Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:41])[C:6]=1[C:7]1[CH:39]=[CH:38][C:10]([C:11]([NH:13][C@@H:14]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)=[O:12])=[CH:9][C:8]=1[F:40].NN>CO.C1COCC1>[NH2:16][CH2:15][C@@H:14]([NH:13][C:11](=[O:12])[C:10]1[CH:38]=[CH:39][C:7]([C:6]2[N:5]([CH3:41])[N:4]=[CH:3][C:2]=2[Cl:1])=[C:8]([F:40])[CH:9]=1)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:37])([F:36])[F:35]
Reactant: Cn1ncc(Cl)c1-c1ccc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1F
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1-c1ccc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.5 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-3-fluorobenzamide (90 mg, 0.15 mmol) in MeOH/THF (2 mL, 1:1) at RT was added hydrazine (0.12 mL, 3.93 mmol). After stirring for 18 h at RT, the reaction solution was concentrated under vacuum and purified via column chromatography (silica, 3% MeOH in DCM (1% NH4OH)) yielding the title compound (14 mg, 21%).
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][C@@H:4]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C:5]([CH2:23][CH:24]=[CH2:25])([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[OH-].[Na+].OO.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:44]>C(OCC)C.O>[OH:44][CH2:25][CH2:24][CH2:23][C:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[C@H:4]([C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])[CH2:3][CH:2]([CH3:36])[CH3:1]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: C=CCC(C(=O)OCc1ccccc1)(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C(=O)OCc1ccccc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CC(C)C[C@@H](C(=O)OCc1ccccc1)C(CCCO)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.47 g of 1,2-dibenzyl 1-tert.butyl 4-methyl-1-(prop-2-en-1-yl)-1,1,2(R)-pentanetricarboxylate in 5 ml of dry diethyl ether was cooled to 0° and 0.325 ml of monochloroborane-methyl sulphide complex was added. The mixture was stirred at room temperature for 2 hours, then cooled to 0° and 0.5 ml of water, 2.3 ml of 1.5M aqueous sodium hydroxide solution and 2.3 ml of 30% aqueous hydrogen peroxide were added. The mixture was stirred at room temperature for 3 hours and then acidified with 5% aqueous citric acid solution. The product was extracted with diethyl ether and the extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (5:1) for the elution. There were obtained 1.098 g of 1,2-dibenzyl 1-tert.butyl 1-(3-hydroxypropyl)-4-methyl-1,1,2(R)-pentanetricarboxylate in the form of a colorless oil; MS: 513 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(NCC)C.C(#N)C.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>[C:1]([O:5][C:6]([C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][C:20]2[CH:21]=[CH:22][C:17]([Br:16])=[CH:18][CH:19]=2)=[CH:11][CH:12]=1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: Brc1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1ccc(C#Cc2ccc(Br)cc2)cc1
Temperature: 40 °C
Reaction time: 72 h

Procedure:
2.8 g (Ph3P)2PdCl2 and 400 mg of CuI are added to a solution of 40.4 g of 4-ethinyl-benzoic acid tert.-butyl ester, 56.6 g of bromoiodobenzene and 1.34 g of Ph3P in 50 ml of diethylamine and 300 ml of absolute acetonitrile and the reaction mixture is stirred for 72 hours at 40° C., suction filtered and dried.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[C:6](Br)[CH:7]=[N:8][CH:9]=2)[NH:4][C:3]1=[O:12].[H][H]>C(O)C.[Pd]>[NH:4]1[C:5]2[C:10](=[CH:9][N:8]=[CH:7][CH:6]=2)[CH2:2][C:3]1=[O:12]
Reactant: [H][H]
Reactant: O=C1Nc2c(Br)cncc2C1(Br)Br
Agent: [Pd]
Solvent: CCO
Product: O=C1Cc2cnccc2N1
Yield: 2.2 %

