Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=2[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:6](=[O:9])[CH2:7][N:8]=1.CC(C)([O-])C.[K+].N1C2C=CC=CC=2C=CC=N1.[Cl:41][C:42]1[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:43]=1[CH2:44]Br>O1CCCC1>[Cl:1][C:2]1[C:3]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=2[N:5]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)[C:6](=[O:9])[CH:7]([CH2:44][C:43]2[CH:46]=[CH:47][C:48]([F:50])=[CH:49][C:42]=2[Cl:41])[N:8]=1
Reactant: COc1ccc(CN2C(=O)CN=C(Cl)c3cc(Cl)ccc32)cc1
Reactant: Fc1ccc(CBr)c(Cl)c1
Agent: C1=Cc2ccccc2NN=C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)C(Cc3ccc(F)cc3Cl)N=C(Cl)c3cc(Cl)ccc32)cc1
Temperature: -78 °C
Reaction time: 0.03 h
Yield: 33.5 %

Procedure:
5,7-Dichloro-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (0.85 g, 3.82 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL) and cooled to −78° C. under nitrogen. Potassium tert-butoxide (0.48 g, 3.82 mmol) was dissolved in anhydrous tetrahydrofuran (4 mL) and added to the benzodiazepine via syringe. After 2 minutes, a solution of the 2-chloro-4-fluorobenzyl bromide (1.27 g, 3.64 mmol) in anhydrous tetrahydrofuran (3 mL) was added. The reaction mixture was stirred at −78° C. for 2 then allowed to warm to room temperature over 1 h. The reaction was quenched with water and the layers partitioned. The organic layer was evaporated onto silica gel and chromatographed eluting with 10-35% ethyl acetate in hexanes to obtain 5,7-dichloro-3-(2-chloro-4-fluorobenzyl)-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (0.6 g, 1.22 mmol).
Reaction SMILES: [CH:1]1[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=2[CH:4]=[C:3]2[C:12]([O:14][C:15](=[O:16])[C:2]=12)=[O:13])=[O:8].C(N(C(C)C)CC)(C)C.[O:26]([C:33]1[CH:34]=[C:35]([CH:48]=[CH:49][CH:50]=1)[CH2:36][NH:37][C@@H:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:41][CH2:40][CH2:39]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH3:51][OH:52]>>[CH3:51][O:52][C:7]([C:6]1[CH:1]=[C:2]([C:15]([N:37]([CH2:36][C:35]2[CH:48]=[CH:49][CH:50]=[C:33]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:34]=2)[C@@H:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH2:41][CH2:40][CH2:39]2)=[O:16])[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]=1[C:10]([OH:9])=[O:11])=[O:8]
Reactant: CO
Reactant: O=c1oc(=O)c2cc3c(=O)oc(=O)c3cc12
Reactant: c1ccc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C(=O)N(Cc2cccc(Oc3ccccc3)c2)[C@H]2CCCc3ccccc32)c(C(=O)O)cc1C(=O)O
Yield: 21 %

Procedure:
1,2,4,5-Benzenetetracarboxylic dianhydride (13.8 mmol), diisopropylethyl amine, N-(3-phenoxybenzyl)-N-[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amine and methanol were processed as described in Example 100. The residue was purified by flash chromatography (silica gel, 95:5 CH2Cl2:methanol to 8:2 CH2Cl2:methanol) to provide the title compounds as an off-white solid (120 mg, 21% yield).
Reaction SMILES: [NH2:1]CCN1CCOCC1.C=C1OC(=O)C1.[O:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][NH:24][C:25](=[O:30])[CH2:26][C:27]([CH3:29])=O)[CH2:18][CH2:17]1.[N+:31]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][C:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=O)[CH:37]=[CH:38][CH:39]=1)([O-:33])=[O:32].C([O-])(=O)C.[NH4+]>C(C(C)=O)C(C)C>[O:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][NH:24][C:25]([C:26]2[C:27]([CH3:29])=[N:1][C:42]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[CH:41][C:40]=2[C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([N+:31]([O-:33])=[O:32])[CH:35]=2)=[O:30])[CH2:18][CH2:17]1
Reactant: NCCN1CCOCC1
Reactant: CC(=O)CC(=O)NCCN1CCOCC1
Reactant: O=C(C=Cc1cccc([N+](=O)[O-])c1)c1ccccc1
Agent: C=C1CC(=O)O1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)CC(C)C
Product: Cc1nc(-c2ccccc2)cc(-c2cccc([N+](=O)[O-])c2)c1C(=O)NCCN1CCOCC1

