Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH:11]([CH3:13])[CH3:12])=[CH:8][CH:9]=2)[S:4][C:3]=1[C:14]([O:16]C)=O.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[C:23]([CH:26]=1)[C:24]#[N:25].Cl>>[C:24]([C:23]1[CH:26]=[C:19]([NH:18][C:14]([C:3]2[S:4][C:5]3=[N:6][C:7]([CH:11]([CH3:12])[CH3:13])=[CH:8][CH:9]=[C:10]3[C:2]=2[OH:1])=[O:16])[CH:20]=[CH:21][C:22]=1[O:27][CH2:28][C:29]([CH3:31])([CH3:30])[CH3:32])#[N:25]
Reactant: COC(=O)c1sc2nc(C(C)C)ccc2c1O
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Agent: Cl
Product: CC(C)c1ccc2c(O)c(C(=O)Nc3ccc(OCC(C)(C)C)c(C#N)c3)sc2n1
Yield: 22.3 %

Procedure:
Methyl 3-hydroxy-6-isopropylthieno[2,3-b]pyridine-2-carboxylate (1.6 g) and 5-amino-2-neopentyloxybenzonitrile (2.6 g) were stirred at 170° C. for 2 hr. Then the reaction mixture was treated with diluted hydrochloric acid and the organic layer was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from water-containing dimethylformamide to give the title compound (0.6 g). melting point: 211-212° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[C:22]([N+:23]([O-])=O)=[CH:21][C:20]([F:26])=[CH:19][N:18]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:17]2[C:22]([NH2:23])=[CH:21][C:20]([F:26])=[CH:19][N:18]=2)=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: O=[N+]([O-])c1cc(F)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(F)cnc1Nc1ccc(OCc2ccccc2)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 24.3 %

Procedure:
A mixture of 4-(benzyloxy)aniline (2.26 g), 2-chloro-5-fluoro-3-nitropyridine (2 g) and K2CO3 (3.13 g) in DMF (20 ml) was stirred at 120° C. for 5 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was suspended in IPE and collected by filtration. The obtained solid was dissolved in EtOH (20 ml), and Pt/C (2 g) was added. Under H2 atmosphere, the mixture was stirred for 1 h, filtered and evaporated. The residue was chromatographed on silica gel eluting with Hexane/AcOEt to give the title compound (0.85 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:13]=[CH:12][C:11]2[N:14]=[CH:15][N:16]([C:17]3[S:21][C:20]([C:22]([O:24]C)=O)=[C:19]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:36])[F:35])[CH:18]=3)[C:10]=2[CH:9]=1)=[O:7].[NH3:38]>CO>[C:22]([C:20]1[S:21][C:17]([N:16]2[C:10]3[CH:9]=[C:8]([C:6]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:7])[N:13]=[CH:12][C:11]=3[N:14]=[CH:15]2)=[CH:18][C:19]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:36])([F:37])[F:35])(=[O:24])[NH2:38]
Reactant: COCCNC(=O)c1cc2c(cn1)ncn2-c1cc(OCc2ccccc2C(F)(F)F)c(C(=O)OC)s1
Reactant: N
Solvent: CO
Product: COCCNC(=O)c1cc2c(cn1)ncn2-c1cc(OCc2ccccc2C(F)(F)F)c(C(N)=O)s1

Procedure:
In a similar manner as described for example 1, 246 mg of methyl 5-{6-[(2-methoxyethyl)carbamoyl]-1H-imidazo[4,5-c]pyridin-1-yl}-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate (compound B8) and 40 ml of a saturated solution of ammonia in methanol give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Cl[CH2:11][CH:12]1[O:17][CH2:16][CH2:15][CH2:14][O:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:13]1[CH2:14][CH2:15][CH2:16][O:17][CH:12]1[CH2:11][NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1]
Reactant: Cc1cccc(C)c1N
Reactant: ClCC1OCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1NCC1OCCCO1

