Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([CH:18]3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:10]=1.[NH2:37][C:38]1[CH:48]=[CH:47]C(Br)=[CH:45][C:39]=1[C:40]([N:42]([CH3:44])[CH3:43])=[O:41]>C1COCC1.C(#N)C.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[NH2:37][C:38]1[CH:48]=[CH:47][C:18]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][N:11]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:28])=[O:29])[C:12]3=[N:13][CH:14]=2)=[CH:45][C:39]=1[C:40]([N:42]([CH3:43])[CH3:44])=[O:41]
Reactant: CN(C)C(=O)c1cc(Br)ccc1N
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(C3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C]([PH+](c2ccccc2)c2ccccc2)[CH]1
Solvent: CC#N
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(N)c(C(=O)N(C)C)c3)cc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
A mixture of 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.5 g, 3 mmol), 2-amino-5-bromo-N,N-dimethyl-benzamide 0.8, 3.3 mmol), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (110 mg, 0.2 mmol) in THF/Acetonitrile/saturated NaHCO3 (5 ml/5 ml/5 ml) was stirred at 100° C. for 4 hours. The mixture was allowed to cool down to room temperature and then extracted with ethyl acetate (3×). The combined organic layers were extracted with brine, dried with Na2SO4, decanted, and concentrated to dryness. Silica gel chromatography of the crude using a gradient of ethyl acetate and hexane afforded 2-amino-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide (1.1 g, 71% yield). 1H NMR (500 MHz, DMSO-d6) δ 2.29 (s, 3H), 2.89 (s, 6H), 3.77 (s, 3H), 6.74 (d, 1H), 7.03 (m, 1H), 7.14 (d, 1H), 7.29 (s, 1H), 7.34-7.41 (m, 4H), 7.55 (d, 1H), 7.94 (s, 2H), 8.01 (d, 2H), 8.54 (s, 1H). MS: m/z 541.1 (M+H+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:14]2[N:15]=[C:16]([O:19][CH2:20][CH2:21][CH2:22][S:23][CH3:24])[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1.[N:25]#[C:26][NH2:27].[K].C([O-])(C)(C)C.BrN1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CO.O.ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:14]2[N:15]=[C:16]([O:19][CH2:20][CH2:21][CH2:22][S:23](=[N:27][C:26]#[N:25])[CH3:24])[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1
Reactant: CSCCCOc1ccc2ncc(-c3cc4ccccc4o3)n2n1
Reactant: N#CN
Agent: CC(C)(C)[O-]
Agent: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CS(CCCOc1ccc2ncc(-c3cc4ccccc4o3)n2n1)=NC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
17.1 g (50.4 mmol) 3-(1-benzofuran-2-yl)-6-[3-(methylsulfanyl)propoxy]imidazo-[1,2-b]pyridazine and 2.65 g (63.0 mmol) cyanamide were dissolved in 86 mL methanol. At 20-25° C. 7.35 g (65.5 mmol) potassium-tert.-butanolate were added in portions. 11.7 g (65.5 mmol) N-bromosuccinimide were added in portions and it was stirred one hour at room temperature. 250 mL dichloromethane were added and stirred a couple of minutes. 64 mL 10% sodium thiosulfate solution and 22 mL water were added. The layers were separated and the aqueous phase was extracted twice with 30 mL of dichloromethane. The combined organic phases were washed twice with 20 mL water, dried over magnesium sulfate, and concentrated. The residue was crystallized from dichloromethane and tert-butyl methyl ether to yield 12.08 g (63%) of a yellow powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:15]2=[CH:16][CH:17]=[N:18][CH:19]=[C:14]2[C:5]2[C:6]([OH:13])=[CH:7][C:8]([CH:10]([CH3:12])[CH3:11])=[CH:9][C:4]=2[O:3]1.[ClH:21].[N:22]1([CH2:28][CH2:29][CH2:30][C:31](O)=[O:32])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C1(N=C=NC2CCCCC2)CCCCC1>>[ClH:21].[CH3:20][C:2]1([CH3:1])[C:15]2=[CH:16][CH:17]=[N:18][CH:19]=[C:14]2[C:5]2[C:6]([O:13][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:7][C:8]([CH:10]([CH3:12])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: CC(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: O=C(O)CCCN1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Product: CC(C)c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
