Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]2([C:37](O)=[O:38])[CH2:36][CH2:35]2)=[O:33])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:37]([C:34]5([C:32]([NH:31][C:28]6[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=6)=[O:33])[CH2:36][CH2:35]5)=[O:38])=[CH:3][CH:4]=4)=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:20][CH2:21]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cn2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3)ccc2n1)C1CC1
Yield: 44.5 %

Procedure:
Using N-[6-(4-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.486 mmol), N,N-dimethylacetamide (3.0 mL), 1-[(4-fluorophenyl)carbamoyl]cyclopropanecarboxylic acid (163 mg, 0.730 mmol), HATU (277 mg, 0.730 mmol) and N,N-diisopropylethylamine (127 μL, 0.730 mmol) and in the same manner as in Example 8, the title compound (111 mg, 44%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O-:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:27]([O:31][CH:32](Br)[CH3:33])(=[O:30])[CH2:28][CH3:29].[I-].[Na+].O>CS(C)=O.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O:20][CH:32]([O:31][C:27](=[O:30])[CH2:28][CH3:29])[CH3:33])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CCC(=O)OC(C)Br
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(=O)OC(C)OC(=O)C1=CCS[C@@H]2C(NC(=O)C(=NOC)c3csc(N)n3)C(=O)N12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.4 %

Procedure:
To a solution of sodium 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer, 4.0 g) in dimethylsulfoxide (40 ml) were added 1-bromoethyl propionate (1.8 g) and sodium iodide (0.18 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into a mixture of cold water and ethyl acetate, and the organic layer was separated. The remaining aqueous layer was extracted with ethyl acetate. The extract and the organic layer were combined, washed with water and dried over magnesium sulfate. The solvent was then distilled off and the residue was subjected to column chromatography using silica gel (50 g), elution being carried out with a mixture of benzene and ethyl acetate (3:2, v/v). The fractions containing the desired product were combined and the solvent was distilled off to give 1-propionyloxyethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 0.83 g), mp 113°-116° C. (decompn.).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:20])[NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[C:1]1([CH2:7][O:8][C:9]([NH:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH:19][S:33]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:35])=[O:34])=[CH:17][CH:18]=2)=[O:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccc(CCNC(=O)OCc2ccccc2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCCc1ccc(NS(=O)(=O)c2ccccc2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.8 %

Procedure:
A solution of 868 mg (3.22. mmol) of Cbz amine from Example 3 in 15 mL of dichloromethane was cooled to 0° C. and treated with 0.286 mL (3.54 mmol) of pyridine followed by 569 mg (0.41 mL, 3.22 mmol) of benzenesulfonyl chloride. The reaction mixture was stirred at room temperature for 2 h and then partitioned between chloroform and water. The organic phase was washed sequentially with 5% aqueous hydrochloric acid and saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated. Purification by recrystallization from ethyl acetate/hexane gave 630 mg (48%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) 7.72 (d, 2H, J=7.2 Hz), 7.48 (m, 1H), 7.39 (m, 2H), 7.33 (m, 5H), 7.02 (d, 2H, J=8.3 Hz), 6.95 (d, 2H, J=8.3 Hz), 6.55 (s, 1H), 5.06 (s, 2H), 4.68 (broad s, 1H), 3.37 (m, 2H), 2.72 (t, 2H, J=6.9 Hz). FAB MS m/z 411 (M+1).
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][CH:7]([OH:17])C1C=CC(O)=C(CO)C=1)([CH3:4])[CH3:3].[C:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=O)C.BrC[C:29]([O:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[OH:39])=O.CC(NCC1C=CC=CC=1)(C)C>>[CH3:29][O:31][C:32](=[O:40])[C:33]1[CH:38]=[C:37]([C:7](=[O:17])[CH2:6][N:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[CH2:18][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:36]=[CH:35][C:34]=1[OH:39]
Reactant: CC(C)(C)NCC(O)c1ccc(O)c(CO)c1
Reactant: O=C(CBr)OC(=O)c1ccccc1O
Reactant: CC(=O)c1ccccc1
Agent: CC(C)(C)NCc1ccccc1
Product: COC(=O)c1cc(C(=O)CN(Cc2ccccc2)C(C)(C)C)ccc1O

