Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:13][NH2:14]>>[CH3:13][NH:14][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)=[O:12]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: CN
Product: CNC(=O)c1ccc2[nH]ccc2c1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-10, using 1H-indole-5-carboxylic acid and methylamine (0.320 g, 59%); MS: 175(M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([NH2:24])[CH2:19]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.ClC1C=C2C(C3N=C(N[C@@H]4CCC[C@H](N)C4)C(F)=CN=3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.[CH3:71][O:72][CH2:73][CH:74]1[CH2:76][O:75]1.[Li+].[OH-]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][CH2:76][CH:74]([OH:75])[CH2:73][O:72][CH3:71])[CH2:19]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCC1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](N)C4)n3)c3cc(Cl)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@@H]4CCC[C@H](N)C4)n3)c3cc(Cl)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COCC(O)CN[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 140 °C

Procedure:
To a solution of (1S,3R)—N1-[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]cyclohexane-1,3-diamine, 20c, (50 mg, 0.09 mmol) in methanol (2 mL) was added 2-(methoxymethyl)oxirane (9.4 mg, 0.11 mmol) and the reaction mixture was heated in the microwave to 140° C. for 10 min. 1M aqueous LiOH (1.0 mL, 1.0 mmol) was added, and the reaction mixture was heated in the microwave to 130° C. for 10 min. The solvent was evaporated under reduced pressure, and the residue was purified by HPLC, using 5-70% CH3CN//H2O with 0.1% TFA over 15 minutes. The purified fractions were concentrated, redissolved in MeOH and passed through a carbonate-PS column to provide the free base of the desired product 1-[[(1R,3S)-3-[[2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-pyrimidin-4-yl]amino]cyclohexyl]amino]-3-methoxy-propan-2-ol, 610.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH3:4][S:5]([C:7](SC)=[CH:8][N+:9]([O-:11])=[O:10])=O>CO>[CH3:4][S:5][C:7]([NH:3][CH2:1][CH3:2])=[CH:8][N+:9]([O-:11])=[O:10]
Reactant: CCN
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Solvent: CO
Product: CCNC(=C[N+](=O)[O-])SC
Yield: 28.4 %

Procedure:
A solution in methanol (5 ml) of ethylamine (225 mg) was added dropwise over 2 minutes to a stirred solution in methanol (30 ml) at 32° of 1-methylsulphinyl-1-methylthio-2-nitroethylene (906 mg). Evaporation of the reaction mixture gave an oil which was crystallised from isopropanol to give the title product (230 mg) m.p. 66°-67.5°.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:14][C:15]=3[N:16]=[C:17]2Cl)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([Mg]Br)[CH3:27].O.C(OCC)(=O)C>O1CCCC1>[CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:14][C:15]=3[N:16]=[C:17]2[CH2:26][CH3:27])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[Mg]Br
Reactant: ClC1=Nc2nc(C3CCCC3)[nH]c2C2=N[C@H](Cc3ccccc3)CN12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCC1=Nc2nc(C3CCCC3)[nH]c2C2=N[C@H](Cc3ccccc3)CN12
Temperature: 60 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
Compound 67a (82 mg, 0.20 mmol) obtained in Example 67 was dissolved in tetrahydrofuran (1 mL), to the solution was added a 1 mol/L solution (2 mL) of ethyl magnesium bromide in tetrahydrofuran, and the mixture was stirred at 60° C. for 1 hour. To the reaction mixture was added water and the mixture was stirred. Ethyl acetate was added to the mixture and the organic layer was washed with water and dried over magnesium sulfate. The organic layer was concentrated and to the residue were added dichloromethane and diisopropyl ether. The deposited crystals were collected by filtration to obtain the title compound (40 mg, 58%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH2:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH3:15])[CH:9]=2)[CH:3]1[C:16]([O:18][CH3:19])=[O:17].[CH2:21]([SH:25])[CH2:22][CH2:23][SH:24].B(F)(F)F.CCOCC>C(O)(=O)C.CCOCC>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:3]([C:16]([O:18][CH3:19])=[O:17])[C:2]([CH3:20])([CH3:1])[CH2:7][C:6]3([S:25][CH2:21][CH2:22][CH2:23][S:24]3)[CH:5]=2)=[CH:9][C:10]=1[CH3:15]
Reactant: SCCCS
Reactant: COC(=O)C1C(c2ccc(F)c(C)c2)=CCCC1(C)C
Agent: FB(F)F
Solvent: CC(=O)O
Solvent: CCOCC
Product: COC(=O)C1C(c2ccc(F)c(C)c2)=CC2(CC1(C)C)SCCCS2
Reaction time: 8 h

