Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:20]([F:21])=[C:19]([F:22])[C:10]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[C:9]([F:23])[C:8]=1[F:24].Cl[CH2:26][C:27]([Cl:29])=[CH2:28].[Cl-].[NH4+]>O1CCCC1.O>[Cl:29][C:27](=[CH2:26])[CH2:28][C:7]1[C:20]([F:21])=[C:19]([F:22])[C:10]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[C:9]([F:23])[C:8]=1[F:24]
Reactant: C=C(Cl)CCl
Reactant: Fc1c(F)c(COC2CCCCO2)c(F)c(F)c1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(Cl)Cc1c(F)c(F)c(COC2CCCCO2)c(F)c1F
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (2.5M in hexane, 2.3 cm3) was added portionwise to a solution of 2-[4-bromo-2,3,5,6-tetrafluorobenzyloxy]tetrahydropyran (1.7 g) in dry tetrahydrofuran (10 cm3) under an atmosphere of dry nitrogen, whilst the reaction temperature was maintained between -30° C. and -20° C. After 15 minutes, copper (I) bromide-dimethyl sulphide complex (1.2 g) was added in one portion and the reaction temperature was maintained at -10° C. for 1 hour, after which time 1,2-dichloroprop-2-ene (1 cm3) was added, the reaction temperature then being allowed to warm to ±15° C. After 3 hours, water followed by saturated aqueous ammonium chloride solution was added to the reaction mixture, which was then extracted into diethyl ether. The organic layer was then washed with water and brine, dried, and the solvent evaporated under reduced pressure. The residue was then subjected to medium pressure column chromatography on a silica gel column using a Gilson apparatus, eluting with petroleum ether (boiling range 30°-40° C.) containing diethyl ether (10% by volume) to give 2-[4-(2-chloroprop-2-en-1-yl)-2,3,5,6-tetrafluorobenzyloxy]tetrahydropyran (1.5 g).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[F:12][C:13]1[CH:14]=[C:15]([C:21](=[O:23])[CH3:22])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>C1COCC1>[F:12][C:13]1[CH:14]=[C:15]([C:21]2([CH3:8])[CH2:22][O:23]2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(C(C)=O)cc1F
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1ccc(C2(C)CO2)cc1F
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(3-fluoro-4-methoxyphenyl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS, the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1B(O)O>>[N:3]1[C:4]2[N:5]([C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH:6]=[CH:7][C:2]=1[C:21]1[CH:20]=[C:19]([F:22])[CH:18]=[CH:17][C:16]=1[NH2:15]
Reactant: Brc1ccn2c(n1)nc1ccccc12
Reactant: Nc1ccc(F)cc1B(O)O
Product: Nc1ccc(F)cc1-c1ccn2c(n1)nc1ccccc12

Procedure:
The title compound was prepared using General Experimental Procedure A (Suzuki coupling reaction) from 2-bromobenzo[4,5]imidazo[1,2-a]pyrimidine and (2-amino-5-fluorophenyl)boronic acid. 2-(Benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)-4-fluoroaniline was obtained as a orange solid. 1H NMR (400 MHz, DMSO-d6): δ 9.75 (d, J=7.6 Hz, 1H), 8.49 (d, J=8.0 Hz, 1H), 8.26 (d, J=7.6 Hz, 1H), 7.99 (dd, J=11.2, 3.2 Hz, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.74 (d, J=7.2 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.29 (m, 1H), 6.95 (dd, J=9.2, 5.2 Hz, 1H); MS (ESI) m/z [M+H]+279.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].CO[C:19]([CH3:21])=[CH2:20].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.CCOC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][CH:19]([CH3:21])[CH3:20])=[O:4]
Reactant: C=C(C)OC
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: COC(=O)c1sc(-c2ccccc2)cc1NC(C)C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To a stirred solution of 3-Amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (1.82 g, 7.8 mmol) in 1,2-dichloroethane (40 mL) was added sequentially 2-methoxypropene (3.0 mL, 31.2 mmol), AcOH (1.8 mL, 31.2 mmol) and NaBH(OAc)3 (3.31 g, 15.6 mmol) and stirred for 2 hrs. It was then diluted with EtOAc and H2O. The aqueous solution was adjusted to pH=7 by adding NaHCO3. The aqueous phase was extracted with EtOAc, the combined extract was washed with brine and dried on MgSO4 and filtered. Purification on bond elute with hexane to 5% EtOAc-hexane furnished 3-Isopropylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester (2.07 g, 96% yield). 1H NMR (CDCl3, 400 MHz): δ 7.62 (d, 2H), 7.40 (m, 3H), 6.91 (s, 1H), 3.84 (s, 3H), 3.71 (m, 1H), 1.35 (d, 6H).
