Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.Br[CH:9]([CH2:15][CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[Cl-].[NH4+].CCCCCC.[C:25]([O:28][CH2:29][CH3:30])(=[O:27])C>O1CCCC1.[Cu]I>[CH2:29]([O:28][C:25](=[O:27])/[C:7](/[CH2:5][CH3:6])=[C:9](/[CH2:15][CH3:16])\[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:30]
Reactant: CCOC(=O)C(Br)CC
Reactant: CCOC(C)=O
Reactant: CC(C)NC(C)C
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(CC)=C(/CC)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 63 %

Procedure:
To a solution of diisopropylamine (654 mg, 6.46 mmol) in anhydrous tetrahydrofuran (5 mL) under the atmosphere of argon was added a 1.58 M n-butyl lithium-hexane solution (3.9 mL, 6.4 mmol) with stirring under ice cooling, and the mixture was stirred at 0° C. for 10 min and at −90° C. for 5 min. To the mixture, a solution of ethyl 2-bromo-n-butyrate (1.00 g, 5.13 mmol) in anhydrous tetrahydrofuran (9.5 mL) was added dropwise at −90° C., and the mixture was stirred for 30 min. Copper (I) iodide (489 mg, 2.56 mmol) was added at the same temperature, and the mixture was vigorously stirred further 5 min. The temperature was raised to 0° C. with stirring, and a saturated aqueous ammonium chloride solution (30 mL) was added. The reaction mixture was directly filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted twice with ethyl acetate, and the combined organic layer was washed sequentially with water and brine and concentrated. The residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 9:1) to give 368.4 mg of the title compound as oil (yield: 63%).
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][OH:29])[N:27]=2)[CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].O>ClCCl>[C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[O:11])[C@H:7]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][O:29][S:38]([CH3:37])(=[O:40])=[O:39])[N:27]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)S[C@H]1C[C@@H](c2nc(CO)cs2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)S[C@H]1C[C@@H](c2nc(COS(C)(=O)=O)cs2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1

Procedure:
To a solution of (2S,4S)-4-acetylthio-2-(4-hydroxymethylthiazol-2-yl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.24 g) in dichloromethane (40 ml) was added triethylamine (2.1 ml) and methanesulfonyl chloride (1.2 ml) at 0° C. After stirring for 30 minutes at the same temperature, water (40 ml) was added thereto. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to give (2S,4S)-4-acetylthio-2-[4-(methanesulfonyloxymethyl)thiazol-2-yl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15](I)[CH:14]=[C:13]([Cl:18])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[C:19]([Cu])#[N:20].CC#N>CN(C=O)C>[Cl:1][C:2]1[CH:16]=[C:15]([C:19]#[N:20])[CH:14]=[C:13]([Cl:18])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: N#C[Cu]
Reactant: O=C(Nc1ccncc1)c1c(Cl)cc(I)cc1Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)c(C(=O)Nc2ccncc2)c(Cl)c1
Temperature: 150 °C
Yield: 22.9 %

