Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:17]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:16][CH:15]=[C:14]([CH3:24])[N:13]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[N:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1
Reactant: Cc1ccc(-c2cccnc2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: Cc1ccc(-c2cccnc2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(C(F)(F)F)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-[3,3′-bipyridin]-2-yl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 471 [M+1]+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.[Na+]>CS(C)=O.C(OCC)(=O)C.[Cu]I>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: O=S([O-])c1ccc(Br)cc1
Reactant: O=Cc1cccc(I)c1
Agent: [Cu]I
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=Cc1cccc(S(=O)(=O)c2ccc(Br)cc2)c1
Temperature: 110 °C
Yield: 35.8 %

Procedure:
3-Iodobenzaldehyde (1.0 g, 4.3 mmol), copper(I) iodide (2.45 g, 12.9 mmol) and sodium 4-bromophenylsulfinate (1.55 g, 5.59 mmol) were combined in dimethylsulfoxide (8.6 mL) and heated to 110° C. for 4 hours. The cooled reaction mixture was diluted with ethyl acetate and filtered through Hyflo®. The filtrate was washed with water (×2) and brine and dried over MgSO4. The solvent was removed in vacuo and the residue purified by flash column chromatography on silica, eluting with 25% ethyl acetate/isohexane, to give 3-[(4-bromophenyl)sulfonyl]benzaldehyde (0.5 g, 35%). δH (400 MHz, d6 DMSO): 10.09 (1H, s), 8.47-8.44 (1H, m), 8.29-8.25 (1H, m), 8.21 (1H, d, J=7.6 Hz), 7.96-7.94 (2H, m), 7.88-7.84 (3H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[N:3]=1.Cl[Si:10]([CH3:13])([CH3:12])[CH3:11]>C[Si](C)(C)N[Si](C)(C)C>[CH3:11][Si:10]([CH3:13])([CH3:12])[N:1]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[N:3]=1)[Si:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: C[Si](C)(C)Cl
Reactant: Cc1nccc(N)n1
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: Cc1nccc(N([Si](C)(C)C)[Si](C)(C)C)n1
Yield: 614.3 %

Procedure:
A slurry of 4-amino-2-methylpyrimidine (2.04 g, 18.69 mmol) in 1,1,1,3,3,3-hexamethyldisilazane (40 mL) and chlorotrimethylsilane (0.36 mL, 2.8 mmol) was heated at 150° C. for 8 h. At this time, the reaction mixture was close to a homogeneous solution. The resulting slightly orange solution was then filtered to remove any remaining solids. The filtrate was concentrated in vacuo to afford 4-(1,1,1,3,3,3-hexamethyl-disilazan-2-yl)-2-methyl-pyrimidine as an off-white solid (2.18 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[CH3:19][O:20][CH2:21][CH2:22][NH2:23]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:23][CH2:22][CH2:21][O:20][CH3:19])=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Reactant: COCCN
Product: COCCNc1c2ccc(Cl)cc2nc2ccc(OC)cc12

Procedure:
Following the general procedure of Example 1 and making non-critical variations but using 6,9-dichloro-2-methoxyacridine and 2-methoxyethanamine, the title compound was obtained; MS (Found M+1=317).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[C:12]3=[N:13][C:14]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[CH:15][CH:16]=[C:11]3[C:10]([CH2:27]O)=[N:9]2)=[CH:5][CH:4]=1.S(Cl)([Cl:33])=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Cl:33][CH2:27][C:10]1[C:11]2[C:12](=[N:13][C:14]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:15][CH:16]=2)[N:8]([CH2:7][C:6]2[CH:29]=[CH:30][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:9]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CNc2ccc3c(CO)nn(Cc4ccc(OC)cc4)c3n2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNc2ccc3c(CCl)nn(Cc4ccc(OC)cc4)c3n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a slurry of {1-(4-methoxybenzyl)-6-[(4-methoxybenzyl)amino]-1H-pyrazolo[3,4-b]pyridin-3-yl}methanol (1.49 g, 3.68 mmol) in chloroform (15 mL) cooled in an ice bath was added thionyl chloride (538 μL, 7.37 mmol). The resulting mixture was then allowed to warm to room temperature and left at room temperature for 30 minutes. The reaction was determined by LCMS monitoring not to be complete not complete, so the reaction mixture was re-cooled in an ice bath, treated with additional thionyl chloride (100 μL), and then stirred at room temperature for 30 minutes. The reaction mixture was then poured into aqueous NaHCO3, extracted into CHCl3 and the solvent removed in vacuo. This residue was purified on a silica gel (120 g) column (0-60% EtOAc/CHCl3 to give the title compound. LRMS (M+1)=422.9
Reaction SMILES: CN1C=CC=C1C(O)=O.C(N1C=CC=C1C(O)=O)C.[CH2:20]([N:22]1[C:26]([S:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:25]([S:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:24]=[C:23]1[C:41]([OH:43])=[O:42])C>>[CH3:20][N:22]1[C:26]([S:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:25]([S:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:24]=[C:23]1[C:41]([OH:43])=[O:42]
Reactant: CCn1c(C(=O)O)cc(Sc2ccccc2)c1Sc1ccccc1
Agent: CCn1cccc1C(=O)O
Agent: Cn1cccc1C(=O)O
Product: Cn1c(C(=O)O)cc(Sc2ccccc2)c1Sc1ccccc1

