Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]([C:8]2[CH:9]=[CH:10][C:11]([CH3:33])=[C:12]([NH:14][C:15](=[O:32])[C:16]3[CH:21]=[C:20]([O:22][CH2:23][C@H:24]4[CH2:28][CH2:27][CH2:26][NH:25]4)[CH:19]=[CH:18][C:17]=3[N+:29]([O-])=O)[CH:13]=2)=[O:7])[CH2:4][CH2:3]1.[CH3:34]O>[Pd].C(O)C>[CH:2]1([NH:5][C:6](=[O:7])[C:8]2[CH:9]=[CH:10][C:11]([CH3:33])=[C:12]([N:14]3[C:15](=[O:32])[C:16]4[C:17](=[CH:18][CH:19]=[C:20]([O:22][CH2:23][C@H:24]5[CH2:28][CH2:27][CH2:26][NH:25]5)[CH:21]=4)[N:29]=[CH:34]3)[CH:13]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(OC[C@H]2CCCN2)ccc1[N+](=O)[O-]
Reactant: CO
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC[C@H]3CCCN3)cc2c1=O
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
N-{5-[(Cyclopropylamino)carbonyl]-2-methylphenyl}-2-nitro-5-[(2R)-pyrrolidin-2-ylmethoxy]benzamide hydrochloride salt (3.32 g) and 10% Palladium on carbon (0.332 g) were stirred in ethanol (65 ml) and methanol (40 ml) under an atmosphere of hydrogen gas for 2 hours at room temperature. The catalyst was removed by filtration through diatomaceous earth (Celite®) and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (65 ml) and stirred with triethylorthoformate (3.14 ml) and glacial acetic acid (0.18 ml) at 80° C. for 1.5 hours and then concentrated. The residue was diluted with ethyl acetate and washed with saturated aqueous NaHCO3 solution, brine, dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting with 20% methanol/ethyl acetate followed by 20% methanol/ethyl acetate+1% aqueous ammonia solution to give N-cyclopropyl-4-methyl-3-[4-oxo-6-[(2R)-pyrrolidin-2-ylmethoxy]quinazolin-3(4H)-yl]benzamide (AZ12304521) (0.763 g) as a yellow/brown foam solid; NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.70 (m, 2H), 1.49 (m, 1H), 1.68 (m, 2H), 1.86 (m, 1H), 2.14 (s, 3H), 2.85 (m, 3H), 3.44 (m, 1H), 3.94 (d, 2H), 7.53 (m, 2H), 7.59 (s, 1H), 7.72 (d, 1H), 7.83 (s, 1H), 7.91 (d, 1H), 8.19 (s, 1H), 8.44 (d, 1H); Mass Spectrum: M+H+ 419.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][C@@H:10]1[CH2:15][CH2:14][C@H:13]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:12]([CH2:27][OH:28])[CH2:11]1.N1C=CN=C1>CN(C=O)C>[Si:1]([O:28][CH2:27][C@@H:12]1[CH2:11][C@H:10]([OH:9])[CH2:15][CH2:14][C@@H:13]1[NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(N[C@H]1CC[C@@H](O)C[C@H]1CO)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@H](O)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 57 %

Procedure:
tert-Butyldimethylsilylchloride (2.78 g, 18.5 mmol) in DMF (30 mL) was added dropwise over 3 h to the alcohol from Step 1 (5.43 g) and imidazole (1.33 g) in DMF (50 mL) at 0° C. After the addition was complete the ice bath was removed and the reaction warmed to room temperature overnight. The DMF solution was diluted with ether (400 mL) then washed with water (2×75 mL), sat'd NaHCO3 (1×75 mL), and brine (1×075 mL). The organic layer was dried over MgSO4, filtered, and then evaporated to dryness. The product was purified by flash chromatography (silica gel, 20-40% ethyl acetate/hexanes) to provide benzyl (1S,2R,4R)-2-((tert-butyldimethylsilyloxy)methyl)-4-hydroxycyclohexylcarbamate (4.15 g) as a color less oil. MS found: (M+H)+=394.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH2:17])=[CH:12][CH:11]=2)[CH:3]=1.[Li]CCCC.