Procedure:
A solution of N-(2-aminoethyl)morpholine (170.5 g) in methyl isobutyl ketone (200 ml) was added portionwise to a solution of diketene (102 ml) in methyl isobutyl ketone (1.3 l) at -30° to -10° C. under stirring and the mixture was stirred at -10° to 0° C. for one hour. To the resultant solution containing N-(2-morpholinoethyl)acetoacetamide, was added 3-(3-nitrophenyl)-1-phenyl-2-propen-1-one (220.4 g) and ammonium acetate (100 g) and the mixture was stirred at 80° C. for 4.5 hours. The reaction mixture was washed with water and dried over magnesium sulfate. To he filtrate containing 1,4-dihydro-3-(2-morpholinoethylcarbamoyl)-2-methyl-4-(3-nitrophenyl)-6-phenylpyridine was added manganese dioxide (700 g) and the resultant mixture was stirred at 80° C. for 2 hours. Manganese dioxide was filtered off and the filtrate was evaporated in vacuo. A mixture of ethyl acetate and water was added to the residue and adjusted to pH 1.0 with 10% hydrochloric acid. The separated aqueous layer was adjusted to pH 9.0 with 20% aqueous potassium carbonate and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was recrystallized from ethanol to give 3-(2-morpholinoethyl-carbamoyl)-2-methyl-4-(3-nitrophenyl)-6-phenylpyridine (154 g), which was identified as the compound of Examples 9-(2) and 24-(3) by their physical data.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][C:4](=O)[CH2:3]1.[C:15]([NH:17][C:18]([NH2:20])=[NH:19])#[N:16].NC1N=C(N)C2C[C@@H](C3C=CC=CC=3)[C@H](C)CC=2N=1>C(O)C>[NH2:16][C:15]1[C:3]2[CH:2]([CH3:1])[CH:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:6][CH2:5][C:4]=2[N:19]=[C:18]([NH2:20])[N:17]=1
Reactant: N#CNC(=N)N
Reactant: CC1CC(=O)CCC1c1ccccc1
Agent: C[C@@H]1Cc2nc(N)nc(N)c2C[C@H]1c1ccccc1
Solvent: CCO
Product: CC1c2c(N)nc(N)nc2CCC1c1ccccc1
Yield: 13.8 %

Procedure:
The mixture of these isomers was prepared in a manner analogous to that of Example 1, using 7.0 grams (0.037 mole) of 3-methyl-4-phenylcyclohexanone and 3.4 grams (0.040 mole) of cyanoguanidine in ethoxyethoxy)ethanoethoxyethoxy)ethanol, yielding 1.3 grams of diamino-5-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline and cis/trans-2,4-diamino-7-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline. The NMR spectrum was consistent with the proposed structures. The cis/trans -2,4-diamino-5-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline is separated from cis/trans-2,4-diamino-7-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline by reverse phase high pressure liquid chromatography. The cis and trans geometric isomers of 2,4-diamino-5-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline and the cis and trans geometric isomers of 2,4-diamino-7-methyl-6-phenyl-5,6,7,8-tetrahydroquinazoline are also separated by reverse phase high pressure liquid chromatography.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[CH2:15](O)[CH:16]=[CH2:17]>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:17][CH:16]=[CH2:15])=[O:7])=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: O=C(O)c1ccc(O)cc1C(F)(F)F
Reactant: C=CCO
Agent: O=S(=O)(O)O
Product: C=CCOC(=O)c1ccc(O)cc1C(F)(F)F
Yield: 59 %

Procedure:
In a manner analogous to Example 1(a) starting with 2 g (9.7 mmoles) of 4-hydroxy-2-trifluoromethylbenzoic acid treated at 100° C. for 12 hours with 20 ml of allyl alcohol and 260 μl of concentrated sulfuric acid, give 1.4 g (59% yield) of the expected ester having a melting point of 82°-83°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][NH2:11])=[CH:5][CH:4]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].Cl>C(OCC)(=O)C.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[N:12]([CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[C:23](=[O:24])[NH:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(CCN[C@@H](CN)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CCN2C(=O)NC[C@H]2c2ccc(OC)cc2)cc1
Yield: 96.9 %

