Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5]Cl)[CH3:2].[S:9]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[CH:11]=[C:10]1[C:17]([C:19]1[CH:20]=[C:21]([CH:25]([CH3:29])[C:26]([O-:28])=[O:27])[CH:22]=[CH:23][CH:24]=1)=[O:18].[Na+]>CN(C)C=O.Cl>[S:9]1[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[CH:11]=[C:10]1[C:17]([C:19]1[CH:20]=[C:21]([CH:25]([CH3:29])[C:26]([O:28][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:7][CH3:8])=[O:27])[CH:22]=[CH:23][CH:24]=1)=[O:18]
Reactant: CC(C(=O)[O-])c1cccc(C(=O)c2cc3ccsc3s2)c1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(CC)CCOC(=O)C(C)c1cccc(C(=O)c2cc3ccsc3s2)c1
Reaction time: 16 h
Yield: 108.1 %

Procedure:
A solution of 2-diethylamino-chloroethane (1.6 g) in dimethylformamide (16 cc) is added dropwise to a suspension of sodium 2-{3-(thieno[2,3-b]thien-2-yl)carbonyl-phenyl}propionate (4 g) [prepared as described in Example 1] in dimethylformamide (16 cc). After 16 hours at 25° C., the reaction mixture is poured into distilled water (400 cc) and extracted three times with diethyl ether (total 300 cc). The combined ether phases are washed with a saturated aqueous sodium bicarbonate solution (75 cc), then three times with distilled water (total 300 cc), dried over anhydrous sodium sulphate in the presence of decolourizing charcoal (0.5 g), filtered and evaporated. The residue obtained (4.75 g), to which is added some product (3.1 g) prepared in the same way, is dissolved in 1N aqueous hydrochloric acid (50 cc). The solution is washed three times with diethyl ether (total 175 cc) and then rendered alkaline to pH 11 by the addition of 1N aqueous sodium hydroxide solution (55 cc). The resulting precipitate is extracted three times with diethyl ether (175 cc). The combined ether solutions are washed three times with distilled water (total 175 cc), dried over anhydrous sodium sulphate in the presence of decolourizing charcoal (0.5 g), filtered and evaporated. 2-Diethylaminoethyl 2-{3-(thieno[2,3-b]thien-2-yl)carbonyl-phenyl}propionate (5.3 g), in the form of an oil, is thus obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.CS(C)=O>CCOC(C)=O>[CH3:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[CH:7]=[C:2]([O:1][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:5]=2)=[CH:13][CH:12]=1
Reactant: Brc1ccccn1
Reactant: COC(=O)c1cc(O)cc(-c2ccc(C)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1cc(Oc2ccccn2)cc(-c2ccc(C)cc2)c1
Temperature: 135 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 5-hydroxy-4′-methylbiphenyl-3-carboxylate (100 mg, 0.41 mmol), potassium carbonate (100 mg, 0.72 mmol), 2-bromopyridine (0.40 mL, 4.2 mmol), and dimethyl sulfoxide (2 mL) was stirred at 135° C. overnight. After cooling, the mixture was diluted with EtOAc and washed with aq. NaHCO3 (sat.), dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (0-20% EtOAc/hexane) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[N:7]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[NH:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.[C:20](Cl)(=[O:22])[CH3:21]>>[C:20]([N:12]1[C:8]2=[N:9][C:10]3[C:5]([C:6](=[O:19])[N:7]2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]1=2)=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=3)(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: O=c1c2ccc(Cl)cc2nc2[nH]c3ccccc3n12
Product: CC(=O)n1c2ccccc2n2c(=O)c3ccc(Cl)cc3nc12

