Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[CH2:13][NH:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9].[CH2:24]=O>C(O)=O>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[CH2:13][N:12]([CH3:24])[CH2:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: C=O
Reactant: COc1cc2c(cc1OC)C(c1ccc(Cl)c(Cl)c1)CNC2
Agent: Cl
Solvent: O=CO
Product: COc1cc2c(cc1OC)C(c1ccc(Cl)c(Cl)c1)CN(C)C2

Procedure:
The free base released from 6.5 g. of rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline hydrochloride is heated at 120°C. (bath temperature) for 1 hour with 10 ml. of formic acid and 10 ml. of 35% formalin solution. After evaporation, extraction with sodium carbonate solution and methylene chloride and acidification with ethanolic hydrogen chloride, there is obtained rac.-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoquinoline hydrochloride which is recrystallized from methanol-ether and then melts at 243°-246°C. (softening at 238°C). The free base melts at 115°-116°C. after recrystallization from ether-petroleum ether.
Reaction SMILES: C([CH:3]([CH:7]1[C:19]2[N:18]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:17]3[C:12](=[CH:13][C:14]([F:29])=[CH:15][C:16]=3Br)[C:11]=2[CH2:10][CH2:9][CH2:8]1)[C:4]([O-:6])=[O:5])C.[Na+].[CH3:31][S:32]([O-:34])=[O:33].[OH-].[Na+].Cl>CN1C(=O)CCC1.C1COCC1.[Cu]I.CO>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:18]2[C:19]3[CH:7]([CH2:3][C:4]([OH:6])=[O:5])[CH2:8][CH2:9][CH2:10][C:11]=3[C:12]3[C:17]2=[C:16]([S:32]([CH3:31])(=[O:34])=[O:33])[CH:15]=[C:14]([F:29])[CH:13]=3)=[CH:26][CH:25]=1
Reactant: CS(=O)[O-]
Reactant: CCC(C(=O)[O-])C1CCCc2c1n(Cc1ccc(Cl)cc1)c1c(Br)cc(F)cc21
Agent: [Cu]I
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1cc(F)cc2c3c(n(Cc4ccc(Cl)cc4)c12)C(CC(=O)O)CCC3
Temperature: 140 °C
Reaction time: 6 h
Yield: 61.8 %

Procedure:
To a solution of 478 mg of the ester prepared in step 2 in 8 mL of NMP, 510 mg of methanesulfinic acid sodium salt and 950 mg of CuI (I) was added successively. The resulting mixture was degassed under a flow of N2, then heated at 140° C. for 8 h under rigorous stirring. The reaction mixture was cooled to room temperature, diluted with minimum amount of a 1:1 mixture of EtOAc/hexane. The resulting mixture was filtered through a pad of silica gel, further eluted with EtOAc. The filtrate was concentrated to about 50 mL, and washed with water and brine. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was purified by flash chromatography over silica gel (30% EtOAc/hexane) to afford 320 mg of desired sulfonated material, which was dissolved in 5 mL of THF plus 5 mL of methanol. To the resulting solution, 5 mL of 2 N of NaOH was added and the resulting mixture was stirred at rt for 6 h. The reaction mixture was neutralized with 1 M HCl aqueous solution and extracted with EtOAc. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was refluxed with hexane under rigorous stirring for 0.5 h. The resulting mixture was cooled to rt under rigorous stirring, and filtered to afford 278 mg of desired acid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1.[C:12]1([CH:18]2[CH2:22][CH2:21][CH2:20][NH:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[CH3:11][C:8]1[N:6]2[N:7]=[C:2]([N:19]3[CH2:20][CH2:21][CH2:22][CH:18]3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: Cc1nnc2ccc(Cl)nn12
Reactant: c1ccc(C2CCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1nnc2ccc(N3CCCC3c3ccccc3)nn12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 7.9 %

