Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:19])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:22]1([OH:28])C=CC=CC=1.C(Cl)(Cl)Cl.Cl>C(O)C.O>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH:22]=[O:28])[C:6]=1[OH:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)CC(C)(C)c1cc(C=O)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
2-t-butyl-4-t-octylphenol (140 g, 0.53 mole) was dissolved in 420 ml of absolute ethanol in a 3 L round bottom flask equipped with a water-cooled condenser. Sodium hydroxide (213 g, 5.3 moles) was dissolved in 200 ml water and added while still hot to the solution of phenol. Chloroform (127 g, 1.06 mole) was added in 2 to 3 ml portions over a 1 hour period. The resulting yellow-brown mixture was stirred for 1 hour while it cooled to ambient temperature. The mixture was diluted into 500 ml of 5M hydrochloric acid. The organic layer was isolated in a separatory funnel and dried over anhydrous magnesium sulfate. The mixture was filtered and rotoevaporated to a thick syrup to yield 26% crude product with an IR spectrum having the characteristic aldehyde carbonyl stretching frequency. The product was used without further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:38])[O:13][CH2:14][C@@H:15]([N:24]([CH3:37])[C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=2[F:36])=[O:26])[CH2:16][CH2:17][CH2:18][O:19][P:20]([OH:23])([OH:22])=[O:21])[N:2]=1.[OH-].[Na+:40]>CO>[P:20]([O-:22])([O-:23])([O:19][CH2:18][CH2:17][CH2:16][C@H:15]([N:24]([CH3:37])[C:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[F:36])=[O:26])[CH2:14][O:13][C:12](=[O:38])[NH:11][C:3]1[N:2]=[CH:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:21].[Na+:40].[Na+:40]
Reactant: CN(C(=O)NCc1cccc(F)c1F)[C@@H](CCCOP(=O)(O)O)COC(=O)Nc1cc2ccccc2cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C(=O)NCc1cccc(F)c1F)[C@@H](CCCOP(=O)([O-])[O-])COC(=O)Nc1cc2ccccc2cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
To a solution of (S)-2-(3-(2,3-difluorobenzyl)-1-methylureido)-5-(phosphonooxy)pentyl isoquinolin-3-ylcarbamate (2.50 g, 4.54 mmol) in MeOH (100 mL) was added NaOH (0.1 N, 90.7 mL, 9.07 mmol) at 0° C. After stirred at 0° C. for 1 h, the mixture was concentrated to give sodium (S)-4-(3-(2,3-difluorobenzyl)-1-methylureido)-5-(isoquinolin-3-ylcarbamoyloxy)pentyl phosphate (2.15 g, 79%) as a white solid. LRMS (M-2Na++3H+) m/z 553.5.
Reaction SMILES: Cl.N1C=CC=CC=1.[CH2:8]([N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18]C)[C:13]1=[S:20])[CH2:9][CH2:10][CH3:11].O>C(OCC)(=O)C>[CH2:8]([N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:13]1=[S:20])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCn1cccc(OC)c1=S
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCCn1cccc(O)c1=S
Temperature: 190 °C
Reaction time: 0.67 h
Yield: 78.4 %