Procedure:
6-Acetyl-3-chlorobenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 3-chlorobenzimidazo[2,1-b]quinazolin-12(6H)one and acetyl chloride.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:4]([NH2:18])[N:3]=1.CC(C)([O-])C.[Na+].[CH3:25][CH:26]([CH3:29])[CH2:27][OH:28]>>[CH3:25][CH:26]([CH3:29])[CH2:27][O:28][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:4]([NH2:18])[N:3]=1
Reactant: Nc1nc(Cl)nc2c1ncn2CC1CCOCC1
Reactant: CC(C)CO
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: CC(C)COc1nc(N)c2ncn(CC3CCOCC3)c2n1
Temperature: 105 °C

Procedure:
2-Chloro-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (0.20 g) was added to a suspension of 2-methyl-1-propanol (2 mL) and sodium tert-butoxide (0.288 g). The mixture was heated in a microwave for 30 minutes at 105° C. The reaction mixture was washed with water after diluting with ethyl acetate (50 mL). The organic was separated and dried by passing through a hydrophobic frit before volatiles were stripped off under reduced pressure to give a pinkish solid. This material was triturated with diethyl ether and filtered to give the title compound as a pinkish solid (91.1 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Br:25])[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)=[O:6].[N:26]1[N:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]2=[C:28]([C:35](Cl)=[O:36])[CH:27]=1>>[Br:25][C:24]1[CH:23]=[CH:22][C:4]([C:5](=[O:6])[NH:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)=[CH:3][C:2]=1[NH:1][C:35]([C:28]1[CH:27]=[N:26][N:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=12)=[O:36]
Reactant: O=C(Cl)c1cnn2ccccc12
Reactant: CN1CCN(c2ccccc2CNC(=O)c2ccc(Br)c(N)c2)CC1
Product: CN1CCN(c2ccccc2CNC(=O)c2ccc(Br)c(NC(=O)c3cnn4ccccc34)c2)CC1

Procedure:
The title compound was prepared from 3-amino-4-bromo-N-(2-(4-methylpiperazin-1-yl)benzyl)benzamide (Ex 5.1, step 1) and pyrazolo[1,5-a]pyridine-3-carbonyl chloride (commercially available) analogously to Example 5.1;
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24]>>[Cl:1][C:2]1[N:3]([C:17]2[CH:18]=[CH:19][C:14]([CH3:13])=[C:15]([N+:23]([O-:25])=[O:24])[CH:16]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1ccc(B(O)O)cc1[N+](=O)[O-]
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Product: Cc1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1[N+](=O)[O-]
Yield: 35 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 4-methyl-3-nitrophenylboronic acid as described in Step 1 of Example 29 to afford 2-chloro-1-(4-methyl-3-nitrophenyl)-1H-indole-3-carboxaldehyde (35% yield) as a light cream solid. ESI/MS 315 (M+H); 356 [(M+1+CH3CN) adduct]; RT 3.35 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:5]=1[CH:6]=[O:7])[CH3:2].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:4]([O:3][CH2:1][CH3:2])=[C:5]([CH:8]=1)[CH:6]=[O:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: CCOc1ccc(O)cc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(OCc2ccccc2)cc1C=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
A mixture of 2-ethoxy-5-hydroxybenzaldehyde (3.72 g), benzyl bromide (5.75 g), anhydrous potassium carbonate (3.10 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 3 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (5.06 g, 88%) of 5-benzyloxy-2-ethoxybenzaldehyde from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Redrystallization from ethyl, acetate-hexane gave colorless prism crystals. melting point: 81-82° C.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH:6]([N:21]2[CH2:26][C@@H:25]([CH3:27])[NH:24][CH2:23][C@@H:22]2[CH3:28])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH:8]=2)=[CH:4][CH:3]=1.[CH2:31](Br)[CH:32]=[CH2:33].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH2:33]([N:24]1[CH2:23][C@@H:22]([CH3:28])[N:21]([CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][Si:14]([C:17]([CH3:19])([CH3:20])[CH3:18])([CH3:16])[CH3:15])[CH:8]=2)[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:30][CH:29]=2)[CH2:26][C@@H:25]1[CH3:27])[CH:32]=[CH2:31]
Reactant: C[C@@H]1CN(C(c2ccc(Br)cc2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)[C@@H](C)CN1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN1C[C@@H](C)N(C(c2ccc(Br)cc2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)C[C@@H]1C
Yield: 99.5 %