Procedure:
A mixture of 6-chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine (200 mg, 1.19 mol), 2-phenylpyrrolidine (200 mg, 1.36 mmol) and K2CO3 (350 mg, 2.5 mmol) in acetonitrile (20 mL) was heated at 100° C. under microwave and stirred for 30 mins. After cooled to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL*3). The combined organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuum. The residue was purified by prep-TLC (silica-gel, DCM: MeOH=20:1) to give product 3-methyl-6-(2-phenylpyrrolidin-1-yl)-[1,2,4]triazolo[4,3-b]pyridazine (Compound 10) as a white solid (30 mg, 12%). 1H NMR (300 MHz, CD3OD) δ 7.73-7.77 (d, 1H, J=10.2 Hz), 7.22-7.34 (m, 5H), 6.84-6.87 (d, 1H, J=10.2 Hz), 5.14-5.18 (m, 1H), 3.92-3.98 (m, 1H), 3.71-3.81 (m, 1H), 2.57 (s, 3H), 2.50-2.54 (M, 1H), 2.03-2.13 (m, 3H); LRMS (M+H+) m/z: calcd 279.15; found 279.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:7]=3[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.Cl.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24]Cl.C(=O)(O)[O-].[Na+].C(Cl)(Cl)Cl>CN(C)C=O.O>[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[O:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:7]=3[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cc(O)ccc2c2oc3ccccc3c12
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(C)CCOc1ccc2c(c1)[nH]c(=O)c1c3ccccc3oc21
Temperature: 120 °C
Reaction time: 16 h
Yield: 133.6 %

