Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.Br[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.Cl.[CH2:17]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=[O:28])=[CH:22][CH:21]=1)[CH2:18][CH3:19]>O1CCCC1>[F:15][C:11]1[CH:10]=[C:9]([C:27]([CH2:26][C:23]2[CH:24]=[CH:25][C:20]([CH2:17][CH2:18][CH3:19])=[CH:21][CH:22]=2)=[O:28])[CH:14]=[CH:13][CH:12]=1
Reactant: Fc1cccc(Br)c1
Reactant: CCCc1ccc(CC(=O)Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCc1ccc(CC(=O)c2cccc(F)c2)cc1
Temperature: -60 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
In a mixture of 48.9 g (248.8 imol) of (4-propylphenyl)acetylchloride, 2.6 g (7.5 mmol) of tris(2,4-pentanedionata)iron (III), and 200 ml of toluene was added dropwise a solution of a Grignard reagent prepared from 56.6 g (323.5 mmol) of 1-bromo-3-fluorobenzene and 8.2 g (335.9 mmol) of Mg in 300 ml of tetrahydrofuran (THF) while maintaining them at a temperature lower than −60° C. After finishing of the dropping, they were stirred at the same temperature for 3 hours. Subsequently, the reaction mixture was raised up to room temperature, 200 ml of a diluted hydrochloric acid was added dropwise thereto, and then extracted with 150 ml of heptane. The organic layer thus obtained was washed with an aqueous sodium bicarbonate solution thrice and with water thrice, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under a reduced pressure, the residue was subjected to silica gel column chromatography (eluent: toluene/heptane=8/2) to obtain 43.3 g of a crude 3-fluoro-4′-propyldeoxybenzoin. This product was recrystallized from methanol to obtain 28.5 g of the subject compound. (Yield: 44.8%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[CH:15][N:16]=[C:17](Cl)[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH2:21][C@@H:22]([C:25]1[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)[CH2:23][OH:24].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[CH:15][N:16]=[C:17]([NH:21][C@@H:22]([C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)[CH2:23][OH:24])[C:12]=3[CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: COc1ccc([C@H](N)CO)cn1
Reactant: N#Cc1cc(Cl)ccc1N1CCc2ncnc(Cl)c2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc([C@@H](CO)Nc2ncnc3c2CN(c2ccc(Cl)cc2C#N)CC3)cn1

Procedure:
A reaction mixture of 5-chloro-2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzonitrile (250 mg, 0.82 mmol) and (S)-2-amino-2-(6-methoxypyridin-3-yl)ethanol (110 mg, 0.68 mmol) in acetonitrile (3 mL) and N,N-diisopropylethylamine (240 μL, 1.4 mmol) was subjected to microwave irradiation at 180° C. for 4 h. The reaction mixture was concentrated and the residue was purified by silica gel column (0-15% MeOH/CH2Cl2) to yield a crude product which was recrystallized from MeOH to yield colorless crystals.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C@H:11]2[N:21]3[C:22]4[N:13]([C:14](=[O:24])[CH:15]=[N:16][C:17]=4[CH:18]=[CH:19][C:20]3=[O:23])[CH2:12]2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[CH:32]([C:34]1[CH:35]=[C:36]([C:44]#[N:45])[C:37]2[O:42][CH2:41][CH2:40][O:39][C:38]=2[CH:43]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO.C(Cl)Cl.CO>[ClH:1].[O:24]=[C:14]1[CH:15]=[N:16][C:17]2=[C:22]3[N:13]1[CH2:12][C@@H:11]([CH2:10][N:7]1[CH2:8][CH2:9][CH:4]([NH:3][CH2:32][C:34]4[CH:35]=[C:36]([C:44]#[N:45])[C:37]5[O:42][CH2:41][CH2:40][O:39][C:38]=5[CH:43]=4)[CH2:5][CH2:6]1)[N:21]3[C:20](=[O:23])[CH:19]=[CH:18]2
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)cnc4ccc(=O)n2c43)CC1
Reactant: N#Cc1cc(C=O)cc2c1OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: N#Cc1cc(CNC2CCN(C[C@@H]3Cn4c(=O)cnc5ccc(=O)n3c54)CC2)cc2c1OCCO2
Reaction time: 0.25 h
Yield: 69.4 %