Procedure:
To the solution of 2,6-dichloro-4-iodo-N-(pyridin-4-yl)benzamide (0.15 g, 0.38 mmol) in DMF (2 mL) was added CuCN (0.17 g, 1.9 mmol). The mixture was heated at 150° C. under the irradiation of microwave for 1 hour. After the completion of the reaction, the mixture was filtered through Celite and purified by acid HPLC(YMC, 150 mm×30 mm, gradient: CH3CN/0.5% TFA, 10-50, 17 min) to afford the desired product (25.4 mg, yield: 23%). 1HNMR (DMSO-d6, 400 MHz): 611.95 (s, 1H), 8.74 (br, 2H), 8.33 (s, 2H), 7.97 (2H). LCMS (ESI) m/z: 292.1 [M+H+]
Reaction SMILES: [O-]S([C:5]([F:8])(F)F)(=O)=O.F[N+]1C(C)=CC(C)=CC=1C.[Br:19][C:20]1[N:24]([CH:25]([CH3:27])[CH3:26])[C:23]2[CH:28]([C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=3)[N:29]([C:32]3[CH:37]=[C:36]([Cl:38])[C:35](=[O:39])[N:34](C)[CH:33]=3)[C:30](=[O:31])[C:22]=2[CH:21]=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCCl>[Br:19][C:20]1[N:24]([CH:25]([CH3:27])[CH3:26])[C:23]2[CH:28]([C:41]3[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=3)[N:29]([C:32]3[CH:37]=[C:36]([Cl:38])[C:35](=[O:39])[N:34]([CH3:33])[C:5]=3[F:8])[C:30](=[O:31])[C:22]=2[CH:21]=1
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cc1)N(c1cc(Cl)c(=O)n(C)c1)C2=O
Agent: Cc1cc(C)[n+](F)c(C)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cc1)N(c1cc(Cl)c(=O)n(C)c1F)C2=O
Temperature: 80 °C
Reaction time: 12 h

Procedure:
1-Fluoro-2,4,6-trimethyl-pyridinium triflate [107264-00-6] (1.476 mmol) was added to a solution of 2-bromo-5-(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate E) (0.738 mmol) in 1,2-dichloroethane (12 mL) and then the mixture was heated to 80° C. in the dark. After 12 h, the reaction mixture was cooled to rt, poured into a 2% aqueous solution of sodium sulfite and extracted with EtOAc (2×). The combined organic layers were successively washed with 1M aqueous citric acid, 1M aqueous NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a pink foam. ESI-MS: tR=1.16 min, [M]+ 512/514/516 (LC-MS 1); TLC: Rf=0.10 (1.1 EtOAc/heptanes).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:30])[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[C:17]([OH:24])=[C:16]([C:25](OC)=[O:26])[C:15]1=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl-].[F:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][NH3+:49])=[C:44]([S:50]([CH3:53])(=[O:52])=[O:51])[CH:43]=1>CO>[F:41][C:42]1[CH:47]=[CH:46][C:45]([CH2:48][NH:49][C:25]([C:16]2[C:15](=[O:29])[N:14]([CH2:13][CH2:12][N:11]([CH3:30])[C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:23]3[C:18]([C:17]=2[OH:24])=[N:19][CH:20]=[CH:21][CH:22]=3)=[O:26])=[C:44]([S:50]([CH3:53])(=[O:52])=[O:51])[CH:43]=1
Reactant: COC(=O)c1c(O)c2ncccc2n(CCN(C)C(=O)OCc2ccccc2)c1=O
Reactant: CS(=O)(=O)c1cc(F)ccc1C[NH3+]
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CN(CCn1c(=O)c(C(=O)NCc2ccc(F)cc2S(C)(=O)=O)c(O)c2ncccc21)C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A solution of methyl 1-{2-[[(benzyloxy)carbonyl](methyl)amino]ethyl}-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.5 g, 1.21 mmol) in MeOH (6 mL) was treated with Hunig's base (0.33 mL, 1.82 mmol) and 1-[4-fluoro-2-(methylsulfonyl)phenyl]methanaminium chloride (0.35 g, 1.46 mmol) and heated in a sealed reaction vessel at 80 degrees C. After overnight, an additional 0.5 equivalents of the amine and 1.5 equivalents of Hunig's base was added and the reaction heated until HPLC showed the starting material gone. The reaction was cooled and the solids that percipitated were collected by filtration to give pure product.
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[F:15][C:16]1[CH:17]=[C:18]([OH:23])[CH:19]=[C:20]([F:22])[CH:21]=1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][O:23][C:18]2[CH:17]=[C:16]([F:15])[CH:21]=[C:20]([F:22])[CH:19]=2)=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Reactant: Oc1cc(F)cc(F)c1
Product: COC(=O)c1cc(Cl)ccc1COc1cc(F)cc(F)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromoethyl)-5-chlorobenzoate and 3,5-difluorophenol:
Reaction SMILES: Br[C:2]1[CH:20]=[N:19][C:5]2[N:6]([CH2:16][CH2:17][CH3:18])[CH2:7][CH2:8][CH2:9][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:4]=2[CH:3]=1.[CH2:21]([O:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32](OB(O)O)=[CH:31][CH:30]=1)[CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:21]([O:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[CH:31][C:32]([C:2]2[CH:20]=[N:19][C:5]3[N:6]([CH2:16][CH2:17][CH3:18])[CH2:7][CH2:8][CH2:9][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:4]=3[CH:3]=2)=[CH:33][CH:34]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCOCCOc1ccc(OB(O)O)cc1
Reactant: CCCN1CCCC(C(=O)OC)=Cc2cc(Br)cnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCCOCCOc1ccc(-c2cnc3c(c2)C=C(C(=O)OC)CCCN3CCC)cc1
Temperature: 115 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
A suspension of methyl 3-bromo-10-propyl-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxylate (820 mg), 4-(2-butoxyethoxy)phenylboric acid (748 mg) and potassium carbonate (868 mg) in toluene (15 ml), ethanol (1.5 ml) and water (1.5 ml) was stirred under an argon atmosphere for 30 minutes. Tetrakis(triphenylphosphine)palladium (140 mg) was added thereto, and the mixture was heated at 115° C. for 6 hours under an argon atmosphere, which was allowed to cool. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1→hexane:ethyl acetate=4:1) to give methyl 3-[4-(2-butoxyethoxy)phenyl]-10-propyl-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxylate (870 mg) as a yellow oily material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[C:12]([C:17]#[N:18])=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.O.O.[Sn](Cl)Cl>C(O)C.O1CCCC1>[NH2:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([C:11]2[C:12]([C:17]#[N:18])=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=1
Reactant: N#Cc1ccccc1-c1cc(F)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccccc1-c1cc(N)cc(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.3 %