Procedure:
Pyridine hydrochloride salt (3.6 g) was added to 1-butyl-3-methoxypyridine-2-thione (2-034-03) (1.4 g), and the reaction mixture was stirred at 190° C. for 40 min. To the reaction mixture were added water and ethyl acetate, and the organic layer was separated, and the organic layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give 1-butyl-3-hydroxypyridine-2-thione (2-034-04) (1.02 g, 78%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:37][C:38]2[CH:42]=[C:41]([C:43](=[O:61])[NH:44][C:45]3[CH:50]=[CH:49][C:48]([C:51]4[CH:55]=[C:54]([C:56]([O:58][CH3:59])=[O:57])[N:53]([CH3:60])[CH:52]=4)=[CH:47][CH:46]=3)[N:40]([CH3:62])[CH:39]=2)=[O:36])=[CH:29][C:6]2[N:7](C(OCC=C)=O)[C@@H:8](OC3CCCCO3)[C@@H:9]3[CH2:15][CH2:14][CH2:13][N:10]3[C:11](=[O:12])[C:5]=2[CH:4]=1.N1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:1][O:2][C:3]1[C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:37][C:38]2[CH:42]=[C:41]([C:43]([NH:44][C:45]3[CH:50]=[CH:49][C:48]([C:51]4[CH:55]=[C:54]([C:56]([O:58][CH3:59])=[O:57])[N:53]([CH3:60])[CH:52]=4)=[CH:47][CH:46]=3)=[O:61])[N:40]([CH3:62])[CH:39]=2)=[O:36])=[CH:29][C:6]2[N:7]=[CH:8][C@@H:9]3[CH2:15][CH2:14][CH2:13][N:10]3[C:11](=[O:12])[C:5]=2[CH:4]=1
Reactant: C=CCOC(=O)N1c2cc(OCCCC(=O)Nc3cc(C(=O)Nc4ccc(-c5cc(C(=O)OC)n(C)c5)cc4)n(C)c3)c(OC)cc2C(=O)N2CCC[C@H]2[C@@H]1OC1CCCCO1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCNC1
Product: COC(=O)c1cc(-c2ccc(NC(=O)c3cc(NC(=O)CCCOc4cc5c(cc4OC)C(=O)N4CCC[C@H]4C=N5)cn3C)cc2)cn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.3 %

Procedure:
Palladium tetrakis[triphenylphosphine](12.17 mg, 10.5 μM, 0.05 equiv) was added to a solution of Alloc-THP-PBD conjugate 15e (179 mg, 0.21 mmol), pyrrolidine (17.91 mg, 0.25 mmol, 1.2 eq) and triphenylphosphine (13.81 mg, 0.25 equiv) in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 h at which point TLC showed completion of reaction. Excess DCM was removed by rotary evaporation under reduced pressure and the resulting residue dried in vacuo to remove pyrrolidone. The product was purified by high performance liquid chromatography (eluted with acetone:water gradient with 1% TFA) to give the product as a light yellowish solid, 16e (48 mg, 34% after HPLC purification).
Reaction SMILES: [O:1]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20].CN(C)CCN(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl>[O:1]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:20]=[CH:19][C:18]([O:22][CH3:23])=[O:21])=[CH:13][CH:12]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(Br)cc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)CCN(C)C
Solvent: ClCCl
Product: COC(=O)C=Cc1ccc(CCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 140 °C
Yield: 92.5 %

