Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.[CH2:25]([SH:27])[CH3:26].B(F)(F)F.C(=O)(O)[O-].[K+]>CCOCC>[CH2:25]([S:27][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1])[CH3:26]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: CCS
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Product: CCS[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2α,3α-Epoxy-5α-pregnane-11,20-dione (50 mg.) in dry ether was treated with ethanethiol (0.8 mls.) and BF3 etherate (3 drops). The reaction mixture was stirred at room temperature for 20 minutes; then ether (5 mls.) and potassium bicarbonate solution (10%, 2.5 ml.) were added. The ether layer was evaporated to about 5 mls. and purified by preparative t.l.c. in ethyl acetate/petroleum ether (2:1) to give a colourless oil (200 mgs.) which was triturated with acetone and petroleum ether to give the title compound (174mg); fine white crystals; m.p. 170°-173°; [α]D + 93° (c 0.6).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][OH:17])=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO[C:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1.[NH+]1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C1(C)C=CC=CC=1>[C:23]1([O:17][CH2:16][C:13]2[N:14]([CH3:15])[C:10]([S:9][C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)=[C:11]([CH:18]([CH3:20])[CH3:19])[N:12]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: CC(C)c1nc(CO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: COC1=CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: CC(C)c1nc(COC2=CCCCC2)n(C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 29.7 %

Procedure:
The compound 14 (166 mg, 0.5 mmol), 1-methoxycyclohexene (280 mg, 2.50 mmol) and p-toluenesulfonic acid pyridinium (132 mg, 0.505 mmol) was dissolved in toluene (4 mL). The reaction mixture was stirred at room temperature for 20 hours. Benzene (60 mL) was added thereto, the reaction mixture was heated under reflux over 45 minutes and concentrated to a small amount. A drop of triethylamine was added to the reaction mixture, and the mixture was filtered to remove the insoluble matter. The filtrate was concentrated under reduced pressure. The residue was extracted with hexane, and filtered off the insoluble matter. The filtrate was purified by chromatography on an alumina column (eluate: toluene) to give the compound 17 (61 mg, 30%) as crystals. Mp 69-71° C. Rf 0.57 (Al2O3 60, Type E, toluene).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:29][S:30]([C:33]1[CH:34]=[C:35]([NH:39][C:40](=O)[O:41]C2C=CC=CC=2)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31]>CS(C)=O.C(OCC)(=O)C>[CH2:20]([O:19][C:13]1[CH:12]=[C:11]2[C:16]([C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:40]([NH:39][C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH:34]=4)=[O:41])=[CH:28][CH:27]=3)=[CH:8][CH:9]=[N:10]2)=[CH:15][C:14]=1[C:17]#[N:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)c1cccc(NC(=O)Oc2ccccc2)c1
Reactant: N#Cc1cc2c(Oc3ccc(N)cc3)ccnc2cc1OCc1ccccc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OCc5ccccc5)c(C#N)cc34)cc2)c1
Temperature: 85 °C
Yield: 100 %

Procedure:
After dissolving 4-(4-aminophenoxy)-7-(benzyloxy)-6-cyanoquinoline (919 mg, 2.5 mmol) in dimethylsulfoxide (10 ml), phenyl N-(3-(methylsulfonyl)phenyl)carbamate (801 mg, 2.75 mmol) was added and the mixture was heated at 85° C. for 2 hours. The reaction solution was diluted with ethyl acetate and then washed with 1N aqueous sodium hydroxide (10 ml), water (20 ml×2) and saturated saline (10 ml) and dried over anhydrous sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure and the residue was suspended in ethyl acetate (30 ml), after which hexane (30 ml) was added, sonication was performed and the precipitated crystals were filtered out and dried under reduced pressure to obtain the title compound (1.43 g, 2.5 mmol) as light brown crystals.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[OH-:10].[Na+].Cl>C1COCC1>[Br:1][C:2]1[C:3](=[O:10])[NH:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]c(Cl)ncc1Br
Yield: 64 %

