Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[NH:10][CH:11]=O.P(Cl)(Cl)(Cl)=O.N1C(C)=CC=CC=1C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O1CCCC1>[C:19]1([CH3:22])[CH:18]=[CH:17][C:16]([S:13]([CH:9]([N+:10]#[C-:11])[C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])(=[O:15])=[O:14])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)C(NC=O)c2cc(F)ccc2F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Solvent: O=P(Cl)(Cl)Cl
Product: [C-]#[N+]C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(C)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a clean a dry nitrogen purged acetone boiled out 100 gallon glass lined reactor was charged, 7.9 Kg of N-[(2,5-Difluoro-phenyl)-(toluene-4-sulfonyl)-methyl]-formamide (24, moles), 16 gallons of tetrahydrofuran and 7.8 Kg of phosphorous oxychloride (51 moles). The batch was allowed to stir at 20° C. for 30 minutes and then cooled to 3.5° C. To the batch was added 15.8 Kg of 2,6-lutidine (146 moles) over 15 minutes. The reaction mixture was allowed to warm to 23° C. and was stirred for 17 hours at 23° C. The reaction was judged complete by HPLC and was charged to a 40 gallon solution of 10% sodium bicarbonate at 22° C., and the contents were allowed to stir for 30 minutes. To the batch was then added 25 gallons of ethyl acetate and the layers were separated. The water layer was backwashed with 9 gallons of ethyl acetate and the product rich ethyl acetate combined with the first wash. The product rich ethyl acetate layers were added to a 10% citric acid solution (20 gallons) and then stirred. The organic layer was checked by HPLC for 2,6 lutidine and then separated. The organic layer was washed with 10 gallons of saturated NaCl and dried over 7.9 Kg of magnesium sulfate. The drying agents were removed by filtration and the cake was washed with 4 gallons of ethyl acetate. The ethyl acetate layer was concentrated to 7 gallons under vacuum at an internal temperature of 24° C. The batch was then added to 11 gallons of IPO at 21° C. and allowed to granulate at 4° C. for 12 hours. The product was isolated via filtration and washed with 4 gallons of 5° C. IPO. The product was then dried at 34° C. for 22 hours with nitrogen bleed to recover 5.0 Kg of the title compound (66% yield).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([C@@H:9]3[CH2:12][C@H:11]([OH:13])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[N:16]1[CH:21]=[C:20](B(O)O)[CH:19]=[N:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.C(O)C.O1CCOCC1>[N:16]1[CH:21]=[C:20]([C:2]2[CH:15]=[CH:14][C:5]3[N:6]=[C:7]([C@@H:9]4[CH2:12][C@H:11]([OH:13])[CH2:10]4)[S:8][C:4]=3[CH:3]=2)[CH:19]=[N:18][CH:17]=1
Reactant: OB(O)c1cncnc1
Reactant: O[C@H]1C[C@@H](c2nc3ccc(Br)cc3s2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: O[C@H]1C[C@@H](c2nc3ccc(-c4cncnc4)cc3s2)C1
Temperature: 140 °C
Yield: 81.1 %

Procedure:
The product of Example 1D (100 mg, 0.35 mmole), pyrimidine-5-boronic acid (65 mg, 0.53 mmole), dichlorobis(triphenylphosphine)palladium(II) (14.8 mg, 0.0021 mmole), 2-(dicyclohexyl-phosphino)biphenyl (7.4 mg, 0.021 mmole), sodium carbonate (1 M solution, 0.53 ml, 0.53 mmole) and 2 ml of ethanol/dioxane (1:1) were mixed under N2 in a capped, sealed vial. The vial was sealed heated in the microwave for 10 minutes at 140° C. using a commercial microwave heating apparatus (i.e. the Emrys Creator). The reaction mixture was quenched with water and extracted with dichloromethane (4×5 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product which was purified by column chromatography (10% methanol in dichloromethane) to give 80.4 mg (84.6% yield) of title compound. 1H NMR (300 MHz, CDCl3) δ ppm 9.25 (s, 1H), 9.03 (s, 2H), 8.14 (d, J=8.48 Hz, 1H), 8.07 (d, J=1.70 Hz, 1H), 7.67 (dd, J=8.48, 2.03 Hz, 1H), 4.40 (m, 1H), 3.50 (m, 1H), 3.01 (m, 2H), 2.46 (m, 2H), 2.17 (brs, 1H). MS: (M+H)+=284.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[NH4+].[Cl-]>CO.O.[Fe]>[I:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:11][CH3:12])[NH2:8]
Reactant: COc1ccc([N+](=O)[O-])cc1I
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COc1ccc(N)cc1I
Yield: 92.3 %

