Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[C:9]([CH2:28][CH2:29][O:30][Si](C(C)(C)C)(C)C)[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[C:9]([CH2:28][CH2:29][OH:30])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1cccc(NC(=O)Nc2ccc(-c3c(CCO[Si](C)(C)C(C)(C)C)sc4ncnc(N)c34)cc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)Nc2ccc(-c3c(CCO)sc4ncnc(N)c34)cc2)c1
Reaction time: 8 h
Yield: 75.7 %

Procedure:
A solution of Example 104C (92 mg, 0.17 mmol) in THF (5 mL) at room temperature was treated dropwise with a solution of 1M TBAF in THF (0.3 mL, 0.3 mmol), stirred overnight, and partitioned between water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the combined extracts were dried (Na2SO4), filtered, and concentrated. The concentrate was recrystallized from dichloromethane to provide 54 mg (75%) of the desired product. MS(ESI) m/e 420 (M+H)+, 418 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H); 2.75-2.80 (t, J=6.6 Hz, 2H); 3.54-3.60 (m, 2H); 4.85-4.89 (t, J=5.7 Hz, 1H); 6.79-6.82 (d, J=7.5 Hz, 2H); 7.14-7.19 (t, J=7.5 Hz, 1H); 7.24-7.32 (m, 4H); 7.61-7.63 (d, J=8.4 Hz, 2H); 8.26 (s, 1H); 8.67 (s, 1H); 8.87 (s, 1H); Anal. Calcd. for C22H21N5O2S.0.4H2O: C, 61.93; H, 5.15; N, 16.41. Found: C, 61.80; H, 4.95; N, 16.31.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([C:8]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[O:18]C)([CH3:10])[CH3:9])[CH:7]=1.C(C1C=C(F)C=CC=1O)(C1C=C(F)C=CC=1O)(C)C>>[C:8]([C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[OH:18])([C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:20])([CH3:10])[CH3:9]
Reactant: COc1ccc(Cl)cc1C(C)(C)c1cc(Cl)ccc1O
Agent: CC(C)(c1cc(F)ccc1O)c1cc(F)ccc1O
Product: CC(C)(c1cc(Cl)ccc1O)c1cc(Cl)ccc1O

Procedure:
2,2'-isopropylidene bis(4-chlorophenol) (m.p. 142° C.) was prepared from 2-(5-chloro-2-hydroxyphenyl)-2-(5-chloro-2-methoxyphenyl)propane following the method described in Example 3 for the preparation of 2,2'-isopropylidene bis(4-fluorophenol).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[OH:9]O>CC(O)=O>[Br:1][C:2]1[C:3]([CH3:8])=[N+:4]([O-:9])[CH:5]=[CH:6][CH:7]=1
Reactant: OO
Reactant: Cc1ncccc1Br
Solvent: CC(=O)O
Product: Cc1c(Br)ccc[n+]1[O-]
Temperature: 70 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a stirred solution of 3-Bromo-2-methyl-pyridine (1.96 g, 11.4 mmol) in glacial HOAc (20 mL) at room temperature was added 50% H2O2 (0.77 mL) and the solution was heated to 70° C. After 2 h, the reaction mixture was cooled to room temperature, additional H2O2 (0.80 mL) was added, and the solution was heated at 70° C. overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (80 mL) and treated with saturated aqueous NaHCO3 (20 mL). The aqueous phase was separated and extracted with CH2Cl2 (4×20 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to provide 3-Bromo-2-methyl-pyridine 1-oxide (1.79 g, 84%) as a white solid. 1H NMR (CDCl3) δ 2.70 (s, 3H), 7.00 (t, 1H, J=7.0 Hz), 7.44 (d, 1H, J=7.9 Hz), 8.23 (d, 1H, J=6.5 Hz). 3-Bromo-2-methyl-pyridine 1-oxide was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([O:12][CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C.O>[CH3:13][O:12][C:8]1[CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]2[N:1]=[C:18]([C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[C:15]([F:14])([F:24])[F:25])[NH:11][C:10]=2[CH:9]=1
Reactant: COc1cc(N)c(N)c(C(=O)O)c1
Reactant: O=Cc1ccccc1C(F)(F)F
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)O)c2nc(-c3ccccc3C(F)(F)F)[nH]c2c1
Temperature: 25 °C
Yield: 40 %