Procedure:
In dry N,N-dimethylformamide was dissolved 6.0 g of 3-hydroxy-5H-benzofuro[3,2-c]quinolin-6-one, and 1.1 g of 2-dimethylaminoethyl chloride hydrochloride and 6.02 g of sodium bicarbonate were added to the solution. The mixture was stirred for 16 hours at 120° C. Into the reaction mixture were poured chloroform and water, and the insolved materials were filtered out. The organic layer was washed with water, dried over magnesium sulfate anhydride, and evaporated under reduced pressure. The residue was washed with ether, and recrystallized from chloroform and ethyl acetate to obtain 3.29 g of 3-(2-dimethylaminoethoxy)-5H-benzofuro[3,2-c]quinolin-6-one.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](O)=[O:46])([CH3:44])[CH3:43])=[CH:33][CH:32]=2)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=1)(=O)C.[NH2:52][CH:53]([CH2:56][OH:57])[CH2:54][OH:55].OCCN1CCNCC1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](=[O:46])[NH:52][CH:53]([CH2:56][OH:57])[CH2:54][OH:55])([CH3:44])[CH3:43])=[CH:33][CH:32]=3)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: NC(CO)CO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCC(=O)NC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: OCCN1CCNCC1
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NC(C)(C)C(=O)NC(CO)CO)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 48 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethyl-carbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and 2-amino-1,3-propanediol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and 1-(2-hydroxyethyl)piperazine, respectively.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][C:8]2[N:11]([CH2:24][CH2:25][CH:26]=O)[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:7]=2[CH2:6]1)(=[O:4])=[O:3].[N:28]1([C:34]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[S:36](=[O:44])(=[O:43])[N:35]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:44]=[S:36]1(=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:34]([N:28]2[CH2:33][CH2:32][N:31]([CH2:26][CH2:25][CH2:24][N:11]3[C:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][C:7]=4[C:13]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)=[N:12]3)[CH2:30][CH2:29]2)=[N:35]1
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCC=O)C1
Reactant: O=S1(=O)N=C(N2CCNCC2)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCN(C3=NS(=O)(=O)c4ccccc43)CC2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
To a stirred solution of 3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propionaldehyde (0.040 g, 0.13 mmol) and 3-piperazin-1-yl-benzo[d]isothiazole 1,1-dioxide (0.050 g, 0.21 mmol) in CH2Cl2 (0.5 mL), glacial AcOH (12 μL, 0.21 mmol) was added and stirred for 15 min at room temperature. NaBH(OAc)3 (0.058 g, 0.27 mmol) was added and stirred under nitrogen overnight. Saturated NaHCO3 (0.5 mL) was then added and stirred for 15 min. The layers separated and the aqueous layer was extracted with CH2Cl2 (0.5 mL). MPLC (silica, 2-15% MeOH/CH2Cl2) afforded the desired product as a white solid (0.048 g, 76%). TLC (silica, 12% MeOH/CH2Cl2): Rf=0.50. MS (electrospray): exact mass calculated for C28H31F3N6O4S2, 636.18; m/z found, 637.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.94 (dd, J=0.8, 7.6 Hz, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.75 (d, J=8.3 Hz, 2H), 7.73-7.63 (m, 2H), 7.68 (d, J=8.3 Hz, 2H), 4.57 (s, 2H), 4.17 (t, J=6.9 Hz, 2H), 4.04 (br s, 4H), 3.69 (t, J=5.7 Hz, 2H), 2.94 (s, 3H), 2.92 (t, J=6.2 Hz, 2H), 2.62 (t, J=5.0 Hz, 4H), 2.44 (t, J=6.6 Hz, 2H), 2.13 (q, J=6.6 Hz, 2H).
Reaction SMILES: [C:1]([S:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:13]=2)[N:8]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[CH:26][CH:25]=2)[C:7]=1[CH2:38][C:39]([CH3:44])([CH3:43])[C:40]([OH:42])=[O:41])([CH3:4])([CH3:3])[CH3:2].C(SC1C2C(=CC=C([O:59]CC3C=CC=CN=3)C=2)N(CC2C=CC(C3C=NC(O)=CC=3)=CC=2)C=1CC(C)(C)C(O)=O)(C)(C)C>>[CH3:37][O:36][C:33]1[N:32]=[CH:31][C:30]([C:27]2[CH:28]=[CH:29][C:24]([CH2:23][N:8]3[C:9]4[C:14](=[CH:13][C:12]([O:15][CH2:16][C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=5)=[CH:11][CH:10]=4)[C:6]([S:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[O:59])=[C:7]3[CH2:38][C:39]([CH3:44])([CH3:43])[C:40]([OH:42])=[O:41])=[CH:25][CH:26]=2)=[CH:35][CH:34]=1
Reactant: CC(C)(C)Sc1c(CC(C)(C)C(=O)O)n(Cc2ccc(-c3ccc(O)nc3)cc2)c2ccc(OCc3ccccn3)cc12
Reactant: COc1ccc(-c2ccc(Cn3c(CC(C)(C)C(=O)O)c(SC(C)(C)C)c4cc(OCc5ccccn5)ccc43)cc2)cn1
Product: COc1ccc(-c2ccc(Cn3c(CC(C)(C)C(=O)O)c(S(=O)C(C)(C)C)c4cc(OCc5ccccn5)ccc43)cc2)cn1

Procedure:
3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(1-oxy-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (M3); the acyl gluconuride of 3-[3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (M4); and 3-[3-tert-butylsulfanyl-1-[4-(6-hydroxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid (M5; which exists also as a pyridon-5-yl tautomer).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH3:24]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH3:24])=[C:4]([Cl:9])[CH:3]=1
Reactant: CCCOCCCl
Reactant: Oc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOCCOc1ccc(Br)cc1Cl
Temperature: 90 °C
Reaction time: 24 h