Procedure:
A cooled (0° C.) suspension of 3′-fluoro-5′-nitrobiphenyl-2-carbonitrile (8.9 g, 37 mmol) in ethanol (70 ml) and tetrahydrofuran (70 ml) was treated with tin(II) chloride dihydrate (29 g, 129 mmol) and the mixture was stirred at ambient temperature for 4 h. The solvent was removed in vacuo and the residue treated with ice-cold 2N sodium hydroxide (400 ml). The resulting slurry was stirred for 30 min then extracted with dichloromethane (2×400 ml). The organics were combined, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by dry flash chromatography on silica, eluting with dichloromethane containing 0.5% triethylamine, afforded 5′-amino-3′-fluorobiphenyl-2-carbonitrile as a white solid (4.5 g, 58%): δH (400 MHz, CDCl3) 3.90 (2H, br), 6.45 (1H, ddd, J 8, 2 and 2), 6.58-6.63 (2H, m), 7.44 (1H, ddd, J 8, 8 and 2), 7.48 (1H, dd, J 8 and 2), 7.62 (1H, ddd, J 8, 8 and 2), 7.74 (1H, dd, J 8 and 2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.C(N(CC)CC)C.[CH3:29][C:30]([CH3:36])([CH3:35])[CH2:31][C:32](Cl)=[O:33].Cl>C1COCC1.C(OCC)(=O)C>[CH3:29][C:30]([CH3:36])([CH3:35])[CH2:31][C:32]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2)=[O:33]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CCOC(=O)c1cc2cc(N)ccc2n1-c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(NC(=O)CC(C)(C)C)ccc2n1-c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under argon, 355 mg (1.27 mmol) of ethyl 5-amino-1-phenyl-1H-indole-2-carboxylate from Example LVII and 141 mg (0.19 ml, 1.39 mmol) of triethylamine are added to 4 ml of THF. The mixture is cooled to 0° C., and a solution of 170 mg (0.18 ml, 1.27 mmol) of 3,3-dimethylbutyryl chloride in 2 ml of THF is added. The mixture is stirred at RT for 2 hours. To bring the reaction to completion, a further 1 eq. of triethylamine and 1 eq. of acid chloride are added and the mixture is stirred at RT for 2 hours. For work-up, the mixture is added to dilute hydrochloric acid and ethyl acetate and extracted. The organic phase is washed with sat. sodium bicarbonate solution, dried with sodium sulphate, filtered and dried under reduced pressure. The resulting crude product is purified by column chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate 3:1-1:1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C@:11]12[N:27]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=4[C:34]4[C:35]5[CH2:40][NH:39][C:37](=[O:38])[C:36]=5[C:24]5=[C:25]([C:26]=43)[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=35)[C@H:15]([O:16]1)[CH2:14][C@@H:13]([NH:41][CH3:42])[C@H:12]2[O:43][CH3:44].C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[CH3:10][C:11]12[N:27]3[C:26]4=[C:25]5[N:17]([C:18]6[C:23]([C:24]5=[C:36]5[C:37](=[O:38])[NH:39][CH2:40][C:35]5=[C:34]4[C:33]4[C:28]3=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:22][CH:21]=[CH:20][CH:19]=6)[CH:15]([O:16]1)[CH2:14][CH:13]([N:41]([C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH3:42])[CH:12]2[O:43][CH3:44]
Reactant: O=C(Cl)c1ccccc1
Reactant: CN[C@@H]1C[C@H]2O[C@@](C)([C@@H]1OC)n1c3ccccc3c3c4c(c5c6ccccc6n2c5c31)C(=O)NC4
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COC1C(N(C)C(=O)c2ccccc2)CC2OC1(C)n1c3ccccc3c3c4c(c5c6ccccc6n2c5c31)C(=O)NC4
Reaction time: 0.17 h

