Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:46]1[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=1)[CH2:10][CH2:11][C@@H:12]1[C@@H:15]([C:16]2[CH:21]=[CH:20][C:19](B3OC(C)(C)C(C)(C)O3)=[CH:18][C:17]=2[O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[N:14]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:13]1=[O:45])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:53]([O:56][C@@H:57]1[C@@H:62]([O:63][C:64](=[O:66])[CH3:65])[C@H:61]([O:67][C:68](=[O:70])[CH3:69])[C@@H:60]([CH2:71][O:72][C:73](=[O:75])[CH3:74])[O:59][C@H:58]1[C:76]1[CH:81]=[CH:80][CH:79]=[C:78](Br)[CH:77]=1)(=[O:55])[CH3:54].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[C:53]([O:56][C@@H:57]1[C@@H:62]([O:63][C:64](=[O:66])[CH3:65])[C@H:61]([O:67][C:68](=[O:70])[CH3:69])[C@@H:60]([CH2:71][O:72][C:73](=[O:75])[CH3:74])[O:59][C@H:58]1[C:76]1[CH:77]=[C:78]([C:19]2[CH:20]=[CH:21][C:16]([C@@H:15]3[C@@H:12]([CH2:11][CH2:10][C@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[C:46]4[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=4)[C:13](=[O:45])[N:14]3[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[C:17]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:33])[CH3:34])[CH:18]=2)[CH:79]=[CH:80][CH:81]=1)(=[O:55])[CH3:54]
Reactant: CC1(C)OB(c2ccc([C@@H]3[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c4ccc(F)cc4)C(=O)N3c3ccccc3)c(O[Si](C)(C)C(C)(C)C)c2)OC1(C)C
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cccc(Br)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
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+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)OC[C@H]1O[C@@H](c2cccc(-c3ccc([C@@H]4[C@@H](CC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(F)cc5)C(=O)N4c4ccccc4)c(O[Si](C)(C)C(C)(C)C)c3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 27 %

Procedure:
The resulting brown oil which is (3R,4S)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-[2-{[tert-butyl(dimethyl)silyl]oxy}-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-phenylazetidin-2-one was dissolved with (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(3-bromophenyl)-D-glucitol in 4.0 mL of toluene and 0.5 mL of ethanol. 0.150 mL of 4 N potassium carbonate was added followed by 7 mg of tetrakis(triphenylphosphine)palladium(0). The entire reaction was degassed three times with argon then heated to reflux for 1.5 h. After this time the reaction was cooled to room temperature and diluted with 25 mL of water and extracted with 1:1 hexane-ethyl acetate (3×75 mL). The organic layers were combine, dried over sodium sulfate, filtered, concentrated and purified by column chromatography (12 g silica gel, 5% to 95% ethyl acetate-hexane) to afford 41.6 mg (27%) of (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(3′-{[tert butyl(dimethyl)silyl]oxy}-4′-{(2S,3R)-3-[(3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)propyl]-4-oxo-1-phenylazetidin-2-yl}biphenyl-3-yl)-D-glucitol as a clear oil.
Reaction SMILES: [H-].[Na+].[CH:3]([O:5][CH2:6][CH3:7])=[O:4].[F:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=O.C(I)C>CCOCC>[CH2:13]([O:12][CH:10]=[C:9]([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:14]
Reactant: CCOC=O
Reactant: CCOC(=O)CF
Agent: [H-]
Agent: [Na+]
Solvent: CCI
Solvent: CCOCC
Product: CCOC=C(F)C(=O)OCC
Temperature: 25 °C

