Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C1C=CC(C=C)=CC=1.Br[C:14]1[CH2:18][CH2:17][O:16][N:15]=1.COC(=O)[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][N:23]=1>>[N:23]1[CH:22]=[CH:27][CH:26]=[C:25]([O:28][C:14]2[CH2:18][CH2:17][O:16][N:15]=2)[CH:24]=1
Reactant: BrC1=NOCC1
Reactant: COC(=O)c1ccc(O)cn1
Agent: C=Cc1ccc(C(F)(F)F)cc1
Product: c1cncc(OC2=NOCC2)c1

Procedure:
3-(pyridin-3-yloxy)-4,5-dihydroisoxazole I-170a and I-170b were prepared in 3 steps from 1-(trifluoromethyl)-4-vinylbenzene using the cycloaddition conditions from Method 5. The resulting bromo-4,5-dihydroisoxazole was reacted with 5-hydroxypicolinic acid methyl ester using Method 5 followed by hydrolysis using the analogous conditions as in example 94. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=353.0 m/z. Activity: A
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])[CH:5]=[CH:6][CH:7]=1.[I:19]Cl>C(O)(=O)C.FC(F)(F)C(O)=O.CCOCC>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])[CH:5]=[CH:6][C:7]=1[I:19]
Reactant: CC(=O)NC[C@H]1CN(c2cccc(F)c2)C(=O)O1
Reactant: ClI
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(=O)NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1

Procedure:
(S)-N-[[3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]- acetamide (PREPARATION 17, 0.280 g, 1.11 mmol) is dissolved in a mixture of acetic acid (20 ml) and trifluoroacetic acid (5 ml) and then treated with iodine monochloride (2.343 g, 14.43 mmol) at 20-25°. The mixture is stirred at 20-25° under nitrogen. After about 24 hr the reaction mixture is diluted with ether and the solids collected under reduced pressure through a medium-porosity sintered glass filter, washing with ether. The crude solids are dissolved in hot chloroform (a little methanol is added), transferred to a separatory funnel, and washed with saturated aqueous sodium bicarbonate, 20% aqueous sodium thiosulfate and brine. The organic phase is separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, mp 185.5-186.5°; [α]25D -37.6° (c 1.0, DMF).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](O)=[O:10])=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:17])=O>ClC(Cl)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([Cl:17])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(C=CC(=O)O)cc1
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C=CC(=O)Cl)cc1
Reaction time: 0.5 h

Procedure:
p-Methoxycinnamic acid (52.7 g=0.45 mole) was slurried under N2 in 500 mL of sieve-dried dichloroethane. Oxalyl chloride (146.0 gm=1.15 moles) was added in one portion followed by three drops of DMF. Complete solution was achieved in 30 minutes. The solution was stirred an additional 2 hours, and then the dichloroethane containing excess oxalyl chloride was removed on a 50° C. rotary evaporator. Fresh dichloroethane was twice added to the residue and removed on the rotary evaporator. The amber oil was used without purification. Yield 90.4 gm.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:14][CH2:13][CH2:12]2)[N:3]=1.[F:15][C@@H:16]1[C@@H:20]([CH2:21][OH:22])[O:19][C@@H:18](N2C=CC(=O)NC2=O)[CH2:17]1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:18]2[O:19][C@H:20]([CH2:21][OH:22])[C@@H:16]([F:15])[CH2:17]2)=[C:4]([N:11]2[CH2:14][CH2:13][CH2:12]2)[N:3]=1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: Nc1nc(N2CCC2)c2nc[nH]c2n1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Nc1nc(N2CCC2)c2ncn([C@H]3C[C@H](F)[C@@H](CO)O3)c2n1
Temperature: 45 °C
Reaction time: 168 h
Yield: 70.6 %