Procedure:
2,6-Dimethylaniline (75 grams), 2-chloromethyl-1,3-dioxane prepared in Example 1 (35 grams), potassium carbonate (30 grams) and dimethyl formamide (50 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was then heated at reflux for a period of about 16 hours. After this time the reaction mixture was filtered and the filtrate was distilled to yield the desired product N-(1,3-dioxan-2-ylmethyl)-2,6-dimethylaniline as a residue which crystallized upon standing at room temperature.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH:6]=1.[F:16][C:17]([F:35])([F:34])[C:18]1[CH:33]=[CH:32][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30]Cl)=[CH:20][CH:19]=1>>[F:16][C:17]([F:34])([F:35])[C:18]1[CH:33]=[CH:32][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][O:14][C:12]2[CH:11]=[CH:10][C:9]3[C:5]([CH2:4][C:3]([OH:2])=[O:15])=[CH:6][O:7][C:8]=3[CH:13]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)Cc1coc2cc(O)ccc12
Reactant: FC(F)(F)c1ccc(COc2ccccc2CCl)cc1
Product: O=C(O)Cc1coc2cc(OCc3ccccc3OCc3ccc(C(F)(F)F)cc3)ccc12

Procedure:
The title compound was prepared in the manner analogous to step 1 of Example 80 using (6-hydroxy-benzofuran-3-yl)-acetic acid methyl ester and 1-(4-trifluoromethyl-benzyloxy)-2-chloromethyl-benzene. MS m/z 471 (M+1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[C:8](=O)[CH2:9][CH3:10].[C:12](=O)([O:14]CC)[NH2:13]>[Cl-].[Zn+2].[Cl-]>[CH3:1][N:2]1[C:3]2[S:4][CH:5]=[CH:6][C:7]=2[C:8]([CH2:9][CH3:10])=[N:13][C:12]1=[O:14]
Reactant: CCC(=O)c1ccsc1NC
Reactant: CCOC(N)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: CCc1nc(=O)n(C)c2sccc12
Temperature: 200 °C

Procedure:
A mixture of 0.59 g of 2-methylamino-3-propionylthiophene, 1.18 g of ethyl carbamate and 0.07 g of zinc chloride is heated at 200°C for 1 hour. After cooling, the reaction mixture is extracted with chloroform. The extracts are combined, washed with water, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue is chromatographed on silica gel using chloroform as an eluent to give 1-methyl-4-ethyl-1,2-dihydrothieno[ 2,3-d]pyrimidin-2-one as crystals having a melting point of 155.5°-156.5°C (after recrystallization from ethanol).
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)=[O:4].Cl[C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1.COCCOC>C([O-])([O-])=O.[Na+].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:19]1[CH:20]=[CH:21][CH:22]=[N:23][C:18]=1[C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:16])([CH3:15])[CH3:1])=[CH:7][CH:8]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(B(O)O)cc1
Reactant: Clc1ncccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)C(=O)Nc1ccc(-c2ncccn2)cc1
Yield: 29.1 %

Procedure:
A mixture of 4-((2,2-dimethylpropanoyl)amino)phenylboronic acid (2.0 g, 9 mmol), 2-chloropyrimidine (0.8 g, 7 mmol), Pd(PPh3)2Cl2 (100 mg, 2 mol %) 1,2-dimethoxyethane (40 ml) and Na2CO3 (2M, 7 ml, 14 mmol) were refluxed under N2 for 5 h. The mixture was diluted with 10% Na2CO3 (20 ml) and extracted with EtOAc (3×50 ml). The organic layer was dried (Na2SO4) and the solvent was removed in vacuo. The crude product was recrystallised from MeOH/water (1:1) yielding 0.52 g (85%) of N-(4-(2-pyrimidinyl)phenyl)-2,2-dimethylpropanamide as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH2:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]2[CH2:29][O:28]2)=[CH:23][N:22]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([NH:19][CH2:29][C@H:27]([OH:28])[C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[N:22][CH:23]=2)[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(N)Cc2ccccc2)cc1OC
Reactant: Clc1ccc([C@@H]2CO2)cn1
Solvent: CO
Product: COc1ccc(C(Cc2ccccc2)NC[C@H](O)c2ccc(Cl)nc2)cc1OC
Temperature: 25 °C

