Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.N1C(F)=NC(F)=NC=1F.[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[CH:20][C:21]2[S:25][C:24]([C:26](O)=[O:27])=[CH:23][C:22]=2[CH:29]=1.[BH4-].[Na+].OS(O)(=O)=O>C(Cl)Cl.CO>[F:30][C:17]([F:16])([F:31])[C:18]1[CH:19]=[CH:20][C:21]2[S:25][C:24]([CH2:26][OH:27])=[CH:23][C:22]=2[CH:29]=1
Reactant: O=C(O)c1cc2cc(C(F)(F)F)ccc2s1
Agent: Fc1nc(F)nc(F)n1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: OCc1cc2cc(C(F)(F)F)ccc2s1
Temperature: -15 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
Pyridine (0.37 ml, 4.72 mmol, 1.5 equiv.) and subsequently cyanuric fluoride (0.53 ml, 6.3 mmol, 2 equiv.) were added to a stirred solution of commercially available 5-(trifluoromethyl)-1-benzothiophene-2-carboxylic acid (776 mg, 3.15 mmol, 1 equiv.) in CH2Cl2 (16 ml), kept under N2, at −20 to −10° C. Precipitation of cyanuric acid occurred and increased gradually as the reaction proceeded. After the mixture was stirred at −20 to −10° C. for 2 h, ice-cold water was added along with 100 ml CH2Cl2. Undissolved solids were filtered off; from the filtrate, the organic phase was separated and the aqueous layer was extracted once more with CH2Cl2 (50 ml). The combined organic layers were washed with ice-cold water (50 ml), dried (Na2SO4) and concentrated under reduced pressure to a small volume (15 ml). NaBH4 (240 mg, 6.3 mmol, 2 equiv.) was added in one portion, and MeOH (6.5 ml) was then added, dropwise, over 15 min at r.t. The reaction mixture was neutralised with 1N H2SO4, and the organic solvents were evaporated under reduced pressure. The residue was taken-up in EtOAc (80 ml) and water (40 ml); the organic layer was separated, and the aqueous layer was extracted with EtOAc (2×60 ml). The combined organic layers were washed with 1N H2SO4 and brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica, using EtOAc/hexane (10-20% gradient) as eluent, to give 400 mg (54.6% yield) of the required product as a white solid. HPLC-MS (method 1) gave one peak with Rt=4.02 min, but no ionization.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:35]=[CH:34][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=O)=[CH:27][CH:26]=3)[N:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].[CH2:36]([S:39]([NH2:42])(=[O:41])=[O:40])[CH:37]=[CH2:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:36]([S:39]([NH:42][C:29](=[O:31])[C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:14]2[N:13]=[C:12]([NH:11][CH2:10][C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:1][CH2:2][CH:3]=[CH2:4])=[CH:35][CH:34]=3)[N:17]=[C:16]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])[N:15]=2)=[CH:33][CH:32]=1)(=[O:41])=[O:40])[CH:37]=[CH2:38]
Reactant: C=CCCOc1ccc(CNc2nc(Nc3ccc(C(=O)O)cc3)nc(OCC(F)(F)F)n2)cc1
Reactant: C=CCS(N)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCOc1ccc(CNc2nc(Nc3ccc(C(=O)NS(=O)(=O)CC=C)cc3)nc(OCC(F)(F)F)n2)cc1
Yield: 84.4 %

Procedure:
4-(4-(4-(but-3-enyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (44 mg, 0.090 mmol), prop-2-ene-1-sulfonamide (13.07 mg, 0.108 mmol), HATU (51.3 mg, 0.135 mmol), and Hunig's Base (0.079 mL, 0.449 mmol) were stirred in DCM (3 mL) for 16 h. The solvent was removed and the crude material was purified by silica gel chromatography using EtOAc to give N-(allylsulfonyl)-4-(4-(4-(but-3-enyloxy)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamide (45 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]1(/[CH:18]=[CH:19]/OB(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.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>[C:12]1(/[CH:18]=[CH:19]/[C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)O/C=C/c1ccccc1
Reactant: COC(=O)c1ccnc(Cl)c1
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: O
Solvent: C1COCCO1
