Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH:16]=[CH:17][CH2:18]O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:20][C:21]1[CH:33]=[C:32]([CH2:34][S:35]([NH:38][CH3:39])(=[O:37])=[O:36])[CH:31]=[CH:30][C:22]=1[NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH:16]=[CH:17][CH2:18][N:23]([C:22]1[CH:30]=[CH:31][C:32]([CH2:34][S:35]([NH:38][CH3:39])(=[O:37])=[O:36])=[CH:33][C:21]=1[Br:20])[C:24](=[O:29])[C:25]([F:26])([F:28])[F:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1C=CCO
Reactant: CNS(=O)(=O)Cc1ccc(NC(=O)C(F)(F)F)c(Br)c1
Product: CNS(=O)(=O)Cc1ccc(N(CC=C[C@H]2CCCN2C(=O)OCc2ccccc2)C(=O)C(F)(F)F)c(Br)c1
Yield: 44 %

Procedure:
(R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxypropene and 2-bromo-4-methylaminosulfonylmethyl-N-trifluoroacetylaniline were used. Column chromatography using elution with 4% acetone in methylene chloride afforded the title compound as a white foam (44%): FAB LRMS (m/z, relative intensity) 620 ([MH+ with 81Br], 618 ([MH+ with 79Br], 98), 576 (50), 574 (63), 512 (17), 484 (33).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]2[N:12]=[C:11]([NH:13][C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH3:15])[N:10]=[C:9]([NH:23][C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[CH:8]=2)[CH2:4]1.[CH2:30]([S:32](Cl)(=[O:34])=[O:33])[CH3:31].C(N(CC)C(C)C)(C)C>ClCCCl>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C@@H:14]([NH:13][C:11]2[N:12]=[C:7]([N:5]3[CH2:4][CH:3]([CH2:2][NH:1][S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])[CH2:6]3)[CH:8]=[C:9]([NH:23][C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[N:10]=2)[CH3:15])=[CH:21][CH:20]=1
Reactant: CCS(=O)(=O)Cl
Reactant: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CC(CN)C2)n1)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCS(=O)(=O)NCC1CN(c2cc(Nc3cnccn3)nc(N[C@@H](C)c3ccc(F)cc3)n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
23 mg of (S)-6-[3-(aminomethyl)azetidin-1-yl]-N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine was dissolved in 2 ml of 1,2-dichloroethane, and 8.1 mg of ethanesulfonyl chloride and 22 μl of N,N-diisopropylethylamine were added thereto, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 15 mg of the objective compound as a brown amorphous solid.
Reaction SMILES: CO.[H-].[Na+].[C:5]([N:9]=[N:10][C:11]([N:14]=[C:15]=[O:16])([CH3:13])[CH3:12])([CH3:8])([CH3:7])[CH3:6].[N-]=[C:18]=[O:19]>O>[C:5]([N:9]=[N:10][C:11]([NH:14][C:15]([O:19][CH3:18])=[O:16])([CH3:13])[CH3:12])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)N=NC(C)(C)N=C=O
Reactant: [N-]=C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)NC(C)(C)N=NC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 50 ml of methanol in a 125 ml erlenmeyer flask stirred with a magnetic stirrer was slowly added 3.1 grams (0.075 moles) of 57% sodium hydride. The reaction mixture was cooled back to 25° C. and 12.7 grams (0.075 moles) of 2-t-butylazo-2-isocyanatopropane (from Example XIV) was added dropwise over 5 minutes. The reaction mixture was stirred for approximately 1 hour, poured into 200 ml water and the product extracted with pentane. The pentane extract was washed with water, 10% NaHCO3 solution, dried over anhydrous Na2SO4, filtered and the pentane evaporated under reduced pressure to leave 11.8 grams (78% crude yield) of a yellow liquid. The product contained a strong carbonyl band at approximately 1740 cm-1 and a sharp NH band at approximately 3375 cm-1 in its infrared spectrum and there was no isocyanate band at 2225 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[OH:12].Cl.C[CH2:15][O:16]CC>[C-]#N.[Zn+2].[C-]#N>[OH:12][C:4]1[C:5]([CH:15]=[O:16])=[CH:6][C:7]2[CH2:8][CH2:9][O:10][C:11]=2[C:3]=1[O:2][CH3:1]
Reactant: CCOCC
Reactant: COc1c(O)ccc2c1OCC2
Agent: Cl
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1c(O)c(C=O)cc2c1OCC2
Reaction time: 2 h

