Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(C)C)[CH:2](C)C.[Li]CCCC.[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=2)[CH:17]=[C:16]([Cl:26])[N:15]=1.CI>C1COCC1>[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=2)[C:17]([CH3:2])=[C:16]([Cl:26])[N:15]=1
Reactant: COc1ccc2cc(Cl)nc(Cl)c2c1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc2c(C)c(Cl)nc(Cl)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
To a solution of i-Pr2NH (1.95 g, 19.3 mmol) in anhydrous THF (40 mL) was added dropwise n-BuLi (7.72 mL, 19.3 mmol, 2.50 M in hexane) at −78° C. under N2 atmosphere. After 30 minutes, 1,3-dichloro-7-methoxyisoquinoline (described in step 2 of Intermediate 12) (4.00 g, 17.5 mmol) in anhydrous THF (20 mL) was added to the reaction. After 15 minutes, MeI (4.97 g, 35.0 mmol) was added dropwise. The resulting mixture was warmed to 25° C. and allowed to stir for 16 hours. The reaction was quenched with H2O (150 mL) followed by an ethyl acetate extraction/workup to give the crude product, which was purified by prep-HPLC (0.1% TFA as additive). Most of CH3CN was removed under reduced pressure and extracted with EtOAc (50 mL×3). The combined organic layers were washed with H2O (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 1,3-dichloro-7-methoxy-4-methylisoquinoline (2.0 g, yield 47%) as an off-white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:27])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.CCOCC.C[Si]([Cl:46])(C)C>CC(CC)=O>[ClH:46].[CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:27])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Agent: O=C(c1cccc(F)c1F)N1CCC2(CC1)N[C@@H](Cc1ccccc1)C(=O)N2Cc1ccccc1
Solvent: CCC(C)=O
Solvent: O
Solvent: CCOCC
Product: Cl
Reaction time: 8 h

Procedure:
1,3-(S)-dibenzyl-8-(2,3-difluorobenzoyl)-1,4,8-triazaspiro[4,5]decan-2-one (370 mg, 0.8 mmol) was dissolved in ethyl methyl ketone (2.9 mL), water (8 μL), ether (30 mL) and TMSCl (108 μL) were added and the mixture was stirred overnight. The solid matter was isolated by filtration, washed with ether, and dried in vacuo. The product 1,3-(S)-dibenzyl-8-(2,3-difluorobenzoyl)-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 317 mg (80%).
Reaction SMILES: OC[CH:3]([NH2:8])[CH:4]1[CH2:7][CH2:6][CH2:5]1.[NH2:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[C:12]([Cl:17])[N:11]=1.[CH2:18]([OH:20])C>C(N(CC)CC)C>[NH2:9][C:10]1[N:15]=[C:14]([NH:8][CH2:3][C:4]2([CH2:18][OH:20])[CH2:5][CH2:6][CH2:7]2)[CH:13]=[C:12]([Cl:17])[N:11]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CCO
Reactant: NC(CO)C1CCC1
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)cc(NCC2(CO)CCC2)n1
Yield: 92.3 %

Procedure:
A mixture of 1-hydroxymethyl-1-cyclobutylmethylamine (5.75 g, 0.05 mol), 2-amino-4,6-dichloropyrimidine (8.20 g, 0.05 mol), ethanol (200 ml) and triethylamine (20 ml) was refluxed for one day. The solvent was distilled away under reduced pressure. The residue was washed with water, dried and recrystallized from acetone to give colorless prism crystals (11.2 g, 92.3%), m.p. 192-194° C. (acetone).
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][CH:15]1[CH2:17][CH2:16]1.[CH3:18][C:19]1[N:20]=[C:21]([N:29]2[C:33](=[O:34])[NH:32][N:31]=[CH:30]2)[S:22][C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH:17]1([CH2:16][N:32]2[C:33](=[O:34])[N:29]([C:21]3[S:22][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:19]([CH3:18])[N:20]=3)[CH:30]=[N:31]2)[CH2:15][CH2:14]1
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Reactant: BrCC1CC1
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(-n2cnn(CC3CC3)c2=O)nc1C
Yield: 83 %