Product: COC(=O)c1ccnc(/C=C/c2ccccc2)c1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a mixture of methyl 2-chloroisonicotinate, Pd(PPh3)4, and [(E)-2-phenylvinyl]boric acid in dioxane was added a 2 M aqueous Na2CO3 solution, followed by stirring at 90° C. for 5 hours. To the reaction mixture was added water, and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgSO4, and the filtrate was then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane:EtOAc) to obtain methyl 2-[(E)-2-phenylvinyl]isonicotinate as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:27])[C@H:10]([NH:13][C:14]1[C:15]2[N:16]([CH:23]=[C:24](Br)[CH:25]=2)[N:17]=[CH:18][C:19]=1[C:20]([NH2:22])=[O:21])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C@H:9]([CH3:27])[C@H:10]([NH:13][C:14]1[C:15]2[N:16]([CH:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:25]=2)[N:17]=[CH:18][C:19]=1[C:20]([NH2:22])=[O:21])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](OCc1ccccc1)[C@@H](CO)Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: C[C@@H](OCc1ccccc1)[C@@H](CO)Nc1c(C(N)=O)cnn2cc(-c3ccccc3)cc12
Temperature: 100 °C
Yield: 73.3 %

Procedure:
A mixture of 4-(((2R,3R)-3-(benzyloxy)-1-hydroxybutan-2-yl)amino)-6-bromopyrrolo[1,2-b]pyridazine-3-carboxamide (2.98 g, 6.88 mmol), phenylboronic acid (1.677 g, 13.75 mmol), palladium (II) acetate (0.309 g, 1.375 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbyphenyl (1.311 g, 2.75 mmol) and potassium phosphate, tribasic, 2M (20.63 mL, 41.3 mmol) in dioxane (50 mL) was heated to 100° C. for 1 hr. After cooling to rt, the reaction mixture was filtered through a celite and the filtrate was partitioned between EtOAc (200 ml) and water (200 ml). The organic layer was washed with brine (150 ml), dried (MgSO4) and concentrated to afford a brown solid that was triturated with ether. Filtration and drying afforded 4-(((2R,3R)-3-(benzyloxy)-1-hydroxybutan-2-yl)amino)-6-phenylpyrrolo[1,2-b]pyridazine-3-carboxamide (2.17 g, 5.04 mmol, 73.3% yield) as a tan solid. 1H NMR (400 MHz, CD3OD) δ 8.16-8.11 (m, 1H), 7.94 (d, J=1.8 Hz, 1H), 7.73-7.67 (m, 2H), 7.45-7.21 (m, 9H), 4.76 (d, J=11.9 Hz, 1H), 4.56 (d, J=11.9 Hz, 1H), 4.44-4.33 (m, 1H), 4.09 (qd, J=6.3, 2.8 Hz, 1H), 3.96-3.83 (m, 2H), 1.31 (d, J=6.4 Hz, 3H). MS (ES+) m/z: 431.1 (M+H); LC retention time: 2.858 min (analytical HPLC Method B).
Reaction SMILES: O.NN.[N+:4]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[N:11][CH:12]=1)([O-])=O.[CH2:19](O)C>[Pd]>[NH2:4][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:11][CH:12]=1
Reactant: CCO
Reactant: O=C(O)CCCc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Agent: NN
Solvent: O
Product: COC(=O)CCCc1ccc(N)cn1
Reaction time: 1 h

Procedure:
Hydrazine hydrate (10 ml) in ethanol (20 ml) was added over 30 minutes to a stirred suspension of 4-(5-nitropyrid-2-yl)butanoic acid (7.5 g, 0.036 mole) and 10% palladium on carbon (1 g) in ethanol (100 ml). The solution was stirred for 1 hour, filtered through hyflo and the filtrate was evaporated to dryness. The residue was dissolved in methanol (250 ml) containing concentrated sulphuric acid (20 ml) and the resulting solution was refluxed for 4 hours, cooled and the solvent was removed under reduced pressure. The residue was dissolved in water (100 ml), basified and extracted with chloroform (3×100 ml). The chloroform extracts were combined, dried over magnesium sulphate, and evaporated to dryness. The residue was distilled in a kugelrohr apparatus (oven temp. 145° C. at 0.05 mmHg) to give the title compound 3.84 g as a straw coloured oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](Cl)=[O:8])[N:4]=[CH:3]1.