Procedure:
A mixture of 2.49 g. (15 mmole) of 2,3-dihydro-7-methoxy-6-benzofuranol, 5.87 g. (50 mmole) zinc cyanide and 100 ml. of dry ether was saturated with hydrogen chloride for 1 hour at 0°, then for 2 hours at room temperature. The mixture was then allowed to stand overnight at room temperature then concentrated in vacuo and the residue treated with 100 ml. of 0.1N HCl for 1 hour at reflux. After cooling, ether extraction provided the product which was purified by chromatography over silica gel (E. Merck 60), eluting with CHCl3, to yield a colorless solid, m.p. 71°-72°.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][N:14]=[N:13][CH:12]=2)=[CH:7][CH:6]=1.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>C(O)(C)(C)C>[C:17]([NH:21][CH2:16][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][N:14]=[N:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)N
Reactant: c1cc(-c2cnns2)ccc1OCC1CO1
Solvent: CC(C)(C)O
Product: CC(C)(C)NCC(O)COc1ccc(-c2cnns2)cc1

Procedure:
A mixture of 1.5 g. of 5-[4(2,3-epoxypropoxy) phenyl]-1,2,3-thiadiazole, 45 ml. of t-butylamine and 5 ml. of t-butanol is stirred at room temperature for 96 hours. It is then evaporated to dryness under reduced pressure and the residue crystallized from methanol-ether to afford the pure 5-[4(3-t-butylamino-2-hydroxypropoxy)phenyl]-1,2,3-thiadiazole, m.p. 133°-134° C; λmax 225-226, 314 nm (ε 760, 12300) ir 3390, 3210, 1655, 1615 cm-1.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:41][O:42][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:10]([NH:12][CH:13]2[C:39](=[O:40])[N:15]3[C:16]([C:23]([O:25][CH:26]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:24])=[C:17]([CH2:20][S:21][CH3:22])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.C(=O)(O)[O-].[Na+]>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:41][O:42][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:10]([NH:12][CH:13]2[C:39](=[O:40])[N:15]3[C:16]([C:23]([O:25][CH:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:24])=[C:17]([CH2:20][S:21][CH3:22])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(N)n3)[C@H]2SC1
Temperature: 35 °C
Yield: 91 %

Procedure:
To a suspension of benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-methylthiomethyl-3-cephem-4-carboxylate (syn isomer) (8.0 g) in methanol (160 ml) wad added conc. hydrochloric acid (5.6 ml), and the mixture was stirred at 35° C. for an hour. The resultant solution was adjusted to pH 5.0 with a saturated aqueous sodium bicarbonate. After distilling methanol under reduced pressure, the residue was dissolved in water (100 ml) and ethyl acetate (200 ml). The ethyl acetate layer was washed with a saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was removed by filtration to give benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-methylthiomethyl-3-cephem-4-carboxylate (syn isomer) (7.0 g), mp 140°-145° C.
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][CH2:26][C:27](OCC)=O)[CH2:22][CH:23]=2)[CH:14]=[CH:15][C:16]=1[F:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][C:27]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:20][CH:19]=2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: ON=C1CCCCCC1
Reactant: CCOC(=O)CCCN1CC=C(c2ccc(F)c(Cl)c2)CC1
Product: Fc1ccc(C2=CCN(CCCc3onc4c3CCCCC4)CC2)cc1Cl

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(3-chloro-4-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate, 3-(3-(4-(3-chloro-4-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=O)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1.[C:23]1([NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH2:29]>[N+](C1C=CC=CC=1)([O-])=O>[NH:29]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:30]=[C:21]1[C:4]1[C:5]2[O:10][CH:9]([C:11]([F:12])([F:14])[F:13])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=[C:2]([Cl:1])[CH:3]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(C=O)c2OC1C(F)(F)F
Reactant: Nc1ccccc1N
Solvent: O=[N+]([O-])c1ccccc1
Product: CCOC(=O)C1=Cc2cc(Cl)cc(-c3nc4ccccc4[nH]3)c2OC1C(F)(F)F
Yield: 43 %

Procedure:
A solution of the aldehyde (Example 76, Step 3) (0.33 g, 0.99 mmol) and 1,2-phenylenediamine (0.11 g, 1.02 mmol) in nitrobenzene (20 mL) was heated to 150° C. for 1.8 hours. The reaction mixture was extracted with ethyl acetate, washed with brine, dried over MgSO4, and concentrated in vacuo and purified by flash chromatography over silica gel (with 1:9 ethyl acetate/hexane as eluant) to give the ester as a brown solid (0.18 g, 43%) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[C:10]1([CH2:16][CH:17]=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O>[CH3:4][C:3]1([CH3:5])[S:6][CH:17]([CH2:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:1][C@H:2]1[C:7]([OH:9])=[O:8]
Reactant: O=CCc1ccccc1
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Solvent: O
Product: CC1(C)SC(Cc2ccccc2)N[C@H]1C(=O)O
Reaction time: 0.5 h

