Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH:7]([CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[CH2:8][C:9]1([C:14]([NH:16][CH:17]2[CH2:22][CH2:21][CH:20]([C:23]([O:25]CC3C=CC=CC=3)=[O:24])[CH2:19][CH2:18]2)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]>[Pd].O.C(O)C>[C:1]([O:5][C:6](=[O:39])[CH:7]([CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])[CH2:8][C:9]1([C:14]([NH:16][CH:17]2[CH2:18][CH2:19][CH:20]([C:23]([OH:25])=[O:24])[CH2:21][CH2:22]2)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COCCOCC(CC1(C(=O)NC2CCC(C(=O)OCc3ccccc3)CC2)CCCC1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: COCCOCC(CC1(C(=O)NC2CCC(C(=O)O)CC2)CCCC1)C(=O)OC(C)(C)C
Reaction time: 18 h

Procedure:
A mixture of benzyl 4-{[(1-{3-tert-butoxy-2-[(2-methoxyethoxy)methyl]-3-oxopropyl}cyclopentyl)carbonyl]amino}cyclohexanecarboxylate (EP 274234), and 10% palladium on charcoal (250 mg) in water (10 ml) and ethanol (50 ml) was hydrogenated at 50 psi and room temperature for 18 hours. The reaction mixture was filtered through Solkafloc®, the filtrate concentrated under reduced pressure and the residue azeotroped with toluene (3×) and then dichloromethane (3×), to give the title compound, 2.0 g, 96%; 1H NMR (CDCl3, 300 MHz) δ: 1.48 (s, 9H), 1.53-1.84 (m, 14H), 1.94-2.10 (m, 5H), 2.60 (m, 2H), 3.40 (s, 3H), 3.41-3.63 (m, 5H), 3.96 (m, 1H), 5.90 (bd, 1H).
Reaction SMILES: [N:1]([C:4]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[N:12][C:11]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[N+]=[N-]>ClC1C=CC=CC=1Cl>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]2[C:13]3[N:12]=[C:11]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[C:4]=3[NH:1][C:19]=2[CH:18]=1
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)nc(-c2ccc(OC)cc2)c1N=[N+]=[N-]
Solvent: Clc1ccccc1Cl
Product: COC(=O)c1cc(-c2ccc(OC)cc2)nc2c1[nH]c1cc(OC)ccc12
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
A solution of methyl 3-azido-2,6-bis(4-methoxyphenyl)isonicotinate (230 mg, 0.589 mmol) in 1,2-dichlorobenzene (5 mL) was heated at 170° C. with gas evolution. After 0.5 hr, the solvent was removed under vacuum and silica gel radial chromatography of the residue (step gradient elution with hexane containing 5 to 20% ethyl acetate) afforded methyl 7-methoxy-2-(4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (153 mg, 72%) as a yellow solid. MS (ESI) m/z 363.1 (M+H). 1H NMR (CDCl3) δ ppm 9.39 (1H, s), 8.29 (1H, d, J=8.55 Hz), 8.13 (1H, s), 8.10 (2H, d, J=8.85 Hz), 7.03 (2H, d, J=8.85 Hz), 6.93-6.99 (2H, m), 4.07 (3H, s), 3.93 (3H, s), 3.88 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:19]=2)[N:14]=[CH:13]1.Br[CH2:30][CH:31]1[CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+].CO>CN(C=O)C.C(OCC)(=O)C>[CH:31]1([CH2:30][N:26]2[CH2:27][CH2:28][N:23]([C:18]3[CH:19]=[C:20]4[C:15](=[CH:16][CH:17]=3)[N:14]=[CH:13][N:12]([C:3]3[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=3[CH3:1])[C:6]([O:8][CH3:9])=[O:7])[C:21]4=[O:22])[CH2:24][CH2:25]2)[CH2:33][CH2:32]1
Reactant: COC(=O)c1ccc(C)c(-n2cnc3ccc(N4CCNCC4)cc3c2=O)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-n2cnc3ccc(N4CCN(CC5CC5)CC4)cc3c2=O)c1