5,5-Dimethyl-8-iso-propyl-10-[4-(piperidino)butyryloxy]-5H-[1]benzopyrano[3,4-d]pyridine hydrochloride is prepared according to the method of Example 29 by reacting equimolar quantities of 5,5-dimethyl-10-hydroxy-8-iso-propyl-5H-[1]benzopyrano[3,4-d]pyridine and γ-piperidinobutyric acid hydrochloride in the presence of dicyclohexyl carbodiimide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:19]([O:21][C:22]([C:24]1[C:32]2[CH2:31][CH2:30][NH:29][C:28](=[O:33])[C:27]=2[N:26]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[N:25]=1)=[O:23])[CH3:20].C([O-])([O-])=O.[K+].[K+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>CS(C)=O.[Cu]I.CCOC(C)=O>[CH2:19]([O:21][C:22]([C:24]1[C:32]2[CH2:31][CH2:30][N:29]([C:14]3[CH:15]=[CH:16][C:11]([C:8]4([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:18])[CH2:10][CH2:9]4)=[CH:12][CH:13]=3)[C:28](=[O:33])[C:27]=2[N:26]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[N:25]=1)=[O:23])[CH3:20]
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCNC2=O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(I)cc2)CC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(C3(NC(=O)OC(C)(C)C)CC3)cc1)C2=O
Temperature: 120 °C
Yield: 46.2 %

Procedure:
Part A. [1-(4-Iodo-phenyl)-cyclopropyl]-carbamic acid tert-butyl ester (0.34 g, 0.95 mmol) and 1-(4-methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (0.30 g, 0.97 mmol) were stirred in DMSO (1 mL). K2CO3 (0.25 g, 1.81 mmol), CuI (87 mg, 0.46 mmol) and 1,10-phenanthroline (83 mg, 0.46 mmol) were added. The resulting mixture was heated at 120° C. for 2.5 h. After cooling, it was extracted with EtOAc (2×), washed with H2O and brine, dried over MgSO4, filtered, and concentrated to dryness. The residue was purified by FCC (silica gel, CH2Cl2:EtOAc=1:1, then EtOAc) to give 6-[4-(1-tert-butoxycarbonylamino-cyclopropyl)-phenyl]-1-(4-methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (0.24 g, yield: 46%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8])([O-:3])=[O:2].[CH2:12]([N:26]=[C:27]=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:12]([NH:26][C:27]([O:11][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][C:7]=1[O:8][C:27]([NH:26][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:28])=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCN=C=O
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Product: CCCCCCCCCCCCCCNC(=O)Oc1ccc([N+](=O)[O-])cc1OC(=O)NCCCCCCCCCCCCCC

Procedure:
Using this procedure, the reaction of 4-nitrocatechol with tetradecyl isocyanate gave 3,4-bis [[(tetradecylamino)carbonyl]oxy]nitrobenzene (mp 100°-104°). The structure was confirmed by the nmr spectrum.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][NH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.NC1C=C([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)C=CC=1CN.C1N=CN(C(N2C=NC=C2)=O)C=1>>[O:12]=[C:8]1[NH:7][CH2:6][C:5]2[C:10](=[CH:11][C:2]([N:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]3)=[CH:3][CH:4]=2)[NH:9]1
Reactant: O=C1NCc2ccc(Br)cc2N1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(CN)c(N)c2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)NC(=O)NC3)CC1
Yield: 75 %

Procedure:
Following the same procedure adopted for the synthesis of compound 13, reaction of compound 20 with CDI afforded 0.73 g (75%) of compound 16 as an off-white solid, m.p. 218-219° C.; IR (KBr) νmax. cm−1: 3211, 3166 (NH), 3037 (Ar—H), 1693 (C═O), 1610, 1519, 1417 (C═C). 1H NMR (500 MHz, CDCl3) S=1.48 (s, 9H, (CH3)3C); 3.00 (m, 4H, 2CH2); 3.56 (m, 4H, 2CH2); 4.48 (s, 2H, CH2); 6.62 (d, 1H, J=2.5 Hz, H-8); 6.64 (d, 1H, J=8.5 Hz, H-5); 6.74 (dd, 1H, J=2.5, 8.4 Hz, H-6); 7.80 (br.s, 1H, NH); 13C NMR (125.7 MHz, CDCl3) δ=28.65 (CH3)3C), 43.31 (CH2), 43.98 (CH2), 50.63 (CH2), 80.18 (CH3)3C), 115.13 (C-8/C-6), 115.21 (C-8/C-6), 117.59 (C-5), 118.35 (C-5), 130.66 (C-5), 147.20 (C-5), 154.91 (C═O), 155.95 (C═O). Calculated (%) for C17H24N4O3 (332.18); C: 61.43, H: 7.28, N: 16.86. found (%) C: 61.37, H: 7.32, N: 16.80.