Procedure:
To 2-iodo-1-methoxy-4-nitrobenzene (485 mg, 1.74 mmol) suspended in methanol (6 mL) a solution of NH4Cl (465 mg, 8.69 mmol) in water (4.9 mL) and powdered Fe (290 mg, 5.192 mmol) were added and the mixture was heated to reflux for 3 h. The precipitate formed was filtered off and the filtrate was evaporated until the methanol was eliminated. After diluting with water and alkalinization with sodium carbonate the mixture was extracted with EtOAc (4×20 mL). The combined organic extracts were washed with brine (3×10 mL), water (10 mL), dried over sodium sulfate and the solvent was removed under vacuum. The crude dark oil was purified by flash chromatography on silica gel (hexane/EtOAc 1/1) to afford 400 mg of solid that was crystallized from n-pentane and diethyl ether to yield the title compound (363 mg, 83%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[Cl:6][C:7]1[N:16]=[C:15](Cl)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1>C(OCC)C>[Cl:6][C:7]1[N:16]=[C:15]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CCNCC
Solvent: CCOCC
Product: CCN(CC)c1nc(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
10.4 ml of diethylamine in 10 ml of diethyl ether were added dropwise to a solution of 10.0 g of 2,4-dichloroquinazoline in 400 ml of diethyl ether and the mixture was stirred for 3 h at room temperature. After distillation of the solvent under vacuum, the residue was taken up with 200 ml of methanol and stirred with 10 g of basic ion exchanger (®Lewatit M600) for 3 h. The ion exchanger was filtered off and the filtrate was concentrated to dryness on a rotary evaporator. The residue was taken up with 200 ml of dichloromethane and the solution was washed with twice 50 ml of water. After the organic phase had been dried over magnesium sulfate and the solvent stripped off, the crude product was treated with 50 ml of diethyl ether/petroleum ether (1/1) and left to crystallize at 4° C. overnight.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][N:8]([C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[F:38][C:39]1[C:52]([O:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH3:59])=[CH:51][C:50]2[O:49][C:48]3[C:43](=[CH:44][C:45]([F:67])=[C:46]([O:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH3:66])[CH:47]=3)[C:42](=[O:68])[C:41]=2[CH:40]=1>C1COCC1.CC1CCCO1.C1COCC1>[C:1]([O:5][C:6](=[O:32])[CH2:7][N:8]([C:17]1[CH:22]=[CH:21][C:20]([C:42]2([OH:68])[C:43]3[CH:44]=[C:45]([F:67])[C:46]([O:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH3:66])=[CH:47][C:48]=3[O:49][C:50]3[C:41]2=[CH:40][C:39]([F:38])=[C:52]([O:53][CH2:54][O:55][CH2:56][CH2:57][O:58][CH3:59])[CH:51]=3)=[CH:19][C:18]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCOCOc1cc2oc3cc(OCOCCOC)c(F)cc3c(=O)c2cc1F
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)c1ccc(Br)cc1OCc1ccccc1
Agent: [Li]C(C)(C)C
Solvent: CC1CCCO1
Solvent: C1CCOC1
Product: COCCOCOc1cc2c(cc1F)C(O)(c1ccc(N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)c(OCc3ccccc3)c1)c1cc(F)c(OCOCCOC)cc1O2
Temperature: -105 °C
Reaction time: 0.17 h
Yield: 69.3 %