Procedure:
Methyl 4-methyl-3-(4-oxo-6-piperazin-1-ylquinazolin-3(4H)-yl)benzoate (1.41 g), (bromomethyl)cyclopropane (0.40 ml), and potassium carbonate (2.1 g) were stirred in DMF (9.4 ml) at 60° C. for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with water (×3). The combined aqueous layers was extracted with EtOAc and the organic layers combined, washed with brine, dried (magnesium sulphate) and concentrated to yield a brown glass. MeOH was added and the resultant solid collected by filtration and washed with ethyl acetate to yield methyl 3-[6-[4-(cyclopropylmethyl)piperazin-1-yl]-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoate as a white solid (0.39 g); NMR Spectrum: (DMSOd6) 0.00 (m, 2H), 0.38 (m, 2H), 0.76 (m, 1H), 2.05 (s, 3H), 2.14 (d, 2H), 2.52 (m, 4H) 3.17 (m, 4H), 3.75 (s, 3H), 7.36 (s, 1H), 7.51 (m, 3H), 7.85 (s, 1H), 7.90 (d, 1H), 7.97 (s, 1H); Mass Spectrum: M+H+ 433.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]([N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)[CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:22][O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[K+].[K+].N#N>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.COCCOC>[CH2:13]([CH:12]([CH2:15][CH3:16])[CH:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([C:29]3[CH:30]=[CH:31][C:26]([C:24]([O:23][CH3:22])=[O:25])=[CH:27][CH:28]=3)[S:3][C:4]=2[CH:10]=1)[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)[CH3:14]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CCC(CC)C(c1ccc2nc(Br)sc2c1)n1ccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CCC(CC)C(c1ccc2nc(-c3ccc(C(=O)OC)cc3)sc2c1)n1ccnc1
Temperature: 80 °C

Procedure:
A solution of 2-bromo-6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazole (93 mg, 0.255 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (50.6 mg, 0.281 mmol), tetrakis(triphenylphosphine)palladium (29.5 mg, 0.0255 mmol), potassium carbonate (106 mg, 0.765 mmol), DME (5 mL) and water (0.8 mL) was degassed, filled with N2, and heated to 80° C. for 6 h. The reaction mixture was evaporated. The crude product was purified by column chromatography using 5% MeOH in DCM as eluent to afford to methyl 4-(6-(2-ethyl-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate as white solid. MS (ES+): m/z 420.28 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][C:11]([OH:18])=[CH:12][C:13]=3[OH:17])[O:8][C:7]=2[C:19](OCC)=[O:20])=[CH:4][CH:3]=1.[NH3:26]>>[OH:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][C:11]([OH:18])=[CH:12][C:13]=3[OH:17])[O:8][C:7]=2[C:19]([NH2:26])=[O:20])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1oc2cc(O)cc(O)c2c(=O)c1-c1ccc(O)cc1
Reactant: N
Product: NC(=O)c1oc2cc(O)cc(O)c2c(=O)c1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl 4',5,7-trihydroxy-2-isoflavonecarboxylate (120 mg) and 28% ammonia (2 ml) was stirred at room temperature for three hours, water was distilled off under reduced pressure, and the solid residue was recrystallized from methanol, affording 65 mg of 4',5,7-trihydroxy-2-isoflavonecarboxamide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]#[N:11])=[CH:2]1.[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18](I)[CH:17]=1)[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O>CS(C)=O.[Cu](I)I.C(OCC)(=O)C>[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]#[N:11])=[CH:2]2)[CH:17]=1)[CH3:13]
Reactant: N#Cc1c[nH]c2ccccc12
Reactant: CCOC(=O)c1cccc(I)c1
Agent: I[Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)c1cccc(-n2cc(C#N)c3ccccc32)c1
Temperature: 75 °C
Reaction time: 72 h
Yield: 66.5 %