Procedure:
A suspension of (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione dihydrochloride (for a preparation see Example 13(k) or 15(d)) (50 mg, 0.100 mmol) in chloroform (4 ml) and methanol (0.121 ml) at rt under nitrogen was treated with triethylamine (0.587 ml, 4.21 mmol) and stirred for 15 min (the suspension turned into a solution). 7-Formyl-2,3-dihydro-1,4-benzodioxin-5-carbonitrile (for a synthesis see WO06014580 Preparation 13 or WO2007122258, Example 31(d)) ((18.95 mg, 0.100 mmol) was then added and the reaction was stirred for 30 min. Sodium triacetoxyborohydride (63.7 mg, 0.301 mmol) was then added and the reaction was stirred for 1 h. LC-MS after 1 h showed some imine intermediate so more sodium triacetoxyborohydride (63.7 mg, 0.301 mmol) was added and the reaction stirred for 2 h. LCMS after this time still showed imine intermediate, More sodium triacetoxyborohydride (63.7 mg, 0.301 mmol) was added and the reaction left stirring overnight (16 h), LCMS after this time showed no starting material. Saturated NaHCO3 (10 mL) was added followed by 20% MeOH/DCM (20 ml) and the aqueous phase was extracted and then separated from the organic layer. The aqueous phase was extracted again with 20% MeOH/DCM (2×20 ml). The combined organic extracts were dried (NaSO4), filtered and evaporated to give crude product. The crude product was purified on a silica column (0-20% MeOH/DCM) to give the free base of the title compound (33 mg, 69.4%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.[C:22]([O:26][C:27](=[O:54])[CH:28]([NH:38][C:39]([C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][CH:48]=2)=[CH:43][CH:42]=1)=[O:40])[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])([CH3:25])([CH3:24])[CH3:23].CCN(CC)CC>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:22]([O:26][C:27](=[O:54])[CH:28]([NH:38][C:39]([C:41]1[CH:42]=[CH:43][C:44]([C:47]2[CH:48]=[CH:49][C:50]([NH:53][C:8](=[O:10])[CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:51][CH:52]=2)=[CH:45][CH:46]=1)=[O:40])[CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])([CH3:23])([CH3:24])[CH3:25]
Reactant: O=C(O)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)CCC(NC(=O)c1ccc(-c2ccc(N)cc2)cc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCC(NC(=O)c1ccc(-c2ccc(NC(=O)Cc3ccccc3)cc2)cc1)C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 12.1 %

Procedure:
A solution of phenylacetic acid (89 mg, 0.65 mmol, 1 equiv) in DMF (10 mL) was added to EDCI (188 mg, 0.98 mmol, 1.5 equiv.). After stirring for 20 min, 2-[(4′-Amino-biphenyl-4-carbonyl)-amino]-pentanedioic acid di-tert-butyl ester (297 mg, 0.65 mmol, 1 equiv.) was added, followed by the addition of Et3N (0.23 mL, 1.64 mmol, 2.5 equiv.) and DMAP (16 mg, 0.13 mmol, 20%). The reaction mixture was allowed to stir at room temperature overnight. Reaction was complete as determined by TLC. DMF was removed and the residue was dissolved in EtOAc. The organic layer was washed with H2O and brine, and then dried over MgSO4. After solvent was evaporated, the crude residue was purified by HPLC to give 45 mg of 2-[(4′-Phenylacetylamino-biphenyl-4-carbonyl)-amino]-pentanedioic acid di-tert-butyl ester in 12% yield. MS (ESI) m/z 573.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].C(N(CC)CC)C>>[C:26]([NH:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(-c2ccccc2)c(-c2ccnc(Nc3ccccc3)n2)s1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(-c2ccccc2)c(-c2ccnc(Nc3ccccc3)n2)s1