Procedure:
The bromide 13 (807 mg, 1.59 mmol) was dissolved in 20 mL THF/2-methyltetrahydrofuran (1:1) and cooled to −105° C. in a liquid N2/diethyl ether bath. After stirring at −105° C. for 10 min, 4.5 mL of tert-butyllithium (1.1 M in pentanes) was added dropwise. Stirring was continued for another 15 min. 2,7-difluoro-3,6-bis-(2-methoxy-ethoxymethoxy)-xanthen-9-one 9 (912 mg, 2.07 mmol) dissolved in THF (10 mL) was added dropwise to the reaction mixture. The mixture was stirred at −105° C. for 30 min, the cooling bath removed, and the reaction solution was then stirred for an additional 15 min. The resulting mixture was added to 150 mL NH4Cl(sat) and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography, eluting with 50% EtOAc in hexane (with 0.1% Et3N) to yield 956 mg (69%) of 14 as a orange-red oil. Rf=0.33 (in 50% EtOAc/hexane); 1H NMR (300 MHz, CDCl3) δ 7.32-7.27 (m, 5H), 6.97 (d, 2H, J=6.98 Hz), 6.86 (m, 3H), 6.72 (m, 2H), 5.30 (s, 4H), 5.05 (s, 2H), 4.02 (s, 4H), 3.85 (m, 4H), 3.56 (m, 4H), 3.36 (s, 6H), 1.38 (s, 18H); 13C NMR (75 MHz, CDCl3) δ 170.5, 150.8, 149.3, 147.6, 145.6, 145.5, 145.4, 145.2, 140.5, 138.4, 136.9, 128.3, 127.7, 127.5, 119.9, 119.8, 119.3, 118.4, 115.2, 114.9, 113.0, 104.9, 94.5, 81.0, 71.4, 70.6, 69.7, 68.1, 58.9, 54.6, 28.0; 19F NMR (282 MHz, CDCl3) δ −139.0 (dd, 2 F); mass spectrum, calculated for C46H55F2NO13 (MH+) 868.4, Found 867.8.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33]Cl)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>C(Cl)Cl.CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][N:53]4[CH2:58][CH2:57][O:56][CH2:55][CH2:54]4)[CH:26]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CCl)c3)c3ccccc23)cc1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCc3ccnc(NC(=O)CN4CCOCC4)c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.2 %

Procedure:
To a solution of N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-chloroacetamide (Intermediate B) (50 mg, 0.08 mmol) in DCM (1.0 mL), DMF (0.1 mL) and DIPEA (21.9 μl, 0.13 mmol) was added morpholine (11.0 μl, 0.13 mmol). The reaction mixture was stirred at RT for 3 hr. LC-MS indicated 20% conversion to product. The reaction mixture was heated to 40° C. and stirred for 12 hr. LC-MS indicated 87% conversion to product. A further portion of morpholine (11.0 μl, 0.13 mmol) was added and the reaction mixture stirred at 40° C. for 5 hr. LC-MS indicated 94% conversion to product. The crude reaction mixture was purified by column chromatography (12 g, 0-10% MeOH in DCM, gradient elution). Product fractions were concentrated in vacuo and the residue triturated with MeOH (5.0 mL). The solid was collected by filtration to afford N-(4-((4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)methyl)pyridin-2-yl)-2-morpholinoacetamide (Example 7) as a light yellow solid (11 mg, 20%): m/z 648 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.27 (9H, s), 2.39 (3H, s), 2.54 (4H, m), 3.20 (2H, s), 3.63 (4H, m), 5.39 (2H, s), 6.35 (1H, s), 7.01 (1H, d), 7.28 (1H, d), 7.35 (2H, d), 7.43 (2H, d), 7.63-7.56 (3H, m), 7.92 (1H, d), 8.37-8.29 (3H, m), 8.58 (1H, s), 8.79 (1H, s), 10.01 (1H, s).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:26])[NH:15][C:16]2[S:17][C:18]3[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:19]=3[N:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.C(N(CC)CC)C>CC(C)=O>[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]([NH:15][C:16]2[S:17][C:18]3[CH:24]=[C:23]([O:25][S:34]([C:31]4[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=4)(=[O:36])=[O:35])[CH:22]=[CH:21][C:19]=3[N:20]=2)=[O:26])[CH2:12][CH2:13]1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2nc3ccc(O)cc3s2)CC1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1)C1CCNCC1
Yield: 76.5 %