Procedure:
Albuterol has been prepared, see Irish Patent Specification No. 31391, Aug. 9, 1972, starting from the appropriate acetophenone derivative methyl-5-(bromoacetyl-2-hydroxybenzoate, by condensation with N-(1,1-dimethylethyl)benzenemethanamine in the presence of base to form the ketonic ester, methyl-5[[(1,1-dimethylethyl)(phenylmethyl)-amino]acetyl]-2-hydroxybenzoate. The ketonic ester is reduced with lithium aluminum hydride in tetrahydrofuran under nitrogen to yield α1 -[[(1,1-dimethylethyl)-(phenylmethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol which is subsequently debenzylated with hydrogen in the presence of palladium on carbon catalyst to produce albuterol.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:8]([N:10]2[CH:14]([C:15](O)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C[CH2:27][N:28](C(C)C)[CH:29](C)C.C(Cl)CCl.CNC>ClCCl.C1COCC1>[CH:1]1([CH2:6][C@@H:7]([C:8]([N:10]2[CH:14]([C:15]([N:28]([CH3:29])[CH3:27])=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)O
Agent: CNC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(C)C(=O)C1CC=NN1C(=O)[C@@H](CC(=O)OC(C)(C)C)CC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of 1-{(2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (353 mg, 1.0 mmol), Hunig's base (0.35 ml, 2.0 mmol), EDC (231 mg, 1.2 mmol) and aza-HOBt (136 mg, 1.0 mmol) in dichloromethane (DCM) (10 ml) was added N-methylmethanamine (1.0 ml, 2.0 mmol), which was in THF. The reaction mixture was stirred at room temperature overnight. The mixture was then washed with water (5 mL), NaHCO3 solution (5 mL×3), and concentrated to provide the crude product which was purified by Combiflash automated silica gel chromatography (0-50% EtOAc in hex) to afford 1,1-dimethylethyl (3R)-3-(cyclopentyl methyl)-4-{5-[(dimethylamino)carbonyl]-4,5-dihydro-1H-pyrazol-1-yl}-4-oxobutanoate (315 mg, 0.83 mmol, 83% yield) as a yellow solid. MS: 380 ([M+H]+).
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].[OH-].[NH4+:13]>C(#N)C>[NH2:13][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)ccc(F)c1F
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC#N
Product: N#Cc1c(F)ccc(F)c1N
Yield: 93 %

Procedure:
2,3,6-Trifluorobenzonitrile (15 g) in ammonium hydroxide solution (28% in water; 80 mL) and acetonitrile (40 mL) was stirred at 70° C. in a pressure vessel for 16 h and the reaction was complete based on GC-MS. Acetonitrile was removed under reduced pressure, and water was added. The white solid precipitate was suction filtered, washed with water and dried under house vacuum over a weekend at room temperature to give 13.7 g (93%) of the crude product; M.P. 90-92° C. GC/MS: m/z 154. 1H NMR (CDCl3): δ 7.07-7.16 (m, 1H), 6.36-6.43 (m, 1H), 4.65 (br s, 2H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20]C1(CC(C)(C)C(C2C=CC=CC=2)=O)OCCO1.Cl>>[CH3:19][O:20][C:9]1[CH:8]=[C:7]([C:2](=[O:6])[CH3:1])[CH:12]=[CH:11][C:10]=1[C:13](=[O:18])[C:14]([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)C(=O)c1ccc(C2(C)OCCO2)cc1
Reactant: COC1(CC(C)(C)C(=O)c2ccccc2)OCCO1
Agent: Cl
Product: COc1cc(C(C)=O)ccc1C(=O)C(C)(C)C

Procedure:
Again following the above procedure and using in place of 4'-(2-methyl-2-dioxolanyl)pivalophenone an equivalent amount of (2-methoxy-2-dioxolanyl)pivalophenone in the presence of a dilute hydrochloric acid in place of concentrated hydrochloric acid, there is obtained 2'-methoxy-4'acetylpivalophenone.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:23]([OH:25])=[O:24])=[CH:6][N:7]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][CH2:34][CH2:35][NH2:36].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:36][CH2:35][CH2:34][NH:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:26])[C:5]([C:23]([OH:25])=[O:24])=[CH:6][N:7]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(Cc3ccccc3)c12
Reactant: NCCNc1ccccn1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1c(NCCNc2ccccn2)c(F)c(N)c2c(=O)c(C(=O)O)cn(Cc3ccccc3)c12
Temperature: 0 °C
Yield: 53.8 %