Procedure:
By replacing 1-methylpyrrole-2-carboxylic acid with an equivalent amount of 1-ethylpyrrole-2-carboxylic acid, the procedure of this example produces 1-ethyl-4,5-bis-(phenylthio)pyrrole-2-carboxylic acid.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[OH:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:26]3[CH:25]=[CH:24][C:23]([OH:22])=[CH:28][CH:27]=3)[CH2:34][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Oc1ccc(N2CCNCC2)cc1
Product: CCc1cc(NC(=O)N2CCN(c3ccc(O)cc3)CC2)c(OC)nc1C
Yield: 58 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(4-hydroxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].[CH2:11]([O:13][C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:22]=2)[C:17]([CH3:31])=[N:16][C:15]=1[C:32](O)=[O:33])[CH3:12]>>[C:2]([O:6][C:7](=[O:10])[CH2:8][NH:9][C:32]([C:15]1[N:16]=[C:17]([CH3:31])[C:18]2[C:23]([C:14]=1[O:13][CH2:11][CH3:12])=[CH:22][CH:21]=[C:20]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:19]=2)=[O:33])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOc1c(C(=O)O)nc(C)c2cc(Oc3ccccc3)ccc12
Agent: Cl
Product: CCOc1c(C(=O)NCC(=O)OC(C)(C)C)nc(C)c2cc(Oc3ccccc3)ccc12

Procedure:
Synthesized from glycine tert-butyl ester hydrochloride and 4-ethoxy-1-methyl-7-phenoxy-isoquinoline-3-carboxylic acid in analogy to Example D-78 c); MS-(+)-ion: M+1=437.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH:14]1([CH:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22][NH:21]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:22][CH2:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:20]3[CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: c1ccc2c(c1)CCNC2C1CCCCC1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2ccccc2C1C1CCCCC1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Cyclohexyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Cl-].[CH:2]1([CH2:5][NH2+:6][CH2:7][CH2:8]Cl)[CH2:4][CH2:3]1.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[N:18]=[C:19]=[S:20]>>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[N:18]=[C:19]1[N:6]([CH2:5][CH:2]2[CH2:3][CH2:4]2)[CH2:7][CH2:8][S:20]1
Reactant: S=C=Nc1ccc(Cl)cc1Cl
Reactant: ClCC[NH2+]CC1CC1
Agent: [Cl-]
Product: Clc1ccc(N=C2SCCN2CC2CC2)c(Cl)c1

Procedure:
2-Hydroxyethylamine was reacted with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopropylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,4-dichlorophenyl isothiocyanate to give 2-(2,4-dichlorophenylimino)-3-(cyclopropylmethyl)-1,3-thiazolidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][NH:13][C:14](=O)[CH3:15])[CH:6]=[CH:5]2>P(Cl)(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:14]([CH3:15])=[N:13][CH:12]=[C:7]1[CH:6]=[CH:5]2
Reactant: CC(=O)NCc1ccc2cc(Br)ccc2n1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ncc2ccc3cc(Br)ccc3n12
Temperature: 25 °C

Procedure:
4c (213 mg, 0.82 mmol) was refluxed in phosphorus oxychloride (5 mL) for 1 hour. The mixture was cooled to room temperature, concentrated, and diluted with saturated aqueous NaHCO3 and EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (50-100% EtOAc in hexanes) to give the desired product, 4d.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:19])[CH:10]=[C:11]([Br:18])[C:12]=3[NH2:17])[C:7](=[O:20])[C:6]=2[C:5]([OH:21])=[CH:4][C:3]=1[O:22][C:23]1C=C[CH:26]=[CH:25][CH:24]=1.C1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C=CC=1>>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:19])[CH:10]=[C:11]([Br:18])[C:12]=3[NH2:17])[C:7](=[O:20])[C:6]=2[C:5]([OH:21])=[CH:4][C:3]=1[O:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: Nc1c(Br)cc(O)c2c1C(=O)c1c(N)c(Oc3ccccc3)cc(O)c1C2=O
Agent: O=C1c2ccccc2C(=O)c2ccccc21
Product: CCCCOc1cc(O)c2c(c1N)C(=O)c1c(N)c(Br)cc(O)c1C2=O