[NH2:10][C:11]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[C:24]3[C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[O:37][CH3:38])=[N:29][N:28]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:25]3=[N:26][CH:27]=2)=[CH:18][C:12]=1[C:13]([N:15]([CH3:17])[CH3:16])=[O:14].N1C=CC=CC=1.ClCCl.C(O)C(N)(CO)CO>ClCCl>[CH3:17][N:15]([CH3:16])[C:13]([C:12]1[CH:18]=[C:19]([C:22]2[CH:23]=[C:24]3[C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[O:37][CH3:38])=[N:29][N:28]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:44])([CH3:46])[CH3:45])[C:25]3=[N:26][CH:27]=2)[CH:20]=[CH:21][C:11]=1[NH:10][C:7]([C:5]1[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=1)=[O:8])=[O:14]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3ccc(N)c(C(=O)N(C)C)c3)cc12
Reactant: Cn1cnc(C(=O)Cl)c1
Agent: NC(CO)(CO)CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3ccc(NC(=O)c4cn(C)cn4)c(C(=O)N(C)C)c3)cc12
Reaction time: 16 h
Yield: 51.7 %

Procedure:
1-Methyl-1H-imidazole-4-carbonyl chloride (0.579 mmol) was suspended in dichloromethane (4 mL) and a solution of 2-amino-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide (150 mg, 0.289 mmol) in 20% v/v pyridine/dichloromethane (1.0 mL) was added. After 16 h, PS-trisamine (Argonaut Technologies, Inc.) was added (3.0 eq. relative to acid chloride) and the suspension was filtered 3 hours later and the resin was rinsed with dichloromethane. After concentration of the filtrates in vacuo, the resulting residue was purified by silica gel chromatography to afford 1-methyl-1H-imidazole-4-carboxylic acid {2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-amide (93.5 mg, 50.5%). MS: m/z 640 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH2:16][C:17]#[CH:18])[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([O:11]C)[CH:8]=2)[C:3]1=[O:15].[ClH:19].N1C=CC=CC=1>O>[Cl:19][C:17](=[CH2:18])[CH2:16][C:2]1([CH3:1])[CH2:10][C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([OH:11])[CH:8]=2)[C:3]1=[O:15]
Reactant: C#CCC1(C)Cc2cc(OC)c(Cl)c(Cl)c2C1=O
Reactant: Cl
Solvent: c1ccncc1
Solvent: O
Product: C=C(Cl)CC1(C)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Temperature: 185 °C

Procedure:
A stirred mixture of 2methyl-2-propargyl-5-methoxy-6,7-dichloro-1-indanone (11 g., 0.039 mole) and pyridine hydrochloride (110 g.) is heated at 185°C. for one hour, then poured into water (500 ml.). The product which separates is recrystallized from ethanol-water affording 6.5 g. of 2-(2-chloroallyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone, m.p. 183°C.
Reaction SMILES: C([Li])CCC.CN1CCNCC1.[C:13]1([C:19]2[C:20]([CH:24]=[O:25])=[CH:21][O:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([Li])(CC)C.Cl[Si:32]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:33][CH3:34]>CCCCCC.O1CCCC1.C1CCCCC1>[C:13]1([C:19]2[C:20]([CH:24]=[O:25])=[CH:21][O:22][C:23]=2[Si:32]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:33][CH3:34])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC[Si](Cl)(CC)CC
Reactant: O=Cc1cocc1-c1ccccc1
Agent: CN1CCNCC1
Agent: [Li]C(C)CC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1occ(C=O)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (a 1.42M solution in hexane, 2.33 ml, 3.31 mmol) was added to a solution of 1-methylpiperazine (331 mg. 3.31 mmol) in tetrahydrofuran (15 ml) at 0 degrees under argon. After 15 minutes the solution was cooled to -78 degrees and 4-phenyl-3-furaldehyde (517 mg, 3.01 mmol) was added. This mixture was warmed to 0 degrees and stirred for 15 minutes, then recooled to -78 degrees before sec-butyllithium (a 1.3M solution in cyclohexane, 2.77 ml, 3.61 mmol) was added dropwise. This solution was stirred 12 hours at -78 degrees C. before chlorotriethylsilane (1.81 g, 12.02 mmol) was added. The mixture was allowed to warm gradually to room temperature and stirred an additional 11/2 hours. The reaction was quenched with ice-cold 5% (V/V) hydrochloric acid and the organics were extracted into ethyl ether. The combined fractions were washed with saturated sodium bicarbonate, H2O and brine. Evaporation of the dried (magnesium sulfate) extracts gave an oil which was purified by flash chromatography on silica using 10% ethyl acetate/hexanes to give the title aldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[C:5]([O:10][CH3:11])=[N:6][C:7]=1[NH:8][CH3:9].