Procedure:
A mixture of 2,3-diamino-5-methoxybenzoic acid 86 (1.1 equiv) and 2-(trifluoromethyl)benzaldehyde 74 (1 equiv) and sodium metabisulfite (3 equiv) in DMF was stirred under reflux for 12 h. Upon cooling to room temperature, the reaction mixture was diluted with water. The resulting solids were collected by filtration and dried to afford 6-methoxy-2-(2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxylic acid 87 as dark yellow solid (40%).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([O:18]C)=[O:17])=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>CO>[C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([OH:18])=[O:17])=[CH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cn(-c2ccccc2)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cn(-c2ccccc2)c2ccccc12
Temperature: 90 °C

Procedure:
To a solution of methyl 1-phenyl-1H-indole-3-carboxylate (108 mg, 0.430 mmol) in MeOH (1433 μl) was added aq KOH (1074 μl, 2.149 mmol, 2 M). The mixture was heated at 90° C. for 1 h then the MeOH was removed under reduced pressure. The residual aqueous layer was acidified with 1M HCl then extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated to afford the title compound as a white solid, which was used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:5])C.[OH-]>C(O)C>[C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(N2CCN(Cc3c[nH]c4ncccc34)CC2)cc1
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(N2CCN(Cc3c[nH]c4ncccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 192 h
Yield: 66.8 %

Procedure:
A suspension of 3-(4-[4-ethoxycarbonylphenyl]piperazin-1-yl)methyl-1H-pyrrolo[2,3-b]pyridine (0.6594 g, 1.81 mmol) in ethanol (50 ml) containing 1M aqueous odium hydroxide (10.5 ml, 10.8 mmol) was stirred at room temperature for eight days, during which time the solid slowly dissolved. The reaction mixture was concentrated to a small volume, diluted with water and neutralised (pH 6-7) with acetic acid to give a gum which solidified on standing. The solid was collected, washed with water and dried in vacuo. Recrystallisation from dimethylformamide/water gave the title compound (0.4069 g, 67%) as a white solid, m.p. >250° C. (dec.); (Found: C, 66.96; H, 5.88; N, 16.30. C19H20N4O2. 0.25H2O requires C, 66.94; H, 6.06; N, 16.44); δH (DMSO-d6) 2.51 (4H, m, 2×piperazinyl CH2), 3.27 (4H, m, 2×piperazinyl CH2), 3.68 (2H, s, CH2N), 6.93 (2H, d, J 9.0 Hz, ArH), 7.04 (1H, dd, J 7.8, 4.7 Hz, 5-H), 7.38 (1H, d, J 2.2 Hz, 2-H), 7.57 (2H, d, J 9.0 Hz, ArH), 8.06 (1H, dd, J 7.8, 1.4 Hz, 4-H), 8.20 (1H, dd, J 4.7, 1.4 Hz, 6-H), and 11.48 (1H, br s, NH); m/z (CI+, NH3) 337 (M+1)+.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:14]([NH:16][C:17]1[CH:18]=[CH:19][C:20]2[C:26]3[C:27]([O:35][CH3:36])=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:25]=3[CH2:24][CH2:23][CH:22]([NH:37][C:38](=[O:40])[CH3:39])[C:21]=2[CH:41]=1)=[O:15])[CH3:13])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@H:12]([C:14]([NH:16][C:17]1[CH:18]=[CH:19][C:20]2[C:26]3[C:27]([O:35][CH3:36])=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:25]=3[CH2:24][CH2:23][CH:22]([NH:37][C:38](=[O:40])[CH3:39])[C:21]=2[CH:41]=1)=[O:15])[CH3:13]
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(NC(=O)[C@H](C)NC(=O)OCc3ccccc3)cc1C(NC(C)=O)CC2
Agent: [Pd]
Solvent: CCO
Product: COc1cc2c(c(OC)c1OC)-c1ccc(NC(=O)[C@H](C)N)cc1C(NC(C)=O)CC2
Yield: 65.5 %

Procedure:
A solution of N-[3-((N-benzyloxycarbonylalanyl)amino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl]acetamide (70 mg, 0.125 mmol), (prepared as described in Example 1), in ethanol (2 ml) was hydrogenated at atmospheric pressure over 5% palladium on carbon (10 mg) for 2 hours. Ethanol (3 ml) was added and the solution was filtered through diatomaceous earth and the filtrate concentrated under reduced pressure. Trituration with ethyl acetate/diethyl ether gave the title compound (35 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.N1C=CC=CC=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[C:16]([C:24]#[N:25])[CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)(=[O:21])=[O:22])=[C:16]([C:24]#[N:25])[CH:15]=1
Reactant: Nc1nccs1
Reactant: N#Cc1cc(Br)ccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: N#Cc1cc(Br)ccc1S(=O)(=O)Nc1nccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.3 %

