Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:19][C:20]([CH3:26])([CH2:24][CH3:25])[C:21](Cl)=[O:22]>>[CH3:19][C:20]([CH3:26])([CH2:24][CH3:25])[C:21]([N:1]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:22]
Reactant: C1COCCOCCOCCOCCOCCN1
Reactant: CCC(C)(C)C(=O)Cl
Product: CCC(C)(C)C(=O)N1CCOCCOCCOCCOCCOCC1

Procedure:
Analogously to Example 14 from 1-aza-4,7,10,13,16-pentaoxacyclooctadecane and 2,2-dimethylbutyryl chloride.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9]C)=[CH:5][C:4]=1[C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1
Reactant: COc1cccc(CC(=O)c2cc(OC)ccc2OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(Cc1cccc(O)c1)c1cc(O)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
To a solution of 1-(2,5-dimethoxyphenyl)-2-(3-methoxyphenyl)ethanone (3.35 g, 11.7 mmol) in DCM (50 mL) at −78° C., boron tribromide (1M in DCM, 48.0 mL, 48.0 mmol) was added dropwise. The reaction mixture was warmed to 0° C., stirred for 30 min, re-cooled to −78° C., and then quenched with methanol (15 mL). The reaction mixture was warmed to room temperature, concentrated on a rotary evaporator and purified by silica gel chromatography to give 1-(2,5-dihydroxyphenyl)-2-(3-hydroxyphenyl)ethanone (1.78 g, 62%) as a yellow solid. 1H NMR (DMSO-d6): δ 11.24 (s, 1H), 9.34 (s, 1H), 9.20 (s, 1H), 7.26 (m, 1H), 7.10 (t, 1H), 6.98 (dd, 1H), 6.83 (d, 1H), 6.70 (m, 3H), 4.24 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[NH2:15][C:16](=[O:30])[CH2:17][S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[NH2:15][C:16](=[O:30])[CH2:17][S:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[CH:4]=2)=[O:26])=[CH:23][CH:22]=1)(=[O:19])=[O:20]
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: NC(=O)CS(=O)(=O)c1ccc(C(=O)O)cc1
Product: NC(=O)CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
2.5 g of 2-bromoacetamide was reacted with methyl 4-mercaptobenzoate via Procedure Q to afford methyl 4-(2-amino-2-oxoethylthio)benzoate. 2.6 g of methyl 4-(2-amino-2-oxoethylthio)benzoate was reacted via Procedure R to give methyl 4-(2-amino-2-oxoethylsulfonyl)benzoate. 1 g of methyl 4-(2-amino-2-oxoethylsulfonyl)benzoate was hydrolyzed via Procedure M to give 4-(2-amino-2-oxoethylsulfonyl)benzoic acid. 150 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-amino-2-oxoethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 4-(2-amino-2-oxoethylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 430.2 (M)+.
Reaction SMILES: C[Si]([Br:5])(C)C.[CH2:6]([O:13][C:14]1[C:23]2[O:22][CH2:21][CH2:20][O:19][C:18]=2[CH:17]=[C:16]([CH2:24]O)[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)(Cl)Cl>[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:18]2[O:19][CH2:20][CH2:21][O:22][C:23]=12)[CH2:24][Br:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[Si](C)(C)Br
Reactant: OCc1cc2c(c(OCc3ccccc3)c1)OCCO2
Solvent: ClC(Cl)Cl
Product: BrCc1cc2c(c(OCc3ccccc3)c1)OCCO2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
0.07 ml of trimethylsilyl bromide is added to a solution of 0.1 g of 5-benzyloxy-7-hydroxymethyl-1,4-benzodioxane in 5 ml of chloroform and the mixture is stirred for a further 15 minutes at room temperature and then concentrated by evaporation in a rotary evaporator. The residue is immediately dissolved in a small amount of ethyl acetate; the same volume of hexane is added and the mixture is filtered through 15 g of silica gel, followed by elution with a mixture (hexane/ethyl acetate=4:1). Concentration of the eluates by evaporation yields the title compound: Rf (hexane/ethyl acetate=3:1)=0.48.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2([CH2:15][F:16])[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2([CH2:15][F:16])[NH:13][C:12](=[S:27])[CH2:11][O:10][CH2:9]2)[CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1COCC(CF)(c2cc(Br)ccc2F)N1
Solvent: C1CCOC1
Product: FCC1(c2cc(Br)ccc2F)COCC(=S)N1