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH:13]=[O:14].[H-].[Na+].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.C(OCC)(=O)C>CN(C)C=O.O>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[C:6]([CH:13]=[O:14])=[C:7]2[CH3:12])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COc1ccc2[nH]c(C)c(C=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(C=O)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: -60 °C
Reaction time: 5 h
Yield: 82.6 %

Procedure:
To a solution of 5-methoxy-2-methyl-1H-indole-3-carboxaldehyde (20 g, 106 mmol) in 210 ml of dry dimethylformamide is added oil free sodium hydride (2.7 g, 111 mmol). The reaction mixture is stirred for five hours at which time it is cooled to -60° C., and freshly distilled 4-chlorobenzoyl chloride (14.4 ml, 117 mmol) is added dropwise. It is stirred for an additional 10 minutes and worked up by pouring the cold paste into cold ethyl acetate and water. The organic phase is washed once with dilute sodium bicarbonate solution, once again with water, and once with a saturated solution of sodium chloride. It is further dried with magnesium sulfate, filtered, and concentrated in vacuo to a solid which is stirred vigorously with 50 ml of methanol for two hours. The solid is filtered and dried to give 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-carboxaldehyde (28.7 g, 82.5%). A portion which is recrystallized from ethyl acetate has a mp of 150.5°-151.5° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][CH2:13][C:14](OCC)=[O:15])=[CH:2]1.[OH-].[Na+]>O1CCCC1.C1(C)C=CC=CC=1.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][CH2:13][CH2:14][OH:15])=[CH:2]1
Reactant: CCOC(=O)CNCCc1c[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCCNCCc1c[nH]c2ccccc12
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 73 %

Procedure:
398 g of the product of Step A were dissolved in 4 liters of tetrahydrofuran cooled to +10° C. and while maintaining this temperature, 400 g of 25% sodium diethyl dihydroaluminate in toluene were introduced. The mixture was stirred for 90 minutes while allowing the temperture to rise to 17° C. The medium was cooled to -10° C. and 400 ml of sodium hydroxide solution in 1200 ml of water were introduced over 80 minutes while keeping the temperature at 0° C. during the introduction. The mixture was stirred for 2 hours at +10° C. then allowed to rise to ambient temperature for 16 hours with slower stirring. After decanting, the organic phase was washed with water and the wash water was extracted with ethyl acetate and methylene chloride. The combined organic phases were diluted with methylene chloride and dried, and the solvents were expelled at 40° C. under reduced pressure. The residue was triturated in 1300 ml of ethyl acetate for one hour, separated, washed with ethyl acetate and dried to obtain 240.8 g of the expected product melting at 92° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][N:7]=1.Br[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:1][C:2]2[N:4]([CH:5]=[CH:6][N:7]=2)[N:3]=1)=[O:12])[CH3:15]
Reactant: Nc1nccnn1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1cnc2nccn2n1
Temperature: 25 °C
Yield: 1.8 %

Procedure:
A solution of 3-amino-1,2,4-triazine (5.0 g, 52 mmol) and ethyl bromopyruvate (11 mL, 88 mmol) in ethanol (50 mL) was heated to reflux for 20 minutes. The reaction was cooled to room temperature, and then partitioned between 200 mL of EtOAc and 200 mL of water. The layers were separated, and the organic layer was dried over MgSO4. The solids were removed by filtration, and then the solvent was removed by rotary evaporation. The residue was purified by chromatography (90 g SiO2, 50 to 70% EtOAc in hexanes) to give the desired product (181 mg, 1.8%). MS (ESI): 192.4 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15]C(=O)C(F)(F)F)=[C:11](I)[CH:10]=1.[CH2:23]([N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37])[CH2:24][C:25]#[CH:26].N1CCCCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O.O1CCCC1>[Cl:8][C:9]1[CH:10]=[C:11]2[C:12](=[CH:13][CH:14]=1)[NH:15][C:25]([CH2:24][CH2:23][N:27]1[C:35](=[O:36])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]1=[O:37])=[CH:26]2