Procedure:
A 250 mL flask was charged with 20 mL of water and 2.0 g (13.4 mmol) of D-penicillamine. To the resulting colorless solution was added 1.6 g (13.3 mmol) of phenyl acetaldehyde dropwise over 2 minutes. The suspension obtained was stirred vigorously for 30 minutes and allowed to stand at room temperature overnight. The solids were collected by suction filtration to yield the crude title thiazolidine which was carried on without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[N:12]([C:13]=1[CH3:14])[CH:11](O)[CH2:10][S:9]2)=[O:5])[CH3:2].O=P(Cl)(Cl)Cl>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[N:12]([C:13]=1[CH3:14])[CH:11]=[CH:10][S:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc2n(c1C)C(O)CS2
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1nc2sccn2c1C

Procedure:
3-hydroxy-5-methyl-2,3-dihydro-imidazo[2,1-b]thiazole-6-carboxylic acid ethyl ester (4.00 mmol) is added to POCl3 (9.3 mL), stirred at reflux for 3 h and concentrated in vacuo. Chloroform and ice-water are added successively and the mixture is neutralized by addition of Na2CO3. The layers are separated and the aq. layer is extracted with chloroform. The combined organic layers are dried over Na2SO4 and concentrated in vacuo to give the desired product which is purified by FC (heptane/EtOAc 1/1 to EtOAc). LC-MS: tR=0.66 min; [M+H]+=211.0.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[C:8]([NH:24][C:25]([NH:27][C:28]2[C:33]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:31]=[CH:30][C:29]=2[CH:37]([CH3:39])[CH3:38])=[O:26])[C:7]1=[O:40])#[N:2].C(=O)([O-])[O-:42].[Na+].[Na+].OO.O>CO.CC(C)=O>[NH2:2][C:1]([CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][N:14]=2)[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[C:8]([NH:24][C:25]([NH:27][C:28]2[C:29]([CH:37]([CH3:39])[CH3:38])=[CH:30][CH:31]=[CH:32][C:33]=2[CH:34]([CH3:36])[CH3:35])=[O:26])[C:7]1=[O:40])=[O:42]
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CCCC#N)c3ncccc23)c1
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CO
Product: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CCCC(N)=O)c3ncccc23)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-[1-(3-cyanopropyl)-4-(3-methoxyphenyl)-l,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (100 mg, 0.19 mmol) in methanol-acetone (3 ml) were added 10% aqueous sodium carbonate solution (1 ml) and 30% hydrogen peroxide (1 ml), and the mixture was stirred at room temperature for three hours. The mixture was poured into water, and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The residue was concentrated under reduced pressure, and purified by preparative thin layer chromatography to give the title compound (96 mg, 0.17 mmol).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[CH:15]=[C:14]([C:16]3[C:21]([OH:22])=[CH:20][C:19]([OH:23])=[CH:18][C:17]=3[O:24][C:25]3[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=3)[O:13][N:12]=2)=[O:10])[CH2:4][CH2:3]1.[O:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1.C=O>>[OH:22][C:21]1[CH:20]=[C:19]([OH:23])[CH:18]=[C:17]([O:24][C:25]2[CH:26]=[CH:27][C:28]([NH:31][CH:35]3[CH2:36][CH2:37][O:32][CH2:33][CH2:34]3)=[CH:29][CH:30]=2)[C:16]=1[C:14]1[O:13][N:12]=[C:11]([C:9]([NH:8][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:10])[CH:15]=1
Reactant: O=C1CCOCC1
Reactant: CN1CCC(NC(=O)c2cc(-c3c(O)cc(O)cc3Oc3ccc(N)cc3)on2)CC1
Agent: C=O
Product: CN1CCC(NC(=O)c2cc(-c3c(O)cc(O)cc3Oc3ccc(NC4CCOCC4)cc3)on2)CC1
Yield: 53 %