Procedure:
A mixture of 7.34 g (22.65 mmol) 5-(5-bromo-2-fluoro-phenyl)-5-fluoromethyl-morpholin-3-one and 5.19 g (12.46 mmol) Lawesson's reagent in 73 ml of THF was refluxed for 1 h. The mixture was concentrated and crystallized from DCM/hexane and recrystallized from EtOH to yield the desired product as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][CH2:29][NH2:30]>>[NH2:30][CH2:29][CH2:28][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[CH2:15][CH2:14]2)=[O:12])=[CH:7]1
Reactant: COc1ccccc1N1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: NCCCl
Product: COc1ccccc1N1CCN(C(=O)c2cn(CCN)c3cc(Cl)ccc23)CC1

Procedure:
Analogous to general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone (prepared herein) with (commercially available) 2-chloro-ethylamine gave the title compound.
Reaction SMILES: [NH:1]([C:3]([S:5][CH3:6])=[NH:4])[NH2:2].[CH3:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH:18]=O)=O)=[CH:12][CH:11]=1>>[CH3:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:4]=[C:3]([S:5][CH3:6])[N:1]=[N:2][CH:18]=2)=[CH:12][CH:11]=1
Reactant: CSC(=N)NN
Reactant: COCc1ccc(C(=O)C=O)cc1
Product: COCc1ccc(-c2cnnc(SC)n2)cc1
Yield: 72 %

Procedure:
5-[4-(methoxymethyl)phenyl]-3-(methylsulfanyl)-1,2,4-triazine (4.0 g, 72%) was prepared from methyl hydrazinecarbimidothioate (7.33 g, 31.46 mmol) and 4-(methoxymethyl)phenylglyoxal (4 g, 22.47 mmol) according to the general procedure of Preparation 2.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][Si:13]([CH3:18])([CH3:17])[CH2:14][CH2:15]O>ClCCl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:15][CH2:14][Si:13]([CH3:18])([CH3:17])[CH3:12])=[O:5]
Reactant: C[Si](C)(C)CCO
Reactant: O=C(O)c1ccc(I)cc1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C[Si](C)(C)CCOC(=O)c1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of 115.5 mg (0.4 mmol) of 2-fluoro-4-iodobenzoic acid (Compound B) in 10 mL of dichloromethane (under a blanket of argon) was added 91.5 mg (0.5 mmol) of 1-(3-dimethylaminopropyl-3-ethyl carbodiimide hydrochloride) and 53 mg (0.4 mmol) of 4-dimethylaminopyridine. To this reaction mixture was added 0.16 ml (132 mg, 1.1 mmol) of 2-trimethylsilylethanol and the resultant mixture was allowed to stir at ambient temperature for 23 hours. The reaction mixture was extracted between ethyl ether and water and the layers were separated. The aqueous phase was washed with ethyl ether (2×50 mL) and the organic phases were combined. The combined organic phase was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to a clear, colorless oil. Purification by flash chromatography (silica, 3% ethyl acetate in hexane) gave the title compound as a clear, colorless oil. PMR (CDCl3): δ 0.07 (9 H, s), 1.13 (2 H, dd, J=8.5, 10.3 Hz), 4.42 (2 H, q, J=8.5, 10.3 Hz), 7.50-7.70 (3 H, m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C:12]([CH3:14])([CH3:13])[N:11]([O:15]CC2C=CC=CC=2)[C:10]1=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C:12]([CH3:14])([CH3:13])[N:11]([OH:15])[C:10]1=[O:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(OCc2ccccc2)C1(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(O)C1(C)C
Yield: 83.1 %

Procedure:
A solution of 14.77 g (0.0461 mole) of (3S)-3-[(t-butyloxycarbonyl)amino]-4,4-dimethyl-1-(phenylmethoxy)-2-azetidinone in 15 ml of ethanol and 85 ml of ethyl acetate was hydrogenated over 0.75 g of 5% palladium-on-carbon catalyst for 1.5 hours at 1 atmosphere. The reaction mixture was filtered and concentrated to give a white solid. Recrystallization from ethyl acetate gave 8.82 g of the title compound, melting point 148°-149° C., [α]D =+31° (C =1, ethyl acetate).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([CH2:34]Cl)=[CH:33][C:28]=2[O:27][CH2:26]1.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C=CC4OCOC=4C=3)N=2)CC1)=O)(C)(C)C>>[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([CH2:34][N:14]3[C:15]4[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=4[C:12]([C:18]4[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=4)=[N:13]3)=[CH:33][C:28]=2[O:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: ClCc1ccc2c(c1)OCO2
Agent: CC(C)(C)OC(=O)N1CCc2nn(Cc3ccc4c(c3)OCO4)c(-c3ccc(Cl)cc3)c2CC1
Product: Clc1ccc(-c2nn(Cc3ccc4c(c3)OCO4)c3c2CCNCC3)cc1
Yield: 45.8 %

