Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([OH:17])[CH2:13][N+:14]([O-:16])=[O:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.N1C=CN=C1.[CH2:23]([Si:25](Cl)([CH2:28][CH3:29])[CH2:26][CH3:27])[CH3:24]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([O:17][Si:25]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:23][CH3:24])[CH2:13][N+:14]([O-:16])=[O:15])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CC[Si](Cl)(CC)CC
Reactant: O=[N+]([O-])CC(O)c1c(Cl)cnc2ccccc12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)OC(C[N+](=O)[O-])c1c(Cl)cnc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a brown clear solution of 1-(3-chloroquinolin-4-yl)-2-nitroethanol (A275-4) (0.423 g, 1.68 mmol) in DMF (4.19 mL) at room temperature was added imidazole (0.342 g, 5.03 mmol) and triethylsilyl chloride (0.341 mL, 2.01 mmol). The mixture was stirred at room temperature. After 2 h, the mixture was quenched with water (50 mL) and extracted with EtOAc (2×50 mL). The organic extract washed with 1 M LiCl (1×50 mL) and brine (1×50 mL), and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a yellow syrup. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a REDISEP pre-packed silica gel column (40 g), eluting with a gradient of 0% to 10% EtOAc in hexane, and dried under high vacuum to give 3-chloro-4-(2-nitro-1-((triethylsilyl)oxy)ethyl)quinoline (A275-5). 1H NMR (400 MHz, DMSO-d6) δ 8.95 (1H, s), 8.67 (1H, d, J=7.4 Hz), 8.10 (1H, dd, J=8.4, 0.8 Hz), 7.84 (1H, td, J=7.6, 1.4 Hz), 7.71-7.79 (1H, m), 6.38 (1H, dd, J=9.8, 2.5 Hz), 5.14-5.23 (1H, m), 5.03-5.11 (1H, m), 0.65-0.74 (9H, m), 0.32-0.51 (6H, m); LCMS (ESI) m/z 367.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH2:21]([NH2:27])[C:22]1[O:26][CH:25]=[CH:24][CH:23]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:27][CH2:21][C:22]2[O:26][CH:25]=[CH:24][CH:23]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCc1ccco1
Product: O=C(NCc1ccco1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (100 mg, 0.27 mmol) and Furfuryl amine (31 mg, 0.32 mmol). The title compound was obtained as a solid (45 mg, 39% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.34 (1H, m), 8.99 (2H, m), 8.48 (1H, s), 7.58 (1H, m), 6.39 (1H, m), 6.29 (1H, m), 4.39 (2H, m). MS m/z: 428.04, 429.99 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20](=S)[NH:19][C:18]3=[O:28])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:35]>C(Cl)(Cl)Cl.CO>[C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([NH2:35])=[N:19][C:18]3=[O:28])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c(=S)c2ccccc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Nc1nc(=O)n(CCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc12

Procedure:
A solution of 1-[3-{4-(diphenylmethyl)piperazin-1-yl}propyl]-4-thioxo-3,4-dihydro-2(1H)-quinazolinone (1.2 g) in chloroform (25 ml) and 20% ammonia in methanol (30 ml) was heated in an autoclave for 15 hours at 100° C. The reaction mixture was concentrated in vacuo and the residue was purified by subjecting to a column chromatography on silica gel using 5% methanol in chloroform for elution to give an oily residue. This oily residue was dissolved in methanol and this solution was acidified with conc.hydrochloric acid solution and then concentrated in vacuo to give a crystal of the object compound, which was recrystallized twice from a mixture of water and isoporpyl alcohol to give 1-[3-{4-(diphenylmethyl)piperazin-1-yl}propyl]4-amino-2(1H)-quinazolinone.2HCl.H2O (0.6 g). m.p. 190°-196° C.
Reaction SMILES: ClC1C=CC=C2C=1NC([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=C2.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][N:26]2[CH3:31]>>[CH3:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[C:25]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)[N:26]2[CH3:31]
Reactant: COc1cccc2c1ccn2C
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Product: COc1cccc2c1cc(B1OC(C)(C)C(C)(C)O1)n2C

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 4-methoxy-1-methyl-1H-indole.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[N+:12]([O-])([O-:14])=[O:13].[K+]>[OH-].[NH4+]>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: O=[N+]([O-])[O-]
Reactant: Brc1cccc2cnccc12
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc(Br)c2ccncc12
Reaction time: 1 h

