Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.Cl>>[OH:14][C@@H:13]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[C:12]1[CH:15]=[CH:16][C:9]([O:8][CH3:7])=[CH:10][CH:11]=1
Reactant: COP([O-])OC
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Product: COc1ccc([C@@H](O)P(=O)(OC)OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 μl, 0.40 mmol) at room temperature. After stirring for 30 minutes at room temperature, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then, p-methoxybenzaldehyde (0.40 mmol) was added thereto. After reacting for 115 hours, 1N hydrochloric acid was added thereto to stop the reaction. The mixture was extracted with ethyl acetate (10 ml×three times), and the combined extracts were washed with brine and dried over Na2SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (S)-hydroxy(p-methoxyphenyl)methylphosphonate as a final product in a yield of 88%. The chemical reaction in this Example is shown in chemical formula 30.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH:14]([Sn](CCCC)(CCCC)CCCC)=[CH2:15]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:14]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1)=[CH2:15]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1ccc2nccc(Br)c2c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccnc2ccc(C#N)cc12
Yield: 64.5 %

Procedure:
To a solution of (c) (1 g, 4.3 mmol) and vinyltributyltin (1.5 mL, 5.17 mmol) in degassed toluene (20 ml) was added tetrakis(triphenylphosphine) palladium (0) (245 mg, 5 mol %) and the mixture was refluxed under argon for 2 hours. Evaporation and flash silica chromatography eluting with chloroform afforded the product as a pale yellow solid (500 mg, 64%).
Reaction SMILES: [N+:1]([CH2:4][CH:5]1[CH2:13][C:8]2(OCC[O:9]2)[CH:7]([CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:6]1[CH:23]=[CH:24][C:25]([OH:37])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([O-:3])=[O:2].O1CCCC1.Cl>O>[OH:37][C:25]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:24]=[CH:23][CH:6]1[CH:5]([CH2:4][N+:1]([O-:3])=[O:2])[CH2:13][C:8](=[O:9])[CH:7]1[CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: CCCCCC(O)(C=CC1C(C[N+](=O)[O-])CC2(OCCO2)C1CC=CCCCC(=O)O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC(O)(C=CC1C(C[N+](=O)[O-])CC(=O)C1CC=CCCCC(=O)O)c1ccccc1

Procedure:
A solution of 0.3 g. of 7-[8-nitromethyl-7-(3-hydroxy-3-phenyl-1-octenyl)-1,4-dioxaspiro[4.4]-non-6-yl]-5-heptenoic acid in 6 ml. of dry tetrahydrofuran was treated at 0° C. with 0.6 ml. of concentrated hydrochloric acid and stirred at 0° C. for 1.5 hours. The reaction mixture was added to water and extracted with ether. After washing with water and drying over magnesium sulfate, the extract was evaporated and the residue chromatographed on silica. Elution with 33% ethyl acetate in hexane gave 0.08 g. of the title product as an oil, λmaxfilm 3.00 (shoulder), 3.40, 5.75, 6.40, 7.20, 10.20, 13.20, 14.18 μ. NMR: δ4.45 (m, 2, --CH2NO2), 5.40 (m, 2, 5 and 6-H), 5.85 (m, 2, 13 and 14-H), 5.90 (s, 2, OH), 7.40 (s, 5, aromatic -H ppm. Mass spectrum: M+ at m/e 471 (theory 471), M+ --H2O at m/e 453 (theory 453).
Reaction SMILES: CS[C:3]([N:7]1[CH2:11][C:10]([CH3:13])([CH3:12])[CH:9]=[N:8]1)=[N:4][CH2:5][CH3:6].[S:14]([NH2:24])(=[O:23])([C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)=[O:15]>C(#N)C>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([S:14]([N:24]=[C:3]([N:7]2[CH2:11][C:10]([CH3:12])([CH3:13])[CH:9]=[N:8]2)[NH:4][CH2:5][CH3:6])(=[O:15])=[O:23])=[CH:17][CH:18]=1
Reactant: CCN=C(SC)N1CC(C)(C)C=N1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Solvent: CC#N
Product: CCNC(=NS(=O)(=O)c1ccc(N)cc1)N1CC(C)(C)C=N1
Yield: 0.3 %