Procedure:
To a solution of 3,3,7-tribromo-5-azaoxindole (6.4 g, 17.3 mmol) in ethanol (1200 ml) was added 10% Pd on charcoal (3.2 g). The mixture was hydrogenated under 3 atm. hydrogen gas for 3 hours using a Parr shaker. The catalyst was removed by filtration of the mixture through a pad of Celite®, washing well with ethanol. On removal of the solvent, a brown solid remained (predominantly the hydrobromide of the desired product), 3.5 g. This was dissolved in water, treated with activated charcoal and filtered through Celite®. The pH of the filtrate was adjusted to 7.5 by the addition of saturated aqueous NaHCO3 solution. The mixture was then extracted with n-butanol (3×). The combined n-butanol extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo to leave a solid. This was triturated with butanone and filtered to collect 5-azaoxindole as a tan solid (1.6 g, 69%). After removal of butanone, the mother liquor yielded a solid which was recrystallized from methanol to yield more of the title compound (50 mg), m.p.>250° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=3)[NH2:14])[CH:9]=2)[NH:4][CH:3]=1.[C:18](O)(=[O:23])/[CH:19]=[CH:20]/[CH2:21][CH3:22].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:14][C:18](=[O:23])/[CH:19]=[CH:20]/[CH2:21][CH3:22])[CH:15]=[CH:16][CH:17]=3)[CH:9]=2)[NH:4][CH:3]=1
Reactant: CC/C=C/C(=O)O
Reactant: Cc1c[nH]c2ncc(-c3cccc(N)c3)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC/C=C/C(=O)Nc1cccc(-c2cnc3[nH]cc(C)c3c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 11.7 %

Procedure:
A solution of 24 (50 mg, 0.2242 mmol) and trans-2-pentenoic acid 25 (24.6 mg, 0.246 eq) in DMF was added EDC.HCl (33 mg, 0.2706 mmol) and HOBt (36.5 mg, 0.2706 mmol). DIPEA (57.9 mg, 0.448 eq) was added to the reaction, stirred 12 h at RT and check the TLC for completion of the reaction and quench the reaction mixture with dilute water. The organic layer was treated with ethyl acetate (25 mL) and was washed with brine solution (25 mL) and dried over sodium sulphate, filtered and concentrated to get the crude product. The resulting oil was purified through silica gel chromatography using a gradient of 4% Ethyl acetate:hexane to afford 8 mg of Compound 26. MS-ES+305.1 1H NMR (400 MHz, DMSO-D6-d6): 11.45 (s, 1H), 10.08 (s, 1H), 8.40 (s, 1H), 8.17 (s, 1H), 7.85 (d, 1H), 7.61 (m, 1H), 7.36 (m, 2H), 7.30 (d, 1H), 5.62 (m, 1H), 2.35 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[N:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:26]2[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=2)[CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2ccncc2)c1
Yield: 71.1 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(pyridin-4-yl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), pyridin-4-ylboronic acid (0.025 g; 0.177 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 18 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.047 g (71%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(pyridin-4-yl)benzamide as a white solid.
Reaction SMILES: N[C:2]1[NH:3][C:4](=[O:21])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]3[OH:14])[C:6]=2[N:7]=1.N([O-])=[O:23].[Na+]>C(O)(=O)C.O>[C@@H:12]1([N:8]2[C:6]3[NH:7][C:2](=[O:23])[NH:3][C:4](=[O:21])[C:5]=3[S:10][C:9]2=[O:11])[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:13]1[OH:14]
Reactant: O=N[O-]
Reactant: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(=O)c2sc(=O)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2[nH]1
Reaction time: 0.5 h

Procedure:
To a suspension of 7 (0.76 g, 2.4 mmol) in glacial acetic acid (150 mL) was added dropwise a solution of sodium nitrite (1.5 g, 21.7 mmol) in water (15 mL) with stirring. After 30 min the suspension became clear and stirring was continued at room temperature overnight. The white solid which had separated was filtered, washed with cold water and dried. Recrystallization from hot water gave fine colorless crystals of 8: yield 0.3 g, 40%: mp 250° C. dec.: UV λmax (pH 1) 293 nm (ε 5500): UV λmax (pH 7) 212 nm (ε 14,200), 301 (6100): UV λmax (pH 11) 204 nm (ε 21,900), 301 (5600). Anal Calcd. for C10H11N3O7S: C, 37.86: H, 3.49: N, 13.24: S, 10.10. Found: C, 37.81: H, 3.42: N, 13.01: S, 10.01.
Reaction SMILES: [S:1]([C:4]1[NH:5][CH:6]=[C:7]([C:9](=[O:25])[C:10]2[CH:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13]([OH:20])=[C:12]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:11]=2)[CH:8]=1)[C:2]#N.[CH2:26](I)C>>[CH3:26][N:5]1[CH:6]=[C:7]([C:9](=[O:25])[C:10]2[CH:11]=[C:12]([C:21]([CH3:22])([CH3:24])[CH3:23])[C:13]([OH:20])=[C:14]([C:16]([CH3:17])([CH3:18])[CH3:19])[CH:15]=2)[CH:8]=[C:4]1[S:1][CH3:2]
Reactant: CC(C)(C)c1cc(C(=O)c2c[nH]c(SC#N)c2)cc(C(C)(C)C)c1O
Reactant: CCI
Product: CSc1cc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cn1C