Procedure:
A mixture of 4-(2-t-butyldimethylsiloxyethyl)bromobenzene (1.00 g), methyl acrylate (0.55 g), palladium(II) acetate (0.010 g), triphenylphosphine (0.017 g) and N,N,N',N'-tetramethylethylenediamine (0.48 ml) was heated at 140° C. for 24 hours under an atmosphere of argon. To the reaction mixture was added methylene chloride (30 ml), the formed insoluble materials were removed by filtration through a celite column, and the filtrate was concentrated under reduced pressure. To the residue was added diethyl ether (30 ml), and the formed insoluble materials were removed by filtration through a celite column. The filtrate was concentrated to dryness to give methyl 4-(2-t-butyldimethylsiloxyethyl)cinnamate (0.94 g) as a brown oily liquid.
Reaction SMILES: O[N:2]=[CH:3][C@:4]12[CH2:42][CH2:41][C@@H:40]([C:43]([CH3:45])=[CH2:44])[C@@H:5]1[C@@H:6]1[C@@:19]([CH3:22])([CH2:20][CH2:21]2)[C@@:18]2([CH3:23])[C@@H:9]([C@:10]3([CH3:39])[C@@H:15]([CH2:16][CH2:17]2)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]2[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][CH:27]=2)=[CH:12][CH2:11]3)[CH2:8][CH2:7]1.[NH4+].[Cl-].[Na]>[Cl-].[Ti+3].[Cl-].[Cl-].CCO>[NH2:2][CH2:3][C@:4]12[CH2:42][CH2:41][C@@H:40]([C:43]([CH3:45])=[CH2:44])[C@@H:5]1[C@@H:6]1[C@@:19]([CH3:22])([CH2:20][CH2:21]2)[C@@:18]2([CH3:23])[C@@H:9]([C@:10]3([CH3:39])[C@@H:15]([CH2:16][CH2:17]2)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]2[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])=[CH:28][CH:27]=2)=[CH:12][CH2:11]3)[CH2:8][CH2:7]1
Reactant: C=C(C)[C@@H]1CC[C@]2(C=NO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Ti+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: C=C(C)[C@@H]1CC[C@]2(CN)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
To the crude product from above containing tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((hydroxyimino)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (100 mg, 0.163 mmol) in a 100 mL pear shape flask was added EtOH (12 mL) to form a clear solution. To this was added excess of NH4Cl (400 mg, 5.19 mmol) and sodium cyanoborohydre (300 mg, 4.77 mmol). The mixture was stirred in an ice bath until cold. To this suspension was added titanium(III) chloride (4 mL, 0.163 mmol) 20% solution. The resulting mixture was blanketed with nitrogen. The ice bath was removed and the stirring was continued at rt for an hour. LCMS show the reaction was complete. At this point, the mixture was dark greenish-blue-purple. A solution of sodium hydroxide (3 mL, 10N in 25 mL water) was added into the reaction mixture, along with methylene chloride (30 mL).
Reaction SMILES: [NH2:1][NH2:2].[O:3]=[C:4]1[CH:9]([CH2:10][C:11](OC)=[O:12])[S:8](=[O:16])(=[O:15])[C:7]2[S:17][C:18]([S:20](=[O:23])(=[O:22])[NH2:21])=[CH:19][C:6]=2[NH:5]1>CO>[S:20]([C:18]1[S:17][C:7]2[S:8](=[O:16])(=[O:15])[CH:9]([CH2:10][C:11]([NH:1][NH2:2])=[O:12])[C:4](=[O:3])[NH:5][C:6]=2[CH:19]=1)(=[O:23])(=[O:22])[NH2:21]
Reactant: COC(=O)CC1C(=O)Nc2cc(S(N)(=O)=O)sc2S1(=O)=O
Reactant: NN
Solvent: CO
Product: NNC(=O)CC1C(=O)Nc2cc(S(N)(=O)=O)sc2S1(=O)=O
Reaction time: 5.5 h

Procedure:
Anhydrous hydrazine (1 ml) was added to a solution of methyl (2,3-dihydro-2,4,4-trioxo-6-sulfamoyl-1H-thieno[2,3-b][1,4]thiazin-3-yl)acetate (1.0 g) in methanol (10 ml) at ambient temperature with stirring. After 5-6 hours, the methanol was removed under reduced pressure and the residue was treated with water (10 ml). The pH was adjusted to 6.5 and the resulting precipitate was collected, rinsed with water and dried under vacuum to give 0.40 g (2,3-dihydro-6-sulfamoyl-2,4,4-trioxo-1H-thieno[2,3-b][1,4]thiazin-3-yl)acetic acid hydrazide, mp 230° C., dec.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([OH:11])=[C:6]([Cl:12])[CH:5]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:5]=[C:6]([Cl:12])[C:7]([O:11][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]([Cl:10])[CH:9]=1
Reactant: COC(=O)c1cc(Cl)c(O)c(Cl)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(OCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,5-dichloro-4-hydroxy benzoic acid methyl ester (5.525 g, 25 mmol), benzyl bromide (5.13 g, 30 mmol) and potassium carbonate (6.91 g, 50 mmol) in N,N-dimethylformamide (100 mL) was stirred overnight at room temperature. The reaction mixture was poured into crushed ice (ca. 300 g) and the product was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The solid residue was recrystallised from ethyl acetate and hexane. Yield: 7.47 g (96%) fine white needles. 1H-NMR (400 MHz, CDCl3) δ=3.93 (s, 3H, —OCH3), 5.12 (s, 2H, —CH2Ph), 7.35-7.44 (m, 3H), 7.54-7.58 (m, 2H), 8.01 (s, 2H). 13C-NMR (100 MHz, CDCl3) δ=52.66, 75.12, 127.18, 128.41, 128.48, 129.79, 130.13, 135.57, 154.57, 164.39.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:14][CH:15]1[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17][CH2:16]1.[O:23]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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]>[O:21]=[S:18]1(=[O:22])[CH2:19][CH2:20][CH:15]([CH2:14][C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:25]4[CH:26]=[CH:27][O:23][CH:24]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:16][CH2:17]1
Reactant: NC(=O)c1cc(Br)cc2c(CC3CCS(=O)(=O)CC3)c[nH]c12
Reactant: OB(O)c1ccoc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cc(-c2ccoc2)cc2c(CC3CCS(=O)(=O)CC3)c[nH]c12
Temperature: 120 °C
Yield: 49.6 %