Procedure:
0.75 g (1 mol equiv.) N-Ethyl-4,4-dimethyl-4,5-dihydro-pyrazole-1-carboximidothioic acid methyl ester and 0.65 g (1.0 mol equiv.) sulfanilamide were added to 10 mL acetonitrile. The reaction mixture was refluxed overnight, and volatiles were removed underreduced pressure. The residue was taken up in ethyl acetate and extracted with 2N NaOH. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Purification by flash chromatography on silica gel (Et2O:EtOAc=1:1) afforded 1.13 g (86%) 4-amino-N-[(4,4-dimethyl-4,5-dihydro-pyrazol-1-yl)-ethylamino-methylene]-benzenesulfonamide. 1H NMR (400 MHz, CDCl3) δ 1.15 (t, J=7.2 Hz, 3H), 1.20 (s, 6H), 3.43-3.51 (m, 2H), 3.74 (br.s., 2H), 3.98 (br.s., 2H), 6.66 (d, J=8.6 Hz, 2H), 6.71 (s, 1H), 7.71 (d, J=8.6 Hz, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:28]=[CH:27][C:8]([CH2:9][N:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.[Cl:29][C:30]1[C:35](Cl)=[N:34][CH:33]=[CH:32][N:31]=1>CN(C=O)C.O>[Cl:29][C:30]1[C:35]([O:17][C@H:14]2[CH2:15][CH2:16][C@H:11]([N:10]([CH2:9][C:8]3[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:28][CH:27]=3)[CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[CH2:12][CH2:13]2)=[N:34][CH:33]=[CH:32][N:31]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)[C@H]2CC[C@H](O)CC2)cc1
Reactant: Clc1nccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)[C@H]2CC[C@H](Oc3nccnc3Cl)CC2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Sodium hydride (0.58 g, 14.5 mmol, 60% dispersion in mineral oil) was added to a solution of trans-4-(bis(4-methoxybenzyl)amino)cyclohexanol (4.30 g, 12.1 mmol) in DMF (50 mL). The mixture was stirred for 30 min at RT before 2,3-dichloropyrazine (1.89 mL, 12.7 mmol) was added dropwise via syringe. The reaction mixture was warmed to 60° C. and stirred overnight. The mixture was diluted with water and extracted with EtOAc (3×). The extracts were combined, washed with water (3×), washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated. The resulting crude oil was purified by silica gel chromatography to give trans-4-(3-chloropyrazin-2-yloxy)-N,N-bis(4-methoxybenzyl)cyclohexanamine as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH3:18])=[CH:12][C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:31][S:32]([N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)(=[O:34])=[O:33]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH3:18])=[CH:12][C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:41][CH:38]2[CH2:39][CH2:40][N:35]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:36][CH2:37]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2cc(OC)c(C)cc2F)c(N)n1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)c2cnc(NC3CCN(S(C)(=O)=O)CC3)nc2N)c(F)cc1C