Procedure:
The title compound (0.035 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using benzo[1,3]dioxol-5-ylmethyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 2-benzo[1,3]dioxol-5-ylmethyl-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C21H20ClN3O2, 381.12; found, m/z 382.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.39-7.32 (m, 4H), 6.67-6.65 (m, 1H), 6.54-6.61 (m, 2H), 5.81 (s, 2H), 5.16 (s, 2H), 2.81-2.79 (m, 4H), 2.76-2.74 (m, 2H), 2.68-2.66 (m, 2H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([C:25]2[NH:26][CH:27]=[CH:28][CH:29]=2)[C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]=2[C:21]=1[C:20]([F:23])=[CH:19][CH:18]=3)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]([C:25]2[NH:26][CH:27]=[CH:28][CH:29]=2)[C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]=2[C:21]=1[C:20]([F:23])=[CH:19][CH:18]=3
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCOc1cc(-c2ccc[nH]2)c2c3c(ccc(F)c13)NC2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [2-[6-fluoro-2-oxo-3-(1H-pyrrol-2-yl)-1,2-dihydro-benzo[cd]indol-5-yloxy]-ethyl]-carbamic acid tert-butyl ester (from Example 18 above) (16.5 mg, 0.2 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid (0.5 mL) at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was quenched with 1.0 N NaOH (2.0 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 5-(2-amino-ethoxy)-6-fluoro-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 11.2 mg, 89.7%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH3:13])[O:8][CH:7]([C:18]([F:21])([F:20])[F:19])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2.[CH3:27]B1OB(C)OB(C)O1.C([O-])([O-])=O.[Cs+].[Cs+].O>COCCOCCOC>[CH2:14]([N:12]([CH3:13])[C:11]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:7]([C:18]([F:21])([F:20])[F:19])[O:8]2)=[CH:3][C:2]=1[CH3:27])[CH:15]([CH3:17])[CH3:16]
Reactant: CB1OB(C)OB(C)O1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(N(C)CC(C)C)cc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOCCOC
Product: CCOC(=O)C1=Cc2cc(C)c(N(C)CC(C)C)cc2OC1C(F)(F)F
Temperature: 115 °C
Yield: 45 %

Procedure:
A mixture of ethyl 6-chloro-7-[isobutyl(methyl)amino]-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 8c (0.50 g, 1.28 mmole), trimethylboroxine (0.38 g, 2.75 mmole), [(tBu3P)PdBr]2 (0.01 g), and Cs2CO3 (0.75 g, 2.31 mmole) in anhydrous diglyme (10.0 mL) was heated to 115° C. under a dry N2 atmosphere for 18 hrs. The contents were poured into water (40 ml) and extracted with EtOAc (2×40 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil which was subject to HPLC (reverse phase) and eluted with 50-85% ACN/water with 0.05% TFA to give yellow solid (0.21 g, 45%). No further purification was performed. GCMS m/z 371.0 (M+). LCMS m/z 372.0 (M+H).
Reaction SMILES: C1(C)C=CC(S(CC[O:12][C:13](=[O:48])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=[C:24]3[S:32]([CH2:34][C:35]3[C:40]([CH3:41])=[C:39]([O:42][CH2:43][CH2:44][CH2:45][O:46][CH3:47])[CH:38]=[CH:37][N:36]=3)=[O:33])(=[O:22])=[O:21])[CH:15]=2)(=O)=O)=CC=1.C([O-])(O)=O.[Na+:54]>CC#N.O>[Na+:54].[CH3:47][O:46][CH2:45][CH2:44][CH2:43][O:42][C:39]1[CH:38]=[CH:37][N:36]=[C:35]([CH2:34][S:32]([C:24]2[N:23]([S:20]([C:16]3[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=3)[C:13]([O-:48])=[O:12])(=[O:22])=[O:21])[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[N:25]=2)=[O:33])[C:40]=1[CH3:41]
Reactant: COCCCOc1ccnc(CS(=O)c2nc3ccccc3n2S(=O)(=O)c2cccc(C(=O)OCCS(=O)(=O)c3ccc(C)cc3)c2)c1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3n2S(=O)(=O)c2cccc(C(=O)[O-])c2)c1C
Temperature: 65 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
To the solution of the 3-[2-[4-(3-methoxy-propoxy)-3-methyl-pyridin-2-yl-methanesulfinyl]-benzimidazole-1-sulfonyl]benzoic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 48, 1.5 g, 2.0 mmol) in 15 mL of CH3CN was added a solution of NaHCO3 (200 mg, 2.4 mmol, 1.2 eq) in 7 mL of H2O at room temperature, and then the mixture was heated to 65° C. for 2.5 h. Thereafter most of CH3CN was removed, the mixture was extracted with EtOAc, and the aqueous layer was lyophilized overnight. The solid was dissolved in CH2Cl2, and then the mixture was filtered to remove insoluble solids. The filtrate was concentrated to near dryness. The residual oil was dissolved in about 2 mL of CH2Cl2 and EtOAc-ether (1:1) was added to precipitate a white solid. The precipitate was collected by filtration, washed with EtOAc-ether (1:1), and dried under vacuum to give 700 mg (60%) of 3-[2-[4-(3-methoxy-propoxy)-3-methyl-pyridin-2-yl-methanesulfinyl]-benzimidazole-1-sulfonyl]benzoic acid sodium salt (Compound 24) as a white solid.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[N:13]1([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:28]3[C:29]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:27])=[CH:21][CH:20]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[C:29]1([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:26]([NH:25][C:22]1[CH:21]=[CH:20][C:19]([N:13]2[CH2:18][CH2:17][N:16]([CH:2]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([O:5][CH3:6])=[O:4])[CH2:15][CH2:14]2)=[CH:24][CH:23]=1)=[O:27]
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1-c1ccccc1
Reactant: COC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2)CC1
Reaction time: 8 h
Yield: 85.3 %