Procedure:
When 5.5 of 1,8-diamino-4,5-dihydroxy-2-phenoxy-7-bromoanthraquinone (preparation see Example 417a) are used in Example 338a instead of the anthraquinone component mentioned there, then 4.5 g, corresponding to 85% of theory, of 1,8-diamino-4,5-dihydroxy-2-n-butoxy-7-bromoanthraquinone are obtained quite correspondingly, the colour shade of which on silica gel is a blue with the Indicator Number 14.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[C:28]([Cl:29])=[C:27]([CH3:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:19]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:15]2[C:28]([Cl:29])=[C:27]([CH3:30])[S:26][C:16]=2[N:17]=1
Reactant: Cc1sc2nc(-c3ccccn3)nc(Cl)c2c1Cl
Reactant: NCCc1ccc2c(c1)OCO2
Product: Cc1sc2nc(-c3ccccn3)nc(NCCc3ccc4c(c3)OCO4)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-methylenedioxyphenethylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C[O:2][C:3](=O)[NH:4][CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)[CH3:7].N>>[Cl:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[C:3](=[O:2])[NH:4][CH2:5][CH:6]2[CH3:7]
Reactant: COC(=O)NCC(C)c1cccc(Cl)c1
Agent: N
Product: CC1CNC(=O)c2ccc(Cl)cc21
Temperature: 120 °C
Reaction time: 2 h
Yield: 20.1 %

Procedure:
Under N2 protection, a mixture of [2-(3-chloro-phenyl)-propyl]-carbamic acid methyl ester (3.0 g, 13.2 mmol) and PPA (polyphosphoric acid) (10 g) in a 100 mL flask was stirred at 120° C. for 2 hours. After cooling to room temperature, the reaction mixture was treated with ice-water and aqueous ammonia solution to adjust the pH to 8. The mixture was extracted with EtOAc, and the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo. The crude product formed was further washed with ether to give the title compound (0.52 g, 20%) as a white solid. MS: 196.1 (M+H+).
Reaction SMILES: C[N+]1([O-])CCOCC1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:19](=[O:25])[CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:12][C:11]=1[CH2:26][OH:27]>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:19](=[O:25])[CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:12][C:11]=1[CH:26]=[O:27]
Reactant: O=C(CC(F)(F)F)NCCc1ccc(Cl)c(CO)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=Cc1cc(CCNC(=O)CC(F)(F)F)ccc1Cl
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
NMO (318 mg, 2.28 mmol) was added to a sol. of N-[2-(4-chloro-3-hydroxymethyl-phenyl)-ethyl]-3,3,3-trifluoro-propionamide (225 mg, 0.761 mmol) in CH2Cl2 (16 mL). The mixture was stirred for 30 min, and tetrapropylammonium perruthenate (26.7 mg, 0.076 mmol) was added. The mixture was stirred for 1 h at rt, and was filtered over Celite. The filtrate was evaporated under reduced pressure. Purification of the crude by FC (CH2Cl2/MeOH 19:1) yielded the title compound (180 mg, 81%). LC-MS: tR=0.88 min; ES+: 335.28.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[N:6][CH:7]=1.[C:9](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:8])[N:4]([CH3:9])[CH:5]=[N:6][CH:7]=1
Reactant: O=c1[nH]cncc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cncc(Br)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 54 %

Procedure:
5-Bromopyrimidin-4(3H)-one (578 mg) was dissolved in N,N-dimethylformamide (15 mL), and potassium carbonate (685 mg) and methyl iodide (247 μL) were added, followed by stirring at room temperature for 24 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 5-bromo-3-methylpyrimidin-4(3H)-one (337 mg) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].[H-].[Na+].C([O:17][C@@H:18]1[C@H:22]([O:23]CC2C=CC=CC=2)[C@@H:21]([CH2:31][O:32]CC2C=CC=CC=2)[O:20][CH:19]1Cl)C1C=CC=CC=1.B(Br)(Br)Br.[NH4+].[OH-]>CC#N.CO.C(Cl)Cl.C(Cl)Cl.C1(C)C=CC=CC=1>[C@@H:19]1([N:1]2[CH:5]=[CH:4][CH:3]=[C:2]2[CH:6]=[O:7])[O:20][C@H:21]([CH2:31][OH:32])[C@@H:22]([OH:23])[C@H:18]1[OH:17]
Reactant: O=Cc1ccc[nH]1
Reactant: ClC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: BrB(Br)Br
Agent: [H-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: ClCCl
Product: O=Cc1cccn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 15.3 %