Procedure:
2-Amino-6-azetidinyl-9H-purine (0.50 g, 2.6 mmoles) and 2',3'-dideoxy-3'-fluorouridine (0.71 g, 3.1 mmoles) were suspended in 50 ml, 10 mM potassium phosphate buffer, pH 7.0, containing 0.04% potassium azide. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase (10,000 I.U.) (Krenitsky et al., Biochemistry, 20, 3615 (1981) and U.S. Pat. No. 4,381,344) immobilized on DEAE cellulose was added to the reaction and the suspension was stirred at 45° C. After 7 days, 170 ml MeOH was added to the reaction. The reaction was applied to a column containing AG1-X2 (OH-- form, 2.5×10 cm) and eluted with MeOH. Fractions containing product were pooled, concentrated, and flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:acetone (7:3). Fractions containing product were pooled, concentrated, and flash chromatographed a second time on silica gel (2.5×20 cm) with dichloromethane:methanol (96:4). Solvent was removed and lyophilization yielded 0.566 g of 2-amino-6-azetidinyl-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-9H-purine (68%): mp 127°-129° C.; TLC Rf 0.70 (silica gel, MeCN:15N NH4OH:H2O/85:5:10);
Reaction SMILES: O[CH2:2][C@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].COC(=O)[C@@H](CC(C)C)N.OCCN.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:25]=1[N:33]=[C:34]=[S:35]>>[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][C:25]=1[N:33]=[C:34]1[NH:8][C@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:35]1
Reactant: Cc1ccc([N+](=O)[O-])cc1N=C=S
Reactant: CC(C)C[C@@H](N)CO
Agent: COC(=O)[C@H](N)CC(C)C
Solvent: NCCO
Product: Cc1ccc([N+](=O)[O-])cc1N=C1N[C@H](CC(C)C)CS1

Procedure:
(1R)-1-(Hydroxymethyl)-3-methylbutylamine was made from (D)-leucine methyl ester according to B1b. The 2-hydroxyethylamine was converted to (1R)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-5-nitrophenyl isothiocyanate was reacted with (1R)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4R)-2-(2-methyl-5-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4R)-2-(N-isobutyl-N-(2-methyl-5-nitrophenyl)amino)-4-isobutyl-1,3-thiazoline HCl salt.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.C1N2CC[N:26](CC2)[CH2:25]1>C(#N)C>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:4]1[N:3]=[C:2]([C:25]#[N:26])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1
Reactant: C1CN2CCN1CC2
Reactant: Cc1ccc(Cn2cnc3c(-c4ccco4)nc(Cl)nc32)cc1
Solvent: CC#N
Product: Cc1ccc(Cn2cnc3c(-c4ccco4)nc(C#N)nc32)cc1
Reaction time: 48 h
Yield: 57.3 %

Procedure:
A solution of 2-chloro-6-(2-furyl)-9-(4-methylbenzyl)-9H-purine (0.10 g, 0.31 mmol) and Et4NCN (0.10 g, 0.62 mmol) in acetonitrile (10 mL) was treated with DABCO (0.07 g, 0.62 mmol), stirred for 48 h, concentrated in vacuo, dissolved in chloroform (50 mL), washed with water (2×30 mL), dried (MgSO4) and concentrated in vacuo to give the title compound (56 mg, 57%) as a pale green solid.
Reaction SMILES: [I:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.IC.[C:12](=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[I:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([O:9][CH3:12])=[O:8])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1csc(I)c1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1csc(I)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.6 %

Procedure:
A mixture of 5-iodothiophene-3-carboxylic acid (3.48 g), iodomethane (2.92 g), potassium carbonate (2.84 g) and DMF (35 ml) was stirred at room temperature for 1 day. The reaction mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (3.62 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:25])=[C:10]([C:23]#[N:24])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[CH:20]([CH3:22])[CH3:21])=[C:4]([CH:26]([CH3:28])[CH3:27])[CH:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+]>[Br-].[Zn+2].[Br-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:25])=[C:10]([C:23]3[NH:31][N:30]=[N:29][N:24]=3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[CH:20]([CH3:22])[CH3:21])=[C:4]([CH:26]([CH3:28])[CH3:27])[CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(C#N)sc(-c2ccc(Cl)cc2C(C)C)c1-c1ccc(Cl)cc1C(C)C
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Product: Cc1c(-c2nnn[nH]2)sc(-c2ccc(Cl)cc2C(C)C)c1-c1ccc(Cl)cc1C(C)C
Temperature: 130 °C
Yield: 91 %