Procedure:
0.035 ml (0.3 mmol) of benzoyl chloride is added at room temperature to a solution of 116.5 mg (0.25 mmol) of staurosporine and 0.065 ml (0.38 mmol) of N,N-diisopropylethylamine in 2 ml of chloroform and the whole is stirred for 10 minutes. The reaction mixture is diluted with chloroform, washed with sodium bicarbonate solution, dried over magnesium sulphate and concentrated by evaporation. The crude product is chromatographed on silica gel (eluant:methylene chloride/ethanol 30:1); m.p. 235°-247° with colour turning brown.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].C=O.[CH2:12]([OH:16])[CH2:13][CH2:14][CH3:15].[CH2:17](NCCCC)CCC.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:17][O:16][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]=1[OH:9]
Reactant: Cc1ccc(O)c(C)c1
Reactant: CCCCNCCCC
Reactant: CCCCO
Agent: C=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCCCOCc1cc(C)cc(C)c1O
Reaction time: 11 h

Procedure:
2,4-Dimethylphenol (3.66 g; 30.0 mmol), 87.3% paraformaldehyde (1.24 g; 36.0 mmol), 1-butanol (14.46 g; 195.0 mmol), dibutylamine (0.39 g; 3.0 mmol) and acetic acid (0.90 g; 15.0 mmol) were mixed together, then the mixture was reacted under reflux with stirring for 11 hours. After completion of the reaction, toluene was added into the resulting mixture for extraction of the resulting product in toluene, and then the toluene phase was separated. After the separated toluene phase was sequentially washed with water, an aqueous 1% dilute sulfuric acid solution, an aqueous 5% sodium hydrogen carbonate solution and water, the toluene phase was distilled under reduced pressure to distill off compounds with low boiling points, to give 2,4-dimethyl-6-butoxymethyl-1-hydroxybenzene.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:33])[CH2:14][CH2:15][NH:16][CH2:17][CH2:18][C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@@H:22]1[C:26]([O:28]C(C)(C)C)=[O:27])=[O:20])=[O:7])(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl.O>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[C:26]([C@H:22]1[CH2:23][CH2:24][CH2:25][N:21]1[C:19](=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:33])([OH:28])=[O:27]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)CCNCCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)[C@H]1CCCN1C(=O)CCNCCC(=O)N1CCC[C@@H]1C(=O)O
Reaction time: 16 h
Yield: 76 %