Procedure:
To a solution of pyrrole-2-carbaldehyde (330 mg, 3.5 mmol) in CH3CN (18 ml), NaH (60% oil dispersion, 152 mg, 3.8 mmol) was added and stirred at room temperature for 45 minutes, followed by addition of a solution of 2,3,5-tri-O-benzyl-D-ribofuranosyl chloride (3.1 mmol) (Non-patent Document 44) in CH3CN (18 ml). The reaction mixture was stirred at room temperature for 4 hours. The product was partitioned between ethyl acetate and water, and the organic layer was washed three times with saturated aqueous sodium chloride, dried over Na2SO4, and then evaporated under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluted with 20% ethyl acetate in hexane) to give crude 1-(2,3,5-tri-O-benzyl-D-ribofuranosyl)pyrrole-2-carboxyaldehyde (506 mg). After the crude 1-(2,3,5-tri-O-benzyl-D-ribofuranosyl)pyrrole-2-carboxyaldehyde (506 mg, 1.0 mmol) was azeotroped with toluene, CH2Cl2 (17 ml) was added to the residue. To this solution, BBr3 (1 M solution, 3.0 ml) was added at −78° C. and stirred for 2.5 hours, followed by addition of a 50% methanol-CH2Cl2 solution (25 ml). After the solution was stirred at −78° C. for 10 minutes, 28% NH4OH (0.5 ml) was added. The reaction mixture was further stirred until it reached room temperature. The product was partitioned between CH2Cl2 and H2O, and the aqueous layer was washed three times with CH2Cl2 and evaporated under reduced pressure to remove the solvent. The product was purified by reversed-phase C18 HPLC to give 1-(β-D-ribofuranosyl)pyrrole-2-carbaldehyde (108 mg, 15%, 2 steps).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]1[CH:17]([C:18]([O:20]CC)=[O:19])[CH:12]1[CH2:11][CH2:10]2)(C)C.[OH-].[Na+]>CO.O>[C:6]([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]1[CH:17]([C:18]([OH:20])=[O:19])[CH:12]1[CH2:11][CH2:10]2)#[CH:5]
Reactant: CCOC(=O)C1C2CCc3cc(C#C[Si](C)(C)C)ccc3C21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#Cc1ccc2c(c1)CCC1C(C(=O)O)C21
Temperature: 65 °C
Yield: 88.3 %

Procedure:
Ethyl 5-[(trimethylsilyl)ethynyl]-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphthalene-1-carboxylate (0.2 g, 0.64 mmol) was dissolved in 4 ml of methanol and the solution of sodium hydroxide (0.05 g, 1.2 mmol) in 2 ml of water was added to the reaction mixture and stirred at heating at 65° C. for 6 h. The extraction of basic reaction mixture into hexane showed that no starting material present. The reaction mixture was acidified with excess of 3M HCl solution (pH=1), and extracted into ethylacetate (3×15 ml). The combined extracts were washed with water and brine, dried over Na2SO4 and concentrated by rotary evaporation to give 0.12 g of mixture of cis/trans:acids (85:15) as white solid. Yield 88%.7
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12](Br)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27](B1OC(C)(C)C(C)(C)O1)([CH3:29])=[CH2:28]>>[C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][C:12]([C:27]([CH3:29])=[CH2:28])=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Product: C=C(C)c1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C(=O)OC)n1

Procedure:
The product was obtained starting from methyl 3-(bis(tert-butoxycarbonyl)amino)-6-bromopyrazine-2-carboxylate (1.13 g, 2.61 mmol) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (672 μl, 3.4 mmol) according to the method described in example A-1, step 1 after extraction with ethyl acetate and purification by silica gel chromatography using a heptane/ethyl acetate gradient as yellow viscous oil (323 mg, 31%).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:28][CH2:29][N:30]([CH2:33]C3CC3)[C:31](=[O:32])[C:10]=12)C1C=CC=CC=1.[H][H].CO>C(O)C.ClCCl.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)[N:11]2[CH2:28][CH2:29][N:30]([CH3:33])[C:31](=[O:32])[C:10]=12
Reactant: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccccn4)CCCC3)n2CCN1CC1CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: CN1CCn2c(CC3(c4ccccn4)CCCC3)nc(=O)c(O)c2C1=O
Yield: 91.8 %