Procedure:
5-bromo-3-[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]-1H-indole-7-carboxamide (30 mg, 0.078 mmol), 3-furanylboronic acid (24.05 mg, 0.215 mmol, 2.76 eq), potassium carbonate (64.6 mg, 6 eq), PdCl2(dppf) (4.56 mg, 0.006 mmol, 0.08 eq), were dissolved in a mixture of 1,4-dioxane (2 mL) and water (1 mL) in a 2-5 mL biotage microwave reaction tube. The mixture was heated in a Biotage microwave at high absorption for 10 minutes at 120° C. The reaction mixture was filtered through a polypropylene cartridge (10 mL tube) on a Bohdan Miniblock in a reaction tube and was then concentrated and purified by Gilson HPLC with a water-acetonitrile with 0.1% TFA buffer. The desired product fractions were combined and concentrated in an EZ2 Genevac evaporator, giving 14.4 mg (44.7%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](C=C[CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].[NH2:32][CH:33](C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.CN1C=CC=C1C(O)=O.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:33][N:32]1[CH:31]=[CH:2][CH:3]=[C:4]1[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6]
Reactant: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cn1cccc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3cccn3C)nn2)cc(OC)c1OC
Yield: 95 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (200 mg, 0.65 mmol), 1-methyl-1H-pyrrole-2-carboxylic acid (106 mg, 0.85 mmol), diisopropylethylamine (0.33 mL, 1.9 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (360 mg, 0.94 mmol) in dimethylformamide (5 mL) gave 1-methyl-N-(1-{3-[(3,4,5-trimethoxyphenyl)-amino]-1,2,4-triazin-6-yl}ethyl)-1H-pyrrole-2-carboxamide (256 mg, 95%) as a yellow solid. MS m/z 412 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][C:9]3([C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:11][CH2:10]3.Br[CH2:15][CH2:16][CH2:17][CH2:18]Br>>[N:1]1([C:2]2[C:7]3[O:8][C:9]4([C:12](=[O:13])[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:10][CH2:11]4)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: BrCCCCBr
Reactant: Nc1cccc2c1OC1(CC1)C2=O
Product: O=C1c2cccc(N3CCCC3)c2OC12CC2
Yield: 19.1 %

Procedure:
7-Aminospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (3.5 g) and 1,4-dibromobutane (4.3 g.) were reacted in the same manner as Example 31, and the product was recrystallized from ethanol to give 7-(1-pyrrolidinyl)spiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (0.87 g.) as yellow needles melting at 101.5° C.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([NH:15][C@@H:16]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:18]([CH2:28][NH:29][CH3:30])[CH2:17]2)=[O:14])=[N:5]1)([CH3:3])[CH3:2].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>>[CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([NH:15][C@@H:16]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[C@H:18]([CH2:28][N:29]([CH3:30])[S:32]([CH3:31])(=[O:34])=[O:33])[CH2:17]2)=[O:14])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CNC[C@@H]1C[C@H](NC(=O)c2nn(C(C)C)c3ccccc23)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Product: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CN(C)S(C)(=O)=O)N(C(=O)OC(C)(C)C)C2)c2ccccc21