Procedure:
A suspension of N-[4-(2-amino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-phenyl-amine (0.25 g, 0.7 mmol), acetic acid anhydride (0.11 mg, 1.1 mmol), triethylamine (0.11 mg, 1.1 mmol) and a catalytic amount of N,N-dimethylaminopyridine is heated at reflux for 18 hours. The volatiles are evaporated under reduced pressure and the product is crystallized by the addition of diethyl ether. Filtering and drying gives the N-[4-(2-acetylamino-4-phenyl-thiazol-5-yl)-pyrimidin-2-yl]-N-phenyl-amine, m.p. >260° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C[N+](C)=CCl.[Cl-].[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH3:26])[C:21]([OH:23])=O)[N:19]=1)=[O:13].Cl.[NH2:28][CH:29]1[C:50](=[O:51])[N:31]2[C:32]([C:37]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=3)=[O:38])=[C:33]([Cl:36])[CH2:34][S:35][C@H:30]12>C(OCC)(=O)C.C[Si](CC(N)=O)(C)C.O>[CH:12]([NH:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH3:26])[C:21]([NH:28][CH:29]2[C:50](=[O:51])[N:31]3[C:32]([C:37]([O:39][CH2:40][C:41]4[CH:42]=[CH:43][C:44]([N+:47]([O-:49])=[O:48])=[CH:45][CH:46]=4)=[O:38])=[C:33]([Cl:36])[CH2:34][S:35][C@H:30]23)=[O:23])[N:19]=1)=[O:13]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Reactant: CON=C(C(=O)O)c1csc(NC=O)n1
Agent: C[N+](C)=CCl
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Yield: 51.8 %

Procedure:
N,(0.16 g.) and phosphorous oxychloride (0.34 g.) were mixed to prepare Vilsmeier reagent in a usual manner, and the resultant Vilsmeier reagent was suspended in dry ethyl acetate. To the suspension was added 2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetic acid (syn isomer, 0.46 g.) under ice-cooling with stirring, and then the solution was stirred at the same temperature for 30 minutes to prepare the activated acid solution. p-Nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride (0.81 g.) was dissolved in a solution of trimethylsilylacetamide (2.10 g.) in ethyl acetate (200 ml.). To the solution was added the activated acid solution obtained above all at once at -20° C., and the solution was stirred at -20°~-5° C. for 1.5 hours. After water and ethyl acetate (100 ml.) were added to the resultant solution at -20° C., the insoluble product was separated by filtration, washed with water and acetone in turn and then dried to give p-nitrobenzyl 7-{2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido}-3-chloro-3-cephem-4-carboxylate (syn isomer, 0.6 g.). After ethyl acetate was removed from the above filtrate, the aqueous layer was extracted with ethyl acetate (50 ml.) twice. The ethyl acetate layer and the extract were combined together, washed with 10% hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn and then dried over magnesium sulfate. After removing ethyl acetate from the solution, diethyl ether was added to the residue. The insoluble product was collected by filtration to give the same object compound (0.25 g.), m.p. 226° to 228° C. (dec.), Total yield 0.85 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][C:22]1[N:23]=[N:24][S:25][C:26]=1[C:27](O)=[O:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:26]3[S:25][N:24]=[N:23][C:22]=3[CH3:21])=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Cc1nnsc1C(=O)O
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: Cc1nnsc1C(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 4-methyl-1,2,3-thiadiazole-5-carboxylic acid, as starting materials, MS (LC/MS): 429.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1/[CH:11]=[CH:12]/[C:13]1[S:14][CH:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=1.O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3](/[CH:11]=[CH:12]/[C:13]2[S:14][CH:15]=[C:16]([CH:18]([CH3:19])[CH3:20])[N:17]=2)[CH:4]=1
Reactant: CC(C)c1csc(/C=C/c2cc([N+](=O)[O-])ccc2Cl)n1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1csc(/C=C/c2cc(N)ccc2Cl)n1
Temperature: 0 °C