Procedure:
A solution of α-(3.4-dimethoxyphenyl)benzeneethanamine (257 mg, 1 mmol, 2 eq) and (R)-(2-chloropyrid-5-yl)oxirane (Example 3, 77 mg, 0.5 mmol) in dry methanol in a gas tight vessel was heated at reflux in an oil bath overnight. The reaction was cooled to room temperature and then the solvent was stripped under vacuum. The yellow residue was purified by flash chromatography on silica gel (eluent: ethylacetate: hexanes:9:1) to give the adduct as a white solid. 1H NMR (400 MHz, CDCl3)δ 8.20 (m, 1H), 7.53 (m, 1H), 7.07-7.30 (m, 6H), 6.71-6.8 (m, 3H), 4.38-4.58 (m, 1H), 3.87 and 3.86 (s, 3H. OCH3), 3.82 (s, 3H, OCH3), 3.70-3.85 (m, 1H), 2.80-3.0 (m, 2H), 2,64-2.73 (m, 1H), 2.35-2.51 (m, 1H).
Reaction SMILES: [F:1][C:2]([CH3:35])([CH3:34])[CH:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:14]2[CH2:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]([CH3:35])([CH3:34])[CH:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:14]2[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)C(NC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CCC2)C(C)(C)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)C(NC(=O)c1nc(-c2ccccc2)n2c1CNCCC2)C(C)(C)F
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To 66D (178 mg, 0.37 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1.12 mL, 14.60 mmol). After 1 hour of stirring, the solution was concentrated under reduced pressure. The residue was brought to pH 8 with a saturated aqueous solution of sodium bicarbonate. The aqueous solution was extracted with dichloromethane. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to yield Compound 604 as a white solid (117 mg, 83%). 1H-NMR (400 MHz, (CD3)2SO) δ: 1.31 (d, 3H), 1.37 (d, 3H), 1.71 (m, 2H), 2.61 (d, 3H), 3.00 (m, 2H), 4.13 (m, 2H), 4.28 (m, 2H), 4.64 (dd, 1H), 7.52 (m, 5H), 7.81 (d, 1H), 8.24 (q, 1H). LCMS (+ESI) m/z 388.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[N:7]([CH2:16][C:17]1[CH:18]=[N:19][C:20]([CH3:35])=[C:21]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=2)[C:22]=1[CH2:23]O)[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].COCCN(S(F)(F)[F:47])CCOC.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([O:5][C:6](=[O:36])[N:7]([CH2:16][C:17]1[CH:18]=[N:19][C:20]([CH3:35])=[C:21]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=2)[C:22]=1[CH2:23][F:47])[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: Cc1ncc(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)c(CO)c1OCc1cccc(C#N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ncc(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)c(CF)c1OCc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a solution of [5-(3-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-(4-cyano-phenyl)-carbamic acid tert-butyl ester (106) (51.1 g, 0.10 mol) in dry dichloromethane (700 mL) was slowly added bis(2-methoxyethyl)aminosulfur trifluoride (39.7 g, 0.18 mol) at 0° C. under nitrogen atmosphere. The reaction was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was then poured into a cold solution of saturated aqueous sodium bicarbonate, and the crude product extracted with dichloromethane, dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a crude residue, which was purified by column chromatography on silica gel using a gradient mixture of dichloromethane:acetone (1:0 to 18:1) as an eluant to give [5-(3-cyano-benzyloxy)-4-fluoromethyl-6-methyl-pyridin-3-ylmethyl]-(4-cyano-phenyl)-carbamic acid tert-butyl ester (107) (41.3 g, 80% yield) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O-:15])=[O:14])[C:10]([CH3:16])=[N:9]2)=[CH:4][CH:3]=1.N(O[CH2:20][CH2:21]C(C)C)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:20][CH3:21])=[O:14])[C:10]([CH3:16])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)CCON=O
Reactant: Cc1nn(-c2ccc(F)cc2)cc1C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)nc1C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