Procedure:
Operating as in Example 24 Step 4, but employing N-(1-methylpiperidin-4-yl)-5-{2-[4-(amino)phenoxy]-4,6-dihydroxyphenyl}isoxazole-3-carboxamide instead of tert-butyl 4-{[(5-{2,4-bis[(2-methoxyethoxy)methoxy]-6-(4-aminophenoxy)phenyl}isoxazol-3-yl)carbonyl]amino}piperidine-1-carboxylate and tetrahydro-pyran-4-one instead formaldehyde, the title compound was obtained in 53% yield.
Reaction SMILES: C(N[C:4]([NH:9][CH2:10][C:11]#C)=[N:5][CH2:6][CH2:7]S)#N.[C:13]([NH:15][C:16]([NH:21][CH2:22][CH2:23][C:24]#[CH:25])=[N:17][CH2:18][CH2:19][SH:20])#[N:14]>>[C:13]([NH:15][C:16]([NH:17][CH2:18][CH2:19][S:20][CH2:11][C:10]1[NH:9][CH:4]=[N:5][C:6]=1[CH3:7])=[N:21][CH2:22][CH2:23][C:24]#[CH:25])#[N:14]
Reactant: C#CCNC(=NCCS)NC#N
Reactant: C#CCCNC(=NCCS)NC#N
Product: C#CCCN=C(NC#N)NCCSCc1[nH]cnc1C

Procedure:
The general procedure of Example 1C is repeated except that the N-cyano-N'-propargyl-N"-(2-mercaptoethyl)guanidine utilized therein is replaced by an equimolar amount of N-cyano-N'-(3-butyn-1-yl)-N"-(2-mercaptoethyl)guanidine, and the title product is thereby produced.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:20])[N:8]([CH2:18][CH3:19])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=O)C.[NH3:21]>>[CH2:18]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)[C:15]([OH:16])=[C:6]([C:4]([NH2:21])=[O:3])[C:7]1=[O:20])[CH3:19]
Reactant: CCOC(=O)c1c(O)c2ccc(C)nc2n(CC)c1=O
Reactant: N
Product: CCn1c(=O)c(C(N)=O)c(O)c2ccc(C)nc21
Reaction time: 4 h

Procedure:
A mixture of 1 g. of 1-ethyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester (prepared as in Example 1) in 20 ml. of a saturated ethanolic ammonia solution was heated in an autoclave placed in a steam bath for 4 hours. The mixture was cooled and was filtered. The filter cake was triturated with 50 ml. of a 20% aqueous acetic acid solution. The insoluble material was collected, air dried and was recrystallized from ethanol to afford 0.4 g. of the title compound, m.p. 240°-2° C.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[O:15]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:25]3[CH2:26][CH2:27][CH:22]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][CH2:24]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: c1ccc(OC2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(Oc2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(phenoxy)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 69% overall yield. FDMS m/e=366 (M+ of free base). α[D]589 =-14.29 (c=0.5, methanol).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].O.O.[OH-].[Li+].Cl>O1CCOCC1.CO>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][C:5]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C1(Cc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)O)CC1
Temperature: 50 °C
Reaction time: 48 h
Yield: 87 %

Procedure:
To a solution of 4-benzylpiperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (1.772 g, 5.315 mmol) in dioxane (24 ml), methanol (12 ml), and water (12 ml) at room temperature was added lithium hydroxide monohydrate (4.460 g, 106.292 mmol). After stirring at 50° C. for 2 days the solution was acidified to pH 6 using 2M HCl and the resulting white precipitate extracted with diethyl ether (2×100 ml). The organic phases were combined, dried over sodium sulphate and concentrated to dryness to give the acid as a white solid (1.477 g, 87%). LC/MS (LCT): Rt 7.37 [M+H]+ 319.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[CH3:30].C1C([N+]([O-])=O)=CC=C([Cl-][C:41]([O-])=[O:42])C=1.[CH3:44][C:45]([CH3:49])([CH3:48])[CH2:46][NH2:47]>ClCCl>[C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:41]([NH:47][CH2:46][C:45]([CH3:49])([CH3:48])[CH3:44])=[O:42])=[C:3]([CH3:30])[CH:4]=3)[CH2:9][CH2:10]2)[CH:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)CN
Reactant: Cc1cc(C(=O)N2CCN(Cc3cccc(C(=O)NC(C)(C)C)c3)CC2)ccc1N
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCN(Cc3cccc(C(=O)NC(C)(C)C)c3)CC2)ccc1NC(=O)NCC(C)(C)C
Reaction time: 1 h
Yield: 14.4 %