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Reactant: O=C(Nc1ccc(Cl)cc1I)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCc1cc2cc(Cl)ccc2[nH]1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Dichlorobis(triphenylphosphine)palladium (II) (43 g, 0.061 mol), copper (I) iodide (20.2 g, 0.106 mol), and triethylamine (782 g, 7.74 mol) is added to a stirred mixture of N-(4-Chloro-2-iodophenyl)-2,2,2-trifluoroacetamide (1800 g, 5.15 mol) and tetrahydrofuran (1.80 L). A solution of 2-(but-3-ynyl)-1H-isoindole-1,3(2H)-dione (1098 g, 5.51 mol) and tetrahydrofuran (11 L) is added to the reaction mixture slowly over 6 hours, maintaining a reaction temperature of 30° C. The reaction mixture is allowed to stir at room temperature overnight. The reaction mixture is filtered under reduced pressure and the triethylammonium iodide cake is washed with tetrahydrofuran (2×550 mL). The filtrate is concentrated under reduced pressure to a volume of less than 6 L, and N,N-dimethylformamide (8 L) is added to the residue. The mixture is concentrated until tetrahydrofuran is removed. Piperidine (535 g, 6.29 mol) is added to the mixture. The mixture is stirred and warmed to 100° C. The mixture is maintained at 100° C. until the product/starting material ratio is >97/3. The mixture is cooled to 32° C. Water (4.2 L) is added to the stirred mixture over >100 min, allowing the temperature of the mixture to rise to 45° C. The mixture is cooled (0-5° C.). The product is collected by filtration and dried to give 2-[2-(5-Chloro-1H-indol-2-yl)-ethyl]-isoindole-1,3-dione (1173 g, 73%, 98.1% purity, largest single impurity 1.2%. 1H NMR (DMSO-d6): δ11.35 (s, 1H), 7.83 (m, 4H), 7.41 (d, 1H, J=2.0 Hz), 7.29 (d, 1H, J=8.6 Hz), 6.99 (dd, 1H, J=2.0, 8.6 Hz), 3.94 (t, 2H, J=7.1 Hz), 3.08 (t, 2H, J=7.1 Hz).
Reaction SMILES: C(O[C:9]([NH:11][C@H:12]([C:17]([NH:19][C@H:20]([CH2:31][OH:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:10])C1C=CC=CC=1.[CH3:33][C:34]1[CH:35]=[C:36]([N:40]=C=O)[CH:37]=[CH:38][CH:39]=1.C(Cl)(Cl)Cl.CO>C(O)C.ClCCl.O1CCCC1.[C].[Pd]>[CH3:33][C:34]1[CH:35]=[C:36]([NH:40][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@H:20]([CH2:31][OH:32])[CH2:21][C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)=[O:18])[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[CH:37]=[CH:38][CH:39]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](CO)Cc1c[nH]c2ccccc12
Agent: [Pd]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC[C@H](C)[C@H](NC(=O)Nc1cccc(C)c1)C(=O)N[C@H](CO)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.6 %

Procedure:
A mixture of N-benzyloxycarbonyl-(L)-isoleucyl-(L)-tryptophanol (0.7 g) in ethanol (30 ml)-tetrahydrofuran (20 ml), palladium-carbon (5%, 0.5 g) was subjected catalytic hydrogenation at room temperature under 1 atmospheric pressure. After the palladium-carbon was filtered off, the filtrate was concentrated under reduced pressure to yield an oily substance. This oily substance was dissolved in dichloromethane (15 ml)-tetrahydrofuran (5 ml), and m-methylphenyl isocyanate (0.225 g) was added at 4° C. After stirring at room temperature for 1.5 hours, the reaction mixture was poured over chloroform-methanol. After the insoluble substances were filtered off, the filtrate was concentrated under reduced pressure, and the residual solid was recrystallized from dichloromethane-methanol-hexane to yield N-(3-methylphenylcarbamoyl)-(L)-isoleucyl-(L)-tryptophanol (0.43 g, 61%).
