Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:19]([CH3:21])[N:20]=2)[CH:9]=[C:10]([C:12]#[C:13][Si](C)(C)C)[CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:19]([CH3:21])[N:20]=2)[CH:9]=[C:10]([C:12]#[CH:13])[CH:11]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(C#C[Si](C)(C)C)cn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)OCC)n2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
720 mg ethyl 8-[(2,6-difluorobenzyl)oxy]-2-methyl-6-[(trimethylsilyl)ethynyl]imidazo[1,2-a]-pyridine-3-carboxylate (Example 37A; 1.63 mmol; 1 equivalent) were initially charged in 16 ml of methanol, and 674 mg of potassium carbonate (4.81 mmol, 3 equivalents) were added. The resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated, water was added and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over magnesium sulphate, and the filtrate was concentrated. This gave 587.7 mg of crude product (which contained 35% of the methyl ester of the target compound; quantitative yield) which was used without further purification for the next reaction.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[F:14][C:15]1[CH:16]=[C:17](O)[CH:18]=[CH:19][CH:20]=1>>[F:14][C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][CH:16]=1)[O:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: Oc1cccc(F)c1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccc(F)c2)C1
Yield: 98.1 %

Procedure:
The title compound (D46) (294.6 mg) was prepared according to the experimental procedure described in Description 40 starting from (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (200 mg, 1.068 mmol, available at Aldrich#532169) and 3-Fluorophenol (0.096 ml, 1.068 mmol).
Reaction SMILES: [C:1](Cl)(=O)C.[Cl:5][C:6]1[C:11]([CH2:12][C:13]([OH:15])=[O:14])=[CH:10][CH:9]=[CH:8][N:7]=1>CO>[Cl:5][C:6]1[C:11]([CH2:12][C:13]([O:15][CH3:1])=[O:14])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: CC(=O)Cl
Reactant: O=C(O)Cc1cccnc1Cl
Solvent: CO
Product: COC(=O)Cc1cccnc1Cl

Procedure:
Acetyl chloride (0.651 mL, 9.16 mmol) was added to a suspension of (2-chloropyridin-3-yl)acetic acid (I117) (1.048 g, 6.108 mmol) in MeOH (30 mL). The mixture was heated at reflux for 20 hours. The volatiles were removed in vacuo and the residue partitioned between DCM (100 mL) and sat. NaHCO3 (100 mL). The layers were separated and the aqueous layer extracted with DCM (2×100 mL). The combined organic layers were washed with brine (100 mL), dried (Na2SO4) and the solvent removed under reduced pressure to yield an oil which was purified by column chromatography on silica gel (0-40% EtOAc in petroleum benzine 40-60° C.) to afford the title compound (I118) (0.863 g, 76%) as a pale yellow oil; 1H NMR (400 MHz, d6-DMSO) δ 8.34 (dd, J=4.8, 1.9 Hz, 1H), 7.88 (dd, J=7.5, 1.9 Hz, 1H), 7.43 (dd, J=7.5, 4.8 Hz, 1H), 3.86 (s, 2H), 3.65 (s, 3H). LCMS Method C: rt 5.04 min; m/z 186 [M+H]+.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([CH2:17][NH:18][CH3:19])[C:10]=1[O:11][C@H:12]1[CH2:16][CH2:15][O:14][CH2:13]1)[NH2:7].C(N(CC)C(C)C)(C)C.[CH2:29]([O:36][C:37]([O:39]N1C(=O)CCC1=O)=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[NH2:7][C:6]1[CH:5]=[C:4]([F:3])[C:10]([O:11][C@H:12]2[CH2:16][CH2:15][O:14][CH2:13]2)=[C:9]([CH:8]=1)[CH2:17][N:18]([CH3:19])[C:37](=[O:39])[O:36][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CNCc1cc(N)cc(F)c1O[C@H]1CCOC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cc(N)cc(F)c1O[C@H]1CCOC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To 39A (640 mg, 2.043 mmol), N,N-diisopropylethylamine (1.424 ml, 8.17 mmol) in DMF (10 ml), was added N-(benzyloxycarbonyloxy) succinimide (560 mg, 2.248 mmol). The mixture was stirred at rt for 1 h, quenched with water, extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography to give 39B (540 mg, 1.442 mmol, 70.6% yield). MS (ESI) m/z: 375.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[NH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1>N1C=CC=CC=1>[S:25]1[CH:26]=[CH:27][N:28]=[C:24]1[NH:23][S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C:2]([F:22])([F:21])[F:1])[CH2:6][CH2:7]2)=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: O=C(N1CCC(c2ccc(S(=O)(=O)Cl)cc2)CC1)C(F)(F)F
Reactant: Nc1nccs1
Solvent: c1ccncc1
Product: O=C(N1CCC(c2ccc(S(=O)(=O)Nc3nccs3)cc2)CC1)C(F)(F)F
Yield: 50.3 %