Procedure:
Following the procedure as described in Example 19, making variation as required to replace 4-(trifluoromethyl)benzyl bromide with (bromomethyl)cyclopropane to react with ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate, the title compound was obtained as a white solid in 83% yield: 1H NMR (300 MHz, CDCl3) δ 8.27 (s, 1H), 4.31 (q, J=7.1 Hz, 2H), 3.63 (d, J=7.1 Hz, 2H), 2.64 (s, 3H), 1.35 (t, J=7.1 Hz, 3H), 1.19-1.04 (m, 1H), 0.53-0.42 (m, 2H), 0.36-0.27 (m, 2H); MS (ES+) m/z 309.2 (M+1).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([CH3:15])=[C:7]([CH3:16])[CH:6]=1)=[O:4].[CH2:17]([NH:20][C:21]([NH:23][CH2:24][CH:25]=[CH2:26])=[S:22])[CH:18]=[CH2:19]>>[BrH:1].[CH2:24]([N:23]1[C:3]([C:5]2[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([CH3:15])=[C:7]([CH3:16])[CH:6]=2)([OH:4])[CH2:2][S:22][C:21]1=[N:20][CH2:17][CH:18]=[CH2:19])[CH:25]=[CH2:26]
Reactant: C=CCNC(=S)NCC=C
Reactant: Cc1cc(C(=O)CBr)cc(S(N)(=O)=O)c1C
Product: Br
Product: C=CCN=C1SCC(O)(c2cc(C)c(C)c(S(N)(=O)=O)c2)N1CC=C

Procedure:
was obtained in a manner analogous to the method described in Example 6 in amorphous form from 3.1 g of 2-bromo-3',4'-dimethyl-5'-sulfamoyl-acetophenone and 1.6 g of 1,3-diallyl-thiourea and the substance was brought to crystallization under ether. M.p. 138°-140° C (decomposition).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([NH:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:9][C@H:8]1[CH2:19][OH:20])=[O:6])[CH:2]=[CH2:3].N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([NH:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:9][C@H:8]1[CH2:19][O:20][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[O:6])[CH:2]=[CH2:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CCOC(=O)N[C@H]1C[C@@H](CO)N(C(=O)OCC=C)C1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OCC=C)C1
Reaction time: 12 h

Procedure:
To a solution of (2S,4S)-1-allyloxycarbonyl-4-(allyloxycarbonylamino)-2-hydroxymethylpyrrolidine (8.73 g in N,N-dimethylformamide (40 ml) were added imidazole (6.76 g) and t-butyldimethylsilyl chloride (5.10 g). The resulting mixture was allowed to stand at ambient temperature for 12 hours. The mixture was diluted with ethyl acetate (200 ml), washed in turn with water and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (100 ml) eluting with a mixture of n-hexane and ethyl acetate (7:3 V/V) to give (2S,4S)-1-allyloxycarbonyl-4-(allyloxycarbonylamino)-2-t-butyldimethylsilyloxymethylpyrrolidine (10.97 g).
Reaction SMILES: Cl.Cl.Cl.[N:4]1([CH2:9][C:10]2[CH:11]=[C:12]([CH:23]=[CH:24][CH:25]=2)[O:13][CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:22])[C:19](=[NH:21])[NH2:20])[CH2:8][CH2:7][CH2:6][CH2:5]1.C(Cl)Cl.[S:29](N1C(=O)C2=CC=CC=C2C1=O)N1C(=O)C2=CC=CC=C2C1=O.Cl>C(O)CC.C(N(CC)CC)C>[NH2:21][C:19]1[C:18]([NH:17][CH2:16][CH2:15][CH2:14][O:13][C:12]2[CH:23]=[CH:24][CH:25]=[C:10]([CH2:9][N:4]3[CH2:8][CH2:7][CH2:6][CH2:5]3)[CH:11]=2)=[N:22][S:29][N:20]=1
Reactant: O=C1c2ccccc2C(=O)N1SN1C(=O)c2ccccc2C1=O
Reactant: N=C(N)C(=N)NCCCOc1cccc(CN2CCCC2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCCO
Solvent: CCN(CC)CC
Product: Nc1nsnc1NCCCOc1cccc(CN2CCCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of N-[3-(3-pyrrolidinomethylphenoxy)propyl]ethanediimidamide trihydrochloride (22.0 g; 53.0 mmoles) [prepared in Example 4, Step A], 200 ml of CH2Cl2 and 22 ml of triethylamine was treated with N,N'-thiobisphthalimide (DMF solvate) (21.2 g; 53.0 mmoles). After stirring at ambient temperature for one hour, the mixture was washed with 100 ml of 20% KOH, dried (MgSO4), filtered, diluted with 100 ml of toluene and concentrated. The product was treated with one equivalent of aqueous HCl in 1-propanol to give 13.2 g (67%) of the hydrochloride salt of the title compound, mp 135°-137° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][NH:11][C:12]([NH2:14])=[S:13]>N1C=CC=CC=1>[C:2]1([C:1]2[N:10]=[N:11][C:12](=[S:13])[N:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:1]([NH:10][NH:11][C:12]([NH2:14])=[S:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NNC(N)=S
Solvent: c1ccncc1
Product: NC(=S)NNC(=O)c1ccccc1
Product: S=C1N=NC(c2ccccc2)=N1