Procedure:
The purified benzhydrylpiperazine (41.0 g, 83.7 mmol) was dissolved in 500 mL of dry tetrahydrofuran with 7.3 mL (84 mmol) of allyl bromide and 22 g (200 mmol) of sodium carbonate and heated at reflux overnight under nitrogen. The cooled reaction solution was filtered and the solvent removed to give 44.1 g of crude (±)-trans-1-allyl-4-(4-bromo-α-(3-(tert-butyldimethyl -silyloxy)phenyl)benzyl)-2,5-dimethylpiperazine as a brown oil. NMR (200 MHz, CDCl3): δ0.15 (s,6H); 0.95 (m,12H); 1.15 (2 overlapping d,J=6 Hz,3H); 1.8 (m,1H); 2.1 (m,1H); 2.35-2.65 (m,3H); 2.7-2.9 (m,2H); 3.35 (dd,J1 =5 Hz,J2 =12 Hz,1H); 5.0-5.2 (m,3H); 5.85 (m,1H); 6.6-7.5 (m,8H).
Reaction SMILES: CO[C:3](=[O:10])[CH2:4][CH2:5][NH:6][C:7](=[O:9])[CH3:8].[CH2:11]([CH2:13][NH2:14])[OH:12]>>[C:7]([NH:6][CH2:5][CH2:4][C:3]([NH:14][CH2:13][CH2:11][OH:12])=[O:10])(=[O:9])[CH3:8]
Reactant: COC(=O)CCNC(C)=O
Reactant: NCCO
Product: CC(=O)NCCC(=O)NCCO

Procedure:
According to scheme V, N-acetyl-β-alanine methyl ester 5 is reacted with ethanolamine neat at 85° C., giving 3-(acetylamino)-N-(2-hydroxyethyl)propanamide 16 which is reacted with oleoyl chloride 1, giving the ester isostere product 2-[[3-(acetylamino)-1-oxopropyl]amino]ethyl-9(Z)-octadecenoate 17. ##STR13##
Reaction SMILES: [F:1][C:2]([F:39])=[CH:3][C:4]1[N:5]=[C:6]([C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29]CC4C=CC(OC)=CC=4)=[CH:25][CH:24]=3)=[N:21][CH:22]=2)[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1>C(O)C.O1CCCC1.[C].[Pd]>[F:39][CH:2]([F:1])[CH2:3][C:4]1[N:5]=[C:6]([C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)=[N:21][CH:22]=2)[N:7]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:14])[CH3:15])[CH:8]=1
Reactant: COc1ccc(COc2ccc(-c3ccc(-c4nc(C=C(F)F)cn4COCC[Si](C)(C)C)cn3)cc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(CC(F)F)nc1-c1ccc(-c2ccc(O)cc2)nc1
Reaction time: 24 h
Yield: 56.6 %

Procedure:
In ethanol (50 mL) and tetrahydrofuran (20 mL) was dissolved 5-[4-(2,2-difluoroethenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-2-{4-[(4-methoxybenzyl)oxy]phenyl}pyridine (0.84 g), 10% palladium-carbon (50% water contained, 395 mg) was added to the solution, and the mixture was stirred under hydrogen atmosphere for 24 hours. The reaction mixture was filtered by using a membrane filter, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 4-{5-[4-(2,2-difluoroethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridin-2-yl}phenol (373 mg).
Reaction SMILES: [CH:1]([N:4]([CH:31]([CH3:33])[CH3:32])[C:5]([C:7]1[NH:29][C:10]2[CH2:11][C@@:12]3([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27]C)[CH:22]=4)[C@H:17]([CH2:18][C:9]=2[C:8]=1[CH3:30])[CH2:16][N:15]([CH2:19][CH3:20])[CH2:14][CH2:13]3)=[O:6])([CH3:3])[CH3:2].B(Br)(Br)Br.[ClH:38].CCOCC>CO>[ClH:38].[CH:31]([N:4]([CH:1]([CH3:2])[CH3:3])[C:5]([C:7]1[NH:29][C:10]2[CH2:11][C@@:12]3([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=4)[C@H:17]([CH2:18][C:9]=2[C:8]=1[CH3:30])[CH2:16][N:15]([CH2:19][CH3:20])[CH2:14][CH2:13]3)=[O:6])([CH3:33])[CH3:32]
Reactant: CCN1CC[C@@]2(c3cccc(OC)c3)Cc3[nH]c(C(=O)N(C(C)C)C(C)C)c(C)c3C[C@@H]2C1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CCN1CC[C@@]2(c3cccc(O)c3)Cc3[nH]c(C(=O)N(C(C)C)C(C)C)c(C)c3C[C@@H]2C1