Procedure:
A solution composed of 3.0 g of (E)-2-[2-(2-chloro-5-nitrophenyl)ethenyl]-4-(1-methylethyl)thiazole, 8.0 g of tin(II) chloride dihydrate and 100 ml of ethyl alcohol was heated to reflux for 1 hr. The reaction mixture was then condensed to half of its original volume, diluted with ice water, basified with 3N sodium hydroxide and extracted with methylene chloride. The combined extracts were washed with water and brine, dried (MgSO4) and condensed in vacuo to yield (E)-2-[2-(5-amino-2-chlorophenyl)ethenyl]-4-(1-methylethyl)thiazole; m.p. 82°-85° C. from hexane.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([NH2:14])=[C:9]([NH2:15])[CH:8]=1)=[O:4].[N:27]([O-])=O.[Na+].[OH-].[NH4+]>C(O)(=O)C.O>[CH3:1][O:2][C:3]([C@H:5]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]2[NH:14][N:27]=[N:15][C:9]=2[CH:8]=1)=[O:4]
Reactant: COC(=O)[C@@H](Cc1cc(C)c(N)c(N)c1)NC(=O)OCc1ccccc1
Reactant: O=N[O-]
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)[C@@H](Cc1cc(C)c2[nH]nnc2c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
To a solution of benzyl (R)-1-(methoxycarbonyl)-2-(3,4-diamino-5-methylphenyl)ethylcarbamate (250 mg, 0.58 mmol) in acetic acid (6 mL) and water (10 mL) was added a solution of sodium nitrite (40 mg, 0.58 mmol) in water (1 mL), dropwise over several minutes at room temperature. The resulting mixture was stirred at room temperature for 30 min, then cooled to 0° C. A mixture of ammonium hydroxide and water (1:1, 15 mL) was added to adjust pH to 11. The mixture was extracted with ethyl acetate twice. The organic layers washed with brine and dried over sodium sulfate. After filtration, solvents were removed in vacuo and the residue was purified by flash column chromatography (1:1 ethyl acetate/hexanes) on silica gel to afford the title compound as a tan solid (155 mg, 72% yield). 1H-NMR (CDCl3, 300 MHz) δ 7.34 (s, 1H), 7.32-7.28 (m, 6H), 6.93 (s, 1H), 5.40 (d, J=8.1 Hz, 1H), 5.13-5.02 (m, 2H), 4.76-4.69 (m, 1H), 3.73 (s, 3H), 3.28 (dd, J=13.9, 5.5 Hz, 1H), 3.16 (dd, J=13.9, 6.2 Hz, 1H), 2.64 (s, 3H). LC/MS: tR=2.30 min, 369 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:25])[C:5]2[O:9][C:8]([CH2:10][CH2:11][N:12]([CH2:18][CH:19](OC)OC)[C:13](=[O:17])[O:14][CH2:15][CH3:16])=[CH:7][C:6]=2[CH:24]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([Cl:25])[C:5]2[O:9][C:8]3[CH2:10][CH2:11][N:12]([C:13]([O:14][CH2:15][CH3:16])=[O:17])[CH:18]=[CH:19][C:7]=3[C:6]=2[CH:24]=1
Reactant: CCOC(=O)N(CCc1cc2cc(Br)cc(Cl)c2o1)CC(OC)OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)N1C=Cc2c(oc3c(Cl)cc(Br)cc23)CC1
Temperature: 25 °C
Yield: 8.9 %