Procedure:
3-Phenyl-1,2,4-triazole-5-thione (E. Hogarth, J. Chem. Soc. (1949) 1163) was prepared by first reacting benzoyl chloride with thiosemicarbazide in pyridine at 0° C. to give benzoyl thiosemicarbazide. Benzoyl thiosemicarbazide was treated with potassium hydroxide or potassium or sodium ethoxide in ethanol to give 3-phenyl-1,2,4-triazole-5-thione. 3-Phenyl-1,2,4-triazole-5-thione (1.77 g) was then dissolved in 50 mL of methanol and treated with 0.57 g of 95% sodium methoxide, and then with 2-bromo-5-nitrothiazole (2.09 g). The mixture was stirred at room temperature for 2 hours and the precipitated sodium bromide was removed by filtration. The methanol was evaporated and the product crystallized from ethanol and water to give 1.5 g of 3-[(5-nitrothiazol-2-yl)mercapto]-5-phenyl-1,2,4-triazole as colorless crystals, MP 155-157° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[S:15][CH:14]=[CH:13][C:12]=2[CH:16]=1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22](=[O:24])[CH3:23])[CH2:18]1.O.C(OCC)(=O)C>CN(C)C=O>[S:15]1[C:11]2[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][CH2:2][N:17]3[CH2:20][CH:19]([NH:21][C:22](=[O:24])[CH3:23])[CH2:18]3)=[CH:16][C:12]=2[CH:13]=[CH:14]1
Reactant: ClCCCOCCc1ccc2sccc2c1
Reactant: CC(=O)NC1CNC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)NC1CN(CCCOCCc2ccc3sccc3c2)C1
Temperature: 90 °C
Reaction time: 12 h
Yield: 37.4 %

Procedure:
0.80 g of 5-(2-(3-chloropropoxy)ethyl)-1-benzothiophene was dissolved in 8 ml of N,N-dimethylformamide. Thereafter, 1.20 g of N-(3-azetidinyl)acetamide was added to the obtained solution, and the obtained mixture was stirred at 90° C. for 12 hours. After cooling, water and ethyl acetate were added to the reaction mixture, and an organic layer was separated. The organic layer was successively washed with water and a saturated saline solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was distilled away under a reduced pressure. The residue was purified by column chromatography (eluent; chloroform:methanol=7:1), so as to obtain 0.39 g of a light yellow oil product, N-(1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)-3-azetidinyl)acetamide.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:12])[CH:8]=2)[N:3]=1.F[C:14]1[C:19]([C:20]2[N:25]=[C:24]([CH3:26])[N:23]=[C:22]([N:27]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[N:21]=2)=[CH:18][CH:17]=[CH:16][N:15]=1>>[CH3:45][O:44][C:41]1[CH:40]=[CH:39][C:38]([CH2:37][N:27]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[C:22]2[N:23]=[C:24]([CH3:26])[N:25]=[C:20]([C:19]3[C:14]([NH:12][C:7]4[CH:8]=[C:9]5[C:4](=[CH:5][CH:6]=4)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]5)=[N:15][CH:16]=[CH:17][CH:18]=3)[N:21]=2)=[CH:43][CH:42]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Reactant: Cc1ccc2cc(N)ccc2n1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc4nc(C)ccc4c3)n2)cc1
Yield: 49.1 %