Procedure:
1.0 g (2.2 mmol) of (±)-trans-2-diisopropylaminocarbonyl-6-ethyl-8a-(3-methoxyphenyl)-3-methyl-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrrolo[2,3-g] isoquinoline were treated with 1.15 ml (12.0 mmol) of boron tribromide as described in example 2. The crude product was dissolved in MeOH and the solution brought to acidic pH with HCl/Et2O . The solvent was evaporated in vacuo and the solid crystallized from acetone, yielding 0.5 g of the title compound. M.p.=263°-265° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[C:16](=[N:17][N:18]([CH2:22][C:23]([NH2:25])=[O:24])[CH:19]=3)[CH2:15]2)[CH2:11][O:10][C@@H:9]1[C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@@H:8]1[C@@H:9]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[F:33])[O:10][CH2:11][C@H:12]([N:14]2[CH2:21][C:20]3[C:16](=[N:17][N:18]([CH2:22][C:23]([NH2:25])=[O:24])[CH:19]=3)[CH2:15]2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3cn(CC(N)=O)nc3C2)CO[C@@H]1c1cc(F)ccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Cn1cc2c(n1)CN([C@H]1CO[C@H](c3cc(F)ccc3F)[C@@H](N)C1)C2

Procedure:
The product from Step A (433 mg, 0.907 mmol) in CH2Cl2 (60 mL) was treated with TFA (60 mL) at RT for 2 h. After removing the TFA/CH2Cl2, the residue was purified on a silica gel column and eluting with 2.5-5% MeOH (containing 10% NH4OH)/CH2Cl2 to give the title compound. LC-MS=378.04 [M+1].
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)([CH3:4])[CH3:3].N1C=CC=CC=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:4][C:2]([CH3:1])([O:5][C:6]([NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([NH:17][S:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:33])=[O:32])=[CH:15][CH:16]=1)=[O:18])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCCOc1ccc(NS(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
To a solution of 314 mg(1.246 mmole) of t-BOC amine from Example 216 in 10 mL of methylene chloride was added pyridine (147 mg, 1.869 mmol, 1.5 eq) followed by benzenesulfonyl chloride (242 mg, 1.370 mmol, 1.1 eq) at room temperature. The reaction mixture was stirred at room temperature overnight and then partitioned between water and chloroform. The organic layer was separated and washed with 1N hydrochloric acid, water and brine and then dried over anhydrous sodium sulfate. The solution was filtered, concentrated and the residue was purified by flash colunto chromatography (eluant 2:1 hexanes/ethyl acetate) to give 248 mg (51%) of the product: 1H NMR (200 MHz, CDCl3) δ8.01 (d, 1H, J=8Hz), 7.67 (d, 2H, J=8Hz), 6.92 (d, 2H, J=9Hz), 6.72 (s, 1H, N-H), 6.70 (d, 2H, J=9Hz), 4.90 (bs, 1H, N-H), 3.89 (t, 2H, J=5.0Hz), 3.40 (q, 2H, J=5.0Hz), 1.40 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]=[N:7][CH:6]=[CH:5]2.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]=[N:7][CH:6]=[CH:5]2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1cc2cnccc2cc1O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4ccncc4cc3C)c2cc1OC
Temperature: 140 °C
Reaction time: 6 h
Yield: 52.5 %