To a tetrahydrofuran solution (50 ml) containing ethyl 5-amino]1-(4-fluorophenyl)-3-methylpyrazole-4-carboxylate (10.5 g) was added isoamyl nitrite (14 g) and the mixture was stirred at a refluxing temperature for 2 h. The mixture was treated with aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. n-Hexane was added to the obtained residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (7.8 g), melting point: 103–104° C.
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[C:7]([CH3:17])=[CH:8][C@H:9]2[C:14]([NH2:16])=O)[CH:2]=[CH2:3].[OH-].C([NH+](CC)CC)C>C(Cl)Cl>[CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[C:7]([CH3:17])=[CH:8][C@H:9]2[C:14]#[N:16])[CH:2]=[CH2:3]
Reactant: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2C(N)=O
Agent: CC[NH+](CC)CC
Agent: [OH-]
Solvent: ClCCl
Product: C=CCON1C(=O)N2C[C@H]1C(C)=C[C@H]2C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
To a solution of (2S,5R)-6-(allyloxy)-4-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carboxamide (Intermediate 16, 146 mg, 0.62 mmol) in DCM (6 mL), under nitrogen, at room temperature was added methoxycarbonylsulfamoyl)triethyl-ammonium hydroxide inner salt (Burgess Reagent) (660 mg, 2.77 mmol) portionwise over 2 hours. The reaction was stirred at room temperature for an additional 30 minutes. The reaction mixture was washed with 1:1 brine:water. The organic layer was dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-25% ethyl acetate/hexanes) afforded (2S,5R)-6-(allyloxy)-4-methyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-ene-2-carbonitrile (112 mg, 83%) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH2:18][CH3:19])[C:14]([O:16]C)=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:20]=[CH:21][CH:22]=[CH:23][C:3]1=2.CO.[OH-].[Na+]>O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH2:18][CH3:19])[C:14]([OH:16])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:20]=[CH:21][CH:22]=[CH:23][C:3]1=2
Reactant: CCC(C(=O)OC)c1ccc2c(=O)c3ccccc3ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
1.075 Ml. of 1.6 molar n-butyllithium in hexane is added to a solution of 0.242 ml. of diisopropylamine in 15 ml. of dry tetrahydrofuran. 0.300 Ml. of hexamethylphosphoric triamide is added and the mixture is cooled to about -60° C. 0.465 G. of methyl (5-oxo-5H-dibenzo[a,d]-cyclohepten-2-yl)acetate is added, and after 15 minutes, 0.137 ml. of ethyl iodide is added. The mixture is warmed slowly to room temperature and a further 0.05 ml. of ethyl iodide is added. After 30 minutes an additional 0.05 ml. of ethyl iodide is added. After 30 minutes, a few drops of methanol are added, and then ether and water are added. The organic layer is washed with water, dilute hydrochloric acid and saturated sodium chloride solution, then dried and evaporated to yield the impure product, which, after chromatography on 40 g. silica gel, eluting with hexane:ether (5:1) affords methyl 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)butyrate. 0.326 G. of methyl 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)butyrate is refluxed for 4 hours in 10 ml. of methanol and 20 ml. of water containing 0.5 g. of sodium hydroxide. The mixture is cooled, washed with ether and acidified with dilute hydrochloric acid. The product is extracted with ether and the extract washed, dried and evaporated to yield 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)butyric acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21]3[C:22]4=[C:23]5[C:18](=[CH:19][CH:20]=3)[CH:17]=[CH:16][C:15]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)=[C:14]5[CH:13]=[CH:12][C:11]4=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:31]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:31][C:17]1[CH:16]=[C:15]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[C:14]2[C:23]3=[C:22]4[C:11]([CH:10]=[CH:9][C:8]([C:5]5[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=5)=[C:21]4[CH:20]=[CH:19][C:18]=13)=[CH:12][CH:13]=2
Reactant: Cc1ccc(-c2ccc3ccc4c(-c5ccc(C)cc5)ccc5ccc2c3c54)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3ccc4c(-c5ccc(C)cc5)cc(Br)c5ccc2c3c54)cc1
Temperature: 25 °C
Yield: 45 %