Procedure:
A solution of 5-amino-1-benzyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (400 mg, 1.11 mmol), N-2-pyridyl-1,2-ethanediamine (305 mg, 2.22 mmol) and triethylamine (0.310 mL, 2.22 mmol) in DMSO (4 mL) was stirred at 100° C. After 4 h the reaction mixture was poured into ice water and the resulting precipitate was removed by filtration, washed with ethanol, and dried to yield 5-amino-1-benzyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylic acid (285 mg, 54%) as a yellow solid.
Reaction SMILES: CC(O)C.[CH2:5]([P:9]([CH2:12][CH:13]([CH3:15])[CH3:14])(=[S:11])[SH:10])[CH:6]([CH3:8])[CH3:7].[OH-].[CH2:17]([N+:21]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20].CCCCCC>O>[CH2:5]([P:9]([CH2:12][CH:13]([CH3:15])[CH3:14])(=[S:10])[S-:11])[CH:6]([CH3:8])[CH3:7].[CH2:30]([N+:21]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:31][CH2:32][CH3:33]
Reactant: CC(C)CP(=S)(S)CC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: CCCCCC
Product: CC(C)CP(=S)([S-])CC(C)C
Reaction time: 1 h

Procedure:
To 40 ml of 2-propanol, 3.63 g diisobutyldithiophosphinic acid and 7.34 g of 55-60% by weight tetrabutylammonium hydroxide in water were added. The mixture was stirred under nitrogen for one hour. The solvent was removed by distillation. To remove residual water, 2-propanol was twice added and subsequently removed by distillation. The liquid was cooled to less than 0 C for 16 hours. To the precipitates that formed, a small amount of hexane was added to give a slurry. The slurry was filtered, washed with hexane, and dried under reduced pressure yielding 6.07 g of a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:24](I)[CH:25]=[CH2:26].O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[N:12]([CH2:26][CH:25]=[CH2:24])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C=CCI
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(=O)c2cccnc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Reaction time: 0.5 h
Yield: 72 %

Procedure:
2.8 g of 1-(m-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was dissolved in 30 ml of dry dimethylformamide. To the solution was added 0.6 g of approximately 50 % sodium hydride and stirring was performed for 30 minutes. To this was added 3.4 g of allyl iodide and the mixture was reacted for 3 hours at room temperature. Then the solvent was evaporated from the mixture under reduced pressure. To the residue obtained was added water to precipitate a crude product. Recrystallization of this product from methanol gave 2.3 g of 1-(m-nitrophenyl)-3-allylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione as pale yellow prisms, melting at 188-189°C.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:4]([CH3:18])=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].[C:28]1([OH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:14]([N:6]1[C:5]2=[C:4]([CH3:18])[N:3]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:2]([O:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7]1=[O:13])[CH:15]([CH3:17])[CH3:16]
Reactant: Oc1ccccc1
Reactant: COc1ccc(Cn2c(Cl)c3c(=O)n(C)c(=O)n(CC(C)C)c3c2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(Cn2c(Oc3ccccc3)c3c(=O)n(C)c(=O)n(CC(C)C)c3c2C)cc1
Temperature: 160 °C
Yield: 74.5 %

Procedure:
5-chloro-1-isobutyl-6-(4-methoxybenzyl)-3,7-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (20 mg, 0.051 mmol) is placed in a Biotage microwave vial, and then phenol (24 mg, 0.25 mmol) and cesium carbonate (50 mg, 0.15 mmol) are added. The mixture is heated at 160° C. in a Biotage microwave instrument for 2 h., and then purified by a semi-preparative HPLC to give 17 mg of pure product as off-white solids. MS (ESI) m/z 448.2 [M+H]+.
Reaction SMILES: [C:1]([O:4][C:5](C(C)(C)C)(C(C)(C)C)[CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13]C(=O)C)(=[O:3])[CH3:2].F[C:26](F)(F)[C:27]([OH:29])=[O:28]>>[CH2:5]([OH:4])[CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13].[CH3:2][C:1]([CH2:26][C:27]([OH:29])=[O:28])=[O:3]
Reactant: CC(=O)OCCOCCOCC(OC(C)=O)(C(C)(C)C)C(C)(C)C
Reactant: O=C(O)C(F)(F)F
Product: CC(=O)CC(=O)O
Product: OCCOCCOCCO