Procedure:
A round-bottomed flask was charged with 4,5-bis(4-chloro-2-isopropylphenyl)-3-methylthiophene-2-carbonitrile (190.5 mg, 0.44 mmol), zinc bromide (338 mg, 1.50 mmol) and sodium azide (97.5 mg, 1.50 mmol). After degassed, DMF (3 mL) was added. The reaction mixture was heated to 130° C. and stirred at this temperature until complete. The reaction was cooled to rt and 30 mL of 0.1 N aqueous HCl was added. The reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulphate and then concentrated. The residue was purified by flash chromatography (hexane:EtOAc:AcOH=30:10:1). 188.7 mg (90%) of product was obtained as a white solid, 1H NMR (CDCl3, 500 MHz) δ 7.25-7.22 (m, 2H), 7.18 (dd, J1=8.18 Hz, J2=2.13 Hz, 1H), 7.09-7.06 (m, 2H), 7.02 (d, J=8.20 Hz, 1H), 3.04 (sep, J=6.75 Hz, 1H), 2.74 (sep, J=6.80 Hz, 1H), 2.37 (s, 3H), 1.12 (d, J=6.80 Hz, 3H), 1.05 (d, J=6.80 Hz, 6H), 0.90 (d, J=6.80 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 150.32, 149.87, 141.11, 140.81, 140.72, 135.33, 134.47, 132.72, 132.02, 131.51, 129.01, 126.30, 126.20, 125.84, 125.52, 30.35, 30.10, 24.76, 23.60, 23.13, 15.78.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:37])[C:18]([C:24]3[CH:25]=[CH:26][C:27]4[O:32][CH2:31][C:30](=[O:33])[N:29]([CH2:34][CH3:35])[C:28]=4[CH:36]=3)([OH:23])[C:19]([F:22])([F:21])[F:20])=[C:13]([Cl:38])[CH:12]=2)=[CH:7][C:6]=1[Cl:39])=[O:4]>CCCCCCC>[Cl:39][C:6]1[CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:37])[C:18]([C:24]3[CH:25]=[CH:26][C:27]4[O:32][CH2:31][C:30](=[O:33])[N:29]([CH2:34][CH3:35])[C:28]=4[CH:36]=3)([OH:23])[C:19]([F:21])([F:22])[F:20])=[C:13]([Cl:38])[CH:12]=2)[CH:9]=[CH:10][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(-c4ccc(C(=O)OC)c(Cl)c4)cc3Cl)C(F)(F)F)cc21
Solvent: CCCCCCC
Product: CCN1C(=O)COc2ccc(C(O)(C(C)c3ccc(-c4ccc(C(=O)O)c(Cl)c4)cc3Cl)C(F)(F)F)cc21

Procedure:
In analogy to Example 56, Step 6, 3,3′-dichloro-4′-[2-(4-ethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-biphenyl-4-carboxylic acid methyl ester (110 mg, 0.19 mmol) was hydrolyzed (3 h, 65° C.). The product was treated with heptane for 17 h, filtred and dried to give the title compound as a white solid. MS (m/e, ISP neg. ion)=566.2 [M−H+].
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]([CH3:35])[CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]([CH3:35])[CH2:24]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: CC1CN(C(=O)c2cnc3c(C(=O)O)cnn3c2NCc2ccccc2)CCC1c1ccccc1
Product: CC1CN(C(=O)c2cnc3c(C(=O)NS(C)(=O)=O)cnn3c2NCc2ccccc2)CCC1c1ccccc1
Yield: 17.3 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-(3-methyl-4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.209 g, 0.445 mmol) obtained in step 6 and methanesulfonamide (0.211 g, 2.23 mmol), the title compound (0.042 g, 17%) was obtained.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]#[N:8].[CH:9]1([C:15](OC)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>C1COCC1>[CH:9]1([C:15](=[O:16])[CH2:6][C:7]#[N:8])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)C1CCCCC1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCCCC1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To 700 mL of THF cooled at −78° C. under inert atmosphere was added n-butyllithium (56 mL, 2.5 M in hexane) followed by CH3CN (7.3 mL, 0.14 mol) maintaining the temperature below −70° C. The mixture was stirred at −78° C. for 20 min then a solution of methyl cyclohexane carboxylate (10 g, 0.07 mol) in dry THF (300 mL) was added dropwise, maintaining the temperature under −60° C. The reaction was stirred an additional 20 min at −78° C., warmed to −20° C. and quenched by addition of saturated aq. NH4Cl. The reaction mixture was diluted with H2O and extracted with t-BuOMe. The solvents were removed under vacuum to give 3-cyclohexyl-3-oxopropanenitrile as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14]2[S:15][C:16]([C:20]([O:22]CC)=[O:21])=[C:17]([CH3:19])[N:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]([CH3:13])[CH3:12])#[N:2].CC(C)=O.O.[OH-].[Li+].Cl>C(OCC)(=O)C.O>[CH3:19][C:17]1[N:18]=[C:14]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[C:3]([C:1]#[N:2])[CH:4]=2)[S:15][C:16]=1[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)c1sc(-c2ccc(OCC(C)C)c(C#N)c2)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: Cc1nc(-c2ccc(OCC(C)C)c(C#N)c2)sc1C(=O)O
Temperature: 25 °C
Yield: 70.8 %