Procedure:
A solution of 4-(6-hydroxybenzothiazol-2-ylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester (intermediate 2) (454 mg, 1.20 mmol), of 4-fluoro-benzenesulfonyl chloride (234 mg, 1.20 mmol) and of triethylamine (320 μl) in 10 ml of acetone is stirred at room temperature for 1 hour. The triethylamine hydrochloride is filtered off and the filtrate is evaporated. The crude reaction product is purified by column chromatography (eluent: EtOAc/heptane (7/3)) to give 400 mg of 4-fluorobenzenesulfonic 2-[(piperidine-4-carbonyl)amino]-benzothiazol-6-yl ester (white solid).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:27](=[O:28])[N:26]([CH3:29])[C:11]3[N:12]([CH3:25])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[NH:20][N:21]=[CH:22][C:23]=2[CH3:24])=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.[CH3:30][O:31][CH2:32]Br>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:27](=[O:28])[N:26]([CH3:29])[C:11]3[N:12]([CH3:25])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:19]2[C:23]([CH3:24])=[CH:22][N:21]([CH2:30][O:31][CH3:32])[N:20]=2)=[CH:15][CH:14]=4)=[CH:4][CH:3]=1
Reactant: COCBr
Reactant: Cc1cn[nH]c1-c1ccc2c(c1)c1cc(-c3ccc(F)cc3)c(=O)n(C)c1n2C
Product: COCn1cc(C)c(-c2ccc3c(c2)c2cc(-c4ccc(F)cc4)c(=O)n(C)c2n3C)n1

Procedure:
The process is carried out as in Example 36 above, using compound from Example 112, 3-(4-fluorophenyl)-1,9-dimethyl-6-(4-methyl-2H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one and bromomethyl methyl ether.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[OH-].[Na+].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>O>[C:18]1([CH2:17][O:16][C:14]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:15])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Yield: 86.9 %

Procedure:
A suspension of L-glutamic acid (23.5 g; 160 mmol) in H2O (100 mL) was stirred, maintaining the pH at 8.5 with 10 M NaOH until complete dissolution. Benzyl chloroformate (35 g; 205 mmol) was added over 15 min to the clear solution. The mixture was stirred, maintaining the pH at 9 by adding 10 M NaOH until the reaction was complete. The cloudy mixture was washed with Et2O (3×150 mL) and then the pH of the resulting solution was adjusted to 2.1 with 1 M HCl. The cloudy aqueous mixture was extracted with Et2O (2×200 mL), the organic layers were collected and evaporated to yield the desired product (39.13 g; 139 mmol). Yield 87%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[C@@H:7]([NH:11][C:12]([C@H:14]1[C@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[C@:17]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)([C:26]#[N:27])[C@H:16]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:15]1)=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.C(OC(=O)[C@@H](NC([C@@H]1[C@@H](C2C=CC=C(Cl)C=2)[C@@](C2C=CC(Cl)=CC=2)(C#N)[C@@H](CC(C)(C)C)N1)=O)C(C)C)(C)(C)C>CO>[CH3:1][O:5][C:6](=[O:40])[C@@H:7]([NH:11][C:12]([C@@H:14]1[C@@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[C@@:17]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)([C:26]#[N:27])[C@@H:16]([CH2:35][C:36]([CH3:37])([CH3:39])[CH3:38])[NH:15]1)=[O:13])[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)[C@H](NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2)[C@H]1c1cccc(Cl)c1)C(=O)OC(C)(C)C
Agent: CC(C)[C@H](NC(=O)[C@H]1N[C@H](CC(C)(C)C)[C@@](C#N)(c2ccc(Cl)cc2)[C@@H]1c1cccc(Cl)c1)C(=O)OC(C)(C)C
Solvent: CO
Product: COC(=O)[C@@H](NC(=O)[C@H]1N[C@H](CC(C)(C)C)[C@@](C#N)(c2ccc(Cl)cc2)[C@@H]1c1cccc(Cl)c1)C(C)C