[CH2:23]([O:30][C@@H:31]1[C@@H:36]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:35]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C@@H:34]([CH2:53][O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[O:33][C:32]1=[O:62])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1>[CH2:23]([O:30][C@@H:31]1[C@@H:36]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:35]([O:45][CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C@@H:34]([CH2:53][O:54][CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[O:33][C:32]1([C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH2:17])=[CH:12][CH:11]=2)[CH:3]=1)[OH:62])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C=Cc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=Cc1ccc(Cc2cc(C3(O)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4-bromo-1-chloro-2-(4-vinylbenzyl)benzene (intermediate AM) (215 mg) in toluene:THF (2:1) (3 mL) at −78° C. was added n-BuLi (0.34 mL, 2.5 M in hexane) dropwise. After 45 min, the above mixture was added dropwise into a pre-cooled (−78° C.) solution of (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-one (453 mg) in toluene (3 mL). After being stirred for 2.5 h at −78° C., the reaction mixture was quenched by saturated NH4Cl and diluted with ethyl acetate. The organic layer was separated, washed with brine and dried over Na2SO4. Concentration gave the crude product which was purified by chromatography to provide intermediate AN (712 mg) as an oil.
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[O:7][C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].[OH-:18].[K+]>O1CCOCC1>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C@H:8]([OH:7])[CH2:9][C@H:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([OH:17])=[O:18])=[CH:11][CH:12]=1
Reactant: CCCC[C@H]1C[C@H](c2ccc(F)cc2)OC1=O
Reactant: [OH-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCC[C@@H](C[C@@H](O)c1ccc(F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the solution of (3S,5R)-3-butyl-5-(4-fluorophenyl)dihydrofuran-2(3H)-one (94.0 mg, 0.40 mmol) in 5 mL dioxane was added 5 mL aqueous 5% KOH at 25° C. After being stirred for 30 min at room temperature the reaction was quenched by the addition of 6 mL of 1M aqueous HCl. The mixture was extracted ethyl acetate (2×10 mL) and the combined organic layers were washed with brine (2×10 mL) before being concentrated under reduced pressure. The crude product was used directly in the next reaction without further purification.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C@@H:10]([OH:22])[CH2:11][C@@H:12]([C:18]([OH:21])([CH3:20])[CH3:19])[C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=O)(C)(C)C.C(OC(N[C@@H](CC1CCCCC1)[C@@H](O)C[C@@H](C(O)(C)C)C(NC)=O)=O)(C)(C)C.[C:58]([O:62][C:63]([NH:65][C@H:66]([C:73]([OH:75])=O)[CH2:67][C:68]1[N:69]=[CH:70][S:71][CH:72]=1)=[O:64])([CH3:61])([CH3:60])[CH3:59].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>>[C:58]([O:62][C:63]([NH:65][C@H:66]([C:73]([NH:8][C@@H:9]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C@@H:10]([OH:22])[CH2:11][C@@H:12]([C:18]([OH:21])([CH3:20])[CH3:19])[C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[O:75])[CH2:67][C:68]1[N:69]=[CH:70][S:71][CH:72]=1)=[O:64])([CH3:59])([CH3:60])[CH3:61]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Reactant: CN(C)C(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)(C)O
Agent: CCOP(=O)(C#N)OCC
Agent: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(C)(C)O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Yield: 71.9 %

Procedure:
