Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](/[C:7]1[CH:8]=[C:9]([CH:13]([C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][CH:32]=2)[CH:14]([C:16]2[CH:30]=[CH:29][C:19]([C:20]([NH:22][CH2:23][CH2:24][C:25]([O:27]C)=[O:26])=[O:21])=[CH:18][CH:17]=2)[CH3:15])[CH:10]=[CH:11][CH:12]=1)=[CH:2]\[CH2:3][CH2:4][CH2:5][CH3:6].CC(C1NC(=O)C(CCSC)NC(=O)C(NC(C(NC(C(NC(C(NC(C(N)CC(O)=O)=O)C(O)C)=O)CCSC)=O)CCCNC(N)=N)=O)CSSCC(C(NC(C(NC(C(NC(C(O)=O)C(C)C)=O)CCC(O)=O)=O)CC2C3C(=CC=CC=3)NC=2)=O)NC(=O)C2N(CCC2)C(=O)C(CCCNC(N)=N)NC(=O)C(CC2C=CC(O)=CC=2)NC(=O)C(C(C)C)NC(=O)C(CCCNC(N)=N)NC(=O)CNC1=O)C>>[CH:1](/[C:7]1[CH:8]=[C:9]([CH:13]([C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][CH:32]=2)[CH:14]([C:16]2[CH:30]=[CH:29][C:19]([C:20]([NH:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:21])=[CH:18][CH:17]=2)[CH3:15])[CH:10]=[CH:11][CH:12]=1)=[CH:2]\[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCC/C=C/c1cccc(C(c2c[nH]c3ccccc23)C(C)c2ccc(C(=O)NCCC(=O)OC)cc2)c1
Agent: CSCCC1NC(=O)C(NC(=O)C(CCCNC(=N)N)NC(=O)C(CCSC)NC(=O)C(NC(=O)C(N)CC(=O)O)C(C)O)CSSCC(C(=O)NC(Cc2c[nH]c3ccccc23)C(=O)NC(CCC(=O)O)C(=O)NC(C(=O)O)C(C)C)NC(=O)C2CCCN2C(=O)C(CCCNC(=N)N)NC(=O)C(Cc2ccc(O)cc2)NC(=O)C(C(C)C)NC(=O)C(CCCNC(=N)N)NC(=O)CNC(=O)C(C(C)C)NC1=O
Product: CCCC/C=C/c1cccc(C(c2c[nH]c3ccccc23)C(C)c2ccc(C(=O)NCCC(=O)O)cc2)c1

Procedure:
The title compound was prepared from the intermediate from Step A using the hydrolysis conditions described in INTERMEDIATE 2, Step G. The crude material was purified by HPLC. 1H NMR (500 MHz, CD3CN): δ 8.97 (s, 1H); 7.55 (d, J=8.3 Hz, 2H); 7.52 (d, J=7.9 Hz, 1H); 7.49 (s, 1H); 7.43 (d, J=8.3 Hz, 2H); 7.33 (d, J=7.5 Hz, 1H); 7.20 (t, J=7.6 Hz, 2H); 7.14 (m, 2H); 7.07 (broad s, 1H); 6.99-6.96 (m, 1H); 6.92-6.89 (m, 1H); 6.40-6.25 (m, 2H); 4.50 (d, J=11.5 Hz, 1H); 3.77-3.69 (m, 1H); 3.49 (q, J=6.4 Hz, 2H); 2.53 (dd, J=14.4, 21.1 Hz, 26H); 1.47-1.33 (m, 4H); 1.08 (d, J=6.8 Hz, 3H); 0.92 (t, J=7.2 Hz, 3H). LC1 3.72 min. (M+1)=509.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(O)C.[CH3:27][C:28]1[CH:29]=[C:30]([C:34]([N:36]=[C:37]=[S:38])=[O:35])[CH:31]=[CH:32][CH:33]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:36][C:34](=[O:35])[C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([CH3:27])[CH:29]=2)=[S:38])=[C:18]([F:23])[CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: Cc1cccc(C(=O)N=C=S)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C)c4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 3-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (68 mg, yield 87%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]([OH:15])=O)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[NH2:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]([NH:16][C:17]3[NH:21][N:20]=[N:19][N:18]=3)=[O:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Nc1nnn[nH]1
Reactant: Cc1ccc(-c2csc(C(=O)O)n2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2csc(C(=O)Nc3nnn[nH]3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
A mixture of 4-(4-methylphenyl)-2-thiazolecarboxylic acid (300 mg, 1.37 mmol) and N,N -carbonyl diimidazole (CDI) (444.3 mg, 2.74 mmol) dissolved in dry DMF (5 ml) was stirred at room temperature for 1 hour. Under the same conditions, a solution of 5-aminotetrazole (139.5 mg, 1.64 mmol) in dry DMF was added thereto, and the resulting mixture was allowed to react at 85° C. for 2 hours. After removing of the solvent from the reaction mixture by distillation, the residue was treated with water and acidified with 1N-HCl to pH 2. The deposited solids were filtered with suction, washed with water and recrystallized from methanol-THF-water to give 258 mg (yield 66%) of 4-(4-methylphenyl)-N-(1H-tetrazole-5-yl)-2-thiazolecarboxamide as pale yellow crystals, m.p. 276°-278° C.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[CH:10][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[CH:4][C:3]=2[O:2]1.[I:14]Cl.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.CC(O)=O>[I:14][C:10]1[C:5]([NH:6][C:7](=[O:9])[CH3:8])=[CH:4][C:3]2[O:2][CH2:1][O:13][C:12]=2[CH:11]=1
Reactant: CC(=O)Nc1ccc2c(c1)OCO2
Reactant: ClI
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)Nc1cc2c(cc1I)OCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.4 %