Procedure:
Ethyl 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylate (8.0 Kg), acetone (80 L), lithium hydroxide monohydrate (1.2 Kg), and water (12 L) were mixed and heated to reflux. The mixture was maintained under reflux until reaction completion. After the reaction was complete, the mass was cooled to about 25° C., ethyl acetate (120 L) was added, and pH was adjusted to about 1 to 2 with hydrochloric acid (3.2 L). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (80 L). The combined organic material was washed with water (3×80 L), and treated with activated carbon at about 50° C. The combined organic material was filtered, and the filtrate was evaporated completely under vacuum below 45° C. Acetonitrile (16 L) was added to the residue and the solvent was distilled. Acetonitrile (80 L) was added to the residue and the mixture was heated to about 65° C. and maintained for about 1 hour. The mass was cooled to about 30° C. and maintained for about 1 hour. The formed solid was filtered and washed with acetonitrile (32 L). The wet solid was dried at about 60° C. to a constant weight to yield 5.2 Kg of the title compound. Purity by HPLC: 99.9%.
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[Cl:26][C:27]1[N:32]=[CH:31][C:30]([NH:33][CH:34]=[C:35]([S:41]([CH3:44])(=[O:43])=[O:42])[C:36]([O:38]CC)=O)=[CH:29][CH:28]=1>>[Cl:26][C:27]1[N:32]=[C:31]2[C:30](=[CH:29][CH:28]=1)[N:33]=[CH:34][C:35]([S:41]([CH3:44])(=[O:42])=[O:43])=[C:36]2[OH:38]
Reactant: CCOC(=O)C(=CNc1ccc(Cl)nc1)S(C)(=O)=O
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CS(=O)(=O)c1cnc2ccc(Cl)nc2c1O
Temperature: 25 °C
Reaction time: 0.62 h

Procedure:
To a flask containing Dowtherm™ A (500 mL) at 250° C. was added ethyl 3-(6-chloropyridin-3-ylamino)-2-(methylsulfonyl)acrylate (8.2 g, 30 mmol) portion wise over 3 to 5 min and the reaction mixture was stirred for an additional 30 to 45 min. The reaction mixture was removed from the heat source, cooled to room temperature and diluted with hexanes to facilitate precipitation. The solids were collected by filtration, filtered, washed with hexanes and dried under vacuum to afford the intermediate 6-chloro-3-(methylsulfonyl)-1,5-naphthyridin-4-ol which was stirred with heat at 70° C. in neat phosphorus oxychloride (31 mL) with catalytic N,N-dimethylformamide for 4 h. The reaction was cooled and poured slowly into a vigorously stirring mixture of ice-cold satd. aq. sodium bicarbonate and ethyl acetate. The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica, hexanes/ethyl acetate) to provide the desired product (2.7 g, 33% over two steps) as a brown solid: 1H NMR (500 MHz, CDCl3) δ 9.50 (s, 1H), 8.46 (d, J=8.8 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 3.41 (s, 3H); ESI MS m/z 278 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8](=[NH:10])[N:7]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[Cl:46][C:47]1[CH:48]=[CH:49][C:50]([O:56][CH3:57])=[C:51]([CH:55]=1)[C:52](O)=[O:53]>O1CCCC1.C(OCC)(=O)C>[C:1]([C:5]1[O:9][C:8](=[N:10][C:52](=[O:53])[C:51]2[CH:55]=[C:47]([Cl:46])[CH:48]=[CH:49][C:50]=2[O:56][CH3:57])[N:7]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)c(=N)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C(=O)N=c1oc(C(C)(C)C)cn1C[C@H]1CCCO1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of Example 13B (1.24 g, 5.53 mmol) in tetrahydrofuran (10 mL) was added N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (1.06 g, 5.53 mmol), 1-hydroxybenzotriazole (0.85 g, 5.55 mmol), triethylamine (0.45 mL, 3.2 mmol) and 5-chloro-2-methoxybenzoic acid (Aldrich) (1.03 g, 5.55 mmol). The mixture was stirred at 80° C. overnight, cooled to room temperature, diluted with ethyl acetate, washed with 1 M aqueous NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in hexanes) to provide the title product. MS (ESI+) m/z 393 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm 1.20 (s, 9H), 1.59-1.71 (m, 1H), 1.83-1.97 (m, 2H), 2.02-2.14 (m, 1H), 3.66 (dd, J=14.2, 7.5 Hz, 1H), 3.75-3.82 (m, 1H), 3.82 (s, 3H), 3.82-3.92 (m, 1H), 4.07 (dd, J=14.2, 2.7 Hz, 1H), 4.13-4.24 (m, 1H), 6.52 (s, 1H), 6.83 (d, J=8.8 Hz, 1H), 7.27 (dd, J=9.0, 2.7 Hz, 1H), 7.74 (d, J=2.7 Hz, 1H).
Reaction SMILES: [I-].Cl[C:3]1C=CC=C[N+:4]=1C.C(N(CC)CC)C.Cl.CN.[C:20]([NH:23][CH2:24][CH2:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[CH:28]=[C:27]1[C:37]([OH:39])=O)(=[O:22])[CH3:21]>ClCCl>[C:20]([NH:23][CH2:24][CH2:25][N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[CH:28]=[C:27]1[C:37]([NH:4][CH3:3])=[O:39])(=[O:22])[CH3:21]
Reactant: COc1ccc2cc(C(=O)O)n(CCNC(C)=O)c2c1
Reactant: C[n+]1ccccc1Cl
Agent: CN
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)c1cc2ccc(OC)cc2n1CCNC(C)=O