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 17 from tert-butyl (2S,4S)-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}-2-[(methylamino)methyl]pyrrolidine-1-carboxylate (step 1 of Example 26) and methanesulfonyl chloride.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].C(OC([N:36]1[C:40]([C:41]#[N:42])=[CH:39][CH:38]=[C:37]1B(O)O)=O)(C)(C)C>>[C:41]([C:40]1[NH:36][C:37]([C:2]2[C:3]([N:22]3[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]3)=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:19])([F:20])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:38][CH:39]=1)#[N:42]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Reactant: CC(C)(C)OC(=O)n1c(C#N)ccc1B(O)O
Product: N#Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2C[C@H](O)[C@@H](O)C2)[nH]1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 29 using 5-bromo-6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 31.1) and (1-(tert-butoxycarbonyl)-5-cyano-1H-pyrrol-2-yl)boronic acid (Stage 29.1) to afford an off-white solid. UPLC-MS (Condition 3) tR=0.94 min, m/z=474.1 [M+H]+, m/z=472.1 [M−H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.02 (d, J=11.86 Hz, 2H) 3.46 (dd, J=11.86, 3.55 Hz, 2H) 3.89 (br. s, 2H) 5.09 (d, J=2.45 Hz, 2H) 6.29 (d, J=3.67 Hz, 1H) 7.03 (d, J=3.67 Hz, 1H) 7.35 (d, J=8.44 Hz, 2H) 7.82-7.90 (m, 2H) 8.07 (d, J=2.45 Hz, 1H) 8.75 (d, J=2.45 Hz, 1H) 10.18 (s, 1H) 12.65 (br. s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:28])[C@H:4]([CH2:24][CH2:25][S:26][CH3:27])[NH:5][C:6](=[O:23])[C@@H:7]([C@@H:19]([CH2:21][CH3:22])[CH3:20])[NH:8][S:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:11])=[O:10].Cl>C(O)C.[OH-].[Na+]>[CH2:12]([S:9]([NH:8][C@@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:28])=[O:2])[CH2:24][CH2:25][S:26][CH3:27])=[O:23])[C@@H:19]([CH2:21][CH3:22])[CH3:20])(=[O:11])=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC[C@@H](C)[C@@H](NS(=O)(=O)Cc1ccccc1)C(=O)N[C@@H](CCSC)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC[C@@H](C)[C@@H](NS(=O)(=O)Cc1ccccc1)C(=O)N[C@@H](CCSC)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of N-(benzylsulfonyl)-D-isoleucyl-L-methionine methyl ester (6.4 g, 14.9 mmol) in ethanol (30 ml), 2N aqueous sodium hydroxide (30 ml) was added and stirred at room temperature. After 1 hour, the reaction mixture was adjusted to pH 2 with 2N aqueous hydrogen chloride and then extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off and the filtrate was concentrated under reduced pressure to give N-(benzylsulfonyl)-D-isoleucyl-L-methionine (6.2 g, 14.9 mmol; yield 100%).
Reaction SMILES: [CH2:1]([N:15]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])CCC(OC)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH:36]O>C(O)(C)C>[CH2:1]([N:15]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[OH:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCN(CCCCCCCCCCCCCC)CCC(=O)OC
Reactant: OO
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCN(O)CCCCCCCCCCCCCC
Yield: 43.5 %

Procedure:
Using the general procedure of Example 2, 57.5 grams (0.116 mol) of the product of Example 7 in 450 ml of isopropanol is oxidized using 5.6 ml (0.15 Mol) of 70% aqueous hydrogen peroxide solution to give 21.5 grams (44% yield) of the above-named product as a white solid melting at 94°-96° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[O:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[CH2:29]1)=[O:27])C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[O:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:42][CH2:43][O:44][CH2:45][CH2:46]2)[CH2:29]1)=[O:27]
Reactant: C=C(C)c1cc(C(=O)N2Cc3cccc(OCCCN4CCOCC4)c3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1cc(C(=O)N2Cc3cccc(OCCCN4CCOCC4)c3C2)c(O)cc1O
Yield: 6 %