Procedure:
The diethyl ether solution from Example 57A was treated with potassium nitrate (10.1 g, 100 mmol). After stirring for one hour, The mixture was poured onto ice and neutralized with concentrated ammonium hydroxide (˜300 ml). The crude product was collected by filtration, dried, and recrystalization from methanol to provide the title compound (8.83 g).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[CH2:3][CH2:4][CH:5]([NH:23][C:24]1[CH:42]=[CH:41][C:27]([C:28]([N:30]2[CH2:35][CH2:34][CH2:33][C@@H:32]([C:36]([O:38]CC)=[O:37])[CH2:31]2)=[O:29])=[CH:26][CH:25]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:8][C:7]=1[CH3:22].C(O)C.[OH-].[Na+].Cl>O1CCCC1>[F:44][C:2]([F:1])([F:43])[CH2:3][CH2:4][CH:5]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([N:30]2[CH2:35][CH2:34][CH2:33][C@@H:32]([C:36]([OH:38])=[O:37])[CH2:31]2)=[O:29])=[CH:41][CH:42]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][N:13]=2)=[CH:8][C:7]=1[CH3:22]
Reactant: CCOC(=O)[C@@H]1CCCN(C(=O)c2ccc(NC(CCC(F)(F)F)c3ccc(-c4ccc(C(F)(F)F)cn4)cc3C)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cn2)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)N2CCC[C@@H](C(=O)O)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
To a reaction mixture of ethyl (3R)-1-(4-((4,4,4-trifluoro-1-(2-methyl-4-(5-(trifluoromethyl)pyridin-2-yl)phenyl)butyl)amino)benzoyl)piperidine-3-carboxylate (0.100 g), ethanol (0.7 mL) and tetrahydrofuran (0.7 mL) was added 1M aqueous sodium hydroxide solution (0.322 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was neutralized with 1M hydrochloric acid at 0° C., and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.055 g).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[C:10](Cl)[S:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Na+].[CH3:18][N:19]([CH3:23])[C:20](=[S:22])[S-:21].[I-].[Na+]>C(O)C>[CH2:1]([N:8]1[C:12](=[O:13])[CH:11]=[C:10]([S:22][C:20](=[S:21])[N:19]([CH3:23])[CH3:18])[S:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(Cl)sn1Cc1ccccc1
Reactant: CN(C)C(=S)[S-]
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(C)C(=S)Sc1cc(=O)n(Cc2ccccc2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a solution of 6.76 g. (0.03 mole) of 2-benzyl-5-chloro-4-isothiazolin-3-one in 25 ml of ethanol was added a solution of 5.37 g. (0.03 mole) of N,N-dimethyldithiocarbamic acid sodium salt dihydrate in 30 ml of ethanol followed by 0.1 g. of sodium iodide. A yellow solid separated spontaneously. The mixture was stirred at room temperature for 3 hours, then cooled and filtered. The solid was triturated with 50 ml of water and recrystallized from 250 ml of boiling EtOH to give 5.6 g. (60% yield) of the named product, mp 184°-186°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[C:9]1=[O:13]
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: N#Cc1cccc(Br)c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2cccc(C#N)c2)C1=O
Yield: 50.9 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 100 mg, 0.5643 mmol) was reacted with 3-bromo-benzonitrile (115 mg, 0.6317 mmol), 1,4-dioxane (20 mL), copper iodide (10.7 mg, 0.0564 mmol), trans-1,2-diamino cyclohexane (19.4 mg, 0.169 mmol) and potassium phosphate (300 mg, 1.413 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3), followed by preparative HPLC afforded 80 mg of the product (49% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][N:12]=[N+]=[N-])[CH:5]=[C:6]([F:8])[CH:7]=1>CO>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH2:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: [N-]=[N+]=NCCCc1cc(F)cc(F)c1
Solvent: CO
Product: NCCCc1cc(F)cc(F)c1
Yield: 96.2 %