[NH2:15][C@H:16]1[CH2:22][N:21]([CH2:23][CH3:24])[CH2:20][CH2:19][N:18]([CH3:25])[CH2:17]1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([NH:15][C@H:16]2[CH2:22][N:21]([CH2:23][CH3:24])[CH2:20][CH2:19][N:18]([CH3:25])[CH2:17]2)=[O:14])[C:5]([O:10][CH3:11])=[N:6][C:7]=1[NH:8][CH3:9]
Reactant: CCN1CCN(C)C[C@@H](N)C1
Reactant: CNc1nc(OC)c(C(=O)O)cc1Br
Solvent: CN(C)C=O
Product: CCN1CCN(C)C[C@@H](NC(=O)c2cc(Br)c(NC)nc2OC)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
A liquid mixture of 18.0 g of 5-bromo-2-methoxy-6-methylamino-3-pyridinecarboxylic acid, 11.7 g of N,N'-carbonyldiimidazole and 50 ml of dimethylformamide was stirred for at room temperature 8 hours. To the reaction mixture then 13.0 g of (R)-6-amino-1-ethyl-4-methylhexahydro-1H-1,4-diazepine was added, followed by 15 hours' stirring at room temperature. The reaction mixture was concentrated under reduced pressure, and to which an aqueous 2N sodium hydroxide solution was added, followed by extraction with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with chloroform-methanol (15:1) and recrystallized from diethyl ether to provide 19.6 g of (R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6-methylamino-3-pyridinecarboxamide 1/4 hydrate (m.p. 52-55° C.).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:6][CH:5]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH2:18]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:11])=[CH:8][CH:9]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccccc1)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
NaH (60% in mineral oil, 1.2 g, 30 mmol) was added to an ice-cooled solution of (4-hydroxy-phenyl)-phenyl-methanone (5 g, 25.2 mmol) in DMF (25 mL). The resulting mixture was stirred for 20 minutes at room temperature (r.t.). Benzyl bromide (6.1 mL, 50 mmol) was added at 0° C. The reaction temperature was raised to r.t. after 1 h and thereafter stirred for additional 2 h. Water (20 mL) was added and the aqueous phase was extracted with dichloromethane (2×30 mL). The combined organic phase was concentrated and purified by flash chromatography (eluent: 100% dichloromethane). Yield: 7.0 g, 96% of 1. 1H NMR (400 MHz, CDCl3): δ 7.83 (d, J=8.4 Hz, 2H), 7.77 (d, J=7.2 Hz, 2H), 7.58-7.52 (m, 1H), 7.50-7.32 (m, 7H), 7.03 (d, J=8.4 Hz, 2H), 5.17 (s, 2H).
Reaction SMILES: [C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=O)[CH:10]=2)[NH2:2].C(=O)(O)[O-].[Na+].Cl.[C:30]1([NH:36][C:37](=[O:40])[NH:38][NH2:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CO>[C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=[N:39][NH:38][C:37]([NH:36][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:40])[CH:10]=2)[NH2:2]
Reactant: NNC(=O)Nc1ccccc1
Reactant: NC(=O)OCC1c2c(O)cc(C=O)cc2N2CC3NC3C1(O)O2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: NC(=O)OCC1c2c(O)cc(C=NNC(=O)Nc3ccccc3)cc2N2CC3NC3C1(O)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
To a solution of 4-formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (50 mg) in methanol (5 ml) were added sodium bicarbonate (27 mg) and 4-phenylsemicarbazide hydrochloride (59 mg). The mixture was stirred for 1 hour at ambient temperature and evaporated in vacuo. The residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (3:1, v/v) to afford 6,9-dihydroxy-4-(4-phenylsemicarbazonomethyl)-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (64 mg).