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(2-fluoro-5-methoxy-4-methyl-phenyl)-methanone (Example 384) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2-fluoro-5-methoxy-4-methyl-phenyl)-methanone as a white solid. MS (M+H)+, 438.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=[C:16]([NH:29][NH2:30])[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1>C(O)C>[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[N:30][NH:29][C:16]2[CH:15]=[C:14]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=2)=[CH:34][CH:33]=1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: Clc1ccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccccc4)cc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
There was dissolved, in ethanol (2 mL), trifluoroacetic acid salt of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (28.5 mg, 0.0529 mM), then 4-chloro-benzaldehyde (7.4 mg, 0.053 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered, the resulting solid was diluted with a saturated aqueous sodium bicarbonate solution and then the solution was extracted with methylene chloride. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, then the solvent was distilled off and the resulting solid was washed with diethyl ether to thus give the title compound (13.0 mg, yield: 57%).
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([O:33][CH2:34][CH2:35][O:36][CH3:37])[CH:30]=[C:29]([F:38])[C:28]=1[C:39]1[N:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[CH:41][C:40]=1[F:48]>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:45](=[O:46])[C:43]2[CH:42]=[CH:41][C:40]([F:48])=[C:39]([C:28]3[C:29]([F:38])=[CH:30][C:31]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:32][C:27]=3[F:26])[N:44]=2)[CH2:6][CH2:7]1
Reactant: COCCOc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Product: COCCOc1cc(F)c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@H](F)CO3)ccc2F)c(F)c1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)-5-fluoropicolinic acid (see US2012/225062) gave 192. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.26 (dd, J=8.6, 4.0 Hz, 1H), 8.11 (t, J=8.9 Hz, 1H), 7.91 (s, 1H), 7.01-6.91 (m, 2H), 4.82 (dd, J=10.3, 3.8 Hz, 1H), 4.32-4.12 (m, 3H), 4.05-3.85 (m, 2H), 3.75 (s, 3H), 3.74-3.65 (m, 2H), 3.32 (s, 3H), 3.06 (dd, J=16.5, 7.8 Hz, 1H), 2.10-2.02 (m, 1H), 1.82-1.57 (m, 5H). LCMS (ES+) m/z 538 (M+1).
Reaction SMILES: [C:1](/[CH:4]=[C:5](\[CH3:24])/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:23])/[CH2:10][CH2:11][C:12](=[O:22])[CH:13]([CH3:21])[CH2:14][S:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])(=[O:3])[NH2:2].ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)Cl>[C:1](/[CH:4]=[C:5](\[CH3:24])/[CH2:6][CH2:7]/[CH:8]=[C:9](\[CH3:23])/[CH2:10][CH2:11][C:12](=[O:22])[CH:13]([CH3:21])[CH2:14][S:15]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:33])(=[O:3])[NH2:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)CSCC(C)C(=O)CC/C(C)=C/CC/C(C)=C/C(N)=O
Solvent: ClCCl
Product: COC(=O)CS(=O)CC(C)C(=O)CC/C(C)=C/CC/C(C)=C/C(N)=O
Reaction time: 1 h

Procedure:
A solution of 500 mg (0.0014 mol) of methyl [[(6E,10E)-11-carbamoyl-2,6,10-trimethyl-3-oxo-6,10-undecadienyl]thio]acetate in 30 ml of methylene chloride is treated at 0° with 270 mg of m-chloroperbenzoic acid. The solution is stirred at 0° for 1 hour under argon. The reaction solution is washed with aqueous potassium carbonate solution. After drying and removing the solvent the residue is chromatographed on silica gel with ether-methanol 3:1. There is obtained methyl [[(6E,10E)-11-carbamoyl-2,6,10-trimethyl-3-oxo-6,10-undecadienyl]sulfinyl]acetate which exhibits the following absorption bands in the IR spectrum: 3329 cm-1, 3197 cm-1, 1734 cm-1, 1671 cm-1, 1639 cm-1, 1610 cm-1, 1439 cm-1, 1307 cm-1, 1218 cm-1, 1193 cm-1, 1148 cm-1, 1016 cm- 1.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[NH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:33][C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)=[O:18])=[CH:20][CH:21]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:24])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Reactant: Nc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)Nc4cccnc4)cc3)oc2C)cc1
Yield: 55.1 %

Procedure:
Method E. Reaction of oxalyl chloride (100 λL, 1.1 mmol) and benzoic acid 4 (207 mg, 0.6 mmol) with subsequent coupling to 3-aminopyridine (58 mg, 0.6 mmol) gave benzamide 5 (148 mg, 59%) as a white powder: mp (EtOAc) 248-250° C.; 1H NMR δ 10.56 (s, 1 H, CONH), 8.94 (d, J=2.2Hz, 1 H, H-2′), 8.33 (dd, J=4.7, 1.5 Hz, 1 H, H-6′), 8.20 (ddd, J=8.3, 2.5, 1.5 Hz, 1 H, H-4′), 8.10 (br d, J=8.6 Hz, 2 H, H-2, H-6), 7.97 (br d, J=8.6 Hz, 2 H, H-3, H-5), 7.69 (br d, J=8.3Hz, 2 H, H-2″, H-6″), 7.38-7.45 (m, 3 H, H-5′, H-3″, H-5″), 4.65 (s, 2 H, CH2SO2), 2.41 (s, 3 H, CH3), 2.16 (s, 3 H, CH3); 13C NMR δ 165.0, 157.9, 150.1, 144.7 (2), 144.5, 142.1, 135.6, 135.5, 129.7 (2), 129.3, 128.6 (2), 128.3 (2), 127.4, 126.1, 125.5 (2), 123.5, 53.0, 21.1, 9.7; MS m/z 448.7 (MH+, 100%). Anal. calcd for C24H21N3O4S: C, 64.41; H, 4.73; N, 9.39. Found: C, 64.18; H, 4.74; N, 9.39%.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][C:12]([O:17][C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:27])[C:7]=2[N:6]=[C:5]1[CH2:28][CH2:29][CH3:30].[BH4-].[Na+]>[Ni](Cl)Cl.CO.ClCCl>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:12]2[CH:13]=[CH:14][C:15]3[C:16]4[N:4]([CH2:3][CH:2]([CH3:31])[CH3:1])[C:5]([CH2:28][CH2:29][CH3:30])=[N:6][C:7]=4[C:8]([NH2:27])=[N:9][C:10]=3[CH:11]=2)=[CH:19][CH:20]=1
Reactant: CCCc1nc2c(N)nc3cc(Oc4ccc([N+](=O)[O-])cc4)ccc3c2n1CC(C)C
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCc1nc2c(N)nc3cc(Oc4ccc(N)cc4)ccc3c2n1CC(C)C
Reaction time: 0.42 h
Yield: 59.7 %