Procedure:
NaH (60% suspension in mineral oil, 15.6 g, 0.39 mole) was washed with and suspended in ether (300 mL). To this suspension, ethyl formate (29.1 mL, 0.36 mole, 1.2 eq) was added and the mixture was cooled in an ice bath. Ethyl fluoroacetate (29.0 mL, 0.3 mole) was added slowly over 1 hour. After 2 hours the ice bath was removed and the reaction was stirred for another hour. After evaporation of the solvent, the residue was redissolved in 350 mL of dry DMF and cooled in an ice bath, and ethyl iodide (48 mL, 0.6 mole) was added dropwise. The solution was allowed to warm to room temperature and stirred overnight, then quenched with saturated aqueous solution of NH4Cl (100 mL). The mixture was diluted with ether and extracted with water. The separated ether layer was washed with sodium thiosulfate, brine and dried over MgSO4. After concentration under vacuum, the residue was distilled to give ethyl 3-ethoxy-2-fluoroacrylate (12, R9 =ethyl, 73°-85° C./14 mmHg) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ1.35 (t, 3H), 1.39 (t, 3H), 4.10 (q, 2H), 4.30 (q, 2H), 6.95 (d, 1H).
Reaction SMILES: CCN(CC)CC.[C:8]([O:12][C:13](=[O:29])[N:14]=[C:15]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])N1C=CC=N1)([CH3:11])([CH3:10])[CH3:9].[NH2:30][CH2:31][C:32]1([C:35]2[O:39][C:38]([CH:40]3[CH2:46][CH2:45][C@@H:44]4[CH2:47][N:41]3[C:42](=[O:56])[N:43]4[O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[N:37][N:36]=2)[CH2:34][CH2:33]1>CO>[C:25]([O:24][C:22]([N:21]=[C:15]([NH:14][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:29])[NH:30][CH2:31][C:32]1([C:35]2[O:39][C:38]([CH:40]3[CH2:46][CH2:45][C@@H:44]4[CH2:47][N:41]3[C:42](=[O:56])[N:43]4[O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[N:37][N:36]=2)[CH2:33][CH2:34]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: NCC1(c2nnc(C3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)CC1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N=C(NCC1(c2nnc(C3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.5 %

Procedure:
Et3N (5 g, 0.05 mol) and tert-butyl(((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (5.5 g, 17.5 mmol) were added to a solution of (5R)-2-(5-(1-(aminomethyl)cyclopropyl)-1,3,4-oxadiazol-2-yl)-6-(benzyloxy)-1,6-diaza-bicyclo[3.2.1]octan-7-one (7 g, 0.017 mol) in CH3OH (500 mL). The mixture was stirred at rt for 4 hrs and then concentrated. The residue was purified by silica gel column chromatography (gradient elution 50 to 66% EtOAc/petroleum ether) to afford (5R)-2-(5-(1-(2,3-bis-(tert-butoxycarbonyl)-guanidinomethyl)cyclopropyl)-1,3,4-oxadiazol-2-yl)-6-(benzyloxy)-1,6-diaza-bicyclo[3.2.1]octan-7-one (9 g, 86%) as a white solid. ESI-MS (EI+, m/z): 612.3 [M+H]+.
Reaction SMILES: S(O[CH2:12][CH2:13][CH:14]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[O:15]1)(C1C=CC(C)=CC=1)(=O)=O.[OH:23][C:24]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C>[OH:23][C:24]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:29][CH2:28][N:27]([CH2:12][CH2:13][CH:14]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:26][CH2:25]1
Reactant: Cc1ccc(S(=O)(=O)OCCC2Cc3ccccc3O2)cc1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: OC1(c2ccccc2)CCN(CCC2Cc3ccccc3O2)CC1
Reaction time: 48 h

Procedure:
The mixture of 4.6 g of 2-(2-tosyloxyethyl)-2,3-dihydrobenzofuran, 2.64 g of 4-hydroxy-4-phenylpiperidine, 10 g of anhydrous sodium carbonate and 100 ml of 4-methyl-2-pentanone is relfuxed for 48 hours. It is filtered, evaporated and the residue recrystallized from isopropanol-petroleum ether, to yield the 2-[2-(4-hydroxy-4-phenylpiperidino)-ethyl]-2,3-dihydrobenzofuran melting at 107°.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[C:28]([F:34])[C:27]=1[O:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1.[Cl:46][C:47]1[N:48]=[C:49]([CH:55]2[CH2:57][CH2:56]2)[NH:50][C:51]=1[C:52](O)=[O:53].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:46][C:47]1[N:48]=[C:49]([CH:55]2[CH2:56][CH2:57]2)[NH:50][C:51]=1[C:52]([NH:33][CH2:32][C:29]1[CH:30]=[CH:31][C:26]([Cl:25])=[C:27]([O:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=[CH:38][CH:37]=2)[C:28]=1[F:34])=[O:53]
Reactant: O=C(O)c1[nH]c(C2CC2)nc1Cl
Reactant: NCc1ccc(Cl)c(Oc2cccc3ccccc23)c1F
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: CN(C)C=O
Product: O=C(NCc1ccc(Cl)c(Oc2cccc3ccccc23)c1F)c1[nH]c(C2CC2)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.1 %