Procedure:
To a stirred solution of 3′,4′-methylenedioxyacetanilide (7.7 g, 43.0 mmol) in DCM (100 mL) and AcOH (6.5 mL) was added a solution of iodine monochloride (6.3 g, 38.8 mmol) in DCM (50 mL). The reaction mixture was stirred at r.t. for 16 h. Aqueous sat. Na2S2O3 (500 mL) was added. The organic fraction was separated, dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 50% EtOAc/hexanes) gave the title compound (7.5 g, 57%) as a brown solid. LCMS (ES+) 306.0 (M+H)+, RT 2.75 minutes (Method 4).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH3:34])[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]3[CH:19]=[C:20]([Br:33])[C:21]4[S:25][C:24]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[N:23][C:22]=4[CH:32]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].CCO.Cl>C1COCC1>[Br:33][C:20]1[C:21]2[S:25][C:24]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[O:28])=[N:23][C:22]=2[CH:32]=[C:18]([C:15]2[CH:16]=[N:17][C:12]([N:9]3[CH2:8][CH2:7][C:6]([CH3:34])([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]3)=[N:13][CH:14]=2)[CH:19]=1
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(Br)c2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cc(Br)c2s1
Temperature: 70 °C
Reaction time: 6 h
Yield: 33.7 %

Procedure:
1-{5-[7-Bromo-2-(3-ethyl-ureido)-benzothiazol-5-yl]-pyrimidin-2-yl}-4-methyl-piperidine-4-carboxylic acid ethyl ester (50 mg) was dissolved in THF (1 mL) and 1 M aq NaOH (1 mL) added. The mixture was heated to 70° C. overnight. LCMS showed approx 50% conversion to product. EtOH (0.5 mL) was added and heating continued for a further 6 h. The mixture was acidified to pH 3 with 1 M HCl (aq) and concentrated under reduced pressure. The mixture was suspended in ˜10% MeOH in DCM and filtered through a syringe filter. The filtrate was concentrated in vacuo to give the desired product as an off-white solid (16 mg) which was used in the next step with no further purification. m/z: 519/521 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH:18]([B-](F)(F)F)=[CH2:19].[K+].C(N(CC)CC)C.O1CCCC1>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.O.CO>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:18]=[CH2:19])=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[B-](F)(F)F
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=Cc1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
The mixture of 50 mg of the t-butyl[(1S)-1-(4-bromophenyl)ethyl]carbamate [106-1], 223.4 mg of dichlorobis(triphenylphosphine)palladium (II), 31.2 mg of potassium vinyltrifluoroborate, 27.9 μL of triethylamine, 0.5 mL of tetrahydrofuran, and 0.5 mL of methanol, was stirred overnight at 100° C. The reaction mixture was cooled back to room temperature, water was added thereto, and was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by preparative thin-layer chromatography, to obtain 24.2 mg of t-butyl[(1S)-1-(4-vinylphenyl)ethyl]carbamate [152-1] as a white solid.
Reaction SMILES: C(Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH2:12].C(N(C)C)C1C=CC=CC=1>CC1C=CC(C)=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][C:11](=[CH:10][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=C(C)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)Cc1ccccc1
Solvent: Cc1ccc(C)cc1
Product: CC(=Cc1ccccc1)c1ccccc1
Yield: 3.3 %