Procedure:
Methyl α-bromo-α-phenylacetate (0.1 mole) was added dropwise to a stirring mixture of intermediate (10) (0.07 mole) and Na2CO3 (13 g) in DMF (300 ml). The mixture was stirred overnight. The solvent was evaporated. The residue was crystallized from methanol. The precipitate was filtered off and dried, yielding 30.2 g of methyl 4-[4-[([1,1′-biphenyl]-2-ylcarbonyl)amino]phenyl]-α-phenyl-1-piperazineacetate (melting point 125° C.) identified as compound No. 52 in the following table F-1.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N:16]3[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]3[CH3:22])=[C:12]([Cl:15])[CH:13]=2)[NH:8][C:7](=[O:23])[C:6]1=[O:24])([OH:3])=O.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O>[CH2:25]([NH:32][C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N:16]3[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]3[CH3:22])=[C:12]([Cl:15])[CH:13]=2)[NH:8][C:7](=[O:23])[C:6]1=[O:24])=[O:3])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(C)n1-c1cc2[nH]c(=O)c(=O)n(CC(=O)O)c2cc1Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(C)n1-c1cc2[nH]c(=O)c(=O)n(CC(=O)NCc3ccccc3)c2cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
1.3 g (3.7 mmol) of 1-(carboxymethyl)-7-chloro-6-(2,5-dimethyl-1-pyrrolyl)-2,3(1H,4H)-quinoxalinedione and 1.6 ml (12.3 mmol) of benzylamine were dissolved in 30 ml of dimethylformamide and, at 0° C., a solution of 0.89 ml (4.1 mmol) of diphenylphosphoryl azide in 10 ml of dimethylformamide was added dropwise. The mixture was stirred at room temperature for 16 h and then poured into ice-water, and the aqueous phase was extracted with ethyl acetate. The organic phase was dried and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase: toluene/acetone=1:1) to yield 1.1 g (67%) of the product.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:15])[CH:8]=2)[N:3]=1.Br[CH2:17][C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CC(C)=O>[CH2:13]([O:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:15])[CH:8]=2)[N:3]2[CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:1]=[C:2]2[CH:11]=1)[CH3:14]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCOc1cc(N)nc2ccc(F)cc12
Solvent: CC(C)=O
Product: CCOC(=O)c1cn2c(cc(OCC)c3cc(F)ccc32)n1
Temperature: 25 °C