Procedure:
HATU (0.113 g, 0.298 mmol) was added to a solution of {[4-chloro-2-fluoro-3-(1-naphthalenyloxy)phenyl]methyl}amine (0.060 g, 0.199 mmol) and 4-chloro-2-cyclopropyl-1H-imidazole-5-carboxylic acid (0.037 g, 0.199 mmol) and diisopropylethylamine (0.052 mL, 0.298 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by reverse phase HPLC (acetonitrile:water with 0.1% TFA) to give the title compound (0.016 g, 14%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.284-8.37 (m, 1H), 8.00-8.13 (m, 1H), 7.95 (dd, 1H), 7.54-7.66 (m, 3H), 7.48 (dd, 1H), 7.25-7.37 (m, 2H), 6.49 (d, 1H), 4.33-4.62 (d, 2H), 1.75-2.03 (m, 1H), 0.85-0.93 (m, 2H), 0.77-0.84 (m, 2H). ES MS: m/z 470 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[N+:14]([C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20])([O-])=O>CO.C1COCC1.[Pd]>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:14][C:17]3[CH:23]=[CH:22][CH:21]=[C:19]([NH2:20])[CH:18]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: CSc1ncnc2cc(N)ncc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cccc(Nc2ncnc3cc(N)ncc23)c1
Temperature: 200 °C
Reaction time: 1.5 h
Yield: 16.4 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (307 mg, 1.60 mmol) (described in a previous experimental) and 3-nitroaniline (2.00 g, 14.5 mmol) is stirred at 200° C. for 1.5 h, and the crude product is suspended in MeOH/THF (4:1, 250 mL) and hydrogenated over 5% Pd/C (2 g) at 60 psi and 20° C. for 24 h. The solution is filtered over celite, washing thoroughly (hot MeOH), and is then absorbed onto alumina and chromatographed on alumina (4-8% EtOH/CHCl3) to give 7-amino-4-(3-aminoanilino)pyrido[4,3-d]pyrimidine (66 mg, 16%) as a green solid,. 1H NMR (DMSO) δ 9.57 (1H, brs), 9.30 (1H, s), 8.33 (1H, s), 7.04 (1H, t, J=2.0 Hz), 6.99 (1H, t, J=8.0 Hz), 6.88 (1H, brd, J=8.0 Hz), 6.55 (2H, brs), 6.40 (1H, s), 6.34 (1H, dd, J=7.9, 1.3 Hz), 5.10 (2H, brs).
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](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:37]=[CH:36][S:35][C:34]=1[C:38]([NH2:40])=[O:39].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(Cl)Cl>[C:38]([C:34]1[S:35][CH:36]=[CH:37][C:33]=1[NH:32][C:28]([CH:9]1[CH: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])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]1)=[O:29])(=[O:39])[NH2:40]
Reactant: NC(=O)c1sccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
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)CC1NC(C(=O)Nc2ccsc2C(N)=O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture 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 (200 mg, 0.43 mmol), 3-aminothiophene-2-carboxylic acid amide (160 mg, 1.1 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 243.3 mg, 0.64 mmol) and iPr2NEt (0.3 mL, 1.67 mmol) in CH2Cl2 (5 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified flash column chromatography (1-100% ethyl acetate/heptane) to afford 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 (2-carbamoyl-thiophen-3-yl)-amide as a off white powder (15.8 mg, 6.2%). HRMS (ES+) m/z Calcd for C28H26Cl2F2N4O2S+H [(M+H)+]: 501.1195. found: 591.1191.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[CH:13][C:12]=1[CH3:25].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][C:12]=1[CH3:25]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Cl
Reaction time: 4 h
Yield: 99.6 %