Procedure:
18.9 g. (50 mMole) of the ester (2) are dissolved at ambient temperature in 30 ml. trifluoroacetic acid and stirred for 2 hours. The solution is evaporated at 35° C. under water pump vacuum, the residue is digested three times with, in each case, 100 ml. diethyl ether and dried in a high vacuum at 45° C. The product (3) can be further used without further purification. Yield: 11.2 g. of colourless oil; 84% of theory.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([O:10]CC)=O)[CH3:2].[NH3:13]>CO>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([NH2:13])=[O:10])[CH3:2]
Reactant: N
Reactant: CCOC(=O)[C@@H]1CCCN1CC
Solvent: CO
Product: CCN1CCC[C@H]1C(N)=O
Temperature: 50 °C

Procedure:
Ethyl (-)-(S)-1-ethyl-2-pyrrolidinecarboxylate (3.4 g, 0.02 mol) was added to a cooled solution of MeOH (10 ml) and liquid NH3 (10 ml) in a stainless steel reaction bottle containing 3 g of 3 A molecular sieves. The bottle was heated at 50° C. for 20 h. After cooling the solvent was allowed to evaporate. The product was dissolved in dry MeOH, filtered and the filtrate was evaporated under reduced pressure to give the title compound as white crystals in a quantitative yield (2.8 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:3]=1[C:4]#[N:5].[N:18]([O-])=O.[Na+]>Cl.O>[CH2:11]([O:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[NH:1][N:5]=[C:4]2[NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1cc(OCc2ccccc2)ccc1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Nc1n[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 0 °C
Yield: 109.4 %

Procedure:
To an ice-cooled suspension of 63.27 g (0.282 mol) of 2-amino-5-(benzyloxy)benzonitrile in 500 ml of concentrated hydrochloric acid, a solution of 23.32 g (0.338 mol) of sodium nitrite in 75 ml of water was added dropwise. After 2 hours the cold suspension was added dropwise to a preformed solution of 509.25 g (2.26 mol) of stannous chloride in 380 ml of concentrated HCl, at 2° C. After 3 hours the cold suspension was filtered and the moist solid was treated with 1.8 l of boiling water and 300 ml of ethanol 950 for 30 min. The hot cloudy solution was clarified by filtration through a cloth filter. The liquors were concentrated to eliminate ethanol and treated dropwise with 0.35 l of 35% NaOH at 4° C. The solid was filtered off and dried under vacuum at 50° C.: 73.82 g of product were obtained as light brown solid. mp=193-195° C. HPLC r.t. 4.7 [M]+=240 [2M+H]+=479
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>ClCCl>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:1][CH2:2][C:3]2([C:6]#[N:7])[CH2:5][CH2:4]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CC1(CO)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2(C#N)CC2)cc1
Reaction time: 0.25 h
Yield: 38.6 %

Procedure:
To a solution of 1-(hydroxymethyl)cyclopropanecarbonitrile (1.0 g) in dichloromethane (15 ml) was added pyridine (4.1 ml) at 0° C., and the mixture was stirred at the same temperature for 15 min. To the obtained reaction mixture was added dropwise p-toluenesulfonyl chloride (3.9 g), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5]Cl.[C-:11]#[N:12].[K+]>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][C:11]#[N:12])[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: [C-]#N
Reactant: ClCc1cc(Cl)cc(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: N#CCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a vigorously stirred solution of 3,5-dichlorobenzylchloride (28 g) in dichloromethane (150 ml) was added a mixture of KCN (27.5 g) and tetrabutylammonium hydrogen sulphate (2.38 g) in water (110 ml). After stirring at room temperature for 22 hours, the mixture was diluted with dichloromethane, the organic phase washed with water and concentrated in vacuo to leave an oil. Filtration through silica with toluene followed by concentration then trituration with hexane gave the desired product as a colourless solid. 15.8 g, mp. 31°-32° C.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[C:6]([O:10][CH3:11])(=[O:9])C=C.[CH3:12][CH2:13]CCCC>>[CH3:11][O:10][C:6]([CH:2]1[CH2:1][CH:5]2[CH2:4][CH:3]1[CH:12]=[CH:13]2)=[O:9]
Reactant: C=CC(=O)OC
Reactant: CCCCCC
Reactant: C1=CCC=C1
Product: COC(=O)C1CC2C=CC1C2