Procedure:
To a stirred solution of 33 mg (0.07 mmol) (R)-1-[3-[3-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-3-oxo-propylamino]-propionyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 5 ml dichloromethane at 0° C. was added dropwise 1.0 ml trifluoroacetic acid and stirring continued for 16 h at room temperature. Concentration in vacuo and azeotroping three times with chloroform on a rotary evaporator afforded, after resuspension in water and subsequent lyophilization, 19 mg (76%) of the title compound as a yellow glassy solid. MS m/e (%): 354 ([M−H]−, 100).
Reaction SMILES: [CH2:1]([PH:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH:2]([CH3:4])[CH3:3].C([Li])[CH2:11][CH2:12][CH3:13].Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29]Br.[NH4+].[Cl-]>C1COCC1.CCCCCC.C(OCC)C>[CH2:1]([P:5]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][P:5]([CH2:6][CH:12]([CH3:11])[CH3:13])[CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][CH:7]([CH3:9])[CH3:8])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CPCC(C)C
Reactant: [Li]CCCC
Reactant: BrCc1ccccc1-c1ccccc1CBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)CP(Cc1ccccc1-c1ccccc1CP(CC(C)C)CC(C)C)CC(C)C
Reaction time: 1 h
Yield: 72 %

Procedure:
Diisobutylphosphine (1.66 grams, 11.37 mmol) was dissolved in THF (25 ml) under nitrogen and cooled with a dry ice/acetone bath. n-Butyllithium (7.11 ml of a 1.6M solution in hexane, 11.37 mmol) was added dropwise to the stirring solution which was then allowed to stir for 1 hour in the cold bath. 2,2'-Bis(bromomethyl)-1,1'-biphenyl (1.89 grams, 5.55 mmol) in THF (10 ml) was added dropwise at -70° C. The solution was allowed to stir overnight at room temperature and was then heated at reflux for 1 hour. Saturated aqueous NH4Cl was added to the solution at room temperature. Diethyl ether was added and the layers were separated in a separatory funnel. The aqueous layer was extracted twice with diethyl ether, and the combined organic solution was then washed twice with water. The solvent was removed on a steam bath under a stream of nitrogen. The oily residue was then placed on a Kugelrohr distillation apparatus to remove low boiling material at about 175° C. and 1 mm Hg leaving 1.88 grams (72% yield) of a thick orange glassy product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([C:7]1[C:8]([NH:18][CH2:19][CH3:20])=[N:9][C:10]([CH:13]([O:16]C)OC)=[CH:11][CH:12]=1)=O.[H-].[Na+].Cl[CH:27]([CH2:33][CH2:34][C:35]([O-])=[O:36])[C:28]([O:30][CH2:31]C)=[O:29]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:7]3[C:8](=[N:9][C:10]([CH:13]=[O:16])=[CH:11][CH:12]=3)[N:18]([CH2:19][CH3:20])[C:35](=[O:36])[C:34]=2[CH2:33][CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:21]=[CH:22][CH:23]=1
Reactant: CCNc1nc(C(OC)OC)ccc1C(=O)c1cccc(Cl)c1
Reactant: CCOC(=O)C(Cl)CCC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)c(CCC(=O)OC)c(-c2cccc(Cl)c2)c2ccc(C=O)nc21