Procedure:
To a solution of 4a (7.75 g, 26.7 mmol) and 1,3-propanedithiol (3.03 g, 28.1 mmol) in 50 mL acetic acid was added boron trifluoride etherate (7.98 g, 56.2 mmol). The solution was stirred overnight, diluted with ether, washed with H2O, saturated NaHC3, and brine and dried (MgSO4). Removal of the volatile in vacuo provided a residue which was crystallized from hexane, wt 8.0 g, mp 100°-101° C. Anal. C20H25FO2S2 : Theory C: 63.12; H:6.62; S:16.85. Found C: 63.45; H:6.58; S: 16.44.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([NH:25][C:26](=O)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:26]([NH:25][C:23]1[N:22]=[CH:21][N:20]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(Nc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(CNc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 43.5 %

Procedure:
To a solution of N-(1-trityl-1H-imidazol-4-yl)-benzamide (0.36 g, 0.83 mmol) in tetrahydrofuran (10 ml) was added portionwise lithium aluminium hydride (0.16 g, 4.14 mmol). The reaction mixture was stirred at 80° C. for 16 hours, then cooled to room temperature and water added dropwise. The mixture was stirred at room temperature for 20 minutes and then extracted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: methanol/dichloromethane 0:100 to 10:90) to yield the title compound as a white solid (0.15 g, 44%); MS (ISP): 416.5 ([M+H]+).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:10]2)=[CH:5][C:4]=1[CH3:23].[Cl-].[NH+]1C=CC=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:23][C:4]1[CH:5]=[C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:14]2)[CH:7]=[CH:8][C:3]=1[OH:2]
Reactant: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1C
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCN(CCc3ccccc3)CC2)ccc1O
Temperature: 210 °C
Yield: 45.2 %

Procedure:
A mixture of 1-(4-methoxy-3-methylphenyl)-4-phenethyl-piperazine (327 mg) and pyridinium chloride (731 mg) was heated to 210° C. and stirred for an hour. The reaction liquid was diluted with 1 mL of toluene, and to which saturated saline solution was added. Further adding saturated aqueous sodium hydrogencarbonate solution to render the system weakly alkaline, the product was extracted with ethyl acetate-tetrahydrofuran (1:1). The organic layer was washed with saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off and the remaining crude product was purified on TLC (developer, chloroform: methanol=15:1) to provide 2-methyl-4-(4-phenethylpiperazin-1-yl)phenol (141 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][CH2:27][CH2:28][C:29](OCC)=[O:30].[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:28]([CH2:27][CH2:26][CH2:25][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=3)[C:29]2=[O:30])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CCCCc1ccccn1
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(CCCc2ccccn2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-(2-pyridyl)pentanoate (1.5 eq., prepared in Synthetic Example 21) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[3-(pyridin-2-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 201 to 202° C./DMF, wherein the product was purified through flash column chromatography and recrystallization.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15](=[O:35])[NH:16][C@@H:17]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=4)=[O:23])[CH2:18]3)[N:14]=2)[CH2:7]1)(=O)=O.[C:36]([O-:39])(=[S:38])[CH3:37].[K+]>CN(C)C=O>[C:36]([S:38][CH:6]1[CH2:7][N:8]([C:10]2[S:11][CH:12]=[C:13]([C:15](=[O:35])[NH:16][C@@H:17]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=4)=[O:23])[CH2:18]3)[N:14]=2)[CH2:9]1)(=[O:39])[CH3:37]
Reactant: CS(=O)(=O)OC1CN(c2nc(C(=O)N[C@@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)cs2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N[C@@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)cs2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-{4-[(3R)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (420 mg, 0.799 mmol) (obtained as described in Reference Example 53(8)) in dimethylformamide (21 ml) was added potassium thioacetate (548 mg, 4.79 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:2)→ethyl acetate:methanol (99:1) as the eluant to afford 3-acetylthio-1-{4-[(3R)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl]-1,3-thiazol-2-yl}azetidine (280 mg, yield 69%) as a pale brown solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]#[N:10])=[N:7][CH:8]=1)=[O:2].C[Si](C)(C)[C:13]([F:16])([F:15])[F:14]>C1COCC1>[F:14][C:13]([F:16])([F:15])[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]#[N:10])=[N:7][CH:8]=1)[OH:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: N#Cc1ccc(C=O)cn1
Solvent: C1CCOC1
Product: N#Cc1ccc(C(O)C(F)(F)F)cn1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 39.2 %