Reaction SMILES: Cl[C:2]1[CH:25]=[N:24][C:5]2=[N:6][C:7]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[N:9]=[C:4]2[CH:3]=1.[CH2:26](B(O)O)[CH3:27].C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:26]([C:2]1[CH:25]=[N:24][C:5]2=[N:6][C:7]([C:17]3[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[N:9]=[C:4]2[CH:3]=1)[CH3:27]
Reactant: CCB(O)O
Reactant: Cc1ccc(-c2nc3cc(Cl)cnc3nc2-c2ccc(C)cc2)cc1
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+]
Product: CCc1cnc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture comprising 7-chloro-2,3-di-p-tolylpyrido[2,3-b]pyrazine (step 1) (2.5 g, 7.24 mmol), ethyl boronic acid (0.748 g, 10.14 mmol) and K2CO3 (2.9 g, 21.73 mmol) was degassed with argon and treated with Pd(PPh3)4(0.418 g, 0.362 mmol). The resulting mixture was flushed with argon and heated at 100° C. for 12 h and heating continued overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated under vacuum. Purification of the crude product by chromatography on silica eluting with 10% EtOAc in hexane afforded the titled compound;
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@H:14]([F:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:17][C:18]1[CH:19]=[C:20]([CH:25]=[C:26]([Br:28])[CH:27]=1)[C:21]([O:23][CH3:24])=[O:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:4]([O:3][C:1]([N:8]1[CH2:15][C@H:14]([F:16])[CH2:13][C@H:9]1[C:10](=[O:12])[NH:17][C:18]1[CH:19]=[C:20]([C:21]([O:23][CH3:24])=[O:22])[CH:25]=[C:26]([Br:28])[CH:27]=1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)O
Reactant: COC(=O)c1cc(N)cc(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(Br)cc(NC(=O)[C@@H]2C[C@@H](F)CN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N-Boc-trans-4-fluoro-L-proline (500 mg, 2.14 mmol), methyl 3-amino-5-bromobenzoate (592 mg, 2.57 mmol) and HBTU (1.22 g, 3.22 mmol) in DMF (6 mL) was added DIPEA (734 μl, 4.29 mmol) and the resulting solution was stirred at RT under nitrogen overnight. The mixture was poured into water and extracted three times with EtOAc. The combined organic layers were washed twice with water, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane 100% to c-hexane/EtOAc 70:30) to give the desired material. TLC, Rf (c-hexane/EtOAc 1:2)=0.8; MS (LC/MS): 467.0/469.0 [M+Na]+, 345.1/347.0 [MH−Boc]+, 443.1/445.1 [M−H]−; tR (HPLC conditions a): 3.77 min.