Procedure:
To a solution of 1H-indole-3-carbonitrile (0.28 g) in dimethyl sulfoxide (3 mL) were added 3-iodobenzoic acid ethyl ester (0.61 g), cesium carbonate (0.65 g), copper iodide (0.038 g) and N,N-dimethyl glycine (0.041 g), this mixture was stirred at 75° C. for 3 days. To this reaction mixture was added ethyl acetate, the insoluble material was removed by filtration and this filtrate was concentrated under reduced pressure. To this residue was added water, the precipitated solid was collected by filtration, and washed with water and n-hexane, and dried under reduced pressure at 40° C. to give the title compound (0.38 g).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C@@H:16]([O:27][C:28](=[O:38])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=O)[C:30]=3[OH:37])[CH2:17][C:18]3[C:23]([Cl:24])=[CH:22][N+:21]([O-:25])=[CH:20][C:19]=3[Cl:26])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.[NH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[OH:46]>CO>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C@@H:16]([O:27][C:28](=[O:38])[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][NH:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=4[OH:46])[C:30]=3[OH:37])[CH2:17][C:18]3[C:23]([Cl:24])=[CH:22][N+:21]([O-:25])=[CH:20][C:19]=3[Cl:26])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:14])[F:15])[CH2:3][CH2:2]1
Reactant: O=Cc1cccc(C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1O
Reactant: Nc1ccccc1O
Solvent: CO
Product: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)c1cccc(CNc2ccccc2O)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of [(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)ethyl]3-formyl-2-hydroxy-benzoate (800 mg, 1.41 mmol), MeOH (5 mL) AcOH (0.5 mL) and 2-aminophenol (184 mg, 1.69 mmol) was stirred at room temperature for 16 hours before adding NaBH3(CN) (444 mg, 7.05 mmol) in one portion. The resulting mixture was stirred at room temperature for 3 h, concentrated in vacuo to a sticky pink oil. The residue was used in the next step without further purification. LCMS (Method 2): [MH+]=661 at 3.68 min.
Reaction SMILES: [NH2:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:19].Br[CH2:21][C:22]1[CH:30]=[CH:29][C:25]2[N:26]=[CH:27][S:28][C:24]=2[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[S:28]1[C:24]2[CH:23]=[C:22]([CH2:21][NH:1][C:2]3[C:12]4[CH2:11][CH2:10][N:9]([C:13](=[O:18])[C:14]([F:17])([F:15])[F:16])[CH2:8][CH2:7][C:6]=4[CH:5]=[CH:4][C:3]=3[Cl:19])[CH:30]=[CH:29][C:25]=2[N:26]=[CH:27]1
Reactant: BrCc1ccc2ncsc2c1
Reactant: Nc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc4ncsc4c3)c2CC1)C(F)(F)F
Temperature: 150 °C

Procedure:
Using a method similar to the General Procedure 5-4, combine 6-amino-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.1 g, 0.35 mmol), 6-bromomethyl-benzothiazole (80 mg, 0.35 mmol), and potassium carbonate (47.0 mg, 0.35 mmol) in anhydrous DMF (1 mL) in a sealed tube. Heat at 150° C. for 3 h to obtain 6-[(benzothiazol-6-yl-methyl)-amino]-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[C@H:3]([NH:31][C:32](=[O:35])[O:33][CH3:34])[C:4](=[O:30])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)=[CH:13][N:14]=1.Br[C:38]1[CH:43]=[CH:42][C:41]([C:44]2[NH:48][C:47]([C@H:49]3[N:54]4[C:55](=[O:72])[C@@H:56]([NH:61][C:62](=[O:71])[O:63][CH2:64][C:65]5[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=5)[CH2:57][CH2:58][C:59](=[O:60])[N:53]4[CH2:52][CH2:51][CH2:50]3)=[N:46][CH:45]=2)=[CH:40][CH:39]=1.C(=O)(O)[O-].[Na+]>C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe].C(O)(C)(C)C>[CH2:64]([O:63][C:62](=[O:71])[NH:61][C@H:56]1[CH2:57][CH2:58][C:59](=[O:60])[N:53]2[CH2:52][CH2:51][CH2:50][C@@H:49]([C:47]3[NH:48][C:44]([C:41]4[CH:42]=[CH:43][C:38]([C:18]5[CH:17]=[CH:16][C:15]([C:12]6[NH:11][C:10]([C@@H:6]7[CH2:7][CH2:8][CH2:9][N:5]7[C:4](=[O:30])[C@@H:3]([NH:31][C:32]([O:33][CH3:34])=[O:35])[CH:2]([CH3:36])[CH3:1])=[N:14][CH:13]=6)=[CH:20][CH:19]=5)=[CH:39][CH:40]=4)=[CH:45][N:46]=3)[N:54]2[C:55]1=[O:72])[C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=1
Reactant: O=C(N[C@H]1CCC(=O)N2CCC[C@@H](c3ncc(-c4ccc(Br)cc4)[nH]3)N2C1=O)OCc1ccccc1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])O
Solvent: CC(C)(C)O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN6C(=O)CC[C@H](NC(=O)OCc7ccccc7)C(=O)N56)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 90 °C
Yield: 32.1 %