Procedure:
Prepared using general procedure 15, method A. A solution of 4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzene-1-sulfonyl chloride (3 g, 8.43 mmol) and 2-aminothiazole (0.84 g, 8.43 mmol) in pyridine (2 ml) was stirred overnight at RT. The reaction was quenched with water, extracted with DCM, dried over Na2SO4, filtered and concentrated. Purification via silica gel chromatography using 0-5% methanol in DCM gave N-(thiazol-2-yl)-4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)benzenesulfonamide (1.78 g, 50% yield). LC/MS: (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z M+1 obs=420.3; tR=1.41 min.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:20])[C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:23]1>CCCCO>[Br:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:23]2)=[C:4]2[C:10]([NH:11][C:12](=[O:20])[C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: Cc1cccnc1C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: CCCCO
Product: Cc1cccnc1C(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 160 °C
Reaction time: 48 h
Yield: 28 %

Procedure:
A solution of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylpicolinamide (197 mg, 0.566 mmol) in n-BuOH (5 mL) was treated with (R)-tert-butyl piperidin-3-ylcarbamate (453 mg, 2.263 mmol) and stirred at 160° C. for 48 hours in a sealed tube. The mixture was concentrated in vacuo, and the residue diluted with water (25 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The filtrate concentrated in vacuo, and the residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 5-85% CH3CN/water gradient; 25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(3-methylpicolinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (83.8 mg, 28% yield) as a solid. LCMS (APCI+) m/z 429.1, 431.1, 531.1 (M+H)+, Retention time=4.32 minutes (Method 2).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:30]=[N:29][N:28]([CH:31]([CH3:33])[CH3:32])[C:16]=2[N:17]=[C:18]([C:20]#[C:21][C:22]2[CH:27]=[CH:26]N=[CH:24][CH:23]=2)[CH:19]=1)=[O:13].O1CCC[CH2:35]1>[Pd].C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:30]=[N:29][N:28]([CH:31]([CH3:33])[CH3:32])[C:16]=2[N:17]=[C:18]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:35]=[CH:24][CH:23]=2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C#Cc3ccncc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: C1CCOC1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(CCc3ccccc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 8 h

Procedure:
To a suspension of palladium on carbon (0.063 g, 0.059 mmol) in ethanol (1 mL) under nitrogen was added N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-6-(4-pyridinylethynyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.13 g, 0.295 mmol) and then ethanol (5 mL) and tetrahydrofuran (THF) (1.5 mL). The suspension was stirred under an atmosphere of hydrogen (ca. 1 atm, balloon) overnight. The reaction mixture was then evacuated with nitrogen, and diluted with 10% MeOH/DCM. Celite was added and the contents stirred for 15 min., and then filtered through Celite (analytical grade) and washed with 10% MeOH/DCM. The filtrate was concentrated in vacuo and purified by silica gel chromatography (eluent: gradient of 5-95%. Dichloromethane/Chloroform containing 10% 2M ammonia (in methanol). The collected solid was dried in vacuum oven at 45° C. for 18 h. The final product was collected as 0.112 g (84%). LCMS E-S (M+H)=445.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (d, J=6.57 Hz, 6 H), 2.13 (s, 3 H), 2.21 (s, 3 H), 3.08-3.18 (m, 2 H), 3.22-3.29 (m, 2 H), 4.36 (d, J=5.05 Hz, 2 H), 5.18 (quin, J=6.69 Hz, 1 H), 5.90 (s, 1 H), 7.28 (d, J=6.06 Hz, 2 H), 7.53 (s, 1 H), 8.26 (s, 1 H), 8.38-8.47 (m, 2 H), 8.72 (t, J=5.05 Hz, 1 H), 11.56 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[C:22]([CH:25]=[O:26])[S:23][CH:24]=1)=[CH:16][CH:15]=3.[CH3:32][Mg]Br>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[C:22]([CH:25]([OH:26])[CH3:32])[S:23][CH:24]=1)=[CH:16][CH:15]=3
Reactant: C[Mg]Br
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(C=O)n4)ccc3n(C)c21
Product: CC(O)c1nc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)cs1