Procedure:
In a 1-liter four-necked flask equipped with a Dimorth reflux condenser and a thermometer, 300 ml of cyclopentadiene and 200 ml of n-hexane was placed, and 250 ml of methyl acrylate was added dropwise over one hour while cooled on an ice bath and stirred, and then stirred for a further 30 minutes, to obtain 2-methoxycarbonyl-5-norbornene.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][CH:9]1[O:13][CH2:12][CH2:11][O:10]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH2:30])[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>CS(C)=O>[O:10]1[CH2:11][CH2:12][O:13][CH:9]1[CH2:8][NH:30][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)=[C:16]([O:15][CH3:14])[CH:17]=1
Reactant: BrCC1OCCO1
Reactant: COc1cc(N)ccc1OCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(NCC2OCCO2)ccc1OCCN1CCCC1
Temperature: 80 °C

Procedure:
A suspension of K2CO3 (235 mg, 1.70 mmol), 2-(bromomethyl)-1,3-dioxolane (400 mg, 1.70 mmol), and 3-methoxy-4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (3.0 g, 14.5 mmol), preparation described in PCT application WO 2002/101146, in DMSO (17 mL) was heated at 80° C. for 24 hr. After removal of any precipitate by filtration, the filtrate was partitioned between EtOAc/H2O (100/20 mL). The organic layer was washed with brine and dried over MgSO4. After removal of the solvent under vacuum, the residue was chromatographed on silica gel using 0%-20% gradient EtOAc/Hexanes to elute the title compound as a yellow brownish oil (150 mg, 27%) MS (ESI) 323 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:24])=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1.Cl.[N:27]1([CH2:32][CH2:33][CH2:34][C:35](O)=[O:36])[CH2:31][CH2:30][CH2:29][CH2:28]1.C1(N=C=NC2CCCCC2)CCCCC1.C(Cl)[Cl:54]>CO.C(Cl)(Cl)Cl>[ClH:54].[CH3:25][C:2]1([CH3:1])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:24][C:35](=[O:36])[CH2:34][CH2:33][CH2:32][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1
Reactant: ClCCl
Reactant: O=C(O)CCCN1CCCC1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCCC2)c2c(c1)OC(C)(C)C1=C2CCC1

Procedure:
3.21 g. (9.37 mmole) of 4,4-Dimethyl-9-hydroxy-7-(3-methyl-2-octyl)-1,2,3,4-tetrahydrocyclopenta[c][1]benzopyran was combined with 1.82 g. (9.37 mmole) of γ-pyrrolidinobutyric acid hydrochloride and 2.06 g. (10.0 mmole) of dicyclohexylcarbodiimide in 150 ml. of methylene chloride and stirred at room temperature for 21/2 hours. The insoluble by-product of dicyclohexylurea was removed by filtration and the filtrate was evaporated to give a residue which crystallized upon standing. The material was triturated with ether and filtered. Recrystallization from benzene/ether gave 3.5 g. (72%) of product as colorless crystals, m.p. 138°-141°. The material was pure by thin layer chromatography (10% MeOH/CHCl3); the infrared and nmr spectra are consistent with the proposed structure.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]([NH2:8])=[O:7])=[O:4].CN(C)C=O.[OH:14][C:15]1[C:20]2[C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:26]=3[C:27]([CH3:30])([CH3:29])[O:28][C:19]=2[CH:18]=[C:17]([CH:31]([CH3:39])[CH:32]([CH3:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:16]=1.C(N(CC)CC)C>O>[OH:14][C:15]1[C:20]2[C:21]3[CH2:22][N:23]([CH2:2][C:3]([NH:5][C:6]([NH2:8])=[O:7])=[O:4])[CH2:24][CH2:25][C:26]=3[C:27]([CH3:29])([CH3:30])[O:28][C:19]=2[CH:18]=[C:17]([CH:31]([CH3:39])[CH:32]([CH3:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:16]=1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Reactant: NC(=O)NC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)NC(N)=O)CC1
Reaction time: 24 h

Procedure:
A solution of 1.50 g. (0.011 mole) of chloroacetylurea in 25 ml. of dimethylformamide was added dropwise to a stirred solution of 3.57 g. (0.01 mole) of 10-hydroxy-5,5-dimethyl-8-(1,2-dimethylheptyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine in 20 ml. of dimethylformamide and 1.11 g. (0.011 mole) of triethylamine. After stirring for 24 hours, 65 ml. of water was added dropwise to the stirred mixture. The solid was filtered and recrystallized from acetonitrile, m.p. 131°-133°.