Procedure:
Column separation from the above example (Example 10a) gave a mixture of (S)-2-{[(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methyl-butyric acid tert-butyl ester and (S)-2-{[(2S,3S,4S,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methyl-butyric acid tert-butyl ester (45.8 mg, 15.6%). The mixture was treated with 2NH2SO4 (catalytic) in MeOH (1 mL) at 120° C. for 10 min using CEM microwave reactor to give after purification by reverse phase chromatography (20-95% of MeCN/water): (S)-2-{[(2S,3S,4S,5R)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methyl-butyric acid methyl ester (13.5 mg, 31.8%).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[CH3:21][CH2:22][O:23]C(C(F)F)=O>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:22](=[O:23])[CH3:21])[CH:15]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CCOC(=O)C(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(=O)c1cc(Br)ccc1F
Temperature: -70 °C
Reaction time: 2.5 h

Procedure:
A solution of 17.78 ml (126 mmol) diisopropyl amine in 375 ml THF was cooled to −78° C. A 1.6 M solution of BuLi in hexanes (79 ml, 126 mmol) was added drop wise. After 15 minutes 20 g of 4-bromo-1-fluoro benzene (114 mmol) was added dropwise while keeping the temperature below −60° C. After stirring for 2.5 h at −70° C. 13.22 ml ethyl difluoro acetate were added. The mixture was warmed to −40° C. and then quenched by pouring the mixture onto 1M HCl. The mixture was extracted with ligroine, dried with MgSO4.H2O, concentrated and purified by column chromatography (silica gel; hexane/5-15% TBME) to give the desired product as a yellow liquid. 1H-NMR (CDCl3, 360 MHz): 8.09 (dd, 1H), 7.82-7.77 (m, 1H), 7.17 (t, 1H), 6.45 (t, 1H, CHF2)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]([N:31]3[CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][C:37]=4[F:40])[CH2:32]3)=[O:30])[CH2:27][C@H:21]2[C:20](=[O:41])[NH:19][C@:18]2([C:43]([O:45]CC)=[O:44])[CH2:42][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CCOCC>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]([N:31]3[CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][C:37]=4[F:40])[CH2:32]3)=[O:30])[CH2:27][C@H:21]2[C:20](=[O:41])[NH:19][C@:18]2([C:43]([OH:45])=[O:44])[CH2:42][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCOC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](OC(=O)N3Cc4cccc(F)c4C3)C[C@H]1C(=O)N2
Agent: CC(C)(C)OC(=O)N[C@H]1COCCC/C=C\[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCOC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](OC(=O)N3Cc4cccc(F)c4C3)C[C@H]1C(=O)N2
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1COCCCC=C[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Temperature: 25 °C
Reaction time: 26 h