Procedure:
A solution of 1-(R)-(4-methoxyphenyl)-N1-[2-(4-methoxy-phenyl)ethyl]ethane-1,2-diamine (446 g, 1.48 mol) in ethyl acetate (2.25 L) is placed in a water bath and 1,1′-carbonyldiimidazole (264 g, 1.62 mol) is added in portions. The reaction is then heated to reflux for 1.5 hours after which the solution is cooled, treated with 1N HCl (2×1.5 L), brine (2×1.5 L), dried over Na2SO4 and set aside in the cold. After standing the precipitate which forms is removed by filtration and the solvent removed under reduced pressure to afford 468 g (96% yield) of the desired product. Chiral HPLC of the product thus obtained to have 99.5% of the desired (R) enantiomer present.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([OH:13])[CH2:11][NH2:12].[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:17][CH:16]=1.C(N(CC)CC)C.O>CS(C)=O>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][NH:12][CH2:11][CH:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[OH:13])=[CH:17][CH:16]=1
Reactant: Cc1ccc(CCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: NCC(O)c1cc2ccccc2o1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(CCCNCC(O)c2cc3ccccc3o2)cc1

Procedure:
A mixture of 2-(2-benzofuranyl)-2-hydroxyethanamine (1.75 g), 3-(4-methylphenyl)-1-(4-methylphenylsulphonyloxy) propane (3.0 g) and triethylamine (1.5 g) was stirred in dimethylsulphoxide for 2 days at ambient temperature. The mixture was poured into water, extracted with ether and the ether layers dried. Removal of the solvent gave an oil which was crystallised and recrystallised from ether to give N-[3-(4-methylphenyl)propyl]-2-(2-benzofuranyl)-2-hydroxyethanamine m.p. 118°-119°.
Reaction SMILES: ClN1C(=O)CCC1=O.[CH2:9]([N:13]1[C:18]([NH:19][NH:20][C:21]([NH:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=S)=[CH:17][C:16](=[O:30])[N:15]([CH2:31][CH2:32][CH3:33])[C:14]1=[O:34])[CH2:10][CH2:11][CH3:12].CCCCCC>C(Cl)(Cl)Cl>[CH2:9]([N:13]1[C:18]2[NH:19][N:20]=[C:21]([NH:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:17]=2[C:16](=[O:30])[N:15]([CH2:31][CH2:32][CH3:33])[C:14]1=[O:34])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCn1c(NNC(=S)NCC(=O)OCC)cc(=O)n(CCC)c1=O
Agent: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CCCCn1c(=O)n(CCC)c(=O)c2c(NCC(=O)OCC)n[nH]c21
Reaction time: 1 h

Procedure:
To a stirred suspension of N-chlorosuccinimide (6.5 g) in chloroform (80 ml) was added in portions 1-butyl-6-(4-ethoxycarbonylmethylthiosemicarbazido)-3-propylpyrimidine-2,4(1H,3H)-dione (18 g) under ice-cooling. The mixture was stirred for one hour, followed by addition of hexane (200 ml) to give an insoluble product. The insoluble product was filtered off.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])(=O)C.[Na+].CCOC(C)=O>[Pd].CO>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Oc3ccc(F)cc3)ccc2c1O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCOC(=O)c1ncc2cc(Oc3ccc(F)cc3)ccc2c1O
Reaction time: 2.5 h
Yield: 97.1 %