Procedure:
6-Hydroxy-7-methylisoquinoline (21 mg), 4-chloro-6,7-dimethoxyquinoline (81 mg), and 4-dimethylaminopyridine (44 mg) were suspended in o-dichlorobenzene (2.5 ml), and the suspension was stirred at 140° C. for 6 hr. The reaction solution was cooled to room temperature, water was then added to reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (24 mg, yield 58%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([O:14][CH3:15])[C:11]([OH:13])=O.[NH2:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=1[F:26]>>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([CH2:17][NH:16][C:11](=[O:13])[CH:10]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[O:14][CH3:15])=[C:19]([F:26])[CH:20]=1)#[N:23]
Reactant: COc1ccc(C(OC)C(=O)O)c(F)c1
Reactant: N#Cc1ccc(CN)c(F)c1
Product: COc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2F)c(F)c1

Procedure:
(RS)-(2-Fluoro-4-methoxy-phenyl)-methoxy-acetic acid (example 15.1) was coupled with 4-aminomethyl-3-fluoro-benzonitrile according to general procedure B to give (RS)-N-(4-cyano-2-fluoro-benzyl)-2-(2-fluoro-4-methoxy-phenyl)-2-methoxy-acetamide. Yellow oil. MS 347.3 ([M+H]+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3I)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C@H:22]12[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:26]1[CH2:25][NH:24][CH2:23]2>>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[N:24]2[CH2:25][C@H:26]3[C@H:22]([CH2:28][N:27]3[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:23]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1cccc(F)c1)c1cnc2c(I)cccc2c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CNC[C@@H]21
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cccc4cc(S(=O)(=O)c5cccc(F)c5)cnc34)C[C@@H]21

Procedure:
0.153 g of (1S,5R)-tert-butyl 3-(3-(3-fluorophenylsulfonyl)quinolin-8-yl)-3,6-diazabicyclo[3.2.0]heptane-6-carboxylate were prepared by analogy to the method of Example 25.4 by coupling of 3-(3-fluorophenylsulfonyl)-8-iodoquinoline and (1S,5R)-tert-butyl 3,6-diazabicyclo[3.2.0]heptane-6-carboxylate.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]([OH:22])=O)[CH:15]=[CH:14][CH:13]=2)=[N:3]1.[C:23]([O:27][C:28](=[O:31])[CH2:29][NH2:30])([CH3:26])([CH3:25])[CH3:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]([NH:30][CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:31])=[O:22])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNC(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 99.1 %

Procedure:
3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propionic acid (0.20 g, 0.64 mmol) as dissolved in N,N-dimethylformamide (3 ml), and glycine tert-butyl ester (0.11 g, 0.67 mmol), WSC (0.25 g, 1.3 mmol) and HOBt (0.18 g, 1.3 mmol) were added successively thereto. The reaction mixture was stirred at room temperature for 17 hrs, concentrated under reduced pressure and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel (15 g) column chromatography. The fractions eluted with hexane-ethyl acetate (1:1, v/v) were collected and concentrated to give the titled compound (0.27 g, 99%) as white crystals.
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7](F)[C:4]=1[C:5]#[N:6]>CS(C)=O>[NH2:1][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:3]([F:2])[C:4]=1[C:5]#[N:6]
Reactant: N
Reactant: COc1cc(F)c(C#N)c(F)c1
Solvent: CS(C)=O
Product: COc1cc(N)c(C#N)c(F)c1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
Ammonia gas was bubbled through a solution of 2,6-difluoro-4-methoxybenzonitrile (1.0 g, 5.91 mmol) in dimethylsulfoxide (11.83 mL) for 10 minutes. The reaction was then sealed and stirred at 90° C. for 24 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo to afford a tan residue. The residue was triturated with water, collected be vacuum filtration, and dried in vacuo to afford the title intermediate (0.9 g, 5.42 mmol) as a white solid. LC/MS (ESI+) m/z=167 (M+H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:17][CH3:18])[C:8]2[CH:9]=[C:10]([B:13]([OH:15])[OH:14])[CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:16])[O:4]1)[CH3:2].[H-].[Na+].[CH3:21]I>C1COCC1>[CH2:17]([C:3]1([CH2:1][CH3:2])[C:8]2[CH:9]=[C:10]([B:13]([OH:14])[OH:15])[CH:11]=[CH:12][C:7]=2[N:6]([CH3:21])[C:5](=[O:16])[O:4]1)[CH3:18]
Reactant: CCC1(CC)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC1(CC)OC(=O)N(C)c2ccc(B(O)O)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.4 %