Procedure:
To a stirred solution of the product of step B (660 mg, 1.52 mmol) in anhydrous dichloromethane (8 mL) at 0° C. was added AlCl3 (810 mg, 6.07 mmol) and the reaction mixture was allowed to warm to ambient temperature over 3 h before being quenched by addition of aqueous sodium bicarbonate solution. The organic layer was separated and the aqueous solution further extracted with dichloromethane (2×20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 9:1 to 1:1 hexanes/ethyl acetate) to give ethyl 9-bromo-7-chloro-4,5-dihydro-3H-benzofuro[2,3-d]azepine-3-carboxylate (50 mg, 9%) as an off-white solid: 1H NMR (CDCl3, 300 MHz) δ 7.56 (d, J=1.7 Hz, 1H), 7.39 (d, J=1.6 Hz, 1H), 7.08-6.82 (m, 1H), 5.88-5.70 (m, 1H), 4.38 (q, J=7.1 Hz, 2H), 3.90 (t, J=5.1 Hz, 2H), 3.26 (t, J=5.0 Hz, 2H), 1.34 (t, J=7.0 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:25])[N:7]2[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([O:23][CH3:24])=[O:22])[CH:15]=1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.ClC1C=CC=C(Cl)C=1N1C2C(=C(C3C=CC(F)=CC=3F)C=C(OC)C=2)CCC1=O>>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:25])[N:7]2[C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([O:23][CH3:24])=[O:22])[CH:15]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: COC(=O)c1ccc(C)c(N2C(=O)CCc3c(Br)cc(OC)cc32)c1
Agent: COc1cc(-c2ccc(F)cc2F)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Product: COC(=O)c1ccc(C)c(N2C(=O)CCc3c(-c4ccccc4Cl)cc(OC)cc32)c1

Procedure:
5-(2-Chlorophenyl)-3,4-dihydro-7-methoxy-1-(3-methoxycarbonyl-6-methylphenyl)-2(1H)-quinolinone was prepared from 5-bromo-3,4-dihydro-7-methoxy-1-(3-methoxycarbonyl-6-methylphenyl)-2(1H)-quinolinone (INTERMEDIATE 16) and 2-chlorophenylboronic acid by a procedure analogous to that described in INTERMEDIATE 2. Mass spectrum (ESI) 436.3 (M+1). 1H NMR (500 MHz, CDCl3): 7.95 (m, 1H); 7.81 (d, J=19.0 Hz, 1H); 7.41 (m, 1H); 7.37 (d, J=8.0 Hz, 1H); 7.27 (m, 2H); 7.21 (m, 1H); 6.35 (s, 1H); 5.76 (s, 1H); 3.81 (s, 3H); 3.55 (s, 3H); 2.65 (m, 4H); 2.11 (d, J=11.5 Hz, 3H).
Reaction SMILES: [C-]#N.[Na+].[CH3:4][NH:5][CH3:6].[C:7]1([C:13]2[C:19]3[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=3[N:17]3[N:25]=[C:26]([CH:28]=[O:29])[N:27]=[C:16]3[CH2:15][N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)(C)C.O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH3:4][N:5]([CH3:6])[C:28]([C:26]1[N:27]=[C:16]2[CH2:15][N:14]=[C:13]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:19]3[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=3[N:17]2[N:25]=1)=[O:29]
Reactant: O=Cc1nc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: CNC
Agent: [Mn+4]
Agent: [C-]#N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(C)O
Product: CN(C)C(=O)c1nc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 0.17 h

Procedure:
2.94 g (0.06 mole) of sodium cyanide is suspended in 100 ml of isopropanol, and 50 ml of a 20% solution of dimethylamine in dioxane added at 0°-5° to the suspension. After 10 minutes, a solution of 4 g (0.0124 mole) of 6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxaldehyde in 50 ml of dioxane is quickly added dropwise, and, after a further 10 minutes, an addition made in two portions of 2.8 g of active manganese dioxide. The whole is stirred for a further 3 hours at 5°, filtered, and the filtrate concentrated in vacuo. After recrystallisation from methylene chloride/hexane, N,N-dimethyl-6-phenyl-8-chloro-4H-s-triazolo[1,5-a][1,4]benzodiazepine-2-carboxamide is obtained, M.P. 135°-137°.
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13]([C:15]1[CH:16]=[C:17]([C:21]2[C:22]([N:42]([CH3:47])[S:43]([CH3:46])(=[O:45])=[O:44])=[CH:23][C:24]3[O:28][C:27]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)=[C:26]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:25]=3[CH:41]=2)[CH:18]=[CH:19][CH:20]=1)=[O:14])(C)(C)C>ClCCCl>[CH2:39]([O:38][C:36]([C:26]1[C:25]2[CH:41]=[C:21]([C:17]3[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=3)[C:13]([OH:14])=[O:12])[C:22]([N:42]([CH3:47])[S:43]([CH3:46])(=[O:45])=[O:44])=[CH:23][C:24]=2[O:28][C:27]=1[C:29]1[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=1)=[O:37])[CH3:40]
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cccc(C(=O)OC(C)(C)C)c3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cccc(C(=O)O)c3)cc12
Yield: 102.2 %