A procedure similar to that described in Example 9(a) was repeated, except that 152 mg of (2S, 4S, 5S)- 5-(t-butoxycarbonylamino)-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N,N-dimethylhexanamide (prepared as described in Preparation 25) were used instead of the (2S, 4S, 5S)-5-(t-butoxycarbonylamino)-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhexanamide, and that 109 mg (0.4 mmoles) of N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine, 0.23 ml (1.66 mmoles) of triethylamine, and 0.064 ml (0.4 mmoles) of diethyl cyanophosphate were also used, to obtain 150 mg of the title compound as a white amorphous substance.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]1[C@H:13]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:12][N:11]2[CH2:24][C:25](=O)[CH2:26][CH2:27][C@@H:10]2[CH2:9]1)=[O:7].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.O.C(O)(=O)C>[F:1][C:2]([F:36])([F:37])[C:3]1[CH:4]=[C:5]([C:6]([N:8]2[C@H:13]([CH2:14][C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH:16]=3)[CH2:12][N:11]3[CH2:24][C@H:25]([N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)[CH2:26][CH2:27][C@@H:10]3[CH2:9]2)=[O:7])[CH:29]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:31]=1.[F:1][C:2]([F:36])([F:37])[C:3]1[CH:4]=[C:5]([C:6]([N:8]2[C@H:13]([CH2:14][C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH:16]=3)[CH2:12][N:11]3[CH2:24][C@@H:25]([N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)[CH2:26][CH2:27][C@@H:10]3[CH2:9]2)=[O:7])[CH:29]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:31]=1
Reactant: O=C1CC[C@@H]2CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3c[nH]c4ccccc34)CN2C1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CC[C@@H](N3CCCC3)CN2C[C@H]1Cc1c[nH]c2ccccc12
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1C[C@H]2CC[C@H](N3CCCC3)CN2C[C@H]1Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of (3R,9aR)-2-[3,5-bis(trifluoromethyl)benzoyl]-3-(1H-indol-3-ylmethyl)-octahydro-2H-pyrido[1,2-a]pyrazin-7-one (0.785 g, see example 3 steps 1–7), pyrrolidine (0.107 g), acetic acid (0.09 g) and sodium triacetoxyborohydride (0.47 g) in 1,2-dichloroethane (60 mL) was stirred for three days at room temperature. The resulting mixture was poured into water, basified with sodium bicarbonate (5% aq. soln.) and extracted with dichloromethane. The organic layer was concentrated and the residue was purified by column chromatography (SiO2, CH2Cl2/MeOH/NH4OH 92:7.5:0.5) to afford 3,5-bis(trifluoromethyl)phenyl-[(3R,7R,9aR)-3-(1H-indol-3-ylmethyl)-7-pyrrolidin-1-yl-octahydropyrido[1,2-a]pyrazin-2-yl]-methanone (0.20 g, Rf 0.23 (CH2Cl2/MeOH/NH4OH 92:7.5:0.5)) (compound 24) and 3,5-bis(trifluoromethyl)-phenyl-[(3R,7S,9aR)-3-(1H-indol-3-ylmethyl)-7-pyrrolidin-1-yl-octahydropyrido[1,2-a]pyrazin-2-yl]-methanone (0.48 g, Rf 0.15 (CH2Cl2/MeOH/NH4OH 92:7.5:0.5)) (compound 25).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:24])=[C:11](/[CH:16]=[C:17](\[CH3:23])/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]=[CH:13][C:14]=1[F:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:32][C:33]1[C:38]([F:39])=[CH:37][C:36](/[CH:40]=[C:41](\[CH3:47])/[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:35][C:34]=1[F:48])C1C=CC=CC=1>CCOC(C)=O.[C].[Pd]>[F:39][C:38]1[CH:37]=[C:36]([CH2:40][CH:41]([CH3:47])[C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:35]=[C:34]([F:48])[C:33]=1[OH:32].[CH2:1]([O:8][C:9]1[C:10]([F:24])=[C:11]([CH2:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]=[CH:13][C:14]=1[F:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C(C)=C/c1ccc(F)c(OCc2ccccc2)c1F