Procedure:
To a solution of 4-bromo-2-chlorophenol (10 g) in DMF (200 ml) were added at room temperature potassium carbonate (9.99 g), sodium iodide (7.95 g) and 2-chloroethylpropylether (6.7 ml), and the mixture was stirred at 90° C. for 24 hours. To the mixture was added water, and the mixture was extracted with hexane. The organic layer was washed with water, 1N sodium hydroxide solution and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give pale yellow oil of 4-bromo-2-chloro-1-(2-propoxyethoxy)benzene (14.91 g).
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[N:16]=[C:15]([OH:17])[CH:14]=[CH:13][N:12]=2)=[CH:8][N:9]=1)(=O)C.O1CCCC1.Cl>C(O)C>[NH2:4][C:5]1[S:6][C:7]([S:10][C:11]2[N:16]=[C:15]([OH:17])[CH:14]=[CH:13][N:12]=2)=[CH:8][N:9]=1
Reactant: CC(=O)Nc1ncc(Sc2nccc(O)n2)s1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ncc(Sc2nccc(O)n2)s1
Yield: 14.4 %

Procedure:
A mixture of 2-acetylamino-5-(4-hydroxypyrimidin-2-ylthio)thiazole (3.7 g) in a mixture of ethanol (100 ml), tetrahydrofuran (40 ml) and aqueous 6N-hydrochloric acid (20 ml) was refluxed for 6.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The solution was adjusted to pH 8.5 using aqueous sodium bicarbonate. The precipitates were collected by filtration, washed with water and dried in vacuo to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 250 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-5-(4-hydroxypyrimidin-2-ylthio)thiazole (0.45 g, yield: 14.5%). mp: 210°-220° C. (dec.) IR (Nujol): 3450, 3350, 3125, 1675, 1510,1230 cm-1
Reaction SMILES: O[C@H:2]1[C@H:6]([CH:7]=[CH2:8])[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.C(N(CC)C(C)C)(C)C.F.F.F.C(N(CC)CC)C.[F:38]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F>C1(C(F)(F)F)C=CC=CC=1.CCOC(C)=O>[F:38][C@@H:2]1[C@H:6]([CH:7]=[CH2:8])[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1
Reactant: C=C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: F
Solvent: CCN(C(C)C)C(C)C
Solvent: FC(F)(F)c1ccccc1
Solvent: CCOC(C)=O
Product: C=C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
To a solution of (3S,4R)-benzyl 3-hydroxy-4-vinylpyrrolidine-1-carboxylate (5.0 g, 20.2 mmol) in PhCF3 (81 mL, 0.25 M solution) was added N,N-diisopropylethylamine (53 mL, 303 mmol), triethylamine trihydrofluoride (19.8 mL, 121 mmol) and perfluoro-1-butanesulfonyl fluoride (PBSF, 3.6 mL, 20.2 mmol). The resulting mixture was stirred at room temperature. After 60 and 120 minutes, additional perfluoro-1-butanesulfonyl fluoride (3.6 mL, 20.2 mmol) was added. After 18 hours, the reaction mixture was transferred to a separatory funnel and was washed twice with 50 mL of 1.0 N HCl (Caution! lots of heat produced), twice with saturated NaHCO3 aqueous solution, and once with H2O and brine. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated to provide a crude brown oil. The pure (3R,4R)-benzyl 3-fluoro-4-vinylpyrrolidine-1-carboxylate was obtained in 81% yield (4.1 g) as a yellow oil by flash column chromatography (SiO2, 10%-30% EtOAc in hexanes). Rf=0.55 (30% EtOAc in hexanes). 1H NMR (CDCl3, 400 MHz): δ 7.37-7.25 (5H, m), 5.9 (1H, m), 5.24 (2H, m), 5.14 (2H, m), 5.03 (1H, dt, J=52.8, 3.2 Hz), 3.9-3.5 (3H, m), 3.53 (1H, m), 2.83 (1H, m). 13C NMR (CDCl3, 100 MHz): δ 154.7, 154.6, 136.6, 131.89, 131.83, 128.48, 128.02, 127.94, 119.00, 118.94, 95.23, 94.47, 93.42, 92.67, 66.99, 66.94, 53.16, 52.94, 52.83, 52.60, 48.17, 48.02, 47.91, 47.83, 47.2, 47.1. LC/MS (uplc): MH+250.0, 0.93 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:44][O:45][C:46]1[CH:47]=[C:48]([N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH:49]=[C:50]([O:52][CH3:53])[CH:51]=1>CN(C=O)C>[CH3:44][O:45][C:46]1[CH:47]=[C:48]([N:54]2[CH2:55][CH2:56][N:57]([C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[O:9])[CH2:58][CH2:59]2)[CH:49]=[C:50]([O:52][CH3:53])[CH:51]=1
Reactant: O=C(O)c1ccncc1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(N2CCN(C(=O)c3ccncc3)CC2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5 g (45.8 mmol) of pyridine-4-carboxylic acid were suspended with stirring in 150 ml of DMF. With further stirring, 6.93 g (68.5 mmol) of N-methylmorpholine and then a solution of 35.6 g (68.5 mmol) of Py-BOP (1-benzotriazolyltripyrrolidinophosphonium hexafluorophosphate) and 10.18 g (45.8 mmol) of 1-(3,5-dimethoxyphenyl)piperazine in 60 ml of DMF were added to this mixture. The mixture was stirred at room temperature for 24 hours, the DMF was distilled off under reduced pressure and the residue was purified on a silica gel column (Kieselgel 60, from Merck AG, Darmstadt) using the mobile phase dichloromethane/methanol/25 percent ammonia (90:10:1 v/v/v).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.Br[CH2:20][CH2:21][O:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27]([CH3:33])=[N:28]2.C(N(CC)C(C)C)(C)C>CC(O)C>[CH3:33][C:27]1[CH:26]=[CH:25][C:24]2[C:29](=[CH:30][CH:31]=[CH:32][C:23]=2[O:22][CH2:21][CH2:20][N:1]2[CH2:2][CH2:3][CH:4]([O:7][C:8]3[CH:17]=[C:16]4[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]4)=[CH:10][CH:9]=3)[CH2:5][CH2:6]2)[N:28]=1
Reactant: O=C1CCc2ccc(OC3CCNCC3)cc2N1
Reactant: Cc1ccc2c(OCCBr)cccc2n1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(OCCN3CCC(Oc4ccc5c(c4)NC(=O)CC5)CC3)cccc2n1
Yield: 46.3 %