Procedure:
Under nitrogen, add 0.12 g of 2-chloro-1-methylpyridinium iodide, 0.32 ml of triethylamine and 0.04 ml of methylamine hydrochloride in dichloromethane to a solution of 0.13 g of the compound obtained in Step C in 20 ml of dichloromethane and then heat at reflux for 14 hours. Dilute the reaction mixture with dichloromethane and wash with saturated aqueous sodium chloride solution. Extract and dry the organic phase over sodium sulfate and then filter and evaporate. Purify the compound by column chromatography on silica gel using as eluant a 19/1 dichloromethane/ethanol mixture. After triturating in diisopropyl ether, the title compound is obtained in the form of a white solid.
Reaction SMILES: [C:1]([NH:20][CH:21]1[CH2:27][CH2:26][CH2:25][CH2:24][NH:23][C:22]1=[O:28])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(O)(C)(C)C>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:31]([N:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH:21]([NH:20][C:1]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:22]1=[O:28])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C1NCCCCC1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)(C)O
Product: O=C1C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)CCCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
To a suspension of 3-(tritylamino)-2-azepanone (2.85 g, 7.69 mmol) in tetrahydrofuran (30 ml) was added 60%-sodium hydride (462 mg, 11.6 mmol) at 0° C., and then stirred at room temperature for 30 minutes. Subsequently, a solution of benzyl bromide (1.0 ml, 8.41 mmol) in tetrahydrofuran (5 ml) was added dropwise thereto at room temperature over a period of 3 minutes, followed by adding thereto tetra-n-butylammonium iodide (57 mg, 0.15 mmol), and the resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was cooled on an ice-water bath and t-butanol (0.7 ml) and water (1 ml) were added thereto at 0° C. The resulting mixture was poured into water and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: n-hexane/chloroform) to obtain 1-benzyl-3-(tritylamino)-2-azepanone (2.22 g, 63%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[C:28](Cl)(=O)[CH2:29][CH2:30][CH2:31][CH3:32]>C(Cl)Cl>[CH2:29]([C:28]1[N:12]([NH:13][C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)NNc1c(N)cnc2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc2cnc3ccccc3c2n1NC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 52 %

Procedure:
A solution of tert-butyl N′-(3-aminoquinolin-4-yl)hydrazinecarboxylate (2.18 g, 7.96 mmol) in 80 mL of anhydrous CH2Cl2 was cooled to 0° C. and treated with triethylamine (1.12 mL, 8.00 mmol) and valeryl chloride (0.95 mL, 8.00 mmol) under an atmosphere of nitrogen. After stirring for 3 h, the reaction mixture was concentrated under reduced pressure and the residue was treated with Et2O and filtered. The filtrate was concentrated and the resulting black tar was dissolved in 80 mL of ethanol and treated with 3 mL of triethylamine and the mixture was refluxed overnight. The reaction mixture was concentrated under reduced pressure. Chromatography (SiO2, 1–5% methanol (MeOH)/CHCl3) gave tert-butyl N-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)carbamate (1.41 g) as a mauve foam.