Reactant: CCOC(=O)/C(C)=C/c1cc(F)c(OCc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)Cc1cc(F)c(O)c(F)c1
Product: CCOC(=O)C(C)Cc1ccc(F)c(OCc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of ethyl (2E)-3-[3-(benzyloxy)-2,4-difluorophenyl]-2-methylprop-2-enoate and ethyl (2E)-3-[4-(benzyloxy)-3,5-difluorophenyl]-2-methylprop-2-enoate (4 g, 12.04 mmol, 1.00 equiv) in EtOAc (50 ml) and palladium carbon (2.5 g). Into the resulting mixture was then introduced H2(g). The resulting solution was stirred overnight at 25° C. The solids were filtered out and the resulting mixture was concentrated under vacuum. The resulting residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4) to yield ethyl 3-(3,5-difluoro-4-hydroxyphenyl)-2-methylpropanoate and ethyl 3-(3-(benzyloxy)-2,4-difluorophenyl)-2-methylpropanoate as colorless oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[N:32]=[C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:34][CH:35]=1.O>CN(C)C=O>[C:14]1([C:12]2[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][N:9]([CH2:8][C:7]3[CH:27]=[CH:28][C:4]([O:3][CH2:30][C:31]4[N:32]=[C:33]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[O:34][CH:35]=4)=[CH:5][CH:6]=3)[CH:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Reactant: ClCc1coc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.5 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-phenyloxazole (290 mg) was added to the mixture, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatograpy, and ethyl 3-[4-phenyl-1-[4-(2-phenyl-4-oxazolylmethoxy)benzyl]-3-pyrrolyl]propionate (550 mg, yield: 72%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:20])([F:19])[C:12]3[N:17]=[N:16][C:15]([NH2:18])=[CH:14][CH:13]=3)=[N:9][N:10]=2)[CH:7]=1.Br[CH2:22][C:23](=O)[C:24]([O:26][CH3:27])=[O:25].C([O-])(O)=O.[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:20])([F:19])[C:12]3[CH:13]=[CH:14][C:15]4[N:16]([CH:22]=[C:23]([C:24]([O:26][CH3:27])=[O:25])[N:18]=4)[N:17]=3)=[N:9][N:10]=2)[CH:7]=1
Reactant: Nc1ccc(C(F)(F)c2nnc3ccc(Br)cn23)nn1
Reactant: COC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1cn2nc(C(F)(F)c3nnc4ccc(Br)cn34)ccc2n1
Temperature: 80 °C

Procedure:
A reaction mixture of 6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)pyridazin-3-amine (11.0 g, 32.2 mmol), methyl 3-bromo-2-oxopropanoate (11.67 g, 64.5 mmol), and NaHCO3 (10.84 g) in dioxane (150 mL) was heated at 80° C. for 4 hrs to provide a red reaction mixture. Solids were filtered off, rinsed with dioxane, and the combined filtrates were concentrated via rotary evaporation. The resulting residue was dissolved in EtOAc and washed with 0.1 N NaOH until the red color no longer persisted. The organic phase was then separated and concentrated to dryness. The resulting material was purified via MPLC (5:95, MeOH/EtOAc) to provide the title compound, 45I (4.0 g, 9.45 mmol, 30%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.88 (s, 3 H) 7.77 (dd, J=9.73, 1.64 Hz, 1 H) 7.85 (d, J=9.60 Hz, 1 H) 7.97-8.08 (m, 1 H) 8.53 (d, J=9.60 Hz, 1 H) 8.98 (d, J=1.01 Hz, 1 H) 9.02 (s, 1 H). ESI-MS:m/z 423.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1)[N:6]2[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH3:28][CH:29]([N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[C:33]([C:45]2[CH:50]=[CH:49][C:48]([N+:51]([O-:53])=[O:52])=[CH:47][CH:46]=2)=[N:32]1)[CH3:30]>>[CH3:30][CH:29]([N:31]1[CH:35]=[C:34]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[C:5]([C:20]2[CH:21]=[CH:22][C:23]([CH:24]=[O:25])=[CH:26][CH:27]=2)[N:6]3[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:33]([C:45]2[CH:46]=[CH:47][C:48]([N+:51]([O-:53])=[O:52])=[CH:49][CH:50]=2)=[N:32]1)[CH3:28]
