Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.[NH:31]1[CH:35]=[CH:34][C:33](B(O)O)=[N:32]1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.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.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:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:35]4[CH:34]=[CH:33][NH:32][N:31]=4)=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Reactant: OB(O)c1cc[nH]n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2c(-c3cc[nH]n3)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 100 °C
Yield: 10.3 %

Procedure:
To a solution of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (Example 33) (160 mg, 0.305 mmol) in 1,4-dioxane (2.5 mL) was added 1H-pyrazol-3-ylboronic acid (51.3 mg, 0.458 mmol), bis(triphenylphosphine)palladium(II) chloride (21.44 mg, 0.031 mmol) and potassium carbonate (127 mg, 0.916 mmol). Then, water (1 mL) was added to the mixture. The reaction mixture was then heated at 100° C. in a microwave for 15 min (×2). Extra tetrakis(triphenylphosphine)palladium(0) (35.3 mg, 0.031 mmol) was added and the mixture heated at 100° C. for another 15 min. The solvent from was then removed in vacuo and the residue dissolved in ethyl acetate (20 mL) and washed with water (20 mL). The aqueous phase was re-extracted with ethyl acetate (20 mL×2). All organic phase were combined, dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified on silica, eluting with a gradient of 0-50% ethyl acetate in cyclohexane and further purified using MDAP (acidic conditions), to give the title compound (16 mg). LCMS (A) m/z: 509 [M−1]−, Rt 1.23 min (acidic).
Reaction SMILES: COC(C1C=C2C(=C([C:18]3[CH:19]=[CH:20][C:21]4[C:28](=O)[CH:27]=[C:26](N)[C:24](=[O:25])[C:22]=4[N:23]=3)N=1)NC1C=CC=CC2=1)=O.C(OC1C=CC=C2C=1N=C(C=O)C=C2)C1C=CC=CC=1.COC(=O)[C@H](CC1C2C(=CC=CC=2)NC=1)N>>[OH:25][C:24]1[CH:26]=[CH:27][CH:28]=[C:21]2[C:22]=1[N:23]=[CH:18][CH:19]=[CH:20]2
Reactant: COC(=O)c1cc2c([nH]c3ccccc32)c(-c2ccc3c(n2)C(=O)C(N)=CC3=O)n1
Agent: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: O=Cc1ccc2cccc(OCc3ccccc3)c2n1
Product: Oc1cccc2cccnc12

Procedure:
Hibino's group has reported the synthesis of demethyllavendamycin methyl ester (C) in Hibino et al., Heterocycles, 20, 1957 (1983). Hibino's group synthesized demethyllavendamycin methyl ester by a Pictet-Spengler type cyclization of 8-benzyloxyquinoline-2-aldehyde with tryptophan methyl ester, followed by aromatization and hydrogenation to give an 8-hydroxyquinoline intermediate. This intermediate was brominated to give the 5,7-dibromo-8-hydroxyquinoline. Oxidation of the 5,7-dibromo-8-hydroxyquinoline yielded the 7-bromoquinolinequinone, and replacement of the bromine with sodium azide, followed by reduction of the azide with sodium hydrosulfite, yielded demethyllavendamycin methyl ester.
Reaction SMILES: [C:1]12([N:11]=[C:12]=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl.[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1.C(N(CC)CC)C.O>CN(C=O)C>[OH:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([NH:15][C:12]([NH:11][C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:13])[CH2:17][CH2:18]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NC12CC3CC(CC(C3)C1)C2)N[C@H]1CC[C@H](O)CC1
Reaction time: 8 h

Procedure:
To a solution of 1-adamantyl isocyanate (10 g, 56.4 mmol) and trans-4-aminocyclohexanol hydrochloride (10.3 g, 67.7 mmol) in DMF (300 mL) was added triethylamine (6.9 g, 67.7 mmol) at 0° C. The reaction mixture was stirred overnight. The reaction mixture was poured into water, and the resulting precipitates were collected and washed with water. The crude product was recrystallized from methanol/water. Yield: 15.5 g (94% of theory). M.P.: 254° C. 1H NMR (300 MHz, DMSO-d6): δ 5.48 (d. J=9 Hz, 1H), 5.38 (s, 1H), 4.48 (d, J=4.7 Hz, 1H), 3.42-3.28 (m, 1H), 3.28-3.13 (m, 1H), 2.02-1.93 (m, 3H), 1.87-1.68 (m, 9H), 1.63-1.54 (m, 7H), 1.24-0.93 (4H).
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:4]=1[CH:5]=[O:6])[CH3:2].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:12]([C:7]1[CH:8]=[C:9]([O:11][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=[C:3]([CH2:1][CH3:2])[C:4]=1[CH:5]=[O:6])[CH3:13]
Reactant: CCc1cc(O)cc(CC)c1C=O
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1cc(Oc2ccccc2)cc(CC)c1C=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.6 %