Procedure:
To 2-AMINOTHIAZOLE (0.21 g, 0.0021 mol) in Pyridine (1 mL, 0.01 mol) was added portion-wise the crude 4-Bromo-2-cyano-benzenesulfonyl chloride (0.40 g, 0.0014 mol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, diluted with Ethyl acetate, washed with 1.0 N HCl, H2O and brine, dried with anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified on ISCO (25% to 100% Ethyl acetate in hexanes). 35 mg of the product was obtained as a light yellow solid.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[C:23]2=[O:38])[O:11][CH:10]1[C@H:39]([OH:70])[C@@H:40]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[NH:41][CH2:42][CH2:43][CH2:44][NH:45][C:46](=[O:62])[C@H:47]([C@@H:59]([OH:61])[CH3:60])[NH:48]C(=O)OCC1C=CC=CC=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:48][C@@H:47]([C@@H:59]([OH:61])[CH3:60])[C:46]([NH:45][CH2:44][CH2:43][CH2:42][NH:41][C@@H:40]([C@H:39]([CH:10]1[C@@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[C@@H:13]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16])[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[C:23]2=[O:38])[O:11]1)[OH:70])[C:63]([O:65][C:66]([CH3:68])([CH3:69])[CH3:67])=[O:64])=[O:62]
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@@H](NC(=O)OCc4ccccc4)[C@H](C)O)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@@H](N)[C@H](C)O)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Yield: 97 %

Procedure:
By using an analogous procedure to that described for Example 2, tert-butyl (5S,12S)-12-[(R)-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-[(11S)-1-hydroxyethyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (146 mg, 0.144 mmol, obtained from Example 10) was hydrogenated in methanol (3 ml) using 10% palladium on carbon (30 mg) to provide tert-butyl (2S,3R)-2-[(3-{[(2S,3S)-2-amino-3-hydroxybutanoyl]amino}propyl)amino]-3-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]-3-hydroxypropanoate (123 mg, 97%) as a white amorphous solid.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([NH2:6])[CH2:4][CH3:5].[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:11](O)=[O:12]>>[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:11]([NH:6][CH:3]([CH2:4][CH3:5])[CH2:2][CH3:1])=[O:12]
Reactant: COc1ccc(C(=O)O)cc1Cl
Reactant: CCC(N)CC
Product: CCC(CC)NC(=O)c1ccc(OC)c(Cl)c1
Yield: 40 %

Procedure:
Prepared in a similar manner to example 4 using 3-pentylamine and 3-chloro-4-methoxy benzoic acid. Yield 40%. MS (M+H, 256.20).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[NH:13][N:12]=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:16][Si:17]([CH3:24])([CH3:23])[CH2:18][CH2:19][O:20][CH2:21]Cl>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:24])([CH3:23])[CH3:16])[N:12]=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(Sc2cnn[nH]2)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nncc1Sc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of compound 63a (360 mg, 1.40 mmol) and 60% NaH (135 mg, 3.40 mmol) in DMF (2 mL) was stirred for 20 min at rt. At that time, 2-(trimethylsilyl) ethoxymethyl chloride (0.558 mL, 3.10 mmol) was added and the resulting mixture was stirred at rt for 12 h. The reaction mixture was diluted with DCM (300 mL) and washed with saturated NH4Cl solution (200 mL), water (200 mL) and brine (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0-50% EtOAc/heptanes) to give compound 63b. Mass Spectrum LCMS, ESI (pos.) Calcd. for C14H20BrN3OSSi: 386.1 [M+H]. found 386.2.
Reaction SMILES: I.CS[C:4]1[CH2:5][CH2:6][C:7]2([CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]3[CH2:20][CH:9]2[CH2:10][CH2:11]3)[N:8]=1.[NH3:21].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>CO.O>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[NH2:21][C:4]1[CH2:5][CH2:6][C:7]2([CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:12]3[CH2:20][CH:9]2[CH2:10][CH2:11]3)[N:8]=1
Reactant: N
Reactant: CSC1=NC2(CC1)C1CCC(C1)C2c1ccccc1
Agent: I
Agent: O=C(O)/C=C/C(=O)O
Solvent: O
Solvent: CO
Product: NC1=NC2(CC1)C1CCC(C1)C2c1ccccc1