Procedure:
In DMF was treated 3-(3-chlorobenzoyl)-2-ethylamino-6-dimethoxymethylpyridine with 60% sodium hydride, followed by the reaction with monoethyl chloroglutarate. Thereafter, the reaction mixture was worked up and purified in a usual manner. The resulting compound was reacted in ethanol in the presence of sodium methoxide under heating, and the reaction mixture was worked up and purified in a usual manner. Then, the resulting compound was reacted in a solution of 6M hydrochloric acid-dioxane (1:1) under heating, and then the reaction mixture was worked up and purified in a usual manner. The resulting compound was further reacted with methyl iodide in DMF in the presence of potassium carbonate, and then the reaction mixture was worked up and purified in a usual manner to obtain methyl 3-[4-(3-chlorophenyl)-1-ethyl-7-formyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]propanoate. NMR1: 10.11 (1H, d, J=0.6 Hz), 2.45-2.95 (4H, m), 1.43 (3H, t, J=7.1 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([CH3:8])[CH:7]=1.[H][H]>[Pd].C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:9])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(F)ccc1N
Yield: 85 %

Procedure:
A mixture of 125 g of 5-fluoro-2-nitrotoluene, 3.0 g of 5% palladium on carbon, and 200 ml of ethanol was reduced in a Parr hydrogenator under 46 p.s.i. hydrogen pressure. After hydrogen uptake had ceased, the catalyst was removed by filtration, and the ethanolic filtrate was evaporated under reduced pressure to give a colorless liquid. Purification by vacuum distillation yielded 85.7 g of 4-fluoro-2-methylaniline, b.p. 67°-71°/4.2 mm.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:4]([CH2:5][C:6](=[O:29])[C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:3]1.[C:30](OC(=O)C)(=[O:32])[CH3:31].C(N(CC)CC)C.Cl>C(Cl)Cl.O.N1(C2C=CN=CC=2)CCCC1>[C:30]([O:1][C@@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@H:4]([CH2:5][C:6](=[O:29])[C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:28])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:3]1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Agent: c1cc(N2CCCC2)ccn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(=O)C[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 95.1 %

Procedure:
A solution of methyl 3α-hydroxy-7-keto-5β-cholanoate (10 g, 24.72 mmoles) in methylene chloride (40 ml) was added with acetic anhydride (3.79 g, 37.1 mmoles), triethylamine (3.63 g, 36 mmoles) and 4-pyrrolidino-pyridine (0.11 g, 0.74 mmoles) and the reaction mixture was left to react for 3 hours under strong magnetic stirring, then it was diluted with methylene chloride (50 ml) and water (50 ml) and acidified with 10% hydrochloric acid. The organic phase was separated and the aqueous phase was extracted with methylene chloride (3×20 ml). The combined organic phases were washed with brine (1×30 ml), dried over sodium sulfate and concentrated under vacuum. The residue (11.0 g) was subjected to flash chromatography on silica, eluting with methylene chloride/methanol 99:1, to obtain 10.5 g of a pure product (95%).
Reaction SMILES: BrC1C=NC(Cl)=NC=1.CC1NC=CN=1.[Br:15][C:16]1[CH:17]=[N:18][C:19]([N:22]2[CH:26]=[C:25](C)[N:24]=[C:23]2[CH3:28])=[N:20][CH:21]=1>>[Br:15][C:16]1[CH:21]=[N:20][C:19]([N:22]2[CH:26]=[CH:25][N:24]=[C:23]2[CH3:28])=[N:18][CH:17]=1
Reactant: Cc1cn(-c2ncc(Br)cn2)c(C)n1
Agent: Cc1ncc[nH]1
Agent: Clc1ncc(Br)cn1
Product: Cc1nccn1-c1ncc(Br)cn1

Procedure:
5-bromo-2-(2-methyl-1H-imidazol-1-yl)-pyrimidine was prepared 5-bromo-2-chloropyrimidine and 2-methylimidazole following a procedure analogous to that described for 5-bromo-2-(2,4-dimethyl-1H-imidazol-1-yl)-pyrimidine in Example 26.