Procedure:
Similarly, by following the procedure of part A above and substituting N-methyl-2-thiocyano-4-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole for 2-thiocyano-4-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole, and substituting methyl iodide for ethyl iodide, there is obtained N-methyl-2-methylthio-4-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole [mp 173°-175° C.; 1H nmr: 1.50s (18H), 2.3s (3H), 3.73s (3H), 5.6s (OH), 6.81m (7.38m (1H), 7.76s (2H)].
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:6][C:7]=1[CH3:8].[O:15]=[CH:16][C:17]1[CH:25]=[CH:24][C:22]([OH:23])=[C:19]([O:20][CH3:21])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:21][O:20][C:19]1[CH:18]=[C:17]([CH:25]=[CH:24][C:22]=1[O:23][CH2:2][C:3]1[N:4]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:6][C:7]=1[CH3:8])[CH:16]=[O:15]
Reactant: COc1cc(C=O)ccc1O
Reactant: Cc1sc(N2CCOCC2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCc1nc(N2CCOCC2)sc1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
A mixture of 4-(4-chloromethyl-5-methyl-1,3-thiazol-2-yl)morpholine (5.0 g), vanillin (3.27 g), potassium carbonate (2.97 g) and N,N-dimethylformamide (100 mL) was stirred at 90° C. for 3 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 3-methoxy-4-[(5-methyl-2-morpholin-4-yl-1,3-thiazol-4-yl)methoxy]benzaldehyde as crystals (7.25 g, yield 96%). Recrystallization from hexane-ethyl acetate gave colorless prism crystals. melting point: 127-128° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][N:14]=[C:13]([N:18]3[CH:22]=[N:21][C:20]([CH:23]4[CH2:25][CH2:24]4)=[N:19]3)[CH:12]=[C:7]12.[F:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:23]1([C:20]2[N:21]=[CH:22][N:18]([C:13]3[CH:12]=[C:7]4[C:8]5[C:3]([CH2:4][CH2:5][N:6]4[C:16](=[O:17])[CH2:15][N:14]=3)=[C:2]([C:30]3[CH:31]=[N:32][C:27]([F:26])=[CH:28][CH:29]=3)[CH:11]=[CH:10][CH:9]=5)[N:19]=2)[CH2:24][CH2:25]1
Reactant: O=C1CN=C(n2cnc(C3CC3)n2)C=C2c3cccc(Br)c3CCN12
Reactant: OB(O)c1ccc(F)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C1CN=C(n2cnc(C3CC3)n2)C=C2c3cccc(-c4ccc(F)nc4)c3CCN12
Temperature: 85 °C
Reaction time: 0.05 h
Yield: 99.7 %

Procedure:
Example 95-2. 9-bromo-2-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (5.7 g, 14.31 mmol), (6-fluoropyridin-3-yl)boronic acid (4.03 g, 28.6 mmol) and a solution of Na2CO3 (7.58 g, 71.6 mmol) in water (28 mL) was treated with DME (114 mL). The suspension was degassed, Pd(PPh3)4 (2.48 g, 2.15 mmol) was added and the mixture was heated at 85° C. for 2 h. The mixture was allowed to warm to RT and the solvent was removed under reduced pressure. The residue was dissolved in DCM and extracted with water, saturated aqueous NaHCO3 solution and brine. The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent: 70% AcOEt in heptane for 3 min, then from 70% AcOEt in heptane to 100% AcOEt in heptane in 50 min, 100% AcOEt in heptane for 10 min) to yield a beige foam (5.91 g). The residue was dissolved in DCM (100 mL) and MP-TMT resin (4.0 g, 0.71 mmol/g) was added and the mixture was stirred for 2.5 h. The resin was filtered off and the solvent was removed under reduced pressure to yield a yellow foam. The foam was crystallized from hot n-butanol (50 mL) to afford the title compound as white crystals (4.8 g). UPLC-MS: MS 415.4 (M+H+); UPLC rt 1.02 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.79-0.87 (m, 2 H), 0.89-0.99 (m, 2 H), 1.98-2.07 (m, 1 H), 2.87 (t, J=6.11 Hz, 2 H), 3.72 (t, J=6.11 Hz, 2 H), 4.30 (s, 2 H), 7.05 (s, 1 H), 7.31 (dd, J=8.44, 2.57 Hz, 1 H), 7.47-7.56 (m, 2 H), 7.89-7.97 (m, 1 H), 8.07 (td, J=8.13, 2.57 Hz, 1 H), 8.30 (d, J=2.45 Hz, 1 H), 9.00 (s, 1 H).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH:8]2[CH:6]([C:7]2([CH3:19])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)[C:5]1=[O:20])[CH:2]=[CH2:3].[Cl-].[Ca+2].[Cl-]>C(O)C.O.[Fe]>[CH2:1]([N:4]1[CH2:9][CH:8]2[CH:6]([C:7]2([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[CH3:19])[C:5]1=[O:20])[CH:2]=[CH2:3]
Reactant: C=CCN1CC2C(C1=O)C2(C)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: C=CCN1CC2C(C1=O)C2(C)c1cccc(N)c1
Yield: 99 %