Reaction SMILES: CC1C(NC(C2SC=CC=2)=O)=C(C2C=CC=CC=2)NN=1.[CH2:21]([N:28]1[C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:31]([NH:39][C:40]([CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=O)[C:30]([CH3:48])=[N:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>P(Cl)(Cl)(Cl)=O>[CH2:21]([N:28]1[C:32]2[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:40]([CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[N:39][C:31]=2[C:30]([CH3:48])=[N:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1nn(Cc2ccccc2)c(-c2ccccc2)c1NC(=O)C1CCCCC1
Agent: Cc1n[nH]c(-c2ccccc2)c1NC(=O)c1cccs1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nn(Cc2ccccc2)c2c1nc(C1CCCCC1)c1ccccc12
Temperature: 120 °C

Procedure:
To a suspension of 462 mg of cyclohexanecarboxylic acid (1-benzyl-3-methyl-5-phenyl-1H-pyrazol-4-yl)-amide thiophene-2-carboxylic acid (3-methyl-5-phenyl-1H-pyrazol-4-yl)-amide in 5.6 mL of phosphorous oxychloride was added 2.57 g of phosphorous pentoxide and the resulting suspension was heated at 120° C. for 5 h. The reaction mixture was cooled to rt and quenched with the addition of ice and water and then neutralized with solid sodium carbonate. The aqueous mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by means of MPLC (12 g SiO2, 40% EtOAc:Heptane) to give the title compound as a tan solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:26][CH2:27][CH3:28])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[N:18]([CH2:22][O:23][CH2:24][CH3:25])[CH:19]=[CH:20][N:21]=2)[CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:6])[CH2:2][CH3:3].[OH-].[Li+]>O1CCCC1.CO.O>[CH2:26]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[N:18]([CH2:22][O:23][CH2:24][CH3:25])[CH:19]=[CH:20][N:21]=2)[CH:16]=1)[C:10]([OH:12])=[O:11])=[O:6])[CH2:27][CH3:28]
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2nccn2COCC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2nccn2COCC)c1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
To a stirred solution of the ester from step 1 (756 mg, 1.95 mmol) in 2:1:1 tetrahydrofuran/methanol/water (12 mL) is added lithium hydroxide (170 mg, 4 mmol). The reaction mixture is stirred at room temperature for 42 h, and concentrated under reduced pressure. The residue is partitioned between water (10 mL) and chloroform (10 mL). The aqueous layer is acidified to pH 4-5 with 1 N hydrochloric acid and extracted with 3:1 chloroform/2-propanol (3×30 mL). The combined organic layers are dried (sodium sulfate), filtered, and concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, CD3OD) δ 8.51 (s, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.49 (s, 1H), 7.17 (s, 1H), 5.39 (s, 2H), 3.62 (q, J=7 Hz, 2H), 3.51 (m, 2H), 3.27 (m, 2H), 1.72 (m, 2H), 1.59 (m, 2H), 1.21 (t, J=7 Hz, 3H), 1.00 (m, 3H), 0.75 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2C2C=CC(C([O-])=O)=CC=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:13])[CH2:11][CH3:12].[OH-:29].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([OH:29])=[CH:16][CH:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:13])[CH2:11][CH3:12]
Reactant: [OH-]
Reactant: CCC(C)COc1ccc(-c2ccccc2-c2ccc(C(=O)[O-])cc2)cc1Br
Agent: [Na+]
Solvent: CCO
Product: CCC(C)COc1ccc(-c2ccc(O)cc2)cc1Br

Procedure:
A mixture of 3'-bromo-4'-(2-methylbutyloxy)-4-biphenylylbenzoate (4.8 g) from step (IV), a 40% aqueous solution (3.2 g) of NaOH and ethanol (100 ml) was heated under reflux for 3 hours, followed by distilling off ethanol, adding toluene, acidifying with 6N hydrochloric acid, heating to dissolve insolubles, separating the solution layer, washing with water, further washing with an aqueous solution of sodium hydrogen sulfite, washing with water to make the solution neutral, drying, distilling off toluene and recrystallizing the residue from n-heptane to obtain 3'-bromo-4'-(2-methylbutyloxy)-4-hydroxybiphenyl (3.0 g). M.p.: 75°~76.5° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3]1=[O:22].Br[CH:24]([CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26]>>[CH2:28]([O:27][C:25]([CH:24]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][N:4]([CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C:3]1=[O:22])[CH2:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:26])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCOC(=O)C(Br)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN1CC(c2cccs2)SCC(N)C1=O
Product: CCCCOC(=O)C(CCc1ccccc1)NC1CSC(c2cccs2)CN(CC(=O)OC(C)(C)C)C1=O

Procedure:
Following the procedure described in Example 42(h), 0.40 g of t-butyl α-[6-amino-5-oxo-2-(2thienyl)perhydro-1,4-thiazepin-4-yl]acetate [prepared as described in Example 49(g)] was N-alkylated using 0.52 g of butyl 2-bromo-4-phenylbutyrate. The resulting product was subjected to silica gel column chromatography eluted with a 1:20 by volume mixture of ethyl acetate and methylene chloride, to separate it into two isomers, A and B, (ascribed to the asymmetric carbon atom to which the phenethyl group is attached).