Procedure:
The process is carried out as indicated in Example 139 above, with compound A, 4-[3-(2,4-dichlorophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]-thiazole-2-carbaldehyde, and methylmagnesium bromide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:65]([O:69][C:70](=[O:76])[NH:71][CH2:72][CH2:73][CH2:74][NH2:75])([CH3:68])([CH3:67])[CH3:66]>C(Cl)Cl>[C:65]([O:69][C:70](=[O:76])[NH:71][CH2:72][CH2:73][CH2:74][NH:75][C:28]([C@H:9]1[C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:31])[C@:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]1)=[O:30])([CH3:68])([CH3:66])[CH3:67]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NCCCNC(=O)OC(C)(C)C)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (800 mg, 1.74 mmol) in methylene chloride (10 mL), HATU (Aldrich, 662 mg, 1.74 mmol) was added followed by the addition of DIPEA (1.74 mmol) and (3-amino-propyl)-carbamic acid tert-butyl ester (Aldrich, 1.74 mmol). The mixture was stirred at rt for 1 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (24 g column, eluent, EtOAc/Hexanes, 20%) to give a white solid. 810 mg.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C:13]2=[O:18])(=[O:11])=[O:10])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1.[CH:22]([O:35][C:36]([NH:38][C:39]1[N:47]=[CH:46][N:45]=[C:44]2[C:40]=1[N:41]=[CH:42][N:43]2[CH2:48][C:49](O)=[O:50])=[O:37])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH:22]([O:35][C:36]([NH:38][C:39]1[N:47]=[CH:46][N:45]=[C:44]2[C:40]=1[N:41]=[CH:42][N:43]2[CH2:48][C:49]([N:15]1[CH2:16][CH2:17][N:12]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][C:5]=2[N+:19]([O-:21])=[O:20])(=[O:11])=[O:10])[C:13](=[O:18])[CH2:14]1)=[O:50])=[O:37])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O)Cn1cnc2c(NC(=O)OC(c3ccccc3)c3ccccc3)ncnc21
Reactant: O=C1CNCCN1S(=O)(=O)c1ccc(F)cc1[N+](=O)[O-]
Agent: Cl
Product: O=C(Nc1ncnc2c1ncn2CC(=O)N1CCN(S(=O)(=O)c2ccc(F)cc2[N+](=O)[O-])C(=O)C1)OC(c1ccccc1)c1ccccc1
Yield: 58.4 %

Procedure:
The title compound (805 mg, 58%) was synthesized by reaction of 1-(4-fluoro-2-nitro-benzenesulfonyl)-piperazin-2-one HCl salt (679 mg, 2.0 mmol) with [6-N-(benzhydryloxycarbonyl)-adenin-9-yl]-acetic acid (807 mg, 2.0 mmol) as per the procedure of example 73. 1H NMR (DMSO-d6) δ 10.95 (s, 1H), 8.59 (s, 0.6H), 8.58 (s, 0.4H), 8.47˜8.40 (m, 1H), 8.33 (s, 0.6H), 8.30 (s, 0.4H), 8.26 (m, 1H), 7.88 (m, 1H), 7.53˜7.27 (m, 10H), 6.82 (s, 1H), 5.38 (s, 1.2H), 5.30 (s, 0.8H), 4.56 (s, 0.8H), 4.27 (s, 1.2H), 4.12˜4.06 (m, 2.4H), 3.91˜3.85 (br. m, 1.6H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3].[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH2:27][CH2:28][C:29](=O)[C:30]([OH:32])=[O:31])=[CH:19]1.C([BH3-])#N.[Na+]>>[C:30]([CH:29]([NH:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3])[CH2:28][CH2:27][C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:18][CH:19]=1)([OH:32])=[O:31]
Reactant: C[C@H](N)C(=O)N1C2CCCCC2C[C@H]1C(=O)O
Reactant: O=C(O)C(=O)CCc1c[nH]c2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](NC(CCc1c[nH]c2ccccc12)C(=O)O)C(=O)N1C2CCCCC2C[C@H]1C(=O)O