Procedure:
A solution of (2,4-bis-benzyloxy-5-isopropenyl-phenyl)-[4-(3-morpholin-4-yl-propoxy)-1,3-dihydro-isoindol-2-yl]-methanone in methanol (5 mL) was hydrogenated at atmospheric pressure over 10% palladium on charcoal (45 mg) for 4 hours. The mixture was filtered through Celite, eluting with methanol, then the filtrate was concentrated in vacuo to give a residue which was purified by preparative HPLC (basic method). This afforded the title compound as a white solid (16 mg, 6% over two steps). 1H NMR (methanol-d4) 7.24 (1H, t), 7.18 (1H, s), 6.89 (1H, d), 6.84 (1H, d), 6.37 (1H, s), 4.87 (2H, br.s), 4.78 (2H, br.s), 4.11-4.04 (2H, m), 3.72-3.66 (4H, m), 3.21 (1H, sept), 2.60-2.42 (6H, m), 2.05-1.92 (2H, m), 1.21 (6H, d). MS: [M+H]+ 441.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@:4]([NH2:28])([C@@H:13]([CH2:21][C:22](=[O:27])[CH:23]=[CH:24][CH2:25][CH3:26])[O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[NH:5][C:6]([O:8]C(C)(C)C)=[O:7].N1C(C)=CC=CC=1C.[Si:38](OS(C(F)(F)F)(=O)=O)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39].[Cl-].[NH4+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])[C@:4]([NH2:28])([C@@H:13]([CH2:21][C:22](=[O:27])[CH:23]=[CH:24][CH2:25][CH3:26])[O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[NH:5][C:6]([O:8][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])=[O:7]
Reactant: CCC=CC(=O)C[C@@H](OC1CCCCO1)[C@](N)(NC(=O)OC(C)(C)C)C(=O)OC
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCC=CC(=O)C[C@@H](OC1CCCCO1)[C@](N)(NC(=O)O[Si](C)(C)C(C)(C)C)C(=O)OC
Reaction time: 0.25 h

Procedure:
To a methylene chloride solution (1.0 ml) of N-(t-butoxycarbonyl)-2-amino-4-pentenoyl-O-(tetrahydropyranyl)threonine methyl ester (37 mg, 0.09 mmol) and 2,6-lutidine (0.021 ml, 0.18 mmol) was added dropwise t-butyldimethylsilyltrifluoromethane sulfonate (TBDMSOTf) (0.031 ml, 0.14 mmol) at room temperature in a nitrogen atmosphere. After the mixture was stirred for 15 minutes, a saturated aqueous solution of ammonium chloride (2 ml) was added to quench the reaction and extraction with ether was conducted. The organic layer was dried over anhydrous magnesium sulfate and filtered. By distilling off the solvent under vacuum, the titled compound was obtained in an amount of 45.8 mg.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[O:12])=[CH:7][CH:6]=1.[CH3:20][NH2:21]>CO>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:21][CH3:20])=[CH:6][CH:7]=2)=[O:12])=[CH:14][CH:15]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Reactant: CN
Solvent: CO
Product: CNCCOc1ccc(C(=O)c2ccc(O)cc2)cc1
Yield: 65 %

Procedure:
According to the same procedure as example 1, step E described, (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (2.0 g, 1.0 eq) was reacted with MeNH2 (30% wt in water, 30 mL) in MeOH (30 mL) under reflux to give the desired product (1.4 g, 65%). 1H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J=8.8 Hz, 2H), 7.60 (d, J=8.8 Hz, 2H), 7.06 (d, J=8.8 Hz, 2H), 6.85 (d, J=8.8 Hz, 2H), 4.18 (t, J=5.6 Hz, 2H), 2.89 (t, J=6.0 Hz, 2H), 2.37 (s, 3H).