Procedure:
In a 10 mL seal tube, methyl (S)-3-methyl-1-oxo-1-((S)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (55 mg, 111 μmol) (Intermediate 1), benzyl (4S,7S)-4-(5-(4-bromophenyl)-1H-imidazol-2-yl)-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepin-7-ylcarbamate (61.2 mg, 111 μmol) (Intermediate 6) and sodium bicarbonate (sat. solution, 600 μl, excess) were combined with tert-butanol (3.00 ml) to give a light brown suspension and degassed for 5 min. PdCl2(DPPF) (8.11 mg, 11.1 μmol) was added and flushed with nitrogen. It was sealed heating at 90° C. for 4 hr then diluted with EtOAc (10 ml), filtered and concentrated. The crude was purified on a silica gel column (CH2Cl2, 2%, 3%, 5%, 8% MeOH/CH2Cl2) to afford {(4S,7S)-4-[5-(4′-{2-[(S)-1-((S)-2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-6,10-dioxo-octahydro-pyridazino[1,2-a][1,2]diazepin-7-yl}-carbamic acid benzyl ester as a light yellow solid (30 mg, 30.6%). ESI-LRMS m/e calcd for C46H51N9O7, [M+] 841. found 842 [M+H]. 1H NMR (DMSO-d6) δ: 12.23 (br. s., 1H), 11.66-11.89 (m, 1H), 7.72-7.85 (m, 5H), 7.58-7.92 (m, 4H), 7.48-7.55 (m, 1H), 7.34-7.43 (m, 3H), 7.22-7.35 (m, 1H), 7.19-7.45 (m, 3H), 5.81 (br. s., 1H), 5.77-5.86 (m, 1H), 5.01-5.13 (m, 3H), 4.92-5.21 (m, 2H), 4.47 (d, J=11.5 Hz, 1H), 4.33-4.59 (m, 1H), 4.00-4.13 (m, 1H), 3.95-4.13 (m, 1H), 3.72-3.86 (m, 1H), 3.81 (br. s., 1H), 3.54 (s, 3H), 3.45-3.64 (m, 2H), 2.82-3.00 (m, 1H), 2.79-2.96 (m, 1H), 2.08-2.35 (m, 2H), 1.76-2.05 (m, 3H), 1.50-1.67 (m, 1H), 0.80-0.95 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:25])[N:18]=[C:19]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[N:12]2[N:11]=1)[CH3:2].[S:26]([Cl:30])(=O)(=[O:28])[OH:27]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:26]([Cl:30])(=[O:28])=[O:27])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:25])[N:18]=[C:19]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[N:12]2[N:11]=1)[CH3:2]
Reactant: CCOc1ccccc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Reactant: O=S(=O)(O)Cl
Product: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° C., 7.0 g (20.7 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-cyclopentyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one (Example 15A) are added carefully to 24.1 g (207 mmol) of chlorosulphuric acid. The mixture is allowed to warm to room temperature and stirred overnight. The solution is carefully added to 200 ml of ice-water and extracted twice with dichloromethane. The combined organic phases are dried over sodium sulphate and the solvent is distilled off under reduced pressure. The sulphonyl chloride is dried under reduced pressure and reacted further to the sulphonamides without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](F)=[C:6]([F:8])[CH:7]=1.O.[NH2:11][NH2:12]>C(O)CC>[NH:11]([C:5]1[C:6]([F:8])=[CH:7][C:2]([Cl:1])=[CH:3][N:4]=1)[NH2:12]
Reactant: NN
Reactant: Fc1cc(Cl)cnc1F
Solvent: CCCO
Solvent: O
Product: NNc1ncc(Cl)cc1F