Procedure:
To a −78° C. solution of 5-formylpicolinonitrile (1.0 g, 7.58 mmol) and tetrabutylammonium triphenyldifluorosilicate (4.9 g, 9.10 mmol) in 60 mL of THF was added a solution of trimethyl(trifluoromethyl)silane (1.62 g, 114 mmol). The mixture was stirred for 20 min at −78° C. Then the cooling bath was changed to an ice bath. After stirring for another 30 min, the reaction was quenched with sat. NH4Cl (aq.). The mixture was extracted with EtOAc (3×). The organic layer was washed with sat. NaHCO3 (aq.), brine, then dried (MgSO4) and concentrated. The product 5-(2,2,2-trifluoro-1-hydroxyethyl)picolinonitrile (600 mg) was obtained by silica gel chromatography (elution with 0-40% EtOAc/Hex).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[CH3:27][CH:28]1[CH2:33][NH:32][CH2:31][CH:30]([CH3:34])[NH:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:32]2[CH2:31][CH:30]([CH3:34])[NH:29][CH:28]([CH3:27])[CH2:33]2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: CC1CNCC(C)N1
Product: CC1CN(C(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)c(Cl)c2)CC(C)N1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2,6-dimethylpiperazine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3,5-dimethylpiperazine-1-carbonyl)benzamide. MS (Q1) 483 (M)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[N+:20]([O-])=O)=[CH:8][CH:7]=1)[CH3:2]>CCO.[Ni]>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[NH2:20])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(Nc2ccc(Br)cc2[N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)Cc1ccc(Nc2ccc(Br)cc2N)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A suspension of [4-(4-bromo-2-nitro-phenylamino)-phenyl]-acetic acid ethyl ester (1.0 g, 2.64 mmol) and Raney Ni (˜0.300 g) in EtOH (20 mL) is stirred for 2.5 h at rt, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of Celite and concentrated. Silica gel column chromatography purification (Hexane/EtOAc, 7:3) of the crude product affords the title compound as a pale pink solid: ES-MS: 351.0 [M+2]+; single peak at tR=4.82 min (System 1); Rf=0.16 (Hexane/EtOAc, 7:3).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].[CH2:6](O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: OCc1ccccc1
Reactant: CCC(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)OCc1ccccc1