Procedure:
A mixture of 1-Bromo-7-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (4.34 g, 10 mmol, see example A-75d), sodium acetate (984 mg, 12 mmol), Pd/C (2.0 g, 10 wt % Pd, 50 wt % water), EtOAc (400 ml) and MeOH (200 ml) was stirred under an H2-atmosphere at ambient pressure and temperature for 2.5 h before the mixture was filtered through a plug of celite. The celite was washed with EtOAc (500 ml). The combined organic phases were concentrated in vacuo. To the residue was added a half concentrated NaHCO3 solution (50 ml) and the mixture was extracted with CH2Cl2 (1×200 ml). The organic phase was dried over MgSO4 and concentrated in vacuo to yield the title compound as a tan oil (3.45 g); MS-(+)-ion M+1=356.1.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH2:25]([O:32][C:33]([NH:35][C@H:36]([C:52](O)=[O:53])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH:40][CH:39]=1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Br.[CH3:56][O:57][C:58](=[O:63])[C@@H:59]([CH3:62])[NH:60][CH3:61]>O1CCCC1>[CH3:56][O:57][C:58](=[O:63])[C@@H:59]([CH3:62])[N:60]([C:52](=[O:53])[C@H:36]([CH2:37][C:38]1[CH:39]=[CH:40][C:41]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)=[CH:42][CH:43]=1)[NH:35][C:33]([O:32][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:34])[CH3:61]
Reactant: CN[C@H](C)C(=O)OC
Reactant: O=C(N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O)OCc1ccccc1
Agent: Br
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](C)N(C)C(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
Diisopropylethylamine (1.29 g.), then diphenylphosphinic chloride (2.37 g.), were added to a solution of N-benzyloxycarbonyl-O-benzyl-L-tyrosine (4.05 g.) in tetrahydrofuran (30 ml.) maintained at -20° C., and the mixture was stirred at that temperature for 10 minutes. A solution of N-methyl-D-alanine methyl ester hydrobromide (1.98 g.) in tetrahydrofuran (20 ml.) was then added, followed by diisopropylethylamine (1.29 g.). The mixture was stirred for two hours at 0° C., then overnight at room temperature, then filtered, stripped of volatiles and distributed between ethyl acetate and aqueous citric acid (5%). The ethyl acetate layer was washed with water, saturated aqueous sodium bicarbonate, water again and saturated aqueous sodium chloride, then dried over magnesium sulfate and concentrated to a yellow gum (about 6 g.). Purification of the yellow gum by high pressure liquid chromatography on silica gel (350 g.) using hexaneethyl acetate (7:3) as the eluant afforded (N-benzyloxycarbonyl-O-benzyl-L-tyrosyl)-N-methyl-D-alanine methyl ester as a clear gum (3.2 g.) containing about a one-sixth molar amount of ethyl acetate as shown by NMR spectral analysis.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:6])#[N:2].[C:25](C(N)(S)C)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C.[C:48](#[N:50])C>>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23][CH2:24][CH2:48][NH:50][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:6])#[N:2]
Reactant: CC(C)(C)OC(=O)C(C)(N)S
Reactant: CC#N
Reactant: CSc1ccc(S(=O)(=O)C[C@@H]2CCCC[C@H]2C(=O)NCC#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCSc1ccc(S(=O)(=O)C[C@@H]2CCCC[C@H]2C(=O)NCC#N)cc1
Temperature: 25 °C

Procedure:
To a solution of trans-N-cyanomethyl-2-(4-methylsulfanylbenzenesulfonylmethyl)-cyclohexanecarboxamide (0.37 g, 1.09 mmol) in acetonitrile (20 mL) were added Boc-aminoethanethiol (0.369 mL, 2.18 mmol) and cesium carbonate (0.713 g, 2.18 mmol). The reaction mixture was heated at reflux for 12 h, and cooled to room temperature. Ethyl acetate (100 mL) was added. The solution was filtered through Celite, concentrated, and purified on a short plug of silica gel (20-50% ethyl acetate/dichloromethane) to yield the desired product. MS [ESI, (M+Na)+] m/z=518 amu.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH:10]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][CH:12]=[CH2:13])[CH:5]=[CH:6][CH:7]=1.[CH2:23]([NH:30][OH:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O.C(OCC)(=O)C>C1COCC1>[CH2:23]([N:30]1[C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[CH2:9][CH:10]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][CH:12]2[CH2:13][O:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C=CCC(CC(=O)c1cccc(Br)c1)O[Si](C)(C)C(C)(C)C
Reactant: ONCc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC1CC2CON(Cc3ccccc3)C2(c2cccc(Br)c2)C1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(3-bromophenyl)-3-(tert-butyldimethylsilyloxy)hex-5-en-1-one (6.84 g, 17.8 mmol) and N-benzylhydroxylamine (2.86 g, 23.2 mmol) in THF (60 mL) is added Ti(OEt)4 (8.14 g, 35.7 mmol). The reaction mixture is heated to 70° C. in a sealed tube. After 2 h, the temperature is increased to 80° C. and stirring is continued for 3 days. The reaction mixture is cooled to room temperature. Water and ethyl acetate are added and the mixture is stirred vigorously for 15 minutes. The solids are allowed to settle and the organic and aqueous layers are decanted through a pad of diatomaceous earth. The layers are separated and the aqueous layer is extracted three times with ethyl acetate. The combined organic layers are washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified by silica gel chromatography eluting with 0% to 20% ethyl acetate in hexanes gradient over 20 minutes to give the title compound as a diastereomeric mixture (7.42 g, 85%). ES/MS m/e (79Br/81Br) 488, 490 (M+1).
Reaction SMILES: [CH2:1]([O:11][C:12]1[N:17]=[C:16]([F:18])[C:15](B(O)O)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Br[C:23]1[S:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:26][N:27]=1>C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.C(O)C.O.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>[CH2:1]([O:11][C:12]1[N:17]=[C:16]([F:18])[C:15]([C:23]2[S:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:26][N:27]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccc(B(O)O)c(F)n1
Reactant: Brc1nnc(-c2ccccc2)s1
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: CCO
Solvent: Cc1ccccc1
Product: CCCCCCCCCCOc1ccc(-c2nnc(-c3ccccc3)s2)c(F)n1
Yield: 81.6 %