Reactant: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: O=Cc1ccc(-c2cc3c(Br)cccc3n2S(=O)(=O)c2ccccc2)cc1
Product: CC(C)n1cc(-c2cccc3c2cc(-c2ccc(C=O)cc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure for Intermediate 100 using 4-[4-bromo-1-(phenylsulfonyl)-1H-indol-2-yl]benzaldehyde and 1-(1-methylethyl)-3-(4-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole provided the title compound. ESMS [M+H]+: 592.4.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[C:25]([O:29][C:30]([NH:32][C:33]1[CH:54]=[CH:53][C:36]([CH2:37][N:38]2[CH2:42][CH2:41][N:40]([C:43]3[S:47][C:46]([C:48](O)=[O:49])=[C:45]([CH3:51])[CH:44]=3)[C:39]2=[O:52])=[CH:35][CH:34]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[NH2:55][CH2:56][C:57]1[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=1>>[CH3:51][C:45]1[CH:44]=[C:43]([N:40]2[CH2:41][CH2:42][N:38]([CH2:37][C:36]3[CH:35]=[CH:34][C:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:28])[CH3:26])=[CH:54][CH:53]=3)[C:39]2=[O:52])[S:47][C:46]=1[C:48](=[O:49])[NH:55][CH2:56][C:57]1[CH:58]=[N:59][CH:60]=[CH:61][CH:62]=1
Reactant: Cc1cc(N2CCN(Cc3ccc(NC(=O)OC(C)(C)C)cc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(NC(=O)OC(C)(C)C)cc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 75 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-(tert-butoxycarbonylamino)benzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a beige solid in 75% yield: 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.53 (d, J=4.5 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.33 (d, J=8.3 Hz, 2H), 7.27 (dd, J=7.8, 4.5 Hz, 1H), 7.21 (d, J=8.3 Hz, 2H), 6.51 (br s, 1H), 6.08 (br s, 2H), 4.58 (d, J=5.8 Hz, 2H), 4.40 (s, 2H), 3.82-3.73 (m, 2H), 3.45-3.37 (m, 2 H), 2.50 (s, 3H), 1.51 (s, 9H); MS (ES+) m/z 522.5 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:26]#[C:27][CH2:28][N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=1)[CH2:7]2.[H][H].C(Cl)(Cl)Cl.CO>C(O)C.[C].[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:17][CH:18]=1)[CH2:7]2
Reactant: [H][H]
Reactant: CN1CCN(CC#Cc2cc(Cl)c3c(c2)CN(Cc2ccc(Oc4ccccc4)cc2)C3=O)CC1
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CN1CCN(CCCc2cc(Cl)c3c(c2)CN(Cc2ccc(Oc4ccccc4)cc2)C3=O)CC1
Yield: 47.6 %

Procedure:
A mixture of 7-chloro-5-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl)-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.073 g, 0.15 mmol) and 10% palladium-carbon (0.015 g) in ethanol (25 mL) was reduced under 45 p.s.i hydrogen. Workup and silica gel column chromatography using 5:1 CHCl3-MeOH afforded 7-chloro-5-[3-(4-methyl-piperazin-1-yl)-propyl]-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.035 g, 50%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.79 (m, 2H), 2.22-2.60 (m, 13H), 2.66 (t, 2H), 4.22 (s, 2H), 4.74 (s, 2H), 6.86-7.38 (m, 11H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][S:8]([CH2:11][C:12]1[CH2:13][CH2:14][N:15]([C:18](=[S:20])[OH:19])[CH2:16][CH:17]=1)(=[O:10])=[O:9].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[N:29]2[CH2:32][C:31](=[O:33])[CH2:30]2)=[CH:24][CH:23]=1>O1CCCC1.O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[N:29]2[CH2:30][C:31]([CH2:7][S:8]([CH2:11][C:12]3[CH2:17][CH2:16][N:15]([C:18](=[S:20])[OH:19])[CH2:14][CH:13]=3)(=[O:9])=[O:10])([OH:33])[CH2:32]2)=[CH:24][CH:23]=1