Procedure:
5-Bromo-2,4-dichloro-pyrimidine (5.0 g, 22 mmol) was stirred in THF (10 mL) with 1N NaOH (30 mL) at r.t. for 3 h. The solution was made slightly acidic with 1N HCl and was extracted with CHCl3. Organics were dried (MgSO4) and concentrated in vacuo. Precipitation from 20% CHCl3/hexanes and collection by filtration gave 2.92 g (64%) of 5-bromo-2-chloro-3H-pyrimidin-4-one as a white solid. 1H NMR (400 MHz, DMSO-d6): δ13.33 (br s, 1H), 8.35 (s, 1H). MS (ES) [m+H] calc'd for C4H2N2OBrCl, 209, 211, 213; found 209, 211, 213.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:11])[CH3:10].C([O-])(O)=O.[Na+].[Cl:17][C:18]1[N:23]=[C:22](Cl)[C:21]([Cl:25])=[CH:20][N:19]=1>C1COCC1.CCO>[Cl:17][C:18]1[N:23]=[C:22]([NH:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9](=[O:11])[CH3:10])[C:21]([Cl:25])=[CH:20][N:19]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(=O)c1ccccc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reaction time: 96 h

Procedure:
1-(2-Amino-phenyl)-ethanone hydrochloride (1.72 g, 1.0 mmol) and NaHCO3 (3.4 g, 4 mmol) were slurried in a mixture of THF (4 mL) and EtOH (16 mL) prior to adding 2,4,5-trichloropyrimidine (1.84 g, 1.0 mmol). The reaction was stirred for 4 days, filtered and washed with water (10×10 mL) to afford -[2-(2,5-dichloro-pyrimidin-4-ylamino)-phenyl]-ethanone as a white solid that was used without further purification in the subsequent step.
Reaction SMILES: C([N:8]([C@@H:16]1[CH2:21][C:20]2[C:22]([O:27][CH3:28])=[CH:23][CH:24]=[C:25]([F:26])[C:19]=2[O:18][CH2:17]1)CC1C=CC=CC=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.C1COCC1.[Pd]>[NH2:8][C@@H:16]1[CH2:21][C:20]2[C:22]([O:27][CH3:28])=[CH:23][CH:24]=[C:25]([F:26])[C:19]=2[O:18][CH2:17]1
Reactant: COc1ccc(F)c2c1C[C@@H](N(Cc1ccccc1)Cc1ccccc1)CO2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)c2c1C[C@@H](N)CO2
Temperature: 50 °C
Yield: 91.4 %

Procedure:
(R)-3-(N,N-Dibenzylamino)-8-fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyran (13.0 g, 34.4 mmol) was dissolved in 265 mL methanol and 115 mL THF. To this was 10% Pd/C (4 g) and ammonium formate (51.5 g, 0.817 mol) added. The reaction was heated to 50° C. for 2.5 h. The reaction was filtered and the solvent was removed in vacuo, the remains were taken into a 2M solution of NaOH and then extracted twice with ether. The combined ether portions were treated with brine, dried (Na2SO4), filtered, and the solvent removed in vacuo to give 6.2 g (91% yield) of the title compound as a clear oil. [α]21D =-15.3° (C=1, CHCl3). GC-MS (70 eV) M=197 (51%).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[CH3:14][O:15][C:16]([C:18]12[CH2:23][CH:22]1[CH2:21][CH2:20][C:19]2=[O:24])=[O:17]>C(O)(C)(C)C>[CH3:14][O:15][C:16]([C:18]1[C:19](=[O:24])[CH2:20][CH2:21][C:22]=1[CH2:23][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:17]
Reactant: COC(=O)C12CC1CCC2=O
Reactant: Sc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)C1=C(CSc2ccccc2)CCC1=O
Reaction time: 0.17 h