Procedure:
To a stirred solution of tert-butyl 4-[N′-(2-chlorophenyl)ureido]-3-methylphenylacetate (1.57 g, 4.19 mmol) in CH2Cl2 (10 ml) was added TFA (6 ml) at room temperature. After 4 h stirring, the mixture was concentrated in vacuo. The residue was triturated by the addition of water to give 4-[N′-(2-chlorophenyl)ureido]-3-methylphenylacetic acid (1.33 g, 100%) as a yellow powder. mp 243–245° C. (dec.); 1H-NMR (CDCl3) δ 2.24 (s, 3H), 3.47 (s, 2H), 6.99–7.08 (m, 3H), 7.28 (t, J=7.6 Hz, 1H), 7.44 (dt, J=8.0, 2.4 Hz, 1H), 7.66 (dd, J=8.3, 1.9 Hz, 1H), 8.13 (dd, J=6.1, 1.7 Hz, 1H), 8.61 (d, J=6.3 Hz, 2H); MS (ESI), m/z 319 (M++1), 321 (M++3); Anal. Calcd for C16H15ClN2O3.0.7TFA: C, 59.33; H, 4.65; Cl, 10.85; N, 8.57. Found: C, 59.23; H, 4.64; Cl, 10.90; N, 8.40.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][N:67]([CH2:70][CH2:71][O:72][Si:73]([C:76]([CH3:79])([CH3:78])[CH3:77])([CH3:75])[CH3:74])[C:66](=[O:80])[CH:65]=1>>[C:76]([Si:73]([CH3:74])([CH3:75])[O:72][CH2:71][CH2:70][N:67]1[CH:68]=[CH:69][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][C:66]1=[O:80])([CH3:77])([CH3:79])[CH3:78]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)cc1=O
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CCO[Si](C)(C)C(C)(C)C)c(=O)c2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 27, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.5 g, 0.86 mmol), was reacted with diisopropylethylamine (0.89 g, 6.9 mmol), diphenylphosphinic chloride (0.82 g, 3.5 mmol), then reacted with 4-amino-1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyridin-2-one (0.23 g, 0.86 mmol) at 60° C. to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-oxo-1,2-dihydro-pyridin-4-yl}-amide as a off white foam (Yield 0.2 g, 32%).
Reaction SMILES: C[Si](Cl)(C)C.Br[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:13][O:14][C:15]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([B:25]2[O:29]C(C)(C)[C:27](C)(C)[O:26]2)[C:16]=1C=O>C1COCC1.[Zn]>[OH:29][B:25]1[C:19]2[CH:16]=[C:15]([O:14][CH3:13])[CH:22]=[C:21]([O:23][CH3:24])[C:20]=2[CH:27]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:26]1
Reactant: COc1cc(OC)c(C=O)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(OC)cc(OC)c21
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 39.3 %

Procedure:
To a mixture of zinc powder (0.65 g, 10.0 mmol) in anhydrous THF (15 mL) was added TMSCl (0.13 mL, 1.0 mmol) at 40° C. The resulting mixture was stirred at 55° C. for 15 min and cooled to 37° C., followed by addition of ethyl 2-bromoacetate (0.45 mL, 4.0 mmol). The reaction mixture was stirred at this temperature for an additional 30 min. To the solution of 2,4-dimethoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzaldehyde (0.29 g, 1.0 mmol) in anhydrous THF (20 mL) cooled at −78° C., was added above prepared solution dropwise. The reaction mixture was allowed to stir at room temperature for 1.5 hr and quenched by aqueous ammonium chloride (20 mL). The reaction mixture was extracted with ethyl acetate (2×15 mL), the combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/PE=1/3) on silica gel to give the title compound as a white solid. (110 mg, Yield: 39.3%). MS (ESI) m/z=281 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.F[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[CH:27]=[N:28][N:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=34)[CH:23]=[CH:22][N:21]=2)=[C:12]([O:35][CH3:36])[CH:11]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([NH:19][C:20]3[N:25]=[C:24]([C:26]4[CH:27]=[N:28][N:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=45)[CH:23]=[CH:22][N:21]=3)=[C:12]([O:35][CH3:36])[CH:11]=2)[CH2:4]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Temperature: 85 °C
Yield: 85.6 %

Procedure:
(3R)—N,N-Dimethylpyrrolidin-3-amine (0.166 mL, 1.31 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 155, 415 mg, 1.09 mmol) and DIPEA (0.227 mL, 1.31 mmol) in DMA (3.2 mL) and the mixture was heated at 85° C. for 1 h. Part purification was achieved by ion exchange chromatography, using an SCX column, eluting with 7M methanolic ammonia. Clean fractions were combined and concentrated. Further purification by FCC, eluting with 0-7% CH3OH in CH2Cl2 gave the title compound (443 mg, 86%) as an orange solid; 1H NMR: 1.77-1.88 (1H, m), 2.13-2.20 (1H, m), 2.23 (6H, s), 2.75-2.84 (1H, m), 3.14-3.26 (3H, m), 3.43-3.51 (1H, m), 3.96 (3H, s), 6.58 (1H, s), 7.08 (1H, td), 7.27 (1H, d), 7.34-7.39 (1H, m), 8.24 (1H, s), 8.35 (1H, d), 8.40 (1H, s), 8.49 (1H, d), 8.78 (1H, s), 8.80 (1H, d); m/z: ES+ MH+ 475.31.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.C[Si](Cl)(C)C.CC1(C)[O:19][C:18](=O)[CH2:17][C:16](=[O:21])[O:15]1>C(Cl)Cl>[O:19]=[C:18]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:17][C:16]([OH:21])=[O:15]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: Nc1cccnc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Product: O=C(O)CC(=O)Nc1cccnc1
Reaction time: 0.5 h
Yield: 26.2 %