Procedure:
To a solution of 3-allyl-6-methyl-6-(3-nitrophenyl)-3-azabicyclo[3.1.0]hexan-2-one (Preparation 50, 10.2 g, 37.5 mmol) in ethanol (850 ml) and water (150 ml) was added iron powder (18.9 g, 337.5 mmol) and calcium chloride (2.1 g, 18.7 mmol). The reaction mixture was refluxed for 5 h, and then filtered to remove the iron powder. The reaction mixture was concentrated in vacuo and the residue was dissolved in dichloromethane:methanol (85:15), filtered and then concentrated in vacuo, dissolved in tetrahydrofuran, filtered and then concentrated in vacuo to give the title compound as a pale yellow foam (9 g, 99%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([C:26]2[N:27]([CH3:35])[C:28]3[C:33]([CH:34]=2)=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:20][C:17]=1[CH:18]=O.C[O-].[Li+].Cl>CN(C=O)C.O>[CH3:14][O:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([C:26]2[N:27]([CH3:35])[C:28]3[C:33]([CH:34]=2)=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:20][C:17]=1[CH:18]=[CH:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[O:3]
Reactant: COc1cc(OC)c(-c2cc3ccccc3n2C)cc1C=O
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)c(-c2cc3ccccc3n2C)cc1C=CC(=O)c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
Ex-37A: To a solution of 4-acetylbenzenesulfonamide (Ex-35A, 0.20 g, 1 mmol) and 2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)benzaldehyde (Ex-15A, 0.30 g, 1 mmol) in DMF (25 ml) was added lithium methoxide (4 ml, 1.0 M in methanol). The mixture was stirred at room temperature overnight. It was poured into water (50 ml) and acidified to pH=1 with 3 N HCl. The yellow precipitate was filtered, washed with water, and dried. Crystallization from EtOAc/hexanes gave 4-{3-[2,4-dimethoxy-5-(1-methyl-1H-indol-2-yl)phenyl]acryloyl}benzenesulfonamide (0.43 g, 90%) as a yellow solid, mp 148–150° C. 1H-NMR (300 MHz, CDCl3) δ 8.17 (d, J=16 Hz, 1H), 8.09 (d, J=9 Hz, 2H), 8.01 (d, J=9 Hz, 2H), 7.68 (s, 1H), 7.64 (d, J=8 Hz, 1H), 7.47 (d, J=16 Hz, 1H), 7.35 (d, J=8 Hz, 1H), 7.22–7.26 (m, 1H), 7.11–7.16 (m, 1H), 6.58 (s, 1H), 6.50 (s, 1H), 4.92 (brs, 2H), 4.02 (s, 3H), 3.90 (s, 3H), 3.58 (s, 3H). MS m/z=477 ([M+H]+, 100%).
Reaction SMILES: N[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11](=[O:15])[CH2:12][CH2:13][Cl:14])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[H+].[B-](F)(F)(F)[F:22]>O>[Cl:14][CH2:13][CH2:12][C:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([F:22])[CH:10]=2)[CH2:6][CH2:7]1)=[O:15]
Reactant: F[B-](F)(F)F
Reactant: Nc1ccc2c(c1)N(C(=O)CCCl)CC2
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: O=C(CCCl)N1CCc2ccc(F)cc21
Temperature: 10 °C
Yield: 74 %