Procedure:
To a solution of 1.50 g (8.42 mmol) 2,6-diethyl-4-hydroxy-benzaldehyde in 60 ml dichloromethane were added 1.64 g (13.5 mmol) phenylboronic acid, 2.29 g (12.6 mmol) copper(II) acetate, 30 g 4 Å molecular sieves and 4.06 ml (50.5 mmol) pyridine. The reaction mixture was stirred at room temperature for 72 h and then filtered through celite. The filtrate was extracted with 1 N aqueous hydrochloric acid, the phases were separated, and the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, ethyl acetate/heptane gradient) to afford 1.64 g (77%) of the title compound as a yellow oil. 1H-NMR (CDCl3): 1.22 (6H, t, CH3), 2.95 (4H, q, CH2), 6.69 (2H, s, ArH), 7.08 (2H, d, ArH), 7.20 (1H, t, ArH), 7.39 (2H, dd, ArH), 10.5 (1H, s, CHO).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#N.[C:8](#N)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:9]1([C:8]#[C:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#Cc1ccccc1
Reactant: N#Cc1ccco1
Product: C(#Cc1ccco1)c1ccccc1
Reaction time: 18 h
Yield: 74 %

Procedure:
The procedure was identical to Example 1, with the exception that 2-furonitrile (0.175 ml; 0.186 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 18 h at 65° C. showed the presence of 1.26 mmol (74% yield) of 2-(phenylethynyl)furan and no remaining 2-furonitrile in the reaction mixture.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[C:17]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:18][C:19]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:20][C:9]1=2)(=O)=O.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3[C:17]([N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[N:18][C:19]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:20][C:9]2=3)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)OCCn1c2ccccc2c2c(N3CCCC3)nc(N3CCCC3)nc21
Product: c1ccc2c(c1)c1c(N3CCCC3)nc(N3CCCC3)nc1n2CCN1CCCCC1

Procedure:
A mixture of 9-(2-methanesulfonyloxyethyl)-2,4-di-1-pyrrolidinyl-9H-pyrimido[4,5-b]indole (IX, EXAMPLE4, 50 g) and piperidine (200 mL) is heated at reflux for 16 hr. Excess piperidine is removed under reduced pressure and the residue is partitioned between methylene chloride and aqueous sodium bicarbonate. The organic phase is washed with saline, dried over sodium sulfate and concentrated to give the title compound, NMR (CDCl3) 7.88, 7.28, 7.20, 7.10, 4.46-4.40, 3.94-3.90, 3.66-3.62, 2.74-2.68, 2.57, 1.98-1.94, 1.64-1.58 and 1.45 δ.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31](O)=[O:32]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:31]([C:30]4[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=4[O:28][C:27]([F:26])([F:38])[F:39])=[O:32])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)c1ccccc1OC(F)(F)F
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccccc4OC(F)(F)F)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2-(trifluoromethoxy)benzoic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: NC1C=CC(C2C=C(C)C=CC=2S(C2C=CC(C)=CC=2C2C=CC(N)=C([N+]([O-])=O)C=2)=O)=CC=1[N+]([O-])=O.[Br:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([S:50]([C:52]3[CH:57]=[CH:56][C:55]([NH2:58])=[C:54]([N+:59]([O-])=O)[CH:53]=3)=[O:51])=[CH:46][CH:45]=2)=[CH:40][CH:39]=1>>[Br:37][C:38]1[CH:39]=[CH:40][C:41]([C:44]2[CH:45]=[CH:46][C:47]([S:50]([C:52]3[CH:57]=[CH:56][C:55]([NH2:58])=[C:54]([NH2:59])[CH:53]=3)=[O:51])=[CH:48][CH:49]=2)=[CH:42][CH:43]=1
Reactant: Nc1ccc(S(=O)c2ccc(-c3ccc(Br)cc3)cc2)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Product: Nc1ccc(S(=O)c2ccc(-c3ccc(Br)cc3)cc2)cc1N