Reaction SMILES: [C:1]([NH:4][C@:5]1([C:20](=[O:26])[NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C@@H:9]([CH2:10][CH:11]=[CH2:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6]1)(=[O:3])[CH3:2].[CH3:27][C:28]1([CH3:35])[C:32]([CH3:34])([CH3:33])[O:31][BH:30][O:29]1>C(Cl)Cl.[Ir].ClC1CCC=CCCC=1.C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([NH:4][C@:5]1([C:20](=[O:26])[NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:30]2[O:31][C:32]([CH3:34])([CH3:33])[C:28]([CH3:35])([CH3:27])[O:29]2)[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC1(C)OBOC1(C)C
Reactant: C=CC[C@H]1CN(C(=O)OC(C)(C)C)C[C@@]1(NC(C)=O)C(=O)NC(C)(C)C
Agent: [Ir]
Agent: ClC1=CCCC=CCC1
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CN(C(=O)OC(C)(C)C)C[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
A stirred solution of (3R,4S)-tert-butyl 3-acetamido-4-allyl-3-(tert-butylcarbamoyl)pyrrolidine-1-carboxylate (5.51 g, 15 mmol) in anhydrous methylene chloride (80 mL) under nitrogen was treated with chloro-1,5-cyclooctadiene iridium dimer (0.252 g, 0.375 mmol) and 1,2-bis(diphenylphosphino)ethane (0.299 g, 0.75 mmol), stirred for 30 min. and cooled (−20° C.). 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (3.30 mL, 22.5 mmol) was added dropwise, and the solution was placed in an ice bath and allowed to reach room temperature overnight (18 h). The mixture was quenched with water (75 mL), stirred 15 min, and extracted with ethyl acetate (400 mL, then 2×100 mL). The combined organic solution was washed with saturated aqueous sodium chloride (150 mL), dried (MgSO4), and concentrated. The solid was recrystallized (2 crops) from acetonitrile to afford (3R,4S)-tert-butyl 3-acetamido-3-(tert-butylcarbamoyl)-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-1-carboxylate (6.13 g, 82%) as a white solid. NMR (CDCl3) δ 6.40-6.60 (m, 1 H), 6.23 (s, 1 H), 3.95-4.05 (m, 1 H), 3.65-3.75 (m, 2 H), 2.90-3.20 (m, 2 H), 2.00 (s, 3 H), 1.45 (s, 9 H), 1.30-1.45 (m, 4 H), 1.33 (s, 9 H), 1.22 (s, 12 H), 0.70-0.80 (m, 2 H). MS (m+1): 496.4.