Procedure:
1.12 g (5.0 mmol) of 6-amino-1-(3-chloropropionyl)indoline (prepared as described in Preparation 6) were suspended in 10 ml of fluoboric acid (as a 42% w/v aqueous solution), and a solution of 380 mg (5.5 mmol) of sodium nitrite in 5 ml of water was added to the suspension while ice-cooling so that the internal temperature was maintained at 10° C. or lower. The mixture was then stirred while ice-cooling for 1 hour. The precipitated salt was collected by filtration and dried in a desiccator under reduced pressure by means of a vacuum pump to obtain 1.20 g (3.7 mmol) of the title compound as a solid (yield: 74%).
Reaction SMILES: C(O)(C(F)(F)F)=O.Cl[C:9]1[CH:14]=[C:13]([N:15]2[CH:24]([CH3:25])[CH2:23][C:22]3[C:17](=[CH:18][C:19]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)=[CH:20][CH:21]=3)[CH2:16]2)[N:12]=[C:11]([NH2:32])[N:10]=1.[CH:33]12[CH2:39][CH:36]([NH:37][CH2:38]1)[CH2:35][N:34]2C(OC(C)(C)C)=O>>[CH:33]12[CH2:39][CH:36]([NH:37][CH2:38]1)[CH2:35][N:34]2[C:9]1[CH:14]=[C:13]([N:15]2[CH:24]([CH3:25])[CH2:23][C:22]3[C:17](=[CH:18][C:19]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)=[CH:20][CH:21]=3)[CH2:16]2)[N:12]=[C:11]([NH2:32])[N:10]=1
Reactant: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(Cl)nc(N)n1
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2
Solvent: O=C(O)C(F)(F)F
Product: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(N2CC3CC2CN3)nc(N)n1

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 118 starting from 4-chloro-6-[3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine and tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (Alfa Aesar, Cat. No. L20131). LCMS (M+H)+: m/z=417.2.
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:4][CH:3]1[CH2:5][C:6]1([OH:19])[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][C:6]1([OH:19])[CH2:7][CH2:8][NH:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CC2CC2(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1(CC2CC2(F)F)CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 11C (1 eq.) in DCM, was added TFA (10 eq.), the reaction mixture was stirred at room temperature for about 2 hours, when TLC detected no s.m. The reaction mixture was concentrated to afford the desired product 11D. The crude product was used for the next step directly without further purification. LC-MS: m/z 192.3 (M+H)+
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][C:4](=O)[C:5]([OH:7])=[O:6].[NH2:10][C@H:11]([C:18]([NH:20][C@H:21]([C:26]([OH:28])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1.C([BH3-])#N.[Na+]>>[C:5]([CH:4]([NH:10][C@H:11]([C:18]([NH:20][C@H:21]([C:26]([OH:28])=[O:27])[CH2:22][CH:23]([CH3:24])[CH3:25])=[O:19])[CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1)[CH2:3][CH:2]([CH3:9])[CH3:1])([OH:7])=[O:6]
Reactant: CC(C)CC(=O)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1c[nH]cn1)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)CC(N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC(C)C)C(=O)O)C(=O)O

Procedure:
In the manner described in Example 54, 4-methyl-2-oxopentanoic acid and L-histidyl-L-leucine are condensed in the presence of sodium cyanoborohydride to yield N-(1-carboxy-3-methylbutyl)-L-histidyl-L-leucine. In this case the product is eluted from the ion exchange resin with 10% ammonia. The mass spectrum shows a molecular ion at 408 m/e for the disilylated species minus 18. The nmr spectrum is consistent with structure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])[CH3:2].C([Sn](CCCC)(CCCC)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1)CCC>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:15]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=3)[CH:17]=[C:18]([CH3:20])[CH:19]=2)=[CH:9][C:8]=1[CH3:33])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3-c3ccccn3)c2)cc1C
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester (0.155 g, 0.289 mmol) and 2-tributylstannyl pyridine (0.210 g, 0.571 mmol) in dry toluene (8 mL) is purged with N2 and then tetrakis(triphenylphospine)pallium (0) (0.033 g, 0.029 mmol) is added. The reaction is heated to 100° C. and stirred for 20 hours under N2. The reaction is cooled, and the solvent is removed in vacuo to give crude 3-{2-methyl-4-[3-methyl-5-(2-pyridin-2-yl-4-trifluoromethyl-phenoxy)-phenoxy]-phenyl}-propionic acid ethyl ester. This ester is dissolved in ethanol (8 mL), treated with 5 N NaOH (2 mL) and heated to reflux until saponification is complete. The mixture is cooled, and the solvent is removed in vacuo to afford a residue that is acidified with 1 N HCl. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to give crude product that is purified by preparative HPLC to afford 0.056 g (38%) of the title compound. 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C29H24NO4F3 507, found 508 (M+1, 100%).