Procedure:
Thiophenol (660 mg: 6 mmol) was added to a solution of potassium t-butoxide (650 mg: 6 mmol) in 5 ml of t-butyl alcohol. The mixture was stirred for 10 minutes. A solution of 2-oxo-bicyclo[3.1.0]hexane-1-carboxylic acid methyl ester of Preparation 2(924 mg, 6 mmol) in 2 ml of t-butyl alcohol was added to the mixture. After stirring the mixture at room temperature for about 30 minutes, most of the solvent was distilled off under reduced pressure. Ether was added to the residue and dilute hydrochloric acid was added to acidify the solution, and the ethereal solution was washed with a saturated aqueous solution of sodium chloride and was dried over anhydrous magnesium sulfate and was filtered. The solvent was distilled off under reduced pressure. The remaining crystals were recrystallized from ether and n-hexane to obtain 2-oxo-5-phenylthiomethyl-cyclopentenecarboxylic acid methyl ester as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[F:11][C:12]([F:33])([F:32])[C:13]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:21][CH:20]=1)([OH:18])[C:14]([F:17])([F:16])[F:15].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[F:33][C:12]([F:11])([F:32])[C:13]([C:19]1[CH:20]=[CH:21][C:22]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=3)=[O:8])[CH2:28][CH2:27]2)=[CH:23][CH:24]=1)([OH:18])[C:14]([F:17])([F:16])[F:15]
Reactant: OC(c1ccc(CN2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=C(O)c1ccc(O)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(O)cc1)N1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reaction time: 2 h
Yield: 9.5 %

Procedure:
4-Hydroxybenzoic acid (2.045 mmol, 0.282 g), 1,1,1,3,3,3-hexafluoro-2-(4-(piperazin-1-ylmethyl)phenyl)propan-2-ol (2.045 mmol, 0.7 g) and triethylamine (6.14 mmol, 0.853 mL, 0.621 g) were combined and stirred at room temperature in dichloromethane (5 mL). 1-Propanephosphonic acid cyclic anhydride (3.07 mmol, 1.826 mL, 1.952 g; 50% solution in ethyl acetate) was added and the reaction stirred for 2 hours. The reaction mixture was washed with saturated sodium bicarbonate solution and the organic layer dried over magnesium sulphate and concentrated under vacuum. The residue was dissolved in dichloromethane with a few drops of methanol and purified by column chromatography (dichloromethane—6% methanol in dichloromethane) to afford the title compound (90 mg). MS (ESI) m/z 463.0 [M+H]+
Reaction SMILES: [CH3:1][N:2]([C:4](=[O:28])[C:5]([NH:7][C:8]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][N:10]1[C:17](=[O:27])[C:18]([OH:26])=[C:19]([C:21]([O:23]CC)=O)[N:20]=[C:9]21)=[O:6])[CH3:3].Cl.Cl.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH2:39])=[C:34]([N:40]2[C:44]([CH3:45])=[CH:43][N:42]=[N:41]2)[CH:33]=1.C(N(CC)CC)C>C(O)C>[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH:39][C:21]([C:19]2[N:20]=[C:9]3[C:8]4([NH:7][C:5](=[O:6])[C:4]([N:2]([CH3:3])[CH3:1])=[O:28])[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16]4)[CH2:11][N:10]3[C:17](=[O:27])[C:18]=2[OH:26])=[O:23])=[C:34]([N:40]2[C:44]([CH3:45])=[CH:43][N:42]=[N:41]2)[CH:33]=1
Reactant: Cc1cnnn1-c1cc(F)ccc1CN
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CC1CCC2(NC(=O)C(=O)N(C)C)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cnnn1-c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1O)CC1CCC2(NC(=O)C(=O)N(C)C)CC1
Temperature: 90 °C
Yield: 23.8 %