Procedure:
Condense 1-[(S)-alanyl]octahydroindole-2(S)-carboxylic acid (preparable as described in Example 1) and 4-(3-indolyl)-2-oxobutyric acid with sodium cyanoborohydride, using the procedure described in Example 5 to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:19]=1[C:20](O)=[O:21]>>[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:19]=1[C:20]([N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([C:14](=[O:16])[CH3:15])=[CH:3][C:2]=2[F:1])[CH2:9][CH2:10]1)=[O:21]
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3Cl)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure D described for example 2 from 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone and 2-chloro-5-methanesulfonyl-benzoic acid (Example B), 72%, white solid, M+H+: 439.1)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1)([CH3:14])[C:6](=[O:13])[NH:7]2.B(Br)(Br)Br.ClCCl>CO>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([N+:23]([O-:25])=[O:24])[CH:16]=1)([CH3:14])[C:6](=[O:13])[NH:7]2
Reactant: COc1ccc(C2(C)C(=O)Nc3cc(Cl)cc(Cl)c3C2=O)cc1[N+](=O)[O-]
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC1(c2ccc(O)c([N+](=O)[O-])c2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Yield: 43.7 %

Procedure:
The objective compound was prepared by the same procedure for the example 13, using a 5,7-dichloro-3-(4-methoxy-3-nitro-phenyl)-3-methyl-1H-quinoline-2,4-dione (0.12 g, 0.30 mmol) and BBr3 (0.90 mL, 1.0 M dichloromethane solution). After normal workup, the objective compound (50 mg, 48%) was obtained as pale yellow solid by a flash column chromatography (dichloromethane:methanol=30:1): 1H NMR (200 MHz, DMSO-d6) δ 1.58 (s, 3H, CH3), 7.05-7.09 (m, 2H, ArH), 7.14-7.31 (m, 2H, ArH), 7.61 (d, J=2.4 Hz, 1H, ArH); m.p. 239-240° C.; MS(EI) m/e 380 [M+], 193, 165, 135; HRMS m/e cacld. for C16H10N2O5Cl2 379.9967, found 379.9968.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:27])[N:3]=1.[O:28]=[C:29]([NH:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31].C([O-])([O-])=O.[Na+].[Na+].C(O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:27][C:4]1[N:3]=[C:2]([C:38]2[CH:37]=[CH:36][C:35]([NH:34][C:29](=[O:28])[C:30]([O:32][CH3:33])=[O:31])=[CH:40][CH:39]=2)[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=1
Reactant: Nc1nc(Cl)cc(OC(c2ccc(-c3cccc(F)c3)cc2)C(F)(F)F)n1
Reactant: COC(=O)C(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)C(=O)Nc1ccc(-c2cc(OC(c3ccc(-c4cccc(F)c4)cc3)C(F)(F)F)nc(N)n2)cc1
Yield: 57.4 %

Procedure:
4-chloro-6-(2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethoxy)pyrimidin-2-amine (320 mg, 0.806 mmol), methyl 2-oxo-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamino)acetate (320 mg, 0.95 mmol), dichlorobis(triphenylphosphine)palladium (79 mg, 0.11 mmol), and Na2CO3 (212 mg, 2.0 mmol) were added to a mixture of ethanol (10 mL) and water (10 mL) in a round-bottom flask. The flask was heated to reflux for 8 hours. The reaction mixture was cooled and solvent was removed. The residue was dissolved in 10 mL of 0.5 M NaOH solution, filtered, and the filtration was extracted with EtOAc. The organic portion was dried and the solvent was removed to get 250 mg of the above-named compound. 1H NMR (300 MHz, CD3OD): δ δ 7.90 (m, 2H), 7.77 (s, 3H), 7.60 (m, 2H), 7.44 (m, 2H), 7.22 (m, 1H), 7.10 (m, 1H), 7.05 (s, 1H), 6.83 (m, 1H), 5.09 (m, 1H), 3.67 (s, 3H); M+1=541.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=O)[CH3:2].C(N(CC)CC)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[N:10]1([CH2:9][CH2:8][CH2:7][N:6]=[C:4]=[N:3][CH2:1][CH3:2])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCNC(=O)NCCCN1CCCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN=C=NCCCN1CCCC1
Temperature: 0 °C
Yield: 66.8 %