Procedure:
To a stirred solution of 9-benzyloxy-2-cyclopropylmethyl-6-(1-pyridin-2-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (448) (40 mg, 0.083 mmol) in ethanol (3 mL), Pd—C (10%, w/w, 10 mg) was added. The reaction mixture was allowed stir for 1 h in a hydrogen atmosphere at balloon pressure while silica thin layer chromatography was performed (10% methanol in dichloromethane; Rf=0.3). After completion of the reaction, the reaction mixture was filtered through a celite bed and concentrated. The resulting crude product was triturated with 70% ethyl acetate in hexane to get 9-hydroxy-2-methyl-6-(1-pyridin-2-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (449) (27 mg, 83%) as an off-white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]([F:18])=[CH:16][CH:15]=[C:14]3[C:9]=2[CH2:10][CH2:11][C:12]([CH3:20])(C)[NH:13]3)[CH2:4][CH2:3]1.C([O:23][CH:24]=[C:25]([C:31](OCC)=O)[C:26]([O:28]CC)=[O:27])C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(=O)(O)(O)O.[OH-].[Na+].Cl>>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[C:9]3=[C:14]4[N:13]([CH:12]([CH3:20])[CH2:11][CH2:10]3)[CH:31]=[C:25]([C:26]([OH:28])=[O:27])[C:24](=[O:23])[C:15]4=[CH:16][C:17]=2[F:18])[CH2:6][CH2:7]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC1(C)CCc2c(ccc(F)c2N2CCC(O)CC2)N1
Agent: Cl
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1CCc2c(N3CCC(O)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 160 °C
Yield: 5.1 %

Procedure:
A mixture of 6.6 g of 5-(4-hydroxy-1-piperidyl)-6-fluoro-2-methyl-1,2,3,4-tetrahydroquinaldine and 6.0 g of diethyl ethoxymethylenemalonate was reacted by heating at 160° C. for 30 minutes. Then, 48 g of polyphosphoric acid prepared from 24 g of phosphorus pentoxide and 24 g of phosphoric acid was added thereto and the resulting mixture was reacted by heating at 150°-160° C. for 1 hour. After completion of the reaction the reaction mixture was poured into 150 g of ice water. Precipitations which formed were collected by filtration, washed with water and dried. To the crystals thus obtained were added 70 ml of a 10% aqueous sodium hydroxide solution and the mixture was reacted at 100°-110° C. for 1 hour. After cooling, the reaction mixture was rendered acidic with concentrated hydrochloric acid to precipitate crystals, which then were collected by filtration, washed with water and recrystallized from ethanol-water to give 440 mg of 8-(4-hydroxy-1-piperidyl)-9-fluoro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. m.p. 244°-247° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([CH3:12])[CH3:11])=[C:7]([C:13](=[O:29])[C:14]3[CH:19]=[C:18]([I:20])[C:17]([CH2:21][CH3:22])=[C:16]([I:23])[C:15]=3[O:24][CH2:25][C:26]([OH:28])=[O:27])[C:6]=2[CH:30]=1.[C:31](Cl)(=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1>>[CH:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:31](=[O:40])[C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)=[CH:30][C:6]=2[C:7]=1[C:13](=[O:29])[C:14]1[CH:19]=[C:18]([I:20])[C:17]([CH2:21][CH3:22])=[C:16]([I:23])[C:15]=1[O:24][CH2:25][C:26]([OH:28])=[O:27])([CH3:12])[CH3:11]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCc1c(I)cc(C(=O)c2c(C(C)C)oc3ccc(N)cc23)c(OCC(=O)O)c1I
Product: CCc1c(I)cc(C(=O)c2c(C(C)C)oc3ccc(NC(=O)c4ccc(OC)cc4)cc23)c(OCC(=O)O)c1I
Yield: 83 %

Procedure:
5-amino-2-isopropyl-3-(3 ,5-diiodo-4-ethyl carboxymethoxybenzoyl)-benzofuran (prepared as in Example 6(d), 150 mg, 0.25 mmol) was treated with anisoyl chloride as described in Example 3(a) to produce 160 mg (yield 83%) of 2-isopropyl-3-(3,5-diiodo-4-ethyl carboxymethoxybenzoyl)-5-(4-methoxybenzamido)benzofuran.