Procedure:
3-(3,5-Difluorophenyl)propylazide (0.034 mol) in methanol (75 ml) was shaken with a slurry of methanol washed Raney nickel under 50 psi hydrogen for 2 hours. The reaction mixture was filtered and the filtrate concentrated to yield 5.6 g (96%) of an oily product.
Reaction SMILES: [CH2:1]([N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:9](=O)[C:7]1=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[C:19]1([CH2:25][C:26]([NH:28][NH2:29])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](/[C:9](=[N:29]/[NH:28][C:26](=[O:27])[CH2:25][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)/[C:7](=[O:8])[N:6]2[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:12][CH:13]=1
Reactant: NNC(=O)Cc1ccccc1
Reactant: CCCCCN1C(=O)C(=O)c2ccc(OC)cc21
Product: CCCCCN1C(=O)/C(=N\NC(=O)Cc2ccccc2)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a yellow solid, using 1-pentyl-6-methoxy-isatin obtained in Example 39(A) and Phenylacetic hydrazide according to the synthetic method E. NMR (CDCl3): δ 0.91 (t, 3H), 1.33 to 1.39 (m, 4H), 1.66-1.69 (m, 2H), 3.62-3.76 (m, 2H), 3.85-3.88 (m, 3H), 4.14 and 4.23 (s for isomers, 1H), 6.38-6.64 (m, 2H), 7.22-7.26 (m 1H), 7.32 (m, 2H), 7.38-7.39 (m, 1H), 7.42 (d, 1H), 7.54 and 7.56 (d for isomers, 1H), 9.25 and 12.44 and 12.99 (br s for isomers, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:12]([O:14][CH3:15])=[O:13])=[C:5]([CH3:11])[NH:6]2.[H-].[Na+].[CH3:18]I>CN(C=O)C.[NH4+].[Cl-]>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:12]([O:14][CH3:15])=[O:13])=[C:5]([CH3:11])[N:6]2[CH3:18]
Reactant: CI
Reactant: COC(=O)c1c(C)[nH]c2cccc(Cl)c12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)n(C)c2cccc(Cl)c12
Reaction time: 0.5 h
Yield: 72 %

Procedure:
Methyl 4-chloro-2-methyl-1H-indole-3-carboxylate (13.45 mmol, 1.0 equiv.) was dissolved in DMF (7 ml) and added at 0° C. to a suspension of NaH (26.90 mmol, 2.0 equiv.) in DMF (13 ml). The mixture was then stirred for 30 min. Methyl iodide (20.17 mmol, 1.5 equiv.) was added dropwise at 0° C. and stirring was carried out for 2 h at 25° C. The reaction mixture was diluted with NH4Cl solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic phases were washed with water and sat. NaCl solution (in each case 50 ml), dried over Na2SO4 and concentrated to dryness under reduced pressure. Yield: 72%
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([NH2:27])=[N:24][O:25][N:26]=2)=[CH:18][CH:17]=1>>[NH2:27][C:23]1[C:22]([C:19]2[CH:20]=[CH:21][C:16]([NH:15][CH:2]3[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]3)=[CH:17][CH:18]=2)=[N:26][O:25][N:24]=1
Reactant: Nc1ccc(-c2nonc2N)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Product: CC(C)(C)OC(=O)N1CCCC(Nc2ccc(-c3nonc3N)cc2)C1

Procedure:
Reaction of tert-butyl 3-oxopiperidine-1-carboxylate and 4-(4-aminophenyl)-1,2,5-oxadiazol-3-amine using the method of Example 3 afforded the title compound.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]2[CH:32]=[CH:31][O:30][N:29]=2)[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO.O1CCCC1>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]2[CH:32]=[CH:31][O:30][N:29]=2)[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: O=CNc1nc(C(=NOCc2ccon2)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(C(=NOCc2ccon2)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Yield: 73.5 %

Procedure:
A solution of 7-[2-(2-formamidothiazol-4-yl)-2-(3-isoxazolylmethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.20 g.) and conc. hydrochloric acid (1.09 g.) in methanol (18 ml.) and tetrahydrofuran (9 ml.) was stirred at room temperature for 2 hours. The solution was treated in a similar manner to that of Example 5-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-(3-isoxazolylmethoxyimino)-acetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.83 g.).
Reaction SMILES: [CH3:1][Si:2]([CH3:24])([CH3:23])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[C:7]([C:20](O)=[O:21])=[CH:6]2.[NH2:25][C:26]1[CH:27]=[N:28][C:29]([N:32]([CH3:34])[CH3:33])=[CH:30][CH:31]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:33][N:32]([CH3:34])[C:29]1[N:28]=[CH:27][C:26]([NH:25][C:20]([C:7]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:9]3[C:5]([CH:6]=2)=[CH:4][C:3]([Si:2]([CH3:23])([CH3:24])[CH3:1])=[CH:11][CH:10]=3)=[O:21])=[CH:31][CH:30]=1
Reactant: CN(C)c1ccc(N)cn1
Reactant: C[Si](C)(C)c1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(C)c1ccc(NC(=O)c2cc3cc([Si](C)(C)C)ccc3n2Cc2cccc(F)c2)cn1
Yield: 49.3 %