Procedure:
In a single-necked flask were combined, 2.1 g. (0.010 mole) of 2-amino-4-ethoxy-6-fluoroquinoline, 2.1 g. (0.011 mole) ethyl bromopyruvate and 30 ml. of acetone. The mixture was refluxed for two hours, cooled to room temperature and the precipitated solid removed by filtration. The solid was partitioned between chloroform and 1N aqueous potassium hydroxide, the organic layer dried over magnesium sulfate and evaporated to dryness to yield 1.7 g. of crude product. This was dissolved in a small amount of chloroformethanol (95:5 v/v) and chromatographed on a column of 50 g. of 60-200 mesh silica gel (J. T. Baker Co.) eluting with the same solvent. Fractions of 50 ml. each were taken when ultraviolet light absorbing material began to come off the column. Fractions 1 through 8 were combined and evaporated to dryness in vacuo to afford 750 mg. of the title compound as a white solid, which upon crystallization from isopropanol melted at 213.5°-214.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].O=S(Cl)Cl.[OH-].[Na+].[NH4+:20].[OH-]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH2:20])=[O:8]
Reactant: [NH4+]
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: Cc1ccc([N+](=O)[O-])c(C(N)=O)c1
Temperature: 0 °C
Yield: 87 %

Procedure:
A mixture of 5-methyl-2-nitrobenzoic acid (12) (36.2 g, 0.2 mol) and SOCl2 (50 mL) was heated under reflux for 20 min, during which a homogeneous solution was obtained. After removal of the excess SOCl2 with the aid of a water aspirator, the residue was dissolved in dry THF (40 mL) and the solution added dropwise with stirring to an ice-cold solution of NaOH (8 g, 0.2 mol) in 28% NH4OH (300 mL). The precipitate was collected, washed with water, and recrystallized from EtOH-H2O to obtain 5-methyl-2-nitrobenzamide (13) (31.5 g, 87%) as a white solid; mp 176°-177° C. [lit. (Findeklee, Ber. 38:3558, 1905) mp 176°-177° C.]; IR (KBr) V 1655 Cm-1 (amide C=O). A solution of 13 (31.5 g, 0.175 mol) in MeOH (250 mL) was shaken With 5% Pd-C (0.5 g) under 3 atm. of H2 for 24 h in a Parr apparatus. A solid formed after the initial heat of reaction subsided. The mixture was heated to boiling to redissolve the product, and was filtered while hot. The filtrate was evaporated under reduced pressure and the residue dried at 90° C. for 1 h (caution: some sublimation may occur) to obtain 2-amino-5-methylbenzamide (14) as a white solid (25.3 g, 96%); mp 173°-175° C. [lit. (Findeklee) mp 179° C.]; 1H-NMR (CDCl3) δ6.60 (d, 1H, J=8 Hz, C3 -H). To an ice-cold suspension of 14 (25.3 g, 0.168 mol) in 3.6N HCl (260 mL) was added dropwise over 25 min a solution of NaNO2 (12.75 g) in H2O (100 mL) while keeping the internal temperature below 5° C. After another 20 min of stirring at this temperature, 10N NaOH (100 mL) was added, causing all the solid to dissolve. The solution was acidified to pH 2 with 12N HCl and chilled. The solid was filtered and recrystallized from EtOH to obtain off-white needles (26.2 g, 97%); mp 217°-218° C. (dec, gas evolution) [lit. (Ferrand et al., Eur. J. Med. Chem. 2:337, 1987) mp 219°-220° C.]; IR (KBr) v 1680 (lactam C=O); 1H--NMR (d6 --DMSO+D2O) δ3.30 (s, 3H, 6--Me), 8.00 (m, 3H, aryl); UV (95% EtOH) λmax 208, 225, 282 nm.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.ClCCl.[C:21](Cl)([O:23][CH2:24][CH:25]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22]>N1C=CC=CC=1>[C:21]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])([O:23][CH2:24][CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]2[C:37]1=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:22]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COC(=O)OCC3c4ccccc4-c4ccccc43)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Thymidine (10 mmol) was dried by coevaporation with dry pyridine (2×30 ml), re-dissolved in dry pyridine (50 ml) and cooled using an acetone/carbon dioxide bath to a temperature of −20° C. The thymidine solution was magnetically stirred and a dichloromethane solution of FMOC-Cl (12 mmol, 1.2 eq. in 20 ml DCM) was added over a period of 60 minutes. The reaction mixture was warmed to room temperature and stirred for additional 60 minutes. The reaction mixture was partitioned between saturated sodium hydrogen carbonate (250 ml) and dichloromethane (3×100 ml). The organic phase was saved, combined, evaporated and dried by coevaporation with toluene (2×50 ml) forming an oily residue. A pure product was crystallized from the oily residue using dichloromethane (30 ml) and benzene (50 ml) as solvent. Yield 76%—white crystals.