Procedure:
The activated esters of type (3) react with alcohols, and also with phenols, thiophenols or mercaptans, to form esters. For example, activated propionic acid and benzyl alcohol in tetrahydrofuran, in the presence of triethylamine, give a very good yield of benzyl propionate.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:20][C:21]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>ClCCl.O>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:23]([C:22]1[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:21]=1[CH3:20])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C(=O)Cl)c1C
Reactant: c1ccc(Cn2ccnc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C(=O)c2nccn2Cc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
To a solution of 1-benzyl-1H-imidazole (1.69 Kg, 10.56 mol) in dichloromethane (14.0 L), at −7° C., was added triethylamine (1.61 kg, 10.56 mol). A solution of 2,3-dimethylbenzoyl chloride (2.0 kg, 11.99 mol) in dichloromethane (6.0 L) was then added dropwise and the reaction mixture was stirred at room temperature for 16 h. The reaction was monitored by Thin layer Chromatography. After completion of the reaction, the reaction mixture was diluted with water (5.0 L) and the mixture was stirred for a further 15 min. The two layers were separated and the organic phase was concentrated in vacuo. To the residue was added toluene (8.0 L) and the solution was cooled to −5° C., before addition of hydrochloric acid (5N, 8.0 L). The two layers were separated and the aqueous layer was adjusted to pH 9-12, by addition of aqueous sodium hydroxide solution (50%), and extracted with toluene (4.0 L and then 8.0 L). The combined organic phases were concentrated in vacuo to give the title compound (2.8 kg).
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]O)=[CH:20][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O>C(Cl)Cl>[CH2:5]([O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][Br:2])=[CH:20][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCOc1ccc(CO)cc1
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCOc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
A solution of PBr3 (2.0 mL, 20 mmol) in anhydrous CH2Cl2 (25 mL) was added slowly to a stirred solution of 4-(dodecyloxy)benzyl alcohol (3.0 g, 10 mmol) in CH2Cl2 (50 mL) at 0° C. The reaction mixture was stirred for 3 h at room temperature and slowly poured into a large amount of water (ca. 600 mL). The product was extracted with CHCl3 (3×50 mL). The combined organic phase was washed with brine (3×20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give a yellow solid (3.01 g, 90%). 1H NMR (300 MHz, CDCl3, δ): 7.32 (d, J=6.6 Hz, 2H), 6.86 (d, J=6.6 Hz, 2H), 4.50 (s, 2H), 3.97 (t, J=6.6 Hz, 2H), 4.05-4.00 (m, 6H), 1.79-1.72 (m, 2H), 1.45-1.21 (m, 12H), 0.90 (t, J=6.3 Hz, 3H).
Reaction SMILES: [CH2:1]([C@:4]1([CH2:30][O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:8][C@@H:7]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[C@H:6]([O:18]C(=O)C)[C@@H:5]1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:2]=[CH2:3].N.[CH:40]1[CH:45]=[CH:44][C:43]([O:46][C:47](Cl)=[S:48])=[CH:42][CH:41]=1>CN(C1C=CN=CC=1)C>[CH2:1]([C@:4]1([CH2:30][O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:8][C@@H:7]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[C@H:6]([O:18][C:47]([O:46][C:43]2[CH:44]=[CH:45][CH:40]=[CH:41][CH:42]=2)=[S:48])[C@@H:5]1[O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH:2]=[CH2:3]
Reactant: S=C(Cl)Oc1ccccc1
Reactant: C=CC[C@]1(COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: N
Product: C=CC[C@]1(COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@H](OC(=S)Oc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 8 h
Yield: 70 %

Procedure:
Compound 8 (5.0 g, 9.6 mmol) was treated with 27% methanolic ammonia solution overnight. After evaporation of the solvent the crude was coevaporated thrice with dry pyridine and dissolved in the same. To this pre-cooled solution was added DMAP (1.17 g, 9.6 mmol) and then dropwise was added phenyl chlorothionoformate (1.6 mL, 11.53 mmol) and reaction stirred overnight. Reaction was quenched with saturated solution of NaHCO3 and extracted with dichloromethane. The organic layer was dried over MgSO4, concentrated and chromatographed over silica gel (10-30% ethyl acetate in cyclohexane, v/v) to give 10 as yellowish foam (4.1 g, 6.72 mmol, 70%). Rf=0.60 (30% ethyl acetate in cyclohexane, v/v). 1H NMR (600 MHz) δ: 8.58 (1H, s, N—H), 7.48 (1H, s, H6), 7.19 (15H, m), 6.44 (1H, d, JH1′,H2′=6.1 Hz, H1′), 5.97 (1H, app t, J=5.8 Hz, H2′), 5.83 (1H, m, H7′), 5.09 (2H, m, H8′-H8″), 4.77 (1H, d, Jgem=11.2 Hz, CH2Bn), 4.55 (3H, m, CH2Bn, H3′), 3.71 (1H, d, JH5′,H5″=10.3 Hz, H5″), 3.48 (1H, d, JH5′,H5″10.3 Hz, H5′), 2.66 (1H, dd, JH6,H6=14.6 Hz, JH6,H7=8.1 Hz, H6″), 2.35 (1H, dd, JH6,H6=14.6 Hz, JH6,H7=8.1 Hz, H6′), 1.51 (3H, CH3, thymine); 13C NMR (125.7 MHz) δ: 194.4 (>C═S), 163.4 (C4), 150.3 (C2), 137.1, 137.2 (aromatic), 135.6 (C6), 132.4 (C7′), 121.6, 126.7, 127.3, 127.6, 127.8, 128.0, 128.1, 128.4, 128.6, 129.3, 129.5 (aromatic), 118.8 (C8′), 111.5 (C5′), 87.1 (C4′), 85.1 (C2′), 82.9 (C1′), 77.8 (C3′), 74.9 (C—CH2Bn), 73.7 (C5′), 73.7 (C—CH2Bn), 37.3 (C6′), 11.9 (CH3, thymine); MALDI-TOF m/z [M+H]+ found 615.16 calcd 615.21.
Reaction SMILES: [CH2:1]1[CH2:10][N:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14](O)=[O:15])[CH2:8][C:7]2[CH:6]=[N:5][C:4]3[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=3[C:2]1=2.C(N(CC)CC)C.CCCP(=O)=O.[CH:37]([C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1)([CH3:39])[CH3:38]>ClCCCl>[CH2:1]1[CH2:10][N:9]([C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([NH:44][C:43]2[CH:45]=[CH:46][C:40]([CH:37]([CH3:39])[CH3:38])=[CH:41][CH:42]=2)=[O:15])[CH2:8][C:7]2[CH:6]=[N:5][C:4]3[CH:20]=[CH:21][CH:22]=[CH:23][C:3]=3[C:2]1=2
Reactant: O=C(O)c1cccc(N2CCc3c(cnc4ccccc34)C2)c1
Reactant: CC(C)c1ccc(N)cc1
Agent: CCCP(=O)=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(NC(=O)c2cccc(N3CCc4c(cnc5ccccc45)C3)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.7 %