Reactant: O=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reactant: CS(=O)(=O)CC1=CCN(C(O)=S)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(CC1=CCN(C(O)=S)CC1)CC1(O)CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
The phenolic ester of 4-({1-[bis(4-chlorophenyl)methyl]-3-hydroxyazetidin-3-yl}methylsulfonylmethyl)-3,6-dihydro-2H-pyridine-1-carbothioic acid is prepared in the following manner: 0.52 g of potassium tert-butoxide is added to a mixture of 0.72 g of the phenolic ester of 4-methylsulfonylmethyl-3,6-dihydro-2H-pyridine-1-carbothioic acid and 0.708 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one in 15 cm3 of dry tetrahydrofuran cooled under an inert atmosphere to −78° C. The reaction mixture is stirred at −78° C. for 4 hours and then 0.354 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one are added. After two hours at −78° C., the temperature is allowed to return to 20° C. The reaction mixture is diluted in 100 cm3 of water and then the tetrahydrofuran is evaporated off under 2.7 kPa at 40° C. The aqueous phase is extracted with twice 100 cm3 of ethyl acetate. The organic extracts are combined and dried over magnesium sulfate, concentrated under 2.7 kPa at 40° C. The residue obtained is chromatographed on silica (200 g of silica, Amicon, 20-45 μm, porosity 60Angstroem, column 5 cm in diameter), eluting with a cyclohexane:ethyl acetate (6:4 by volume) mixture. The fractions with an Rf=11/64 (cyclohexane:ethyl acetate 6:4, silica plate, Merck reference 1.05719, Merck KGaA, 64721 Darmstatd, Germany) are combined and concentrated under 2.7 kPa at 40° C. to give 240 mg of the phenolic ester of 4-({1-[bis(4-chlorophenyl)methyl]-3-hydroxyazetidin-3-yl}methylsulfonylmethyl)-3,6-dihydro-2H-pyridine-1-carbothioic acid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:13](=[O:26])[NH:14][CH:15]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[C:16](=[O:19])[NH:17][CH3:18])[C:9]([CH3:12])([CH3:11])[CH3:10])(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[NH2:7][CH:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:13]([NH:14][CH:15]([CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)[C:16](=[O:19])[NH:17][CH3:18])=[O:26]
Reactant: CNC(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)C1CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)C(NC(=O)C(N)C(C)(C)C)C1CCCCC1

Procedure:
Compound 64 was kept in dichloromethane-trifluoroacetic acid 2:1 for 1 h at rt and concentrated to dryness. The residue was dried in a vacuum for 16 hrs. Reversed phase C18 HPLC showed >95% purity M+H+283.1.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.O.[CH3:17][O:18][C:19]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:17][O:18][C:19]1[C:24]([C:2]2[C:3]([O:8][C:9]3[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: COc1ncccc1B1OC(C)(C)C(C)(C)O1
Reactant: Nc1ccc(Oc2nccnc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ncccc1-c1nccnc1Oc1ccc(N)cc1
Temperature: 100 °C

Procedure:
To a glass microwave vial was added 4-(3-chloropyrazin-2-yloxy)aniline (1.0591 g, 4.78 mmol), 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine hydrate, trans-dichlorobis(triphenylphosphine) palladium (II) (0.268 g, 0.382 mmol), and sodium carbonate (2.53 g, 23.89 mmol) in DME (7.65 mL) and water (1.911 mL). The reaction mixture was stirred and heated in a Biotage Initiator microwave reactor at 100° C. for 15 min. The crude product was adsorbed onto a plug of silica gel and chromatographed to provide 4(3-(2-methoxypyridin-3-yl)pyrazin-2-yloxy)aniline. MS (ESI, pos. ion) m/z:295.2.