Reaction SMILES: [CH3:1][N:2]1[C:14]([CH2:15][CH:16]([CH3:18])[CH3:17])=[C:13]2[C:4]([C:5]([NH2:19])=[N:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=32)=[N:3]1.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>C(Cl)(Cl)Cl.[Pt](=O)=O>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[CH3:1][N:2]1[C:14]([CH2:15][CH:16]([CH3:17])[CH3:18])=[C:13]2[C:4]([C:5]([NH2:19])=[N:6][C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=32)=[N:3]1
Reactant: CC(C)Cc1c2c(nn1C)c(N)nc1ccccc12
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(C)Cc1c2c3c(nc(N)c2nn1C)CCCC3
Reaction time: 24 h

Procedure:
A solution of 2-methyl-1-(2-methylpropyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (0.6 g, 2 mmol), prepared as described in Example 3, in trifluoroacetic acid (10 mL) was treated with platinum (IV) oxide (0.5 g) and shaken under hydrogen pressure (50 psi, 3.4×105 Pa) for 24 hours. The reaction mixture was diluted with chloroform (20 mL) and filtered through a layer of CELITE filter agent. The filtrate was concentrated under reduced pressure and dissolved in chloroform (50 mL). The solution was adjusted to pH 12 with the addition of ammonium hydroxide and stirred for 20 minutes. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was recrystallized from acetonitrile to provide 0.3 g of 2-methyl-1-(2-methylpropyl)-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine trifluoroacetate as a white powder, mp 204-206° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH:9]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH3:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:19]I>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]([CH3:19])([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(C(=O)c1ccc(Cl)cc1)n1cncn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C(=O)c1ccc(Cl)cc1)n1cncn1
Reaction time: 0.17 h
Yield: 79.3 %

Procedure:
4'-Chloro-2-(1H-1,2,4-triazol-1-yl)propiophenone (2 g.) in dry tetrahydrofuran (30 ml) was added to a suspension of sodium hydride (480 mg. of a 60% dispersion in oil) in dry tetrahydrofuran (20 ml) at 0° under a nitrogen atmosphere. After stirring for 10 minutes, methyl iodide (2.28 g.) in dry tetrahydrofuran (10 ml.) was added dropwise and the reaction mixture was then stirred at 0° for 1 hour and then at room temperature overnight. The reaction mixture was then diluted with water (20 ml), extracted with ether (3×25 ml), and the combined organic extracts were washed with water and dried (MgSO4). The residue obtained after removal of the solvent was flash chromatographed on silica (150 g.) using ethyl acetate/hexane/diethylamine (50:50:3 v/v/v) for elution and the product-containing fractions on evaporation followed by crystallisation of the residue from ethyl acetate/hexane furnished the title compound, (1.68 g., 84% yield), m.p. 118°-9°.
Reaction SMILES: [C:1]1(=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:2]1.F[B-](F)(F)F.[CH3:18][O+:19]([CH3:21])C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:18][O:19][C:21]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:1][N:2]=1
Reactant: C[O+](C)C
Reactant: O=C1CCCCCCCCCN1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC1=NCCCCCCCCCC1
Temperature: 25 °C

Procedure:
2-Azacycloundecanone (0.87 g) was dissolved in 20 mL methylene chloride and stirred at room temperature under nitrogen. 1.5 g Trimethyloxonium tetrafluoroborate was added and the reaction stirred overnight. The mixture was added to saturated aqueous sodium bicarbonate and extracted with methylene chloride (2×). The combined organic layers were washed with brine, dried over magnesium sulfate, and the solvent evaporated to provide crude 2-methoxyazacyclododec-1-ene.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([Mg]Cl)(C)C.[CH3:16][O:17][C:18]1[CH:35]=[CH:34][C:21]([CH2:22][N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:32])[C:24]2=[O:33])=[CH:20][CH:19]=1.Cl>O1CCCC1.ClCCCl>[OH:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([C:25]2([OH:32])[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:23]([CH2:22][C:21]3[CH:34]=[CH:35][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[C:24]2=[O:33])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COc1ccc(CN2C(=O)C(=O)c3ccccc32)cc1
Reactant: N#Cc1ccc(O)cc1O
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCCl
Product: COc1ccc(CN2C(=O)C(O)(c3cc(C#N)c(O)cc3O)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
To a stirred solution of 2,4-dihydroxybenzonitrile (4.33 g, 32.1 mmol) in tetrahydrofuran (50 mL) and 1,2-dichloroethane (400 mL) was added isopropylmagnesium chloride (17.7 mL, 2.0 M solution in tetrahydrofuran, 35.4 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h and at ambient temperature for 2 h, and 1-(4-methoxybenzyl)-1H-indole-2,3-dione (8.58 g, 32.1 mmol) was added to the reaction mixture. The mixture was stirred at reflux for 18 h, cooled to 0° C. and 5% v/v hydrochloric acid was added. The organic layer was separated and washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography and eluted with ethyl acetate/hexanes (1/1) to afford 2,4-dihydroxy-5-[3-hydroxy-1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile (10.30 g, 79%): 1H NMR (300 MHz, DMSO-d6) δ 10.81 (s, 1H), 10.35 (s, 1H), 7.80 (s, 1H), 7.32 (d, J=9.0 Hz, 1H), 7.14-7.08 (m, 1H), 6.88-6.84 (m, 4H), 6.75-6.72 (m, 1H), 6.63 (s, 1H), 6.30 (s, 1H), 4.79 (ABq, 2H), 3.70 (s, 3H); MS (ES+) m/z 384.8 (M−17).