Procedure:
To a mixture of 3-(1,4-dihydrobenzo[c]-2,7-naphthyridin-3(2H)-yl)benzoic acid (0.20 mmol, 61 mg) and triethylamine (0.40 mmol, 0.056 mL) in 2.0 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.24 mmol, 0.143 mL). After 10 min at rt, 4-isopropylaniline (0.30 mmol, 0.043 mL) was added and the reaction stirred at rt for 1 hour. Then an additional 0.015 mL 4-isopropylaniline was added, the reaction heated at 60° C. for 5 min, then continued at rt for 3 hours. The reaction was quenched into dilute aqueous Na2CO3 solution, extracted into EtOAc, the EtOAc layer washed with H2O, dilute aqueous Na2CO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was recrystallized from EtOAc/hexane to give the title compound as an off-white solid (52 mg, 62%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([Si:11]([CH3:25])([CH3:24])[O:12][C:13]1[C:21]2[O:20][C:19]([CH2:22]Cl)=[CH:18][C:17]=2[CH:16]=[CH:15][CH:14]=1)([CH3:10])([CH3:9])[CH3:8].O>O1CCCC1.CN(C)C=O.C(O)(C)C>[C:7]([Si:11]([CH3:25])([CH3:24])[O:12][C:13]1[C:21]2[O:20][C:19](=[CH2:22])[CH2:18][C:17]=2[CH:16]=[CH:15][CH:14]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2cc(CCl)oc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(C)O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=C1Cc2cccc(O[Si](C)(C)C(C)(C)C)c2O1
Reaction time: 0.25 h

Procedure:
LiAlH4 (1.0M in tetrahydrofuran, 4.5 ml, 4.5 mmol) is added dropwise to a suspension of CrCl3 (1.4 g, 8.85 mmol) in tetrahydrofuran (10 ml), kept at 0° C. and the mixture is stirred for 15 minutes. The solution is then diluted with dimethylformamide (18 ml) and isopropanol (1.35 ml). tert-Butyldimethyl-(2-chloromethylbenzofuran-7-yloxy)silane (15) (1.05 g, 3.54 mmol) in dimethylformamide (15 ml) is added to the solution obtained, kept at 0° C. The mixture is stirred at room temperature for 18 hours and then poured into water and extracted with pentane. The organic phase is dried over Na2SO4, filtered and concentrated under reduced pressure. A colorless liquid is obtained (0.78 g) which is used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.[OH:15][CH:16]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]1>>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[O:15][CH:16]1[CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: Clc1ncccn1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CC(Oc2ncccn2)C1

Procedure:
Compound P23 was prepared according to the general procedure described in the preparation of P21 in Preparation 21, except that 2-chloropyrimidine was employed instead of 2-bromopyridine, to afford P23. 1H NMR (400 MHz, CDCl3) δ 1.42 (s, 9H), 4.02 (m, 2H), 4.30 (m, 2H), 5.29 (m, 1H), 6.97 (t, J=4.9 Hz, 1H), 8.50 (d, J=4.9 Hz, 2H). Compound P23 was deprotected with trifluoroacetic acid as described for t-butyl 3-hydroxyazetidine-1-carboxylate in the preparation of C19 in Example 3, before being used in the coupling step.