Procedure:
7.5 g of the compound obtained in Step 3 and 9.57 ml of hydrazine monohydrate were added to 50 ml of n-propanol, the resulting mixture was refluxed for 6 hours, and distilled under a reduced pressure to remove the solvent. The resulting residue was dissolved in 80 ml of chloromethane, washed with water, and dried over anhydrous magnesium sulfate. The dried organic layer was concentrated under a reduced pressure to obtain 7.26 g of the title compound.
Reaction SMILES: C([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29](=[O:31])[CH3:30])[C:19]2=[O:32])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])C.N[C@H](C(O)=O)C.O>C(Cl)Cl>[OH:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH:28][C:29](=[O:31])[CH3:30])[C:19]2=[O:32])[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Agent: C[C@H](N)C(=O)O
Solvent: ClCCl
Solvent: O
Product: COc1ccc([C@@H](CS(C)(=O)=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)cc1O
Reaction time: 1 h

Procedure:
To a stirred solution of (S)—N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide (0.55 mmol) in anhydrous CH2Cl2 at room temperature, is added Ala (1.10 mmol). After stirring for 1 hour, water is added. The product is extracted into CH2Cl2 and is dried over Na2SO4. The solvent is removed to give crude (S)—N—{2-[1-(3-hydroxy-4-methoxy-phenyl)-2-methanesulfonyl-ethyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide. The product is purified by chromatography or recrystallization.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]1[C@H:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][O:13][C@@:12]([CH2:23][CH:24]=[CH2:25])([CH3:22])[C:11]1=[O:26])=[O:4].B1C2CCCC1CCC2.[OH-:42].[Na+].OO>C1COCC1.CCO>[CH:16]1([C@H:15]2[N:10]([C:9]3[CH:8]=[C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:30])[CH3:31])[S:6][C:5]=3[C:3]([OH:2])=[O:4])[C:11](=[O:26])[C@:12]([CH2:23][CH2:24][CH2:25][OH:42])([CH3:22])[O:13][CH2:14]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: [OH-]
Reactant: C=CC[C@@]1(C)OC[C@@H](C2CCCCC2)N(c2cc(C#CC(C)(C)C)sc2C(=O)OC)C1=O
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)C#Cc1cc(N2C(=O)[C@@](C)(CCCO)OC[C@H]2C2CCCCC2)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-((2R,5R)-2-allyl-5-cyclohexyl-2-methyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (50 mg, 0.11 mmol, 1.0 equiv) in THF (1.0 mL) was added 9-BBN (0.5 M solution in THF, 0.55 ml, 0.27 mmol, 2.5 equiv) at 0° C. The reaction mixture was then stirred at room temperature for 2 hours. To the solution was then cooled in an ice water bath and was added EtOH, followed by aq. NaOH solution and H2O2 aq. solution. During addition the reaction internal temperature was kept between 5° C. and 10° C. The reaction mixture was then heated to reflux for 90 minutes. After cooled at room temperature, the reaction mixture was extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by prep-HPLC to give the product 26 mg. MW: 462.2 [M+H]+. 1H-NMR (400 MHz, MeOD): δ 6.91 (s, 1H), 4.23 (d, 1H), 3.94 (d, 1H), 3.62 (m, 1H), 3.55 (m, 2H), 1.96-1.52 (m, 10H), 1.45 (s, 3H), 1.32 (s, 9H), 1.21 (m, 4H), 1.05 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[C:24]1(=[O:30])[O:29][C:27](=[O:28])[CH:26]=[CH:25]1>O>[C:24]([O:12][C:10]1[CH:11]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:7])=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:9]=1)(=[O:30])/[CH:25]=[CH:26]\[C:27]([OH:29])=[O:28]
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)c1cc(OC(=O)/C=C\C(=O)O)cc(C(C)(C)C)c1O