Procedure:
The title compound was prepared in an analogous manner to that described in Example 164 using 2-methylquinolin-6-amine (Acros Organics) and 4-(2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine. Purification using an ISCO Combiflash Companion (12 g column, 20-60% EtOAc in hexanes over 30 min, product eluted with 35-45% EtOAc) gave the title compound as a yellow amorphous solid (49.1%). 1H NMR (400 MHz, d6-DMSO) δ 12.19 (s, 1H); 8.84 (dd, J=7.8, 2.0 Hz, 1H); 8.45 (dd, J=4.7, 2.0 Hz, 1H); 8.39 (d, J=2.2 Hz, 1H); 8.08 (d, J=8.2 Hz, 1H); 7.78-7.83 (m, 1H); 7.71-7.77 (m, 1H); 7.34 (d, J=8.4 Hz, 1H); 7.26 (dd, J=8.6, 6.3 Hz, 4H); 6.98 (dd, J=7.8, 4.7 Hz, 1H); 6.90 (t, J=8.3 Hz, 4H); 4.84 (d, J=17.6 Hz, 4H); 3.72 (d, J=14.5 Hz, 6H); 2.62 (d, J=2.0 Hz, 6H). m/z (ESI, +ve ion) 584.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].F[C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[N+:25]([O-:27])=[O:26]>CS(C)=O>[F:24][C:20]1[C:21]([F:23])=[CH:22][C:17]([NH:1][C:2]2[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[C:3]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:18]([N+:25]([O-:27])=[O:26])[CH:19]=1
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2cc(F)c(F)cc2[N+](=O)[O-])sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-aminobenzo[b]thiophene-3-carboxylate, 2,4,5-trifluoronitrobenzene and dimethyl sulfoxide, ethyl 2-(4,5-difluoro-2-nitroanilino)benzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[S:12][C:11]1[C:10]([C:16]3[O:17][C:18]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:19][C:20](=[O:22])[CH:21]=3)=[CH:9][CH:8]=[CH:7][C:6]=1[S:5]2.F[B-](F)(F)F.[H+].N(OCCCC)=[O:36].C(OCC)C>C(O)C.O>[OH:36][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[S:12][C:11]1[C:10]([C:16]3[O:17][C:18]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[CH:19][C:20](=[O:22])[CH:21]=3)=[CH:9][CH:8]=[CH:7][C:6]=1[S:5]2
Reactant: Nc1ccc2c(c1)Sc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Reactant: CCCCON=O
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: O=c1cc(-c2cccc3c2Sc2ccc(O)cc2S3)oc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.7 %

Procedure:
To a solution of 2-(7-Amino-thianthren-1-yl)-6-morpholin-4-yl-pyran-4-one (21) (575 mg, 1.4 mmol) was suspended in ethanol (5 mL) was added tetrafluoroboric acid (54 wt % in ether, 3 ml, 1.68 mmol). The mixture was stirred at room temperature for 10 minutes before being cooled to 0° C. Butyl nitrite (220 μl, 2.8 mmol) was then added dropwise and the mixture stirred for 30 minutes before the addition of diethyl ether (40 ml) which caused a precipitate to form. The solid was collected by filtration and washed with cold diethylether (30 ml) then added to a solution of cupric nitrate trihidrate (210 g, 870 mmol) and cuprous oxide (190 mg, 1.31 mmol) in water (300 ml). The reaction was stirred for 12 hours and then filtered. The filtrant was washed with water, dried in a desiccator and used without further purification give the title compound (0.58 g, 100%). NMR (300 MHz, CDCl3): δH=10.08 (1H, bs); 7.76 (1H, dd); 7.60 (1H, dd); 7.46 (1H, dd); 7.35 (1H, dd); 7.02 (1H, d); 6.74 (1H, dd); 6.24 (1H, d); 5.55 (1H, d); 3.69 (H, m), 3.36 (4H, m); m/z (LC-MS, ESP), RT=3.83 min, (M++1)=412
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4].[F:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:21][C:20]1[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=1[F:18])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(C)cccc2c1Cl
Reactant: Nc1ccccc1F
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(C)cccc2c1Nc1ccccc1F
Yield: 68.6 %