Procedure:
Following the procedure described in Example 2 but using as a starting material instead of (4-amino-3-nitrophenyl)-4-methylphenyl sulfoxide a corresponding amount of 1-(4-bromophenyl)-4-(4-amino-3-nitrophenylsulfinyl)-benzene, the title compound is obtained; M.P.=161°-164° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:36]=[CH:35][N:34]([CH3:37])[N:33]=4)[C:28](=[O:38])[N:27]([CH3:39])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.CC(O)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:36]=[CH:35][N:34]([CH3:37])[N:33]=4)[C:28](=[O:38])[N:27]([CH3:39])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1ccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: Cn1ccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a solution of 140c (270 mg, 0.50 mmol) in THF (5 mL), propan-2-ol (5 mL), and water (2 mL) was added lithium hydroxide (36 mg, 1.5 mmol). The reaction mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was diluted with dichloromethane (20 mL) and water (10 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×15 mL). The combined organic layer was washed with brine and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 140 (53 mg, 20%) as a white solid. MS-ESI: [M+H]+ 530.3. 1H NMR (500 MHz, DMSO-d6) δ 8.56 (d, J=5.0 Hz, 1H), 8.53 (d, J=2.0 Hz, 1H), 8.21 (s, 1H), 8.03 (d, J=2.5 Hz, 1H), 7.89 (s, 1H), 7.78-7.5 (m, 1H), 7.51-7.48 (m, 2H), 7.39 (d, J=2.5 Hz, 1H), 6.07 (d, J=2.0 Hz, 1H), 4.91 (s, 1H), 4.42 (s, 2H), 3.71 (s, 3H), 3.58 (s, 3H), 1.39 (s, 9H)
Reaction SMILES: [CH:1]1([C:5]2[C:12]([C:13]3[NH:17][C:16]([O:18][CH3:19])=[N:15][N:14]=3)=[CH:11][C:8]([C:9]#[N:10])=[C:7]([CH3:20])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[NH4+].[OH-:22].OO>CCO>[CH:1]1([C:5]2[C:12]([C:13]3[NH:17][C:16]([O:18][CH3:19])=[N:15][N:14]=3)=[CH:11][C:8]([C:9]([NH2:10])=[O:22])=[C:7]([CH3:20])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: [OH-]
Reactant: COc1nnc(-c2cc(C#N)c(C)cc2C2CCC2)[nH]1
Agent: OO
Agent: [NH4+]
Solvent: CCO
Product: COc1nnc(-c2cc(C(N)=O)c(C)cc2C2CCC2)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a solution of 4-cyclobutyl-5-(5-methoxy-4H-1,2,4-triazol-3-yl)-2-methylbenzonitrile (compound 89.7, 0.15 g, 0.53 mmol) in EtOH (10 mL) was added NH4OH (0.18 mL, 2.66 mmol, 14.8 M in H2O), followed by H2O2 (1.8 mL, 26.6 mmol, 50% in H2O). The mixture was stirred at room temperature overnight, then cooled to 0° C. and carefully quenched with 1 M Na2S2O3 solution (26 mL). The mixture was extracted with EtOAc (×2) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (5% MeOH in CH2Cl2) to yield 0.1 g (63%) of the title compound as a white solid. m/z (ES+) 287(M+H)+. 1H NMR (400 MHz, Methanol-d4) δ7.50 (s, 1H), 7.33 (s, 1H), 4.03 (s, 3H), 3.95-4.05 (m, 1H), 2.51 (s, 3H), 2.23-2.11 (m, 2H), 2.11-1.88 (m, 3H), 1.83-1.71 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([S:13](Cl)(=[O:15])=[O:14])=[CH:5][CH:4]=1.[CH:17]12[CH2:25][CH2:24][CH:21](C[CH2:23]1)[CH2:20][NH:19][CH2:18]2.CCN(C(C)C)C(C)C>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([S:13]([N:19]2[CH2:18][CH:17]3[CH2:23][CH:21]([CH2:24][CH2:25]3)[CH2:20]2)(=[O:15])=[O:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)c2ccccc12
Reactant: C1CC2CCC1CNC2
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)N2CC3CCC(C3)C2)c2ccccc12