Procedure:
7-(Piperidin-4-yloxy)-3,4-dihydro-1H-quinolin-2-one (0.064 g, 0.25 mmol) and 5-(2-bromoethoxy)-2-methylquinoline (0.069 g, 0.25 mmol) were mixed together in propan-2-ol (20 mL), N,N-diisopropylethylamine (0.336 g, 2.6 mmol) added and the mixture heated at reflux for 48 h. The volatiles were removed by evaporation to dryness under reduced pressure and the residue partitioned between ethyl acetate and saturated NaHCO3 aq. The phases were separated, the organic phase washed with water, dried (MgSO4) and evaporated to dryness under reduced pressure. Chromatography on SiO2, eluting with a gradient of ethyl acetate in 60–80° C. petroleum ether, gave the title compound (0.05 g, 45%) as a white solid, after trituration under 60–80° C. petroleum ether.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH:11][CH:12]3[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.Cl.[F:20][CH2:21][CH2:22][NH2:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[F:20][CH2:21][CH2:22][NH:23][CH:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)[CH2:13][CH2:14]1
Reactant: O=C1CCC(Nc2cccc3cnccc23)CC1
Reactant: NCCF
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: FCCNC1CCC(Nc2cccc3cnccc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.1 %

Procedure:
4-(5-Isoquinolylamino)-1-cyclohexanone (intermediate 4) (60 mg) and 2-fluoroethylamine hydrochloride (50 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was stirred and was then concentrated. The residue was purified by HPLC g [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was then added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (18 mg) and a syn-form compound (12 mg).
Reaction SMILES: [CH3:1][C@@:2]1([OH:20])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[C:19]2[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=2[N:12]=[CH:11]1.[Br:21]N1C(=O)CCC1=O>CN(C=O)C>[Br:21][C:11]1[N:10]([C:19]2[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=2[N:12]=1)[C@@H:3]1[O:4][C@H:5]([CH2:8][OH:9])[C@@H:6]([OH:7])[C@@:2]1([CH3:1])[OH:20]
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)ncnc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1c(Br)nc2c(N)ncnc21
Reaction time: 48 h
Yield: 21.1 %

Procedure:
To a solution of 2′-C-methyladenosine[for preparation, see J. Med. Chem. 41: 1708 (1998)] (138 mg, 0.5 mmol) in DMF (4 mL) was added N-bromosuccinimide (231 mg, 1.35 mmol). The solution was stirred protected from light at rt for 2 d and then evaporated in vacuo. The crude product was purified on a silica gel column (3×9 cm) using dichloromethane/methanol (25/1, 20/1 and 15/1) as eluent. Fractions containing the product were pooled and evaporated in vacuo to give the desired product (38 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].[C:21]([O:25][C:26]([NH:28][C@H:29]1[C@H:33]([CH3:34])[CH2:32][NH:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:21]([O:25][C:26]([NH:28][C@H:29]1[C@H:33]([CH3:34])[CH2:32][N:31]([C:3]2[C:2]([Cl:1])=[C:11]3[C:6]([C:7](=[O:18])[C:8]([C:15]([OH:17])=[O:16])=[CH:9][N:10]3[CH:12]3[CH2:14][CH2:13]3)=[CH:5][C:4]=2[F:19])[CH2:30]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: C[C@@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: C[C@@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)C[C@H]1NC(=O)OC(C)(C)C
Yield: 102.7 %

Procedure:
A mixture of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (2.2 g), anhydrous acetonitrile (22 ml), trans-3-t-butoxycarbonylamino-4-methylpyrrolidine (reference example 5; 2.4 g) and DBU (1.22 g) was refluxed for 5 hours. The reacting mixture was concentrated under reduced pressure, the resulting residue was dissolved in chloroform and washed with 10% aqueous citric acid solution. The chloroform layer was further washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in hot methanol (20 ml) and, after cooling, the resulting precipitate was collected by filtration to give 7-(trans-3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (3.62 g) as yellow needle, mp 210°-213° C. (decompd.).
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=2[Cl:19])=[N:5][CH:4]=1)#[N:2].[Br:20]Br.C(OCC)(=O)C>ClC(Cl)C(Cl)Cl>[Br:20][C:4]1[N:5]=[C:6]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:17])([F:16])[F:18])=[CH:10][C:9]=2[Cl:19])[NH:7][C:3]=1[C:1]#[N:2]
Reactant: BrBr
Reactant: N#Cc1cnc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)C(Cl)Cl
Product: N#Cc1[nH]c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1Br
Temperature: 90 °C
Yield: 169.2 %

Procedure:
A mixture of 5-cyano-2-(2,6-dichloro-4-trifluoromethylphenyl)imidazole (1.0 g, 0.0033 mol) and bromine (1.9 g, 0.64 ml, 0.13 mol) in 1,1,2,2-tetrachloroethane (20 ml) was stirred and heated at 90° C. for 7 hours. Ethyl acetate (50 ml) was added and the solution was washed with water (50 ml), aqueous sodium metabisulphite solution (50 ml), water (50 ml), dried over anhydrous sodium sulphate and evaporated to dryness. The solid residue was purified by chromatography on silica gel eluting with a mixture of ethyl acetate and petroleum ether (b.p. 60°-80° C.)(3:10) to give 4-bromo-5-cyano-2-(2,6-dichloro-4-trifluoromethylphenyl)imidazole (2.15 g) as a white solid m.p. 270.5°-272° C.