Procedure:
Nickel(II)chloride (0.044 g, 0.34 mmol) was added to a solution of 1-(2-methylpropyl)-7-(4-nitrophenoxy)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.436 g 1.04 mmol), prepared as described in Example 35, in 20:80 dichloromethane methanol (30 mL). Sodium borohydride (0.300 g) was added in small portions to the resulting solution, and the reaction was stirred for 25 minutes. A solid formed in the reaction and was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform, and the resulting solution was washed with water. The organic solution was stirred with AMBERLITE IRA-756 ion exchange resin for 30 minutes, and the resin was then removed by filtration. The filtrate was concentrated under reduced pressure to provide a brown oil, which was purified by flash chromatography using a 10 g silica gel cartridge (RediSep, ISCO, 230-400 mesh) attached to a gradient pump system, 254 nm UV detector and fraction collector (ISCO COMBIFLASH Sg100c system). The column was equilibrated with 1% methanol in dichloromethane and the reaction mixture was injected onto the column. The mixture was eluted at 35 mL/minute, with a linear gradient program consisting of 1% methanol/dichloromethane to 5% methanol/dichloromethane over five minutes and holding at 5% methanol/dichloromethane to elute the desired compound. Fractions were examined by TLC and those containing the desired compound were combined and concentrated. The product was then recrystallized from acetonitrile to yield 0.242 g of 7-(4-aminophenoxy)-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as a tan, crystalline solid, mp 190-191° C.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH3:16]I.[H-].[Na+]>C1COCC1.C(OCC)C>[C:12]([O:11][C:9]([N:1]([CH3:16])[C@H:2]([CH:3]([CH3:5])[CH3:4])[C:6]([OH:8])=[O:7])=[O:10])([CH3:13])([CH3:15])[CH3:14]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)[C@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.6 %

Procedure:
To a solution of N-Boc-D-Val-OH (1.0 g, 4.60 mmol) in THF (15.3 mL) at 0° C. was added MeI (2.88 mL, 46.0 mmol, 10.0 equiv). NaH (60%, 1.84 g, 46.0 mmol, 10.0 equiv) was added as a solid to the suspension over a period of 2 hours. After stirring for 12 hours at room temperature, the reaction mixture was diluted with diethyl ether and quenched with water slowly. Aqueous layer was extracted with diethyl ether followed by acidified to pH 3 with 10% citric acid and extraction with ethyl acetate. Combined organic layer was washed with brine, dried with Na2SO4, filtered and concentrated in vacuo to afford compound 3.3a (1.07 g) which was used for the next step without further purification. MS m/z (M+Na) 254.2. 1H NMR (400 MHz, CDCl3) 4.02-4.17 (m, 1H), 2.88 (s, 3H), 2.40-2.14 (m, 1H), 1.54-1.39 (m, 9H), 1.03 (d, J=6.60 Hz, 3H), 0.92 (d, J=6.70 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=O.C(O)=O.C([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=O.Cl>O>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cc1ccsc1C=O
Reactant: O=CN1CCCCC1
Agent: Cl
Solvent: O=CO
Solvent: O
Product: Cc1ccsc1CN1CCCCC1

Procedure:
A mixture of 3-methyl-2-thiophenecarboxaldehyde (20 g), formic acid (6 ml) and N-formyl piperidine (44.4 ml) was heated under