Procedure:
50 mmoles of 5'-methylthio-3-phenyl-spiro[bicyclo[2.2.1]-heptane-2,2'-5-pyrroline] hydriodide are treated with 250 ml of aqueous ammonia at 70° C. andunder a nitrogen pressure of 80 bars for 24 hours. After stripping off the solvent, an oil which slowly solidifies is obtained. After conversion intothe addition salt of fumaric acid, colorless crystals of melting point 242° C. (from methanol/water 1:1) are obtained.
Reaction SMILES: [CH3:1][Si:2]([CH3:10])([CH3:9])[O:3][C:4]([CH3:8])([C:6]#[CH:7])[CH3:5].[Li]CCCC.[C:16]([C:18]1[CH:19]=[C:20]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:21](N(OC)C)=[O:22])#[N:17]>C1COCC1>[CH3:31][O:30][C:29]1[CH:28]=[CH:27][C:20]([C:21](=[O:22])[C:7]#[C:6][C:4]([CH3:8])([O:3][Si:2]([CH3:10])([CH3:9])[CH3:1])[CH3:5])=[CH:19][C:18]=1[C:16]#[N:17]
Reactant: COc1ccc(C(=O)N(C)OC)cc1C#N
Reactant: C#CC(C)(C)O[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C#CC(C)(C)O[Si](C)(C)C)cc1C#N
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
To a −78° C. stirred solution of trimethyl(2-methylbut-3-yn-2-yloxy)silane (1.9 g, 12.501 mmol) in dry THF (25 mL), n-BuLi (2.80 mL, 4.50 mmol, 1.6 M in hexane) was added dropwise over 10 minutes under an inert atmosphere. The reaction was stirred for 30 min at −78° C., and then a solution of 3-cyano-N,4-dimethoxy-N-methylbenzamide (1.10 g, 5.01 mmol) in dry THF (10 mL) was added to reaction mixture and stirring was continued for an additional 3 h at −78° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 5% EtOAc in hexanes to afford 2-methoxy-5-(4-methyl-4-(trimethylsilyloxy)pent-2-ynoyl)benzonitrile (0.8 g, 56%) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]2[CH:14]=[CH:13][C:12](=[O:15])[C:11]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[CH:10]2)=[N:4][CH:5]=[CH:6][C:7]=1I.[Cl:26][C:27]1[C:28](B2OC(C)(C)C(C)(C)O2)=[C:29]2[CH:35]=[CH:34][N:33]([Si](C(C)C)(C(C)C)C(C)C)[C:30]2=[N:31][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[Cl:26][C:27]1[C:28]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([N:9]3[CH:14]=[CH:13][C:12](=[O:15])[C:11]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[CH:10]3)[C:2]=2[F:1])=[C:29]2[CH:35]=[CH:34][NH:33][C:30]2=[N:31][CH:32]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(B3OC(C)(C)C(C)(C)O3)c(Cl)cnc21
Reactant: COc1ccc(COc2cn(-c3nccc(I)c3F)ccc2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1ccc(COc2cn(-c3nccc(-c4c(Cl)cnc5[nH]ccc45)c3F)ccc2=O)cc1
Temperature: 135 °C

Procedure:
To a room temperature solution of 132 mg (0.292 mmol) 3′-fluoro-4′-iodo-3-[(4-methoxybenzyl)oxy]-4H-1,2′-bipyridin-4-one in 2 mL THF in a 5 mL microwave vial (Biotage) were added 253 mg (0.584 mmol) 5-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine, 1 mL 1.0 M cesium carbonate (1.0 mmol), and 23.8 mg (0.029 mmol) 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex. The vial was sealed and the reaction mixture was heated at 135° C. under microwave irradiation for 15 minutes, then cooled. The organic layer was separated, washed with 1 mL water, dried over Na2SO4, filtered, stirred over Quadrapure TU resin (Aldrich), concentrated in vacuo, and used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][N:7]1[C:18]([O:20][CH3:21])=[O:19].CCO.C(#N)C>C(=O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][C@@H:6]1[CH2:11][C@@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][N:7]1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cccc(F)c1
Agent: O=C=O
Solvent: CCO
Solvent: CC#N
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@H]1Cc1cccc(F)c1
Yield: 36 %

Procedure:
Trans-methyl 2-(3-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (214 mg, 0.64 mmol) was subjected to chiral preparative HPLC (Column: Chiralcel OJ (250×30), 5 μm particle size, mobile phase: 10% EtOH in CO2 (175 bar), flow rate 150 mL/min) to yield (2S,4S)-methyl 2-(3-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate 77 mg (38.5%), Chiral purity 99.6% ee, Optical rotation [α]D20=+64.9 (acetonitrile, c=1)
Reaction SMILES: [B:1]1(B2OC(C)(C)C(C)(C)O2)[O:5]C(C)(C)C(C)(C)[O:2]1.[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([O:27][CH3:28])[N:21]=1>CCCCCCC.C(OCC)(=O)C.C[OH2+].C[OH2+].C1CC=CCCC=C1.C1CC=CCCC=C1.[Ir].[Ir]>[Cl:26][C:25]1[CH:24]=[C:23]([B:1]([OH:5])[OH:2])[C:22]([O:27][CH3:28])=[N:21][C:20]=1[Cl:19]
Reactant: COc1ccc(Cl)c(Cl)n1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [Ir]
Agent: C1=C\CC/C=C\CC/1
Agent: C[OH2+]
Solvent: C1=CCCC=CCC1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1nc(Cl)c(Cl)cc1B(O)O
Reaction time: 0.17 h