Procedure:
0.448 g (2 millimols) of palladium acetate, 28.11 g (0.2 mol) of benzoyl chloride, 23.64 g (0.2 mol) of α-methylstyrene and 27.04 g (0.2 mol) of N-benzyldimethylamine in 400 ml of p-xylene are stirred for 11 hours at 130° C. The mixture is extracted by shaking with 400 ml of 2 NHCl and 400 ml of 2 N NaOH and is then dried over magnesium sulfate. The crude product is chromatographed on silica gel in methylene chloride and subsequently recrystallised from n-pentane. 1.3 g (3% of theory) of α-methylstilbene are obtained as colourless crystals of melting point 79.0° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([CH:12]3[C:17](=[O:18])[N:16]([C:19]4[CH:24]=[CH:23][C:22]([NH:25]C(=O)OC(C)(C)C)=[CH:21][CH:20]=4)[CH2:15][CH:14]=[C:13]3[CH3:33])[CH2:9][CH2:8][C:6]=2[N:7]=1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>CO.C1COCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:17](=[O:18])[N:16]([C:19]4[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=4)[CH:15]=[CH:14][C:13]=3[CH3:33])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CC1=CCN(c2ccc(NC(=O)OC(C)(C)C)cc2)C(=O)C1N1CCc2nc(N)ncc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccn(-c2ccc(N)cc2)c(=O)c1N1CCc2nc(N)ncc2C1
Reaction time: 4 h
Yield: 87.7 %

Procedure:
Tert-butyl (4-(5-(2-amino-7,8-dihydropyrido[4,3-d]p yrimidin-6(5H)-yl)-4-methyl-6-oxo-5,6-dihydropyridin-1(2H)-yl)phenyl)carbamate (150 mg, 0.334 mmol) was dissolved into a 1:1 mixture of MeOH/THF (˜10 mL) and treated with CF3COOH drop wise and the reaction was allowed to stir for 4 h. One the reaction was completed, the residual CF3COOH was neutralized with NaHCO3 (aq). The reaction was then extracted with EtOAc (3×10 mL) and brine (˜10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and then concentrated in vacuo. The crude organic oil was then purified via column chromatography (MeOH/CHCl3 gradient). Concentration of the appropriate fractions provided the title compound (102 mg, 88%). 1H NMR (DMSO) δ: 7.92 (s, 1H), 7.45-7.52 (m, 2H), 7.41 (d, J=6.7 Hz, 1H), 7.24-7.31 (m, 2H), 6.28 (s, 2H), 6.17 (d, J=7.0 Hz, 1H), 3.96 (br. S, H), 3.29 (s, 2H), 2.66 (t, j=5.3 Hz, 2H), 2.18 (s, 3H).
Reaction SMILES: Cl[CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[CH3:12])=[O:4]>S(=O)(=O)(O)O>[CH3:11][C:9]1[CH:8]=[CH:7][C:6]([CH3:12])=[C:5]2[C:10]=1[CH2:13][CH2:2][C:3]2=[O:4]
Reactant: Cc1ccc(C)c(C(=O)C(C)Cl)c1
Agent: O=S(=O)(O)O
Product: Cc1ccc(C)c2c1CCC2=O
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
The crude 2-(2-chloropropionyl)-1,4-dimethylbenzene was slowly added to concentrated sulfuric acid (400 ml), preheated to 105° C. The solution was then stirred at 105°-110° C. for 30 minutes. The cooled mixture was poured onto cracked ice and the precipitate collected to give 4,7-dimethylindan-1-one (59.4 g, 65.6%) as a pale solid, mp 70° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)=[O:7].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)[CH:13]=[CH:12][CH:11]=1
Reactant: CCC(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1cccc(Cl)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(3-chlorophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 427.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH2:9][C:10]([OH:12])=O)[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].Cl.Cl.[CH3:15][C:16]1[CH:25]=[C:24]([CH2:26][O:27][C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.N1CC(=O)NC1=O>>[CH3:1][C:2]1([CH2:9][C:10]([NH:32][C:31]2[CH:30]=[CH:29][C:28]([O:27][CH2:26][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:16]([CH3:15])[CH:25]=3)=[CH:34][CH:33]=2)=[O:12])[C:3](=[O:8])[NH:4][C:5](=[O:7])[NH:6]1
Reactant: CC1(CC(=O)O)NC(=O)NC1=O
Reactant: Cc1cc(COc2ccc(N)cc2)c2ccccc2n1
Agent: Cl
Agent: O=C1CNC(=O)N1
Product: Cc1cc(COc2ccc(NC(=O)CC3(C)NC(=O)NC3=O)cc2)c2ccccc2n1
Yield: 15.9 %