Procedure:
(6-Decyloxy-2-fluoropyrid-3-yl)boronic acid (3.7 g, 12.4 mmol) and 2-bromo-5-phenyl-1,3,4-thiadiazole (1.0 g, 4.15 mmol) are refluxed for 6 hours in a mixture of sodium carbonate (3.95 g), toluene (50 ml), ethanol (25 ml) and water (25 ml) and tetrakis(triphenylphosphine)palladium(0) (5 mol %) as catalyst. Aqueous work-up and column chromatography (SiO2, CH2C12) give 1.4 g (82% of theory) of 2-(6-decyloxy-2-fluoropyrid-3-yl)-5-phenyl-1,3,4-thiadiazole.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15][CH:14]=1.[NH4+].[Cl-].CN(C=O)C.O>[Fe].CCO>[NH2:31][C:29]1[CH:28]=[CH:27][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[C:11]#[C:12][C:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:15][CH:14]=2)=[C:2]([F:1])[CH:30]=1
Reactant: CC(C)(C)OC(=O)NC1CC=C(C#Cc2cnccc2Oc2ccc([N+](=O)[O-])cc2F)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC1CC=C(C#Cc2cnccc2Oc2ccc(N)cc2F)CC1
Temperature: 100 °C
Yield: 103.3 %

Procedure:
A mixture of tert-butyl 4-(2-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)ethynyl)cyclohex-3-enylcarbamate (110 mg, 0.24 mmol), iron powder, ˜325 mesh (150 mg, 2.7 mmol), NH4Cl (280 mg, 5.3 mmol), DMF (1 mL), H2O (1 mL) and EtOH (1 mL) was heated at 100° C. for 30 minutes. The mixture was filtered through a pad of Celite® using DMF to wash the filter cake and the filtrate made basic to pH 8 with saturated aq. NaHCO3 solution. The mixture was extracted twice with EtOAc and dried (MgSO4) and concentrated in vacuo to give the title compound (105 mg) which was used without any further purification. MS(ESI+): m/z 424.27 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:15])[C:8](=[CH:13][CH:14]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH:23]=[CH2:24]>CN(C=O)C.C(OCC)(=O)C>[CH2:24]([O:15][C:7]1[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])[CH:23]=[CH2:22]
Reactant: COC(=O)c1ccc(NC(C)=O)cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1cc(NC(C)=O)ccc1C(=O)OC
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of 10 g (47.8 mmol) of methyl 4-acetylaminosalicylate in 30 ml of DMF is added 19.8 g (143.4 mmol) of finely ground potassium carbonate in a single portion at room temperature, followed by 8.3 ml (95.6 mmol) of allyl bromide in a similar fashion. The reaction mixture is heated to 60° C. and stirred at that temperature for 4 hours. After cooling to room temperature the reaction mixture is diluted with ethyl acetate and washed with water. The organic layer is dried over MgSO4, filtered and concentrated. Flash chromatography (10% ethyl acetate/hexane) provides methyl 2-allyloxy-4-acetylaminobenzoate which can be used directly in the next step.
Reaction SMILES: CC([CH:5]1[CH2:10][N:9]([CH2:11][CH:12]2[C:21]3[C:16](=[CH:17][C:18]([C:24]#[N:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[CH2:15][CH2:14][O:13]2)[CH2:8][CH2:7][N:6]1C([O-])=O)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16]([CH2:15][CH2:14][O:13][CH:12]2[CH2:11][N:9]2[CH2:10][CH2:5][NH:6][CH2:7][CH2:8]2)=[CH:17][C:18]=1[C:24]#[N:25]
Reactant: COc1cc2c(cc1C#N)CCOC2CN1CCN(C(=O)[O-])C(C(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(cc1C#N)CCOC2CN1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1,1-dimethylethyl-4-{[6-cyano-7-(methyloxy)-3,4-dihydro-1H-isochromen-1-yl]methyl}piperazine-1-carboxylate (270 mg, 0.697 mmol) in 5 mL of DCM was added 5 mL of TFA and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to afford 7-(methyloxy)-1-(piperazin-1-ylmethyl)-3,4-dihydro-1H-isochromene-6-carbonitrile. The residue was directly used in next step.