Procedure:
To a round-bottomed flask was added (1,5-cyclooctadiene)(methoxy)-iridium(i) dimer (0.223 g, 0.337 mmol), 4,4-di-tert-butyl-2,2-dipyridyl (0.181 g, 0.674 mmol) and bis(pinacolato)diboron (2.85 g, 11.23 mmol) in heptane (112 ml). The reaction mixture was vacuumed and refilled with dry nitrogen (3×). After stirring for 10 minutes, 2,3-dichloro-6-methoxypyridine (2.0 g, 11.23 mmol) was added. The resulting reaction mixture was stirred at rt overnight. The reaction was diluted with ethyl acetate and washed twice with 1N HCl solution. The organic layer was extracted twice with 1N sodium hydroxide solution, and the combined aqueous layers were acidified with concentrated HCl solution and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford (5,6-dichloro-2-methoxypyridin-3-yl)boronic acid as an oily light yellow solid. m/z (ESI) 222.1 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:20]=[O:21])[O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:22][C:23]1[N:28]=[C:27]([NH:29][NH2:30])[C:26]([F:31])=[C:25]([N:32]2[CH2:35][C:34]([CH3:41])([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:33]2)[N:24]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[Cl:22][C:23]1[N:28]=[C:27]([NH:29][NH:30][C:8](=[O:10])[C@H:7]([CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:11][N:12]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH:20]=[O:21])[C:26]([F:31])=[C:25]([N:32]2[CH2:33][C:34]([CH3:41])([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:35]2)[N:24]=1
Reactant: CC1(N2CCCC2)CN(c2nc(Cl)nc(NN)c2F)C1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OC1CCCCO1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC1(N2CCCC2)CN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OC3CCCCO3)c2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
A mixture of (2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoic acid (112 mg, 0.374 mmol), 2-chloro-5-fluoro-4-hydrazino-6-[3-methyl-3-(1-pyrrolidinyl)-1-azetidinyl]pyrimidine (assumed 112 mg of free base, 0.374 mmol), EDC (86 mg, 0.449 mmol), HOAt (56 mg, 0.411 mmol), and NMM (0.25 mL, 2.24 mmol) in DMF (5 ml) was stirred at room temperature overnight. The reaction mixture was then purified via RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[3-methyl-3-(1-pyrrolidinyl)-1-azetidinyl]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (145 mg, 66%). LCMS: (M+H)+: 582.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:25]([O:27]C)=[O:26])[CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH3:24])[CH:16]=2)=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]([NH:12][C@H:13]([C:25]([OH:27])=[O:26])[CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH3:24])[CH:16]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](Cc1cn(C)c2ccccc12)NC(=O)C=Cc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(C[C@H](NC(=O)C=Cc2ccc(F)cc2)C(=O)O)c2ccccc21
Yield: 80.8 %

Procedure:
The same procedures as in Example 64 were carried out from the compound obtained in Example 23 (2.7 g), 1 mol/L of an aqueous sodium hydroxide solution (10.5 mL), and methanol (110 mL), to give the captioned compound (2.1 g, 80%) as crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8]1([C:16](=[O:17])[NH:15][C:14](=[O:18])[NH:13]1)[CH2:7]2)([O-:3])=[O:2].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]O)=[CH:23][CH:22]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:15]2[C:16](=[O:17])[C:8]3([CH2:7][C:6]4[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)[CH2:9]3)[NH:13][C:14]2=[O:18])=[CH:23][CH:22]=1
Reactant: O=C1NC(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2)N1
Reactant: COc1ccc(CO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)NC3(Cc4ccc([N+](=O)[O-])cc4C3)C2=O)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of (±)-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione (1.4 g, 5.66 mmol, described in Intermediate 6), 4-methoxybenzyl alcohol (0.94 g, 6.80 mmol), diethyl azodicarboxylate (1.48 g, 8.49 mmol), and triphenylphosphine (2.23 g, 8.49 mmol) in THF (15 mL) was stirred at ambient temperature for 3 days. The solvent was removed under reduced pressure and the residue was partitioned between saturated aqueous NaHCO3 (15 mL) and CH2Cl2 (50 mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—90:10 to 60:40, to give the title compound. MS: m/z=368 (M+1).