Procedure:
Commercially available (+/−)-2-amino-2-methyl-pentanedioic acid (1.00 g, 6.8 mmol) was dissolved in 10 mL boiling water and treated portionwise with potassium cyanate (1.20 g, 14.8 mmol). After 15 min, 10% aq HCl (15 mL) was added and the reaction refluxed for 30 min after which the solvent was evaporated off and the white solid filtered, washed with cold water, and dried to give 870 mg (75%) of hydantoin derivative. MS found:(M+H)+=173. (103b) 5-methylhydantoin-5-acetic acid (50 mg, 0.30 mmol) and 4-[(2-methyl-4-quinolinyl)methoxy]-aniline bis-HCl salt (101 mg, 0.30 mmol) were coupled using general coupling method A to give 20 mg (13%) of the product hydantoin. MS found:(M+H)+=419.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:21]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)[CH:22]([CH3:24])[CH3:23].[F-].[K+].C1(C)C=CC=CC=1>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.O>[CH2:21]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:7]([S:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:27][CH:26]=1)[CH:22]([CH3:24])[CH3:23]
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)c2cccnc2Cl)cc1
Reactant: CC(C)Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)Cc1ccc(-c2ncccc2S(=O)(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Yield: 55.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.076 g) was added to a deoxygenated mixture of 4-nitrophenyl 2-chloropyridine-3-sulphonate (0.69 g), 4-isobutylphenylboronic acid (0.47 g), potassium fluoride (0.38 g), toluene (15 ml) and water (2.5 ml) and the mixture was stirred and heated under reflux for 24 hours. Water (50 ml) was added and the mixture was extracted with ethyl acetate (2×80 ml). The organic extracts were washed with saturated sodium chloride solution and then combined and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with dichloromethane/hexane (1:1-1:0 v/v) then dichloromethane/hexane/ethyl acetate (10:9:1 v/v) through a silica gel Mega Bond Elut column followed by recrystallisation from ethyl acetate/hexane to give 4-nitrophenyl 2-(4-isobutylphenyl)pyridine-3-sulphonate (0.50 g), m.p. 123-124° C.; 1H NMR (d6-DMSO): 0.9 (d, 6H), 1.9 (m, 1H), 2.55 (d, 2H), 7.2-7.3 (m, 4H), 7.5 (d, 2H), 7.7 (dd, 1H), 8.2 (d, 2H), 8.4 (dd, 1H), 9.0 (dd, 1H); mass spectrum (+ve FAB, NBA/DMSO): 413 (M+H)+.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[CH3:11][CH2:12][N:13](C(C)C)[CH:14](C)[CH3:15].[Br:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=O.C(NCC)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[Br:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([N:13]([CH2:14][CH3:15])[CH2:12][CH3:11])=[O:25]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCNCC
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 129.8 %

Procedure:
HOBT (2.72 g, 10.08 mmol), DIPEA (3.52 mL, 20.16 mmol), 2-bromo benzoic acid (4.08 g, 10.08 mmol), and diethyl amine (2.08 mL, 10.08 mmol) were dissolved in DCM (100 mL) and stirred at r.t. for about 30 minutes. EDCI (3.86 g, 10.08 mmol) was added, and the mixture was stirred at r.t. for about 16 hours. The reaction was concentrated to an oil, and the oil was purified via column chromatography to give 2-bromo-N,N-diethyl-benzamide (3.35 g, 68%) as a yellow oil.
Reaction SMILES: [NH:1]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@@H:2]([C:13]([NH:15][C@H:16]([C:24](OCC1C=CC=CC=1)=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH3:41]>>[NH:1]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@@H:2]([C:13]([NH:15][C@H:16]([C:24]([NH2:41])=[O:25])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: N
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(N)=O
Reaction time: 18 h

Procedure:
A mixture of Boc-D-Trp-Phe-OBzl (1.0 g) and 24% methanolic ammonia (20 ml) was allowed to stand at room temperature in a sealed tube for 18 hours. After evaporation, the residual crystals were collected and recrystallized from a mixture of water and ethanol to give Boc-D-Trp-Phe-NH2 (0.63 g).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15].[CH3:20][O:21][CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([N+:32]([O-:34])=[O:33])=[C:28]([CH:31]=1)[CH:29]=[O:30].C(O)(=O)C>O1CCCC1>[OH:30][CH:29]([C:28]1[CH:31]=[C:24]([O:23][CH2:22][O:21][CH3:20])[CH:25]=[CH:26][C:27]=1[N+:32]([O-:34])=[O:33])[C:15]#[C:14][C:13]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: C#CC(=O)OCC
Reactant: COCOc1ccc([N+](=O)[O-])c(C=O)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C#CC(O)c1cc(OCOC)ccc1[N+](=O)[O-]
Reaction time: 1.5 h
Yield: 135.8 %