Procedure:
The title compound was prepared by reacting 4-methoxy-1-naphthalenesulfonyl chloride (0.27 g) with 3-azabicyclo[3.2.2]nonane (0.16 g) in the presence of DIEA (0.30 g) using a procedure similar to that of Example 5. Yield: 0.34 g of a white solid, mp: 136.2°-138.6° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6](=[CH:12][N:13](C)C)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=O.O.[NH2:21]N>C(O)(=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][NH:13][N:21]=1
Reactant: NN
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1Cl
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1c[nH]nc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 1.41 g of ethyl 2-(2-chlorobenzoyl)-3-(N,N-dimethylamino)acrylate (a compound described in JP-A 7-101940), 0.30 g of hydrazine monohydrate and 5 ml of acetic acid was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure. Water was poured into the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain ethyl 3-(2-chlorophenyl)-1H-pyrazole-4-carboxylate of the formula:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=3)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[CH2:30][C:31](=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(#N)C>[CH2:35]([O:34][C:32]([C:31]1[N:1]=[C:2]2[CH:7]=[C:6]([NH:8][C:9]([C:11]3[N:12]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=4)=[O:10])[CH:5]=[CH:4][N:3]2[CH:30]=1)=[O:33])[CH3:36]
Reactant: Nc1cc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)ccn1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CC#N
Product: CCOC(=O)c1cn2ccc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)cc2n1
Yield: 27.8 %

Procedure:
The compound is prepared according to a process similar to that described in step 4.3, by reacting 0.2 g (0.53 mmol) of N-[2-aminopyrid-4-yl]-5-fluoro-1-[(3-fluorophenyl)-methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 10.1, with 0.21 g (1.06 mmol) of ethyl 3-bromo-2-oxopropionate in 8 mL of acetonitrile. 70 mg of the expected product are thus obtained.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([N:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35]([OH:37])=[O:36])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CO>[Pd].CN(C)C=O>[NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([N:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35]([OH:37])=[O:36])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: C[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: C[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
The solution of 2.06 g. (3 mmoles) of Z-Tyr-D-Ala-Gly-Phe-Pro-OH (3rd step of Example 5) in a mixture of 40 ml. of methanol and 10 ml. of dimethyl formamide are hydrogenated in the presence of palladium as catalyst. At the end of the reaction the catalyst is filtered off, washed with a 1:1 mixture of methanol and dimethyl formamide, the combined solutions are evaporated, the residue is rubbed with ether, filtered, washed with ether, dried, redissolved in 4 ml. of ethanol and precipitated with ethyl acetate. The precipitate is filtered, washed with ethyl acetate and dried. Yield: 1.16 g. (70%) of the named pentapeptide; Rf4 0.3-0.4. Aminoacid analysis: Pro=1.02; Gly=1.0; Ala=0.98; Tyr=1.0; Phe=1 (reference basis).
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[CH3:13][S:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:19][C:18]2[CH:20]=[CH:21][C:15]([S:14][CH3:13])=[CH:16][CH:17]=2)=[CH:6][CH:5]=1
Reactant: CSc1ccc(N)cc1
Reactant: O=Cc1ccc(OC(F)F)cc1
Product: CSc1ccc(N=Cc2ccc(OC(F)F)cc2)cc1
Yield: 91 %

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-difluoromethoxybenzaldehyde and 4-methylthioaniline as starting materials, N-(4-difluoromethoxybenzylidene)-4-methylthioaniline was obtained in a yield of 91%. This aniline compound and trimethylsilyl cyanide were then reacted together in a similar manner to that described in Example 1(ii), to give the title compound as a slightly yellow powder (yield 80%).
Reaction SMILES: [CH2:1]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=O)[CH3:17]>C1(C)C=CC=CC=1>[CH2:1]([C:2]1[CH:3]=[CH:4][C:5]([N:6]=[C:1]([CH3:9])[C:2]2[CH:8]=[CH:7][CH:5]=[CH:4][CH:3]=2)=[CH:7][CH:8]=1)[C:9]1[CH:15]=[CH:14][C:12]([N:13]=[C:16]([CH3:17])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][CH:10]=1
Reactant: Nc1ccc(Cc2ccc(N)cc2)cc1
Reactant: CC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=Nc1ccc(Cc2ccc(N=C(C)c3ccccc3)cc2)cc1)c1ccccc1