Procedure:
To a suspension of pyridine-3-amine (1 g, 10.6 mmol) in DCM (100 mL) was added TMSCl (1.3 mL, 10.6 mmol) at room temperature. The reaction mixture was stirred for 30 min. 2,2-Dimethyl-1,3-dioxane-4,6-dione (1.44 g, 10.6 mmol) was added and the combined mixture stirred overnight and concentrated under reduced pressure. The residue was dissolved in dilute NaHCO3 solution and washed with EtOAc. The aqueous phase was collected and acidified with conc. HCl to pH˜3 and extracted with EtOAc. The extract was dried over anhydrous Na2SO4, filtered and concentrated. The remaining solid was purified by flash chromatography (eluent CHCl3/MeOH/AcOH 8:1:0.1) to afford the title compound 39 as a white solid (0.5 g, 26% yield). 1H NMR (DMSO-d6) δ (ppm): 12.04 (bs, 1H), 9.67 (s, 1H), 8.18 (d, 1H), 8.01 (d, 1H), 7.29 (m, 1H), 2.97 (s, 2H). MS (m/z): 181.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[NH:14][C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:16]3[C:21]=2[CH:20]=[CH:19][C:18]([Cl:22])=[CH:17]3)=[O:12])[O:6][CH2:5][CH2:4][O:3]1.[Na].[CH3:30]OS(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O.CO>[CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]([CH3:30])[C:15]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[C:16]3[C:21]=2[CH:20]=[CH:19][C:18]([Cl:22])=[CH:17]3)=[O:12])[O:3][CH2:4][CH2:5][O:6]1
Reactant: CC1(CCCNC(=O)c2[nH]c(-c3ccccc3)c3cc(Cl)ccc23)OCCO1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1c(C(=O)NCCCC2(C)OCCO2)c2ccc(Cl)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 24.0 g. of 5-chloro-3-phenylisoindole-1-carboxylic acid [3-(2-methyl-1,3-dioxolan-2-yl)-propyl]amide in 160 ml. of dimethylformamide is treated under an atmosphere of argon at 0°-5° C. with a solution of 2.1 g. of sodium in 40 ml. of methanol. The mixture is then stirred at room temperature for 30 minutes and subsequently added dropwise to a solution of 18.6 g. of p-toluenesulfonic acid methyl ester in 20 ml. of dimethylformamide. The mixture is subsequently stirred at room temperature for 30 minutes and then at 80° C. for 1 hour. After cooling, the mixture is poured on to 400 ml. of ice-water and, after the addition of 20 g. of sodium chloride, the separated product is removed by filtration under suction, washed with water and then dissolved in methylene chloride. The organic phase is washed with water, dried over sodium sulfate and evaporated to dryness. The residue obtained is chromatographed on 500 g. of silica gel using methylene chloride/ethyl acetate (4:1) for the elution. The uniform fractions are combined and evaporated, and there is obtained 5-chloro-2-methyl-3-phenylisoindole-1-carboxylic acid [3-(2-methyl-1,3-dioxolan-2-yl)-propyl]amide having a melting point of 137°-139° C. Recrystallization from ethanol yields colorless crystals of the same melting point.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([CH3:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:32][CH2:33]2)=[S:22])=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1
Reactant: COc1nc2c(cc1NC(=S)Oc1ccccc1)CCCC2
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: COc1nc2c(cc1NC(=S)N1CCN(c3cc(C)cc(C)c3)CC1)CCCC2
Yield: 54 %

Procedure:
Phenyl N-(2-methoxy-5,6,7,8-tetrahydroquinolin-3-yl)thiocarbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:6]2[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=[C:2]([Cl:1])[N:7]=2)=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)n1
Reactant: Nc1ccc(Cl)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1cc(Nc2ccc(Cl)cc2)nc(Cl)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 2,4-dichloro-6-trifluoromethyl-pyrimidine (90 mg, 0.41 mmol) in n-butanol (1 mL), was added 4-chloro-phenylamine (52 mg, 0.416 mmol) and DIPEA (72 uL, 0.416). The mixture was stirred at 100° C. for overnight. The LC-MS showed the desired product mass [MS:(ESI), M/Z, 308 (M+1). Retention time: 2.70 min (FA-polar)]. This intermediate was used in situ without purification.