Procedure:
To a stirred solution of 4,4-diethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-ylboronic acid (4.85 g, 19.50 mmol) in THF (100 mL) at 0° C. was added sodium hydride (3.12 g-60%, 78 mmol). After 10 minutes, methyl iodide (9.7 to mL, 156.0 mmol) was added and the reaction was allowed to warm to room temperature. After one week, the reaction was quenched with ammonium chloride solution (sat.) and extracted with ethyl acetate several times. The organic layers were washed with brine, dried over magnesium sulfate and concentrated. Trituration with ether gave 4,4-diethyl-1-methyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-ylboronic acid as a yellow solid (3.97 g, 77%). 1H NMR (DMSO-d6): δ 8.03 (s, 2H), 7.78 (dd, J=8.2, 1.3 Hz, 1H), 7.60 (d, J=1.3 Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 3.28 (s, 3H), 1.99 (m, 4H), 0.78 (t, J=7.4 Hz, 6H). MS (ESI) m/z 264 ([M+H]+); MS (ESI) m/z 262 ([M−H]−); Anal. calcd for C13H18BNO4: C, 59.35; H, 6.90; N, 5.32. Found: C, 58.97; H, 6.98; N, 4.73.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[CH2:7].[H][H]>[Pd].CO>[CH2:6]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:10]([O:11][CH3:12])=[CH:9][CH:8]=1)[CH3:7]
Reactant: C=Cc1ccc(OC)c(OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(OC)c(OC)c1
Yield: 98.8 %

Procedure:
In an atmospheric pressure hydrogenation equipment 10.0 g (60.9 mM) of 3,4-dimethoxystyrene, 0.5 g of palladium charcoal and 200 ml of methanol were charged and introduced with hydrogen. The reaction was continued until the absorption of hydrogen was terminated. Palladium charcoal was filtered off from the reaction mixture. Methanol was distilled off from the filtrate. The residue was distilled under vacuum to obtain 10.0 g (60.2 mM) of 4-ethylveratrole as a colorless transparent liquid having a boiling point of 84°-85° C./2 mmHg
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[C:5]([Cl:15])[C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1.[F:16][C:17]([F:24])([F:23])[C:18]1[CH:22]=[CH:21][NH:20][N:19]=1>>[Cl:12][C:10]1[C:9]2[C:4](=[C:5]([Cl:15])[C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=[C:2]([N:20]2[CH:21]=[CH:22][C:18]([C:17]([F:24])([F:23])[F:16])=[N:19]2)[CH:11]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: COc1ccc2c(Cl)cc(Cl)nc2c1Cl
Product: COc1ccc2c(Cl)cc(-n3ccc(C(F)(F)F)n3)nc2c1Cl
Temperature: 120 °C
Yield: 50.9 %

Procedure:
A mixture of compound 220d (5 g, 19 mmol) and 3-trifluoromethylpyrazole 233a (7.76 g, 57 mmol) was heated at 120° C. for 4-6 hrs and the reaction was followed by LCMS and TLC. The reaction mixture was purified by silica gel column (mono and dipyrazole were separated) using DCM and heptane as mobile phase to yield compound 235a (3.5 g) in 51% yield.