Procedure:
A mixture of ethyl 10-(((dimethylamino)(oxo)acetyl)amino)-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylat (30 mg, 0.076 mmol), (4-fluoro-2-(5-methyl-1H-1,2,3-triazol-1-yl)phenyl)methanamine, bis-hydrochloride salt (42.7 mg, 0.153 mmol) and triethylamine (0.1 ml, 0.717 mmol) in ethanol (2 mL) was heated at 90° C. for 18 h. The reaction mixture was then cooled, concentrated and purified on preparative reversed phase HPLC to afford the title compound (10 mg, 21% yield) as an off-white solid. 1H NMR (500 MHz, CDCl3) δ: 1.66-1.77 (m, 2 H) 1.90-2.01 (m, 2 H) 2.14-2.24 (m, 2 H) 2.27 (s, 3 H) 2.39-2.47 (m, 2 H) 2.50 (br. s., 1 H) 2.89 (s, 3 H) 3.19 (s, 3 H) 4.15 (d, J=3.97 Hz, 2 H) 4.23 (d, J=6.41 Hz, 2 H) 6.99 (dd, J=8.24, 2.44 Hz, 1 H) 7.26-7.33 (m, 2 H) 7.62-7.68 (m, 2 H) 8.86 (t, J=6.10 Hz, 1H) 11.73 (br. s., 1 H). LCMS (M+H)=553.22. HPLC purity: >95%.
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20](C)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[N:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33][CH:32]=1>>[C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20]([C:35]2[CH:36]=[N:31][CH:32]=[N:33][CH:34]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)c(C)c2ccccc2c1-c1ccc(Cl)cc1
Reactant: OB(O)c1cncnc1
Product: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1-c1cncnc1

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-4-(pyrimidin-5-yl)naphthalen-2-yl)acetic acid (139) was prepared in a manner similar to 2-tert-butoxy-2-(1-(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)acetic acid of Example 125, except using pyrimidin-5-yl-boronic acid in the Suzuki reaction, giving the title compound (mono trifluoroacetic acid salt). 1H-NMR: (400 MHz, DMSO-d6): δ 12.87 (s, broad, 1H), 9.39 (s, 1H), 8.89-8.86 (m, 2H), 7.76-7.68 (m, 2H), 7.58-7.55 (s, 1H), 7.49-7.44 (m, 3H), 7.28 (d, J=8.2 Hz, 1H), 7.20 (d, J=8.2 Hz, 1H), 5.15 (s, 1H), 2.27 (s, 3H), 0.97 (s, 9H). 19F-NMR: (377 MHz, DMSO-d6): δ−73.9 (s) LCMS-ESI+ (m/z): [M+H]+ calcd for C27H26ClN2O3: 461.2; Found: 461.2.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[C:9]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5](=[O:8])[N:6]([CH3:9])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cnc(Cl)cn1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(Cl)ncc1=O
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a solution of 5-chloro-pyrazin-2-ol (100 mg, 0.76 mmol) in DMF (3 mL) was added K2CO3 (211 mg, 1.53 mmol) and CH3I (0.25 ml, 4 mmol) at room temperature. The mixture was stirred overnight, quenched by H2O, and extracted with EtOAc. The organic phase was concentrated to give the crude product, which was purified by TLC to give 5-chloro-1-methyl-1H-pyrazin-2-one (70 mg, 64%). 1H NMR (CD3OD): δ3.52 (s, 3H), 7.78 (s, 1H), 7.87 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].[H-].[Na+].F[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([N+:23]([O-:25])=[O:24])=[CH:15][CH:14]=1.CO>C1COCC1>[N+:23]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([O:9][CH2:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[NH2:1])=[CH:14][CH:15]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(F)c2ccccc12
Reactant: Nc1cnccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cnccc1COc1ccc([N+](=O)[O-])c2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82 %