Procedure:
Compound No. 7 was prepared according to a process similar to that described in stage 5.4, by reacting 0.3 g (0.88 mmol) of 5-trimethylsilyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid, prepared according to the protocol described in stage 3.6, with 181 mg (1.32 mmol) of 3-amino-6-(dimethylamino)pyridine in the presence of 185 mg (0.97 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) and of 131 mg (0.97 mmol) of 1-hydroxybenzotriazole (HOBT) in 10 ml of dimethylformamide. The product obtained is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and acetone. The solid obtained after evaporation of the solvent under reduced pressure is recrystallized from isopropyl alcohol. 200 mg of the expected product are thus isolated.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](SC)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Na].[CH2:22]([OH:24])[CH3:23]>>[NH2:1][C:2]1[N:3]=[C:4]([O:24][CH2:22][CH3:23])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CCO
Reactant: CSc1nc(N)nc2ccc(-c3ccc(F)cc3)nc12
Agent: [Na]
Product: CCOc1nc(N)nc2ccc(-c3ccc(F)cc3)nc12
Yield: 72 %

Procedure:
To a solution of the 2-amino-4-methylthio-6-(4-fluorophenyl)-pyrido(3,2-d)pyrimidine of example 8 (700 mg) in ethanol (20 ml) was added 276 mg sodium. The reaction mixture was refluxed for 5 hours and then cooled down. The solvents were evaporated in vacuo and the crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of ethanol and dichloromethane, in a volume ratio gradually ranging from 3% to 5% ethanol, thus providing 490 mg of the pure title compound (72% yield), which was characterized by its mass spectrum as follows: MS (m/z): 285 ([M+H]+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11](=[O:24])[N:10]([CH2:25][CH2:26][CH2:27][CH3:28])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>>[CH2:17]([N:12]1[C:13](=[O:16])[C:14]2[NH:15][C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:30][CH:29]=3)=[N:8][C:9]=2[N:10]([CH2:25][CH2:26][CH2:27][CH3:28])[C:11]1=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCCCn1c(=O)n(Cc2ccccc2)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2)c(=O)c2[nH]c(Cc3ccc(NS(C)(=O)=O)cc3)nc21
Yield: 35 %

Procedure:
8-(4-Amino-benzyl)-1-benzyl-3-butyl-3,7-dihydro-purine-2,6-dione was condensed with methanesulfonyl chloride under the conditions previously described to give the stated sulfonamide as a pale brown solid (35%); 1H NMR(DMSO-d6, 300 MHz) δH13.54 (s, 1H), 9.76 (s, 1H), 7.45–7.25 (m, 7H), 7.22 (d, J=8.4 Hz, 2H), 5.14 (s, 2H), 4.10 (s, 2H), 4.04 (t, J=7.1 Hz, 2H), 3.03 (s, 3H), 1.80–1.65 (m, 2H), 1.40–1.25 (m, 2H), 0.96 (t, J=7.3 Hz, 3H); EI-HRMS m/e calculated for C24H27N5O4S (M+) 481.1784, found 481.1781.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7](Cl)=[O:8].C(N(CC)CC)C.[OH:26][CH:27]([CH2:35][OH:36])[CH2:28][NH:29][CH2:30][CH:31]([OH:34])[CH2:32][OH:33].C(#N)C>O1CCOCC1.O>[NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([N:29]([CH2:28][CH:27]([OH:26])[CH2:35][OH:36])[CH2:30][CH:31]([OH:34])[CH2:32][OH:33])=[O:8]
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)Cl)c1I
Reactant: OCC(O)CNCC(O)CO
Solvent: C1COCCO1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)N(CC(O)CO)CC(O)CO)c1I
Temperature: 90 °C
Reaction time: 17 h
Yield: 92.8 %

Procedure:
5-Amino-3-acetoxymethyl-2,4,6-triiodobenzoyl chloride (19.9 g, 32.9 mmol) was dissolved in dioxane (45 ml) and triethylamine (3.32 g, 32.9 mmol) was added. To this solution was added bis-(2,3-dihydroxypropyl)amine (5.43 g, 32.9 mmol), and the mixture was stirred at 90° C. for 17 h. After cooling to room temperature, acetonitrile (150 ml), water (70 ml), and a strongly acidic ion exchange resin (Amberlyst 15, 60 g) were added to bring the pH to 4. After stirring at room temperature for 20 min, the resin was filtered off and the filtrate was evaporated to dryness. The semicrystalline dark residue was filtered through a short column of silica using a mixture of methylene chloride and methanol (70/30) as the eluent. The solvent was evaporated and 22.4 g (93%) of a tan coloured crystalline product was obtained. This product was acetylated without further purification.
Reaction SMILES: O[C:2]1[C:7](CCC(C)C)=[C:6]([O:13][CH2:14][O:15][CH3:16])[CH:5]=[C:4](OCOC)[C:3]=1[C:21](=[O:23])C>CO>[CH3:16][O:15][CH2:14][O:13][C:6]1[CH:7]=[CH:2][C:3]([CH:21]=[O:23])=[CH:4][CH:5]=1
Reactant: COCOc1cc(OCOC)c(C(C)=O)c(O)c1CCC(C)C
Solvent: CO
Product: COCOc1ccc(C=O)cc1
Yield: 100.3 %