Procedure:
A mixture of 4,4'-methylenedianiline (198 g; 1 mole), acetophenone (240 g; 2 moles) and a catalytic amount of stannous chloride was refluxed in toluene (3L) for 30 hours using a Dean-Stark trap. The theoretical amount of water was removed from the system. The toluene was then removed under vacuum.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]([CH2:13][CH2:14][S:15][CH3:16])[NH:9][C:8]2=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S([O-])(O[CH3:22])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:22][N:9]1[CH:10]([CH2:13][CH2:14][S:15][CH3:16])[C:11](=[O:12])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]1=[O:17]
Reactant: CSCCC1NC(=O)N(c2ccccc2)C1=O
Reactant: COS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSCCC1C(=O)N(c2ccccc2)C(=O)N1C

Procedure:
A solution in acetone of 250 g (1 mole) of 3-phenyl-5-methylthioethyl hydantoin (compound no. 27) and 126 g (1 mole) of methyl sulphate is heated under reflux for 8 hours, accompanied by the addition with stirring of 138 g (1 mole) of potassium carbonate. The concentration of the acetone solution is between 0.5 and 1 mole per liter. On completion of the reaction, the potassium salts are separated by filtration and the acetone eliminated by evaporation. The residue crystallises on cooling. It can be recrystallised from methanol.
Reaction SMILES: [Cl:1][C:2]1[C:3](OS(O)(=O)=O)=[C:4]2[C:9](=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[NH:8][C:7](=[O:16])[C:6]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])=[C:5]2C.[CH2:28]([O:30][CH:31]([O:35][CH2:36][CH3:37])[CH2:32][CH2:33][NH2:34])[CH3:29]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:11]=1)[NH:8][C:7](=[O:16])[C:6]([C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])=[C:5]2[NH:34][CH2:33][CH2:32][CH:31]([O:35][CH2:36][CH3:37])[O:30][CH2:28][CH3:29]
Reactant: CCOC(CCN)OCC
Reactant: Cc1c(C(=O)C(C)C)c(=O)[nH]c2c(C(F)(F)F)cc(Cl)c(OS(=O)(=O)O)c12
Product: CCOC(CCNc1c(C(=O)C(C)C)c(=O)[nH]c2c(C(F)(F)F)cc(Cl)cc12)OCC
Yield: 72.4 %

Procedure:
6-Chloro-3-isobutyryl-4-methylsulfoxy-8-trifluoromethyl-2-quinolinone (379 mg, 1 mmol) and 3,3-diethoxypropylamine (147 mg, 1 mmol) were used and the reaction was carried out as in the above process of example 1 to obtain the desired product (335 mg, yield: 78%).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[C:38]1[CH:39]=[N:40][N:41]([CH2:43][CH2:44][N:45]([CH3:53])[CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:42]=1>C(O)C.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>[CH3:3][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:38]3[CH:39]=[N:40][N:41]([CH2:43][CH2:44][N:45]([CH3:53])[CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH:42]=3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:1]
Reactant: CN(CCn1cc(Br)cn1)Cc1ccccc1
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3cnn(CCN(C)Cc4ccccc4)c3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 90 °C

Procedure:
1-Methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (300 mg, 0.721 mmol, for a preparation see Intermediate 52), potassium carbonate (149 mg, 1.081 mmol) and 2-(4-bromo-1H-pyrazol-1-yl)-N-methyl-N-(phenylmethyl)ethanamine (317 mg, 1.078 mmol, for a preparation see Intermediate 53) were stirred in ethanol (3 mL) and toluene (3.00 mL). The mixture was degassed, tetrakis(triphenylphosphine)palladium(0) (41.6 mg, 0.036 mmol) added, the mixture degassed again and heated to reflux (90° C.) under nitrogen for 4.5 hours. The mixture was cooled to room temperature, loaded on to a 5 g SCX cartridge, eluted with MeOH (50 ml), 2M methanolic ammonia (25 ml) and the basic fractions evaporated to dryness. The residue was loaded on to a 12+M Biotage silica column and eluted with a gradient of 0 to 5% 2M methanolic ammonia in DCM. The product containing fractions were evaporated to a colourless gum (223 mg).