Procedure:
3,5-di tert.butyl-4-hydroxyphenyl hydrogen maleate was prepared by stirring a mixture of 15.5 grams of 2,6-di tert.butyl hydroquinone, 10 grams of trifluoroacetic acid and 8.6 grams maleic anhydride for 12 hours at 35° C. to 40° C. Addition of 100 milliliters of water resulted in the precipitation of a light brown paste which crystallized when mixed with petroleum ether. The solid was filtered off and washed twice with petroleum ether yielding 10.5 grams of product melting at 120° C. to 125° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([CH2:12][OH:13])[CH:4]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)(=O)C.CCCCCC>ClCCl>[CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([CH:12]=[O:13])[CH:4]=1
Reactant: COc1cc(CO)cc2c1OCO2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(C=O)cc2c1OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
(7-Methoxybenzo[3,4-d]1,3-dioxolan-5-yl)methan-1-ol prepared in Step 4(7.0 g, 38.42 mmol) was dissolved in dichloromethane(150 ml), pyridiniumchlorochromate(16.6 g, 76.84 mmol) was added thereto, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was filtered through cellite, filtered under reduced pressure and the filtrate was concentrated. The residue was subjected to silica gel column chromatography(eluent: ethyl acetate/n-hexane=1/3, v/v) to give the title compound(5.68 g, Yield 82%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:2]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)#[CH:19]>CCCCCCC.CCOC(C)=O>[F:29][C:26]([F:27])([F:28])[C:23]1[CH:24]=[CH:25][C:20]([C:18]#[C:19][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:21][CH:22]=1
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccnc2)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(C#Cc2cccnc2)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid pyridin-3-yl ester and 1-ethynyl-4-trifluoromethyl-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 8:2; yield (87 mg, 70%); 1H NMR δ (CDCl3): 8.75-8.73 (m, 1H), 8.49-8.52 (m, 1H), 7.76-7.73 (m, 1H), 7.49-8.46 (m, 2H), 7.23-7.19 (m, 1H), 6.87-6.84 (m, 2H); LCMS m/z: 247.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:8]=2[CH:9]=O)=[C:4]([N+:19]([O-])=O)[CH:3]=1.[H][H]>O1CCCC1.[Ni]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[O:6][C:7]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:8]=3[CH2:9][NH:19][C:4]=2[CH:3]=1
Reactant: COc1ccc(C=O)c(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)Oc1ccc(Cl)cc1NC2
Yield: 60.1 %

Procedure:
3.50 g of 2-(4-chloro-2-nitrophenoxy)-4-methoxy-benzaldehyde, prepared as described above in Example 5, in tetrahydrofuran (THF) (35 mL) was shaken in a Parr hydrogenator at 5 psi hydrogen with Raney nickel at 25° C. for 6 hours. The catalyst was filtered from the reaction and the solution evaporated in vacuo. The crude product was chromatographed, as described above in Example 2, through silica gel 60 using hexane:ethyl acetate (2:1), and recrystallized from ethanol (3A) to yield 1.79 g (60.1%) of product as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[CH2:10][N:11]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][N:11]([CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: O=C(CN(CCc1ccccc1)Cc1ccccc1)Nc1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Fc1ccc(NCCN(CCc2ccccc2)Cc2ccccc2)cc1

Procedure:
In a manner similar to Preparation 2 react N-(4-fluorophenyl)-2-[(2-phenylethyl)(phenylmethyl)amino]acetamide with lithium aluminum hydride to obtain the title compound.