Procedure:
To a solution of 31.0 g (0.156 mol) N-ethyl-N′-3-(1-pyrrolidinyl)propyl-urea in 500 mL dichloromethane was added 62.6 g (0.62 mol) triethylamine and the solution was cooled to 0° C. To this solution were then added 59.17 g (0.31 mol) 4-toluenesulfonyl chloride in 400 mL dichloromethane dropwise at such a rate as to maintain the reaction at 0-5° C. After the addition was complete, the reaction mixture was warmed to room temperature and then heated to reflux for 4 hours. After cooling to room temperature, the reaction mixture was washed with saturated aqueous potassium carbonate (3×150 mL). The aqueous phases were combined and extracted with dichloromethane. All organic phases were combined and concentrated under reduced pressure. The resultant orange slurry was suspended in 250 mL diethyl ether and the solution decanted off from the solid. The slurry/decantation process was repeated 3 more times. The ether solutions were combined and concentrated under reduced pressure to give 18.9 g (67%) of the desired product as a crude orange oil. A portion of the oil was distilled under vacuum to give a colorless oil distilling at 78-82° C. (0.4 mm Hg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[O:31][CH2:32][CH2:33][OH:34])[C:5]2=[CH:4][CH:3]=1.[CH3:36][Si:37]([C:40]#[CH:41])([CH3:39])[CH3:38].CCN(CC)CC>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:41]#[C:40][Si:37]([CH3:39])([CH3:38])[CH3:36])[CH:27]=[CH:26][C:25]=3[O:31][CH2:32][CH2:33][OH:34])[C:5]2=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2OCCO)N1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(OCCO)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 76 °C

Procedure:
To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (6.05 g, 9.71 mmol) prepared in example 190c in DMF (80 mL) were added trimethylsilylacetylene (10 mL), CuI (40 mg), Et3N (50 mL), PdCl2(Ph3P)2 (Aldrich, 205 mg, 0.29 mmol) were added. The mixture was purged with nitrogen and heated at 76° C. for 1.5 h, then cooled to room temperature. The mixture was poured into water, extracted with EtOAc several times. The extracts were combined and dried with sodium sulfate and dried to give a foam. The foam was purified by chromatography to give the title compound as a light yellow solid. Yield 3.28 g, 57%.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH3:40])[C:4]([C:34]2[N:38]([CH3:39])[N:37]=[CH:36][CH:35]=2)=[CH:5][C:6]=1[C:7]([NH:9][C@@H:10]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31])[CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22])=[O:8].C1C(=O)N([Cl:48])C(=O)C1>O1CCCC1>[Cl:1][C:2]1[N:3]([CH3:40])[C:4]([C:34]2[N:38]([CH3:39])[N:37]=[CH:36][C:35]=2[Cl:48])=[CH:5][C:6]=1[C:7]([NH:9][C@@H:10]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31])[CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22])=[O:8]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c(Cl)n1C
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c(Cl)n1C
Reaction time: 1 h

Procedure:
A solution of 2-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-1-methyl-5-(1-methyl-1H-pyrazol-5-yl)-1H-pyrrole-3-carboxamide (125 mg, 0.22 mmol) and NCS (29 mg, 0.22 mmol) in tetrahydrofuran (2.2 ml) was stirred at 70° C. in a sealed tube. LCMS showed a 1:1 mixture of two chlorination products along with starting material. Additional NCS (29 mg, 0.22 mmol) was added and the solution stirred an additional 1 h where LCMS showed complete conversion to the two chlorination products. The resulting solution was partitioned between DCM-H2O and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated, dry loaded onto silica and purified by column chromatography (2% MeOH in DCM (1% NH4OH)) affording an inseparable mixture of the desired title compound along with a chloro-regioisomer: LCMS (ES) m/e 604, 606 (M, M+2)+.