Procedure:
To a solution of (3-amino-pyridin-4-yl)-methanol (13) (4.00 g, 32.2 mmol) in anhydrous THF (160 mL) at 0° C. was added sodium hydride (1.55 g, 38.7 mmol, 60 wt %). After stirring for 20 min, 1-fluoro-4-nitronaphthalene (14) (6.16 g, 32.2 mmol) was added, the ice bath was removed and the reaction mixture left to warm to RT and stirred for 12 hr. The reaction mixture was partitioned between EtOAc (200 mL) and saturated aq NaHCO3 solution (150 mL). The remaining yellow solid was collected by filtration and washed sequentially with water (50 mL), MeOH (50 mL) and diethyl ether (100 mL) and was identified as the desired product by LC-MS and 1H NMR. The filtrate was returned to a separating funnel; the organic phase was collected and washed with brine (100 mL), dried and concentrated in vacuo to afford an orange residue. Trituration of the orange residue with MeOH (200 mL) afforded an orange solid which was washed with diethyl ether (200 mL). LC-MS and 1H NMR analysis of the orange solid was identical to that observed for the insoluble solid obtained earlier. The two products were combined to afford the title compound (15) (7.80 g, 77%): m/z 296 (M+H)+ (ES+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]([CH3:32])[C:17]([C:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[O:21][C:20]=3[CH2:28][CH2:29][CH2:30][CH3:31])=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:34][C:35]([O:37][CH3:38])=[O:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:38][O:37][C:35](=[O:36])[CH2:34][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][N:16]([C:17]([C:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[O:21][C:20]=3[CH2:28][CH2:29][CH2:30][CH3:31])=[O:18])[CH3:32])=[CH:13][CH:14]=2)=[CH:3][C:2]=1[Br:1]
Reactant: COC(=O)CBr
Reactant: CCCCc1oc2ccccc2c1C(=O)N(C)Cc1ccc(-c2ccc(O)c(Br)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1C(=O)N(C)Cc1ccc(-c2ccc(OCC(=O)OC)c(Br)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A mixture of N-[(3′-bromo-4′-hydroxy-1,1′-biphenyl-4-yl)methyl]-2-butyl-N-methyl-1-benzofuran-3-carboxamide (1.01 g, 2.04 mmol), prepared in step 7 of Example 6, methyl bromoacetate (213 μL, 2.25 mmol) and potassium carbonate (1.41 g, 10.2 mmol) in 20 ml of DMF was stirred under nitrogen at room temperature for 23 h (overnight). The reaction was partitioned between ethyl acetate and water. The organic layer was separated, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give methyl[(3-bromo-4′-{[[(2-butyl-1-benzofuran-3-yl)carbonyl](methyl)amino]methyl}-1,1′-biphenyl-4-yl)oxy]acetate (1.07 g, 93%) as a yellow oil, MS (ESI) m/z 564 [M+H]+. Elemental Analysis for C30H30BrNO5. Calc'd: C, 63.83; H, 5.36; N, 2.48. Found: C, 63.42; H, 5.40; N, 2.39.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:13](=O)[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[C:11]([OH:12])=[C:6]2[CH:5]=[N:4]1)[CH3:2].Cl.[NH2:23]O>N1C=CC=CC=1>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]3[C:13]([C:14]4[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=4)=[N:23][O:12][C:11]3=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(O)c(C(=O)c3cccc(C)c3)cnc21
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCn1ncc2c3onc(-c4cccc(C)c4)c3cnc21

Procedure:
1-Ethyl-4-hydroxy-5-(3-methylbenzoyl)-1H-pyrazolo[3,4-b]pyridine (4.25 g) was refluxed overnight in 75 ml of pyridine containing 4.5 g of hydroxylamine hydrochloride. The pyridine was then removed under reduced pressure and the residue triturated with 5% hydrochloric acid. The product was then filtered off and recrystallized from methanol to give 2.63 g of analytically pure product, mp 122°-123° C.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1.N1C=CC=CC=1>O1CCCC1>[N:15]1([S:2]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)(=[O:4])=[O:3])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: c1ccc2c(c1)CCN2
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C1Cc2cc(S(=O)(=O)N3CCc4ccccc43)ccc2N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 110.5 %