Procedure:
1.5N butyllithium (14.9 ml, 22.4 mmole) was added under the argon atmosphere to a solution of diisopropylamine (3.3 ml, 23.8 mmole) in tetrahydrofuran (40 ml) at -78° C., and the mixture was stirred for 1.5 hours. Next, a solution of ethyl propiolate (2.7 ml, 26.8 mmole) in tetrahydrofuran (10 ml) and a solution of 5-methoxymethoxy-2-nitrobenzaldehyde (3.15 g, 14.9 mmole) in tetrahydrofuran (10 ml) were added in this sequence, and the reaction mixture was stirred at -78° C. for further 1 hour. After a solution of acetic acid (2.6 ml, 46.2 mmole) in tetrahydrofuran (10 ml) was added, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous saline in this sequence. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure to give ethyl 4-hydroxy-4(5-methoxymethoxy-2-nitrophenyl)-2-butynoate as an oil (6.26 g).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[C:12]([CH3:14])([CH3:13])[C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[CH:9][CH:10]=2)[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:30][CH2:31][C@H:32]([OH:34])[CH3:33]>C1(C)C=CC=CC=1>[CH3:16][O:15][C:8]1[CH:7]=[C:6]2[C:11]([C:12]([CH3:14])([CH3:13])[C:4]3[CH:3]=[CH:2][N:30]([CH2:31][C@H:32]([OH:34])[CH3:33])[C:5]=32)=[CH:10][CH:9]=1
Reactant: C[C@@H](O)CN
Reactant: COc1ccc2c(c1)C(=O)C(CC=O)C2(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C2(C)C
Yield: 59.3 %

Procedure:
A solution of 4.94 g of (RS)-2-(2-oxoethyl)-6-methoxy-3,3-dimethyl-1-indanone and 220 ml of p-toluenesulfonic acid in 200 ml of anhydrous toluene was heated on a water separator. A solution of 6.39 g of (R)-1-amino-2-propanol in 40 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes, during which the solvent was reduced to a volume of 40 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 7:3). 3.42 g (60%) of (R)-1-(7-methoxy-4,4-dimethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])([O-:3])=[O:2].C1C=C[NH+]=CC=1.Br[Br-]Br.[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+]>C1COCC1.C(Cl)(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]>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[C:7]2[CH2:13][CH2:14][N:15]1[C:16](=[O:25])[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]1=[O:24])([O-:3])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc([N+](=O)[O-])cc12
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1CCc1c(-c2ccccc2)[nH]c2ccc([N+](=O)[O-])cc12

Procedure:
2-[2-(5-Nitro-1H-indol-3-yl)-ethyl]-isoindole-1,3-dione (1 mmol) is dissolved in THF/chloroform (1:1) and treated with pyridine hydrobromide perbromide at 0° C. for 90 min, then eluted from a silica column with chloroform-methanol. The product is dissolved in toluene-ethanol (1:1) and treated with phenylboronic acid (1.5 equiv), sodium carbonate (2.5 equiv), lithium chloride (3 equiv), and palladium tetrakis(triphenylphosphine) (5 mol %). The mixture is refluxed 4 h, concentrated in vacuo, and the oil chromatographed on silica eluted with ethyl acetate-hexane to afford 2-[2-(5-nitro-2-phenyl-1H-indol-3-yl)-ethyl]-isoindole-1,3-dione. This compound is dissolved in ethanol (6 mL) and refluxed with ethylenediamine (3 equiv) 18 h. The solvent is removed in vacuo and the material acetylated with pyridine-acetic anhydride (1:1, 6 mL). The solvent is removed in vacuo and the residue chromatographed on silica eluted with ethyl acetate-hexane. This product is hydrogenated and transformed to the carbamic acid methyl ester as in the example above. Purified product is isolated by reverse-phase HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=3)[N:12]=[C:11]([C:22]([O:24]CC)=[O:23])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=3)[N:12]=[C:11]([C:22]([OH:24])=[O:23])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2cccc(C#N)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: N#Cc1cccc(-n2nc(C(=O)O)cc2-c2cc(F)cc(Cl)c2)c1
Reaction time: 6 h

Procedure:
The preparation of the title compound takes place starting from the compound of Example 64A in analogy to the synthesis of the compound of Example 71A but with stiffing for 6 hours. 1.21 g of the title compound with 53% purity are obtained.