Reaction SMILES: [CH3:1][C:2]([CH3:58])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:55])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:54])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42]([NH:44][C@H:45]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=4[Cl:53])[CH3:46])=[O:43])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:57])[CH3:56])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].FC(F)(F)C(O)=O>ClCCl>[Cl:53][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[C@@H:45]([NH:44][C:42](=[O:43])/[CH:41]=[CH:40]/[C@:23]12[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]1[C@@H:25]1[C@@:20]([CH3:54])([CH2:21][CH2:22]2)[C@@:19]2([CH3:55])[C@@H:28]([C@:29]3([CH3:32])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:56])([CH3:57])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:58])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]3)[CH2:27][CH2:26]1)[CH3:46]
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@@H](C)c2ccccc2Cl)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)N[C@@H](C)c2ccccc2Cl)CC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-(((S)-1-(2-chlorophenyl)ethyl)amino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (150 mg, 0.183 mmol), trifluoroacetic acid (1 mL, 12.98 mmol) in dichloromethane (4 mL) stirred at rt. The reaction mixture was stirred at rt for 2 h. The reaction mixture was evaporated and then purified by preparative-HPLC (Mobile Phase A: Water (0.05% TFA), B: ACN; Gradient 89-89% B in 0-7.5 min, stop at 12 min; Flow Rate (ml/min) 30.00; Retention Time (min) 7.0) to give the title compound (70 mg, 0.092 mmol, 50.1%) as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ=7.43-7.32 (m, 2H), 7.32-7.18 (m, 2H), 6.81 (d, J=15.8 Hz, 1H), 6.01 (d, J=15.8 Hz, 1H), 5.41 (q, J=6.9 Hz, 1H), 4.48 (dd, J=5.1, 11.2 Hz, 1H), 3.30-3.24 (m, 1H), 2.94-2.81 (m, 1H), 2.72-2.49 (m, 2H), 2.30-0.75 (m, 50H); LC/MS: m/z calculated 761.4. Found 762.3 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[Cl:19][C:20]1[CH:21]=[C:22]([S:27](Cl)(=[O:29])=[O:28])[CH:23]=[C:24]([Cl:26])[CH:25]=1>CN(C)C1C=CN=CC=1>[Cl:26][C:24]1[CH:23]=[C:22]([S:27]([NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])(=[O:28])=[O:29])[CH:21]=[C:20]([Cl:19])[CH:25]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Agent: CN(C)c1ccncc1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1cc(Cl)cc(Cl)c1
Yield: 74.6 %

Procedure:
Prepared according to the procedure described for Example 116 using 3-amino-4-methoxy-N-phenyl-benzamide (0.7296 g, 3.00 mmol), 3,5-dichlorobenzenesulfonyl chloride (0.7327 g, 3.00 mmol), and 4-dimethylaminopyridine to obtain the product (1.01 g); m.p. 222-228° C.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][CH2:7][C@@H:8]([F:27])[CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH2:17][C@H:18]([O:23][CH:24]([CH3:26])[CH3:25])[C:19]([O:21]C)=[O:20])[CH:14]=[CH:15][CH:16]=2)=[C:4]([C:30]#[N:31])[CH:3]=1.C(OC)(C)(C)C.Cl>O1CCCC1.O.[OH-].[Na+]>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][CH2:7][C@@H:8]([F:27])[CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH2:17][C@H:18]([O:23][CH:24]([CH3:26])[CH3:25])[C:19]([OH:21])=[O:20])[CH:14]=[CH:15][CH:16]=2)=[C:4]([C:30]#[N:31])[CH:3]=1
Reactant: COC(=O)[C@H](Cc1cccc(OC[C@H](F)COc2ccc(Cl)cc2C#N)c1)OC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)O[C@@H](Cc1cccc(OC[C@H](F)COc2ccc(Cl)cc2C#N)c1)C(=O)O
Reaction time: 3.5 h
Yield: 103.5 %

Procedure:
Methyl (2S)-3-[3-[(2S)-3-(4-chloro-2-cyanophenoxy)-2-fluoropropoxy]phenyl]-2-isopropoxypropionate (186 g, 0.41 mol) was suspended in tetrahydrofuran (928 mL) and water (928 mL), followed by adding dropwise a 2N NaOH aqueous solution (309 mL, 0.62 mmol) to the reaction mixture at room temperature and the mixture was stirred for 3.5 hours. Tert-butylmethyl ether (1,856 mL) and water (928 mL) were added to the reaction mixture to separate an aqueous layer. Tert-butylmetyl ether (1,856 mL) was added to the aqueous layer, followed by adding dropwise a 2N hydrochloric acid aqueous solution (371 mL, 0.74 mol) at room temperature to separate an organic layer. The organic layer was washed with water (928 mL) and then subjected to vacuum concentration to obtain 185 g of the title compound (yield: 90%).