Procedure:
To a mixture of 5-chlorosulfonyl-2-oxindole (5 g, 21.6 mmol) and indoline (2.9 mL, 26 mmol) in tetrahydrofuran (20 mL) was added pyridine (3.4 g, 43 mmol). After stirring at room temperature for 1 day the precipitate was collected by vacuum filtration, washed with water in ethanol (20%), dried, washed with 60 mL of hot ethanol and dried under vacuum to give 7.5 g of 5-(2,3-dihydro-indole-1-sulfonyl)-1,3-dihydro-indol-2-one as a pink solid. 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 10.76 (br s, 1H, NH), 7.62 (m, 2H), 7.43 (d, 1H), 7.13–7.18 (m, 2H), 6.95 (dt, 1H), 6.90 (d, 1H), 3.87 (t, 2H, CH2), 3.51 (s, 2H, CH2), 2.91 (t, 2H, CH2). MS m/z 315 [M+1].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C@:6]12[CH2:14][C@H:13]1[C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)=[N:20][NH:21]2)=[CH:17][CH:16]=1.[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>C(Cl)Cl>[F:46][C:45]([F:48])([F:47])[C:43]([OH:49])=[O:44].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C@:6]12[CH2:14][C@H:13]1[C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:24]3[CH:29]=[CH:28][C:27]([CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[CH:26][CH:25]=3)=[N:20][NH:21]2)=[CH:17][CH:16]=1
Reactant: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)n[nH]c3c1)C(=O)N2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(-c4ccc(C5CCNCC5)cc4)n[nH]c3c1)C(=O)N2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 19.1 %

Procedure:
To a solution of tert-butyl 4-(4-(6-((1R,2S)-5′-methoxy-2′-oxospiro[cyclopropane-1,3′-indoline]-2-yl)-1H-indazol-3-yl)phenyl)piperidine-1-carboxylate (102 mg, 0.181 mmol) in CH2Cl2 (5 mL) was added TFA (0.4 mL, 5.4 mmol). The resulting reaction mixture was stirred at rt for 2.5 h. The crude reaction mixture was concentrated under reduced pressure to dryness, and purified by preparative HPLC to give the title compound as a yellow solid (20 mg, 72%). 1H NMR (400 MHz, MeOD) δ 7.89 (d, J=8.2 Hz, 3H), 7.47 (s, 1H), 7.41 (d, J=8.2 Hz, 2H), 7.01 (d, J=8.6 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.91 (dd, J=8.4, 2.4 Hz, 1H), 5.60 (d, J=2.3 Hz, 1H), 3.56-3.50 (m, 2H), ), 3.39-3.32 (m, 1H), 3.25 (s, 3H), 3.17 (t, J=11.9 Hz, 2H), 3.02-2.92 (m, 1H), 2.25-2.22 (m, 1H), 2.19-2.01 (m, 3H), 2.02-1.91 (m, 2H); MS ESI 465.3 [M+H]+, calcd for [C29H28N4O2+H]+ 465.22.
Reaction SMILES: [CH3:1][N:2]([S:25]([CH3:28])(=[O:27])=[O:26])[C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]2[CH2:17][CH:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][C:14]2=[O:24])[CH:12]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+].CO>O1CCCC1>[CH3:1][N:2]([S:25]([CH3:28])(=[O:27])=[O:26])[C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N:13]2[CH2:17][CH:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][C:14]2=[O:24])[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cc(N2CC(c3ccccc3)CC2=O)cc(N(C)S(C)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(c1cc(C(=O)O)cc(N2CC(c3ccccc3)CC2=O)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 91 %

Procedure:
A mixture of methyl 3-[methyl(methylsulfonyl)amino]-5-(2-oxo-4-phenylpyrrolidin-1-yl)benzoate obtained in Reference Example 18 329 mg (0.32 mmol), 2N aqueous sodium hydroxide solution (0.5 mL), methanol (0.5 mL) and tetrahydrofuran (0.5 mL) was stirred at room temperature for 15 hours. The solvent was concentrated and the mixture was adjusted by adding 1N hydrochloric acid to pH=3 and the mixture was extracted with ethyl acetate. After drying of the mixture on magnesium sulfate, the solvent was evaporated to give 113 mg (0.291 mmol) of the title compound (yield: 91%).