Procedure:
To a stirred solution of 3-((4-(4-amino-3-methylbenzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide (0.153 mmols 62.5 mg) in dichloromethane (2 mL) was added 4-nitrophenylchloroformate (0,153 mmol, 30.8 mg). After 1 hour stirring, 2,2-dimethylpropan-1-amine (0.306 mmol, 26.7 mg) was added and stirring continued for 1 hour. The reaction was concentrated under vacuum and the residue dissolved in methanol (1 mL). Purification by basic reverse phase HPLC gave the title compound (11.5 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8](OS(C(F)(F)F)(=O)=O)=[CH:7][C:6]=1[Cl:21].[CH3:23][N:24](C=O)C>[Cl-].[Na+].O.[C-]#N.[C-]#N.[Zn+2].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>[Cl:21][C:6]1[CH:7]=[C:8]([C:23]#[N:24])[C:9]([O:11][CH3:12])=[CH:10][C:5]=1[CH2:4][C:3]([O:2][CH3:1])=[O:22]
Reactant: COC(=O)Cc1cc(OC)c(OS(=O)(=O)C(F)(F)F)cc1Cl
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Cl-]
Solvent: O
Product: COC(=O)Cc1cc(OC)c(C#N)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of methyl(2-chloro-5-methoxy-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)acetate (200 mg, 0.551 mmol), Zn(CN)2 (39 mg, 0.331 mmol) and Pd(PPh3)4 (50 mg, 0.043 mmol) in 10 mL of DMF was heated at 110˜120° C. under N2 overnight. Cooled to ambient temperature and the mixture was poured into brine (50 mL) and extracted with EtOAc (3*50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-TLC to give methyl (2-chloro-4-cyano-5-methoxyphenyl)acetate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[CH:15]=O)[CH3:2].CC([O-])(C)C.[K+]>C(COC)OC>[CH2:1]([O:3][C:4]([C:5]1[O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[CH:15]=1)=[O:17])[CH3:2]
Reactant: CCOC(=O)COc1ccc(OC)cc1C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCOC(=O)c1cc2cc(OC)ccc2o1
Yield: 25.5 %

Procedure:
The above prepared (2-formyl-4-methoxy-phenoxy)-acetic acid ethyl ester (34.36 g, 144 mmol) was dissolved in 340 mL of dimethoxyethane and treated at −15° C. with KOtBu (6.47 g, 0.4 eq.). After 15 Min., the reaction mixture was poured onto crashed ice/NH4Cl, twofold extracted with AcOEt, washed with water and brine, dried over magnesium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=9/1) gave finally 8.10 g of the title compound as white crystals.
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([Br:19])[CH:18]=[C:11]3[C:12]=2[C:7](=[CH:8][CH:9]=[C:10]3[N+:20]([O-])=O)[C:6]1=[O:23])[CH:2]=[CH2:3].N1[CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:4][N:5]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([Br:19])[CH:18]=[C:11]3[C:12]=2[C:7](=[CH:8][CH:9]=[C:10]3[N:20]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[C:6]1=[O:23])[CH:2]=[CH2:3]
Reactant: C=CCON1C(=O)c2ccc([N+](=O)[O-])c3cc(Br)cc(c23)C1=O
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCON1C(=O)c2ccc(N3CCCC3)c3cc(Br)cc(c23)C1=O

Procedure:
Following the procedure of Example W1, a mixture of the 2-allyloxy-5-bromo-7-nitro-benzo[de] isoquinoline-1,3-dione from above, pyrrolidine (0.43 g, 6.0 mmol) and triethyl amine (1.2 g, 12 mmol) in DMF (10 mL) was reacted to give 0.91 g of the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH:5]=[N:4][C:3]1=2.[CH2:25]([O:27][C:28](=[O:35])[CH:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1)[CH3:26]>CS(C)=O>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([N:31]3[CH2:32][CH2:33][CH2:34][CH:29]([C:28]([O:27][CH2:25][CH3:26])=[O:35])[CH2:30]3)=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: CCOC(=O)C1CCCNC1
Reactant: O=C(CCn1cnc2c(=O)[nH]cnc21)Oc1ccc([N+](=O)[O-])cc1
Solvent: CS(C)=O
Product: CCOC(=O)C1CCCN(C(=O)CCn2cnc3c(=O)[nH]cnc32)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
0.300 g (0.9111 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, 4-nitrophenyl ester (AIT-0081) was placed into a 10 ml round bottom flask with 2 ml dry dimethylsulfoxide and a magnetic stirring bar. 150 mg of (+ -)-ethylnipecotate was added to the solution. The solution immediately turned green and was stirred at room temperature (25°) for two hours. The dimethylsulfoxide was removed under reduced pressure with gentle heating. 10 ml of ether was added to the yellow residue and the solid was broken up with a spatula. The solution was stirred until a fine white homogeneous precipitate was obtained. The solution was filtered and the solid washed with ether to yield 285 mg of 1-[3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-1-oxopropyl]-3-piperidinecarboxylic acid, ethyl ester (AIT-0103) as a white solid. Yield: 90%. m.p.: 171°-175°.