was diluted with dichloromethane and washed with saturated sodium bicarbonate. The aqueous layer was extracted with dichloromethane two more times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g gold column, eluting with 0-5% methanol/dichloromethane). 3-(2-acetyl-2,8-diazaspiro[4.5]decan-8-yl)-5-amino-4-chlorobenzonitrile (70 mg) was obtained as a light yellow oil.