Procedure:
(2R,6S,13aS,14aR,16aS,Z)-ethyl 6-(tert-butoxycarbonylamino)-2-(4-fluoroisoindoline-2-carbonyloxy)-5,16-dioxo-2,3,5,6,7,9,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(i) pyrrolo[1,2-e][1,5,8]oxadiazacyclopentadecine-14a-carboxylate (0.16 g, 0.25 mmol) in THF (2 mL) was added 0.1 N NaOH solution (6.22 ml, 0.62 mmol) in H2O. The reaction was stirred at rt for 26 hr. Water (5 mL) and ether (15 mL) was added. The aqueous layer was separated and acidified by saturated potassium hydrogen sulfate solution to pH=2-3. The aqueous layer was extracted with EA (2×15 mL), washed with brine and dried over sodium sulfate. After removal of solvent, it gave (2R,6S,13aS,14aR,16aS,Z)-6-(tert-butoxycarbonylamino)-2-(4-fluoroisoindoline-2-carbonyloxy)-5,16-dioxo-2,3,5,6,7,9,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(i) pyrrolo[1,2-e][1,5,8]oxadiazacyclopentadecine-14a-carboxylic acid as white solid (0.13 g, 80%). MS: Calcd.: 630. Found: [M+H]+ 631. 1H NMR (400 MHz, d6-DMSO) M2.33 (s, 1H), 8.05 (d, J=19.6 Hz, 1H), 7.32 (m, 1H), 7.05-7.17 (m, 2H), 6.91 (m, 1H), 5.49 (m, 1H), 5.30 (m, 1H), 5.25 (s, 1H), 4.63 (s, 4H), 4.42 (m, 1H), 4.34 (m, 1H), 4.07 (m, 1H), 3.77 (m, 1H), 3.60 (m, 1H), 3.44 (m, 2H), 2.13-2.30 (m, 4H), 1.46-1.55 (m, 3H), 1.38 (m, 1H), 1.26 (m, 1H), 1.13-1.14 (m, 10H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:33][CH2:34][CH3:35])=[C:16]([CH:22]4[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]4)[C:17]([F:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10](I)[C:3]=12.N1C=CC=[CH:38][CH:37]=1.C(B1OB(C=C)OB(C=C)O1)=C.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:33][CH2:34][CH3:35])=[C:16]([CH:22]4[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]4)[C:17]([F:21])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH:37]=[CH2:38])[C:3]=12
Reactant: CCOc1c(C(C)n2nc(I)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Reactant: c1ccncc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C=CB1OB(C=C)OB(C=C)O1
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: C=Cc1nn(C(C)c2cc(Cl)c(F)c(C3CN(C(=O)OC(C)(C)C)C3)c2OCC)c2ncnc(N)c12
Temperature: 100 °C
Yield: 65.4 %

Procedure:
A mixture of tert-butyl 3-{3-[1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl}azetidine-1-carboxylate (1.32 g, 2.14 mmol), pyridine-trivinylboroxin (1:1) (0.51 g, 2.1 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (90 mg, 0.1 mmol) and potassium carbonate (0.89 g, 6.4 mmol) in 1,4-dioxane (10 mL)/water (7 mL) was heated at 100° C. overnight. After cooled to room temperature, the reaction mixture was diluted with water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined extracts were washed with brine, dried over MgSO4, concentrated and purified on a silica gel column to give the desired product (0.71 g, 64%). LCMS calculated for C25H31ClFN6O3 (M+H)+: m/z=517.2; Found:517.2
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].Cl.[NH:17]1[CH2:38][CH2:37][CH2:36][C@H:18]1[C:19]([N:21]1[CH2:35][CH2:34][CH2:33][C@H:22]1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[O:20]>>[NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([N:17]1[CH2:38][CH2:37][CH2:36][C@H:18]1[C:19]([N:21]1[CH2:35][CH2:34][CH2:33][C@H:22]1[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])=[O:20])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 70 %

Procedure:
Starting from 13.79 g (63.45 mmol) of BOC-Val-OH and 21.5 g (63.45 mmol) of HCl.H-Pro-Pro-OBzl (VIII) and operating as described in Step 7, 22.28 g (70% yield) of compound IX were obtained as an oil after purification by column chromatography on silica gel (Merck) 0.040-0.063 mm eluting with ethyl acetate: methanol=98:2.