Procedure:
3-Butyryl-4-chloro-8-methylquinoline (2.48 g, 10 mmol), 2-fluoroaniline (1.45 ml, 15 mmol) and 1,4-dioxan (10 ml) were stirred at room temperature overnight then heated at reflux for 30 minutes. The hydrochloride salt was filtered off, converted to free base and recrystallised from aqueous ethanol to give 3-butyryl-4-(2-fluorophenylamino)-8-methylquinoline (2.21 g), m.p. 109°-111°.
Reaction SMILES: [C:1](Cl)([Cl:3])=[O:2].[OH:5][CH2:6][C:7]#[C:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>C1C=CC=CC=1>[Cl:3][C:1]([O:5][CH2:6][C:7]#[C:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:2]
Reactant: CCOC(=O)C#CCO
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)C#CCOC(=O)Cl
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To 40 ml of a benzene solution of phosgene (containing 6.2 g (62.5 millimoles) of phosgene), 6.4 g (50 millimoles) of ethyl 4-hydroxy-2-butynoate was rapidly added under cooling with ice, and the mixture was stirred for 30 minutes under cooling with ice. The reaction mixture was returned to room temperature and left to stand for one night. Then, the reaction mixture was concentrated under reduced pressure to distil off benzene, whereby 8.1 g (yield: 85%) of oily ethyl 4-(chlorocarbonyloxy)-2-butynoate was obtained as the residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16](N(C)C)=[O:17])=[N:11][C:10]([OH:21])=[C:9]([OH:22])[C:8]=2[C:7]1=[O:23].[CH3:28][O-:29].[Mg+2].C[O-].Br[CH2:34][CH2:35][CH2:36][CH2:37][Cl:38]>CO.CS(C)=O.C(OCC)(=O)C>[Cl:38][CH2:37][CH2:36][CH2:35][CH2:34][N:11]1[C:10](=[O:21])[C:9]([OH:22])=[C:8]2[C:13]([CH2:14][CH2:15][N:6]([CH2:5][C:4]3[CH:24]=[CH:25][C:26]([F:27])=[C:2]([Cl:1])[CH:3]=3)[C:7]2=[O:23])=[C:12]1[C:16]([O:29][CH3:28])=[O:17]
Reactant: C[O-]
Reactant: CN(C)C(=O)c1nc(O)c(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Reactant: ClCCCCBr
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CO
Product: COC(=O)c1c2c(c(O)c(=O)n1CCCCCl)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-N,N-dimethyl-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxamide (0.80 g, 2.19 mmol) and magnesium methoxide in methanol (10.6 mL, 6-10% methanol solution available from Aldrich) in DMSO (22 mL) was heated at 60° C. for one hour. Methanol was exhaustively removed under vacuum over 45 minutes. The resulting DMSO solution was treated with 1-bromo-4-chlorobutane (1.80 g, 10.50 mmol) and stirred at 60° C. under an atmosphere of nitrogen for one hour. The reaction mixture was diluted with ethyl acetate and washed with dilute hydrochloric acid. The organic extract was washed with 10% aqueous potassium carbonate, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was triturated with diethyl ether. The solid precipitated was collected by filtration to provide the title compound. ES MS M+1=471
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[F:13][CH:14]([F:55])[C:15]1[N:19]([C:20]2[N:25]=[C:24]([NH:26][CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[C:23]([N+:40]([O-])=O)=[C:22]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)[N:21]=2)[C:18]2[CH:49]=[CH:50][CH:51]=[C:52]([O:53][CH3:54])[C:17]=2[N:16]=1>O1CCOCC1.O>[F:13][CH:14]([F:55])[C:15]1[N:19]([C:20]2[N:25]=[C:24]3[C:23]([NH:40][C:1](=[O:2])[N:26]3[CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)=[C:22]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)[N:21]=2)[C:18]2[CH:49]=[CH:50][CH:51]=[C:52]([O:53][CH3:54])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c(N2CCOCC2)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2[nH]c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
1,1′-Carbonyldiimidazole (689 mg, 4.25 mmol) was added to a solution of the above amine (244 mg, 0.425 mmol) in 1,4-dioxane (25 mL) and the mixture was refluxed under nitrogen for 4.5 hrs. Additional 1,1′-carbonyldiimidazole (689 mg, 4.25 mmol) was added, and the mixture refluxed for additional 17.5 hrs. The mixture was cooled to room temperature and diluted with water. The resulting precipitate was collected by filtration, washed with H2O, and dried. Chromatography on silica, eluting with CH2Cl2/MeOH (100:0 to 97:3), gave tert-butyl 4-[2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-8-oxo-7,8-dihydro-9H-purin-9-yl]-1-piperidinecarboxylate (176 mg, 69%): mp (CH2Cl2/i-Pr2O) 269-272° C.; 1H NMR (CDCl3) δ 10.94 (br s, 1H), 7.73 (dd, J=8.3, 0.3 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 7.36 (t, JHF=53.6 Hz, 1H), 6.81 (d, J=7.8 Hz, 1H), 4.49 (tt, J=12.1, 4.1 Hz, 1H), 4.38 (br s, 2H), 4.06 (s, 3H), 3.89 (dd, J=5.6, 3.6 Hz, 4H), 3.82 (dd, J=5.6, 3.7 Hz, 4H), 2.85 (m, 2H), 2.56 (m, 2H), 1.83 (d, J=11.0 Hz, 2H), 1.48 (s, 9H); Anal. Calcd. for C28H34F2N8O5.0.1 i-Pr2O: C, 56.2; H, 5.8; N, 18.3. Found: C, 56.2; H, 5.90; N, 18.0%.
Reaction SMILES: C[Mg]Br.[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[O:11][C:10]([CH3:18])([CH3:17])[CH2:9][C:8]2=O.[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1.ClCCl>[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[O:11][C:10]([CH3:18])([CH3:17])[CH:9]=[C:8]2[CH3:20]
Reactant: COc1cc2c(cc1Br)C(=O)CC(C)(C)O2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C[Mg]Br
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc2c(cc1Br)C(C)=CC(C)(C)O2
Temperature: 10 °C