Reaction SMILES: [C:1]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:43])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:42])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH3:34])=[CH:29][CH:28]=2)[CH3:19])[CH2:12][CH2:11]1.C(N(CC)CC)C.[C:57](Cl)(=[O:66])[O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1.C(=O)([O-])O.[Na+]>ClCCl>[C:1]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([CH3:19])[C:20](=[O:42])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([C:27]2[CH:28]=[CH:29][C:30]([N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])[CH3:34])=[CH:31][CH:32]=2)[C:57](=[O:66])[O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[CH2:12][CH2:11]1)=[O:43]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc(N(C)C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCN(C(=O)OCc1ccccc1)c1ccc(N(C)C(=O)OC(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
The compound (257 mg, 0.383 mmol) obtained in Example 83b was dissolved in dichloromethane (4 mL), triethylamine (107 mL, 0.766 mmol) and benzyl chlorocarbonate (0.082 mL, 0.58 mmol) were added, and the mixture was stirred at 50° C. for 2 hours. A saturated aqueous sodium hydrogencarbonate solution was added, the mixture was extracted with methylene chloride (×3), and the resulting organic layer was dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was dissolved in tetrahydrofuran (4 mL), 55% sodium hydride-paraffin (25.0 mg, 0.573 mmol) and benzyl chlorocarbonate (0.082 mL, 0.58 mmol) were added, and the mixture was stirred. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and dichloromethane was further added to separate the layers. The resulting organic layer was separated and dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography to give the title compound (235 mg; yield, 76%) as a brown oily substance.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([C:13]([CH3:50])([CH3:49])[C:14]([N:16]([CH3:48])[C:17]2[C:18]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=3[CH3:47])=[CH:19][C:20]([C:23]#[C:24][CH2:25][C@:26]([NH:32]C(OC(C)(C)C)=O)([CH3:31])[C:27]([O:29][CH3:30])=[O:28])=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]([CH3:50])([CH3:49])[C:14]([N:16]([CH3:48])[C:17]2[C:18]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=3[CH3:47])=[CH:19][C:20]([C:23]3[CH2:24][CH2:25][C@:26]([CH3:31])([C:27]([O:29][CH3:30])=[O:28])[N:32]=3)=[N:21][CH:22]=2)=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:51])[F:52])[CH:8]=1
Reactant: COC(=O)[C@@](C)(CC#Cc1cc(-c2ccc(F)cc2C)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1)NC(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@]1(C)CCC(c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)=N1
Temperature: 20 °C
Yield: 100.4 %

Procedure:
Methyl (2R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)pyridin-2-yl]-2-[(tert-butoxycarbonyl)amino]-2-methylpent-4-ynoate (Intermediate 22, 1.23 Kg) was suspended in 6.2 L DCM at room temperature under inert atmosphere. The mixture was then heated to reflux (clear solution obtained at 30° C.). TFA (990 ml) was added dropwise over one hour. The resulting solution was stirred for at least 6 h at reflux and then was cooled to 20° C.±5° C. Water (6.15 L) was added and the biphasic mixture was stirred for 15 min. Layers were separated and the aqueous layer (top) was discarded. 6.1 L10% w/w aqueous potassium carbonate was added to the DCM layer and the biphasic mixture was stirred for 15 min. Layers were separated and the top layer (aqueous) was discarded. The DCM layer was dried over magnesium sulfate and was filtered. Acetonitrile (620 ml) was added to the above DCM solution and silver triflate (128.4 g,) was also charged to the vessel. The resulting mixture was then heated to reflux and stirred for 24 h. It was then cooled to 20° C. and quenched with 8.6 L. saturated ammonium chloride. The mixture was stirred for 1 h at 20° C. and was then cooled to 0° C. and stirred for 1 h. The silver chloride precipitate was then filtered cold and the resulting biphasic solution was allowed to warm to 20° C. Layers were separated. The top aqueous layer was discarded. The organic layer was dried over magnesium sulfate, filtered and evaporated to dryness under vacuum to give the title compound (1067.6 g).