Procedure:
Next, a mixed solution of 2.6 g of 1,6-bis(4-methylphenyl)pyrene, 1.2 g of N-bromosuccinimide and 60 ml of dimethylformamide was stirred under a nitrogen gas stream at 60° C. for 5 hours. The solution was cooled to room temperature and 60 ml of water was poured into the solution, followed by extraction with 100 ml of dichloromethane. The organic layer was washed twice with 50 ml of water, dried over magnesium sulfate and then evaporated. The resulting solid was recrystallized from toluene and then vacuum-dried to obtain 1.4 g of 3-bromo-1,6-bis(4-methylphenyl)pyrene.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[S:21][C:22]([C:28]2[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[S:21][C:22]=3[C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)=[O:26])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C)sc3-c3cccc(C)c3)n2)o1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:10][C@H:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH2:8][CH2:7][C@@H:6]1[N:21]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:22]1=[O:37])(=[O:3])[CH3:2].[CH2:38](N(CC)CC)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]([NH:4][C@@H:5]1[CH2:10][C@H:9]([N:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[CH3:38])[CH2:8][CH2:7][C@@H:6]1[N:21]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:22]1=[O:37])(=[O:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: COc1ccc(CN[C@@H]2CC[C@H](N3CC[C@H](NC(=O)OCc4ccccc4)C3=O)[C@H](NC(C)=O)C2)cc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CN(C)[C@@H]2CC[C@H](N3CC[C@H](NC(=O)OCc4ccccc4)C3=O)[C@H](NC(C)=O)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A sample of benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(4-methoxybenzylamino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (54.45 g, 107 mmol) was dissolved in dichloromethane (400 mL). The resultant solution was cooled to 0° C. under N2 stream and then charged sequentially with triethylamine (29.8 mL, 214 mmol), aqueous formaldehyde (11.96 mL of a 37% solution, 161 mmol), and sodium triacetoxyborohydride (34.0 g, 161 mmol). The ice bath was removed and the reaction was stirred at RT for 2 h before being diluted with 750 mL EtOAc and washed with sat. NaHCO3 (2×250 mL). The organic phase was concentrated in vacuo and the resultant residue was dissolved in EtOAc (750 mL). The organic phase was washed with acid [2×(200 mL 1N HCl/300 mL H2O)]. The acidic washes were combined and then basified with 6N NaOH (80 mL) and sat. NaHCO3 (70 mL). The mixture was extracted with EtOAc (3×500 mL). The organic extracts were combined, washed with brine (1×100 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue was dissolved in methylene chloride and concentrated; this was repeated twice to afford benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-((4-methoxybenzyl)(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (54.14 g, 104 mmol, 97% yield) as a hard white microcrystalline foam after pumping on high vacuum. LC/MS found [M+H]+=523.6.
Reaction SMILES: C([N:8]([C@H:16]([C@@H:24]([OH:42])[CH2:25][C@@H:26]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)CC1C=CC=CC=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CCO.O.[Pd]>[NH2:8][C@H:16]([C@@H:24]([OH:42])[CH2:25][C@@H:26]([NH:34][C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of the product from Example 19C (150 gm, 250 mmol) dissolved in absolute EtOH (2 liters) was treated with 10% Pd/C (18 gm, pre-wetted), followed by addition of ammonium formate (78.6 gms, 1.25 moles) dissolved in H2O (200 ml). The resulting mixture was stirred at reflux for 2.5 hours. The mixture was cooled to room temperature and filtered through a pad of infusorial earth (20 g). The filter cake was washed 3 times with EtOH (70 ml each). The filtrate was concentrated in vacuo. The residue was dissolved into EtOAc (1L) and washed (1N NaOH, followed by H2O, followed by brine), dried (Na2SO4), filtered and concentrated in vacuo. to a constant weight of 95 gms. (99.2 % of theory). The light yellow solid (91.5 gm of the 95 gm) was slurried in hot heptane (600 ml) (steam bath) and treated with isopropanol (45 ml), and swirled to effect solution. The solution was allowed to slowly cool to room temperature over 3 hours, kept at room temperature for 2 more hours and filtered. The filter cake was washed 10 times with 9/1 hexane-isopropanol (30 ml each) to give the desired product as an off-white finely crystalline solid which was dried to constant weight of 57.5 gm.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][N:6]1[C:16]2[C:11](=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:13]=[C:14]([I:17])[CH:15]=2)[C:9](=[O:10])[C:7]1=[O:8])[CH3:2].[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:22]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:16]2[C:11](=[C:12]([C:18]([F:20])([F:21])[F:19])[CH:13]=[C:14]([I:17])[CH:15]=2)[C:9]([OH:10])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]1=[O:8])[CH3:23]
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c1cc(I)cc2C(F)(F)F
Reactant: Br[Mg]c1ccccc1
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2)c2c1cc(I)cc2C(F)(F)F
Yield: 53 %

Procedure:
The title compound (53%) was prepared from 1-(2-diethylaminoethyl)-6-iodo-4-trifluoromethylisatin and phenylmagnesium bromide by the procedure similar to that described in Example 1. The compound obtained was further purified by reverse phase HPLC with water-acetonitrile-trifluoroacetic acid.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9])=[O:10]
Reactant: COc1ccccc1C(=O)Cl
Reactant: COc1ccc(OC)cc1
Product: COc1ccc(OC)c(C(=O)c2ccccc2OC)c1
Temperature: 200 °C

Procedure:
A mixture of o-anisoyl chloride (25.8 g, 0.15 mmol) and 1,4-dimethoxybenzene (37.2 g, 0.27 mol) was heated for 20 hours at 200° C., under N2. Distillation led to recovered 1,4-dimethoxybenzene (18.7 g), b.p. 232° C. (8 mm) followed by the title product, shown below, (25.4 g, 63%), b.p. 232° C. (7 mm) which was suitable for carrying forward to the next step. ##STR3##