Procedure:
In 3 ml of methanol were dissolved 1.40 g of the 2'-hydroxy-4',6'-bis(methoxymethoxy)-3'-isopentylacetophenone obtained in Production Example 16 and 715 mg of the p-methoxymethoxybenzaldehyde obtained in Production Example 25, and a 50% ethanol solution of sodium hydroxide (4.0 g/8 ml) was added to the solution and the mixture was stirred at room temperature for 1 day to effect a reaction.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]2[C:9]([CH3:12])=[N:10][O:11][C:7]=2[CH:6]=1)(=[O:3])[CH3:2].[Li+].CC([N-]C(C)C)C.I[CH2:24][C:25]1[N:26]=[C:27]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=2[Cl:40])[O:28][C:29]=1[CH:30]([CH3:32])[CH3:31].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]2[C:9]([CH2:12][CH2:24][C:25]3[N:26]=[C:27]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=4[Cl:40])[O:28][C:29]=3[CH:30]([CH3:32])[CH3:31])=[N:10][O:11][C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(C)noc2c1
Reactant: CC(C)c1oc(-c2ccc(Cl)cc2Cl)nc1CI
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2c(CCc3nc(-c4ccc(Cl)cc4Cl)oc3C(C)C)noc2c1
Reaction time: 1 h
Yield: 65.7 %

Procedure:
6-Acetamido-3-methyl-1,2-benzisoxazole (571 mg, 3.00 mmol) was dissolved in dry THF (18 mL). 2M of LDA (3.1 mL, 6.2 mmol) was dropwise added to the solution for 10 minutes under nitrogen atmosphere at −78° C. A solution of 4-iodomethyl-5-isopropyl-2-(2,4-dichlorophenyl)oxazole (1.19 g, 3.00 mmol) in THF (3.0 mL) was dropwise added to the resulting mixture for 7 minutes. The mixture was stirred for 1 hour under the same conditions. The mixture was allowed to room temperature. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the mixture. The organic layer was washed with water and saline, and dried over anhydrous sodium sulfate. Ethyl acetate was removed under reduced pressure. The residue was purified by column chromatography on silica gel with chloroform/methanol (80/1) to give the desired compound (904 mg) as pale yellow oil (yield 70%).
Reaction SMILES: [OH-].[Li+].C([O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][C:8]=1[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])(=O)C.C1COCC1.CO.O.Cl>C1COCC1>[OH:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=1[CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20]
Reactant: COC(=O)c1ccc(OC(C)=O)c(CC=C(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)=CCc1cc(C(=O)O)ccc1O
Temperature: 25 °C
Yield: 75.4 %

Procedure:
Lithium hydroxide (85 mg, 2.02 mmol) was added to a mixture of methyl ester 7 (106 mg, 0.405 mmol) in 0.5 mL of a 3/1/1 THF/MeOH/H2O solution. The reaction mixture was stirred at reflux for 14 hours, cooled to room temperature, and diluted with THF (1 mL). The solution was acidified the solution to pH=3 by the dropwise addition of 6 M HCl. The layers were separated and the organic phase was dried (Na2SO4), filtered, and concentrated to afford acid 8 (63 mg, 75%) as a red oil that was suitable for use without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[C:15]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=3)=[C:17]([CH3:18])[N:8]1[CH2:7][CH2:6]2>CO.[Pd]>[NH2:25][C:21]1[CH:20]=[C:19]([C:16]2[C:15]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:9]3[C:10]4[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=4)[CH2:6][CH2:7][N:8]3[C:17]=2[CH3:18])[CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1c(-c2cccc([N+](=O)[O-])c2)c(C)n2c1-c1cc(OC)c(OC)cc1CC2
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1c(-c2cccc(N)c2)c(C)n2c1-c1cc(OC)c(OC)cc1CC2

Procedure:
4.5 g (10.31 mmol) of ethyl 8,9-dimethoxy-3-methyl-2-(3-nitrophenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-1-carboxylate (Example 2) were dissolved in 500 mL of warm methanol, 2.03 g of 10% strength palladium on charcoal were added, and the compound was hydrogenated at atmospheric pressure. The reaction mixture was filtered through a filter aid, the filtrate was evaporated under reduced pressure to a volume of approx. 150 mL, and the resulting precipitate was filtered off to give the title compound.