Procedure:
TFA (2 mL, 26.0 mmol) was added to a stirring solution of ethyl 5-(3-(tert-butoxycarbonyl)phenyl)-2-(4-fluorophenyl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxylate (100 mg, 0.176 mmol) in DCE (9 mL) at 25° C. It was allowed to stir for several hours then concentrated to give the titled compound (92 mg, quant). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.05-8.12 (3H, m), 7.92-8.03 (3H, m), 7.65-7.75 (1H, m), 7.53-7.64 (1H, m), 7.44 (2H, t, J=8.91 Hz), 4.33 (2H, q, J=7.03 Hz), 3.12 (3H, s), 2.93 (3H, s), 1.26 (3H, t, J=7.15 Hz). LC-MS retention time: 1.17 min; m/z (MH−): 510. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:13][C:14]1([CH:29]=O)[CH2:18][CH:17]2[CH:19]([CH3:28])[C:20]([N+:25]([O-:27])=[O:26])=[C:21]([CH3:24])[C:22]([CH3:23])=[C:16]2[O:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.O.C(O)(=O)C>[N+:25]([C:20]1[CH:19]([CH3:28])[CH:17]2[CH2:18][C:14]([CH2:13][NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[NH:12][N:11]=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)([CH3:29])[O:15][C:16]2=[C:22]([CH3:23])[C:21]=1[CH3:24])([O-:27])=[O:26]
Reactant: CC1=C2OC(C)(C=O)CC2C(C)C([N+](=O)[O-])=C1C
Reactant: Nc1ccc(-c2ccn[nH]2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CC1=C2OC(C)(CNc3ccc(-c4ccn[nH]4)cc3)CC2C(C)C([N+](=O)[O-])=C1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
0.77 g of 5-(4-aminophenyl)pyrazole and 1.00 g of 2,4,6,7-tetramethyl-5-nitrodihydrobenzofuran-2-aldehyde were dissolved in 33 ml of methylene chloride and 0.5 ml of acetic acid was added, followed by stirring at room temperature for 30 minutes. To the resulting reaction solution, 1.70 g of sodium triacetoxyborohydride was added, followed by stirring at room temperature for 20 hours. After the completion of the reaction, the reaction solution was poured into water, neutralized with an aqueous sodium hydroxide solution and then extracted with chloroform. The organic layer was washed with hydrochloric acid water, neutralized with an aqueous sodium hydroxide solution, and then the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to obtain 1.5 g of the objective product.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)(C)(C)C.[CH3:28][N:29]([CH2:31][C:32]#[CH:33])[CH3:30]>>[CH3:28][N:29]([CH3:30])[CH2:31][C:32]#[C:33][C:13]1[CH:12]=[C:11]2[C:16]([C:7](=[N:6][OH:5])[CH:8]=[C:9]([C:18]3[N:19]=[CH:20][C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:10]2)=[CH:15][CH:14]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Reactant: C#CCN(C)C
Product: CN(C)CC#Cc1ccc2c(=NO)cc(-c3cc4ccccc4cn3)oc2c1

Procedure:
7-(3-dimethylamino-prop-1-ynyl)-2-isoquinolin-3-yl-chromen-4-one oxime was prepared in 20% overall yield using the method described in example 24, starting from 7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (example 2B) and N,N-dimethylamino-2-propyne. The title compound was purified by preparative HPLC (gradient 70-55% Water/acetonitrile+0.05% trifluoroacetic acid) and isolated as an orange solid and as a 85/15 mixture of Z/E oxime isomers.