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([F:31])[CH:24]=3)[N:11]([C:14]3[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[C:18]([Cl:20])[CH:19]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:32][O:33][C:34]1[N:39]=[C:38]([O:40][CH3:41])[C:37](B(O)O)=[CH:36][N:35]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.COC1C(B2OC(C)(C)C(C)(C)O2)=CN=C(N)N=1>>[Cl:20][C:18]1[CH:19]=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:37]4[C:38]([O:40][CH3:41])=[N:39][C:34]([O:33][CH3:32])=[N:35][CH:36]=4)[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]=3[CH:10]2[C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([F:31])[CH:24]=2)[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(C#N)c(F)c1)N(c1cc(Cl)cn(C)c1=O)C2=O
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ncc(-c2cc3c(n2C(C)C)C(c2ccc(C#N)c(F)c2)N(c2cc(Cl)cn(C)c2=O)C3=O)c(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 25 but 4-[2-bromo-5-(5-chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-6-yl]-2-fluoro-benzonitrile (Intermediate BD) and 2,4-dimethoxypyrimidine-5-boronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine respectively to afford the title compound as a white solid. tR: 1.04 min (HPLC 3); ESI-MS: tR=1.01 min, [M+H]+ 563/565 (LC-MS 1); TLC: Rf=0.27 (EtOAc).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:27]C(=O)OC(C)(C)C)[CH2:10][CH2:11][N:12]2[CH:16]=[C:15]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22]C(=O)C4)[CH:14]=[N:13]2)=[CH:4][CH:3]=1.[C:35]([OH:41])(C(F)(F)F)=[O:36]>C(Cl)Cl>[NH2:27][C@@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([C:17]2[CH:25]=[CH:24][C:23]3[NH:22][C:35](=[O:36])[O:41][C:19]=3[CH:18]=2)[CH:14]=[N:13]1
Reactant: CC(C)(C)OC(=O)N[C@H](CCn1cc(-c2ccc3c(c2)CC(=O)N3)cn1)Cc1ccc(Cl)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](CCn1cc(-c2ccc3[nH]c(=O)oc3c2)cn1)Cc1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
tert-Butyl(S)-1-(4-chlorophenyl)-4-(4-(2-oxoindolin-5-yl)-1H-pyrazol-1-yl)butan-2-ylcarbamate was dissolved in DCM (2 mL), TFA (2 mL, 26 mmol) was added, and the mixture was stirred for 2 hours. The mixture was concentrated by vacuum distillation and partially purified with reverse-phase HPLC (Phenomenex Synergi 4m Max RP 80 A column, 150×21 mm, 20 mL/min, 10-95% CH3CN/H2O 0.1% TFA, 10.5 minute gradient). After concentrating the sample by vacuum distillation, the residue was dissolved in MeOH and loaded onto an Agilent AccuBOND II SCX solid phase extraction column. After washing with MeOH, the desired compound was eluted with 2M NH3 in MeOH. The residue was partially purified using column chromatography (2M NH3 in MeOH/DCM 0-5%). The residue was purified SFC chromatography (Princeton Chromatography Pyridine column 21×250 mm, 5 um, 65 mL/min, 40° C., outlet pressure 100 bar, 220 nm, 10-50% MeOH 2% DEA/CO2, 5 minute gradient) to give a tan film (7.1 mg, 4%). HRMS (TOF) Calcd for C20H20ClN4O2+: 383.1269, found: 383.1268.