Procedure:
A solution of methylmagnesium bromide (3.0 M in THF, 1.67 mL, 5.0 mmol) was added slowly into a solution of 6-bromo-7-methoxy-2,2-dimethyl-chroman-4-one (Compound 4, 710 mg, 2.5 mmol) in 10 mL of THF at −30° C. The mixture was stirred and warmed to 10° C. for 2 h. The reaction mixture was quenched with 10% HCl and extracted with ethyl acetate. The combined organic layers were washed with a saturated solution of NH4Cl, dried (MgSO4) and concentrated at reduced pressure to give a crude oil, which was then dissolved in 10 mL of dichloromethane and cooled to 0° C. with an ice bath. To this solution was added p-toluenesulfonic acid (100 mg). After stirring for 3 h at 0° C., the reaction mixture was quenched with water, extracted with dichloromethane, washed with brine, dried (MgSO4) and concentrated at reduced pressure to give a colorless oil. Purification by flash chromatography (silica gel, 95.5 hexane/ethyl acetate) gave the title compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[CH:3]=1.[H-].[Na+].[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br.Cl>CN(C=O)C.CCOCC>[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2
Reactant: Fc1ccccc1CBr
Reactant: Oc1ccc2cc(O)ccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Oc1ccc2cc(OCc3ccccc3F)ccc2c1
Reaction time: 2 h
Yield: 53.5 %

Procedure:
A stirred solution of 15.0 g (94.0 mM) of 2,6-dihydroxynaphthalene in 60 mL of DMF was treated with 3.21 g (80.0 mM) of NaH under nitrogen. The resulting dark solution was treated dropwise with a solution of 5.94 g (31.0 mM) of 2-fluorobenzyl bromide in 20 mL of Et2O over 0.75 h. The mixture was stirred an additional 2 h then treated cautiously with 200 mL 1N HCl. The mixture was stirred 8 to 16 hours then filtered. The solid was washed thoroughly with water and dried. Flash chromatography produced a solid which was recrystallized from i-PrOH to afford 4.51 g (56%) of product as gray crystals mp 143-144° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[C@@H:10]([CH2:19][OH:20])[NH:11]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:30]>>[ClH:30].[CH2:1]([O:8][C:9](=[O:21])[C@@H:10]([CH2:19][OH:20])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N[C@H](CO)C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of Boc-(D)-serine benzyl ester (1.1 g) in 1/1 mixture of the TFA and methylene chloride was stirred for 1 hour and then concentrated and azeotroped from toluene to give D-serine benzyl ester HCl salt. The residue was dissolved in methylene (15 ml), and added methyl benzimidate HCl (732 mg) and TEA (0.5 ml). The mixture was stirred at room temperature for 3 hours and then concentrated. Purification by flash chromatography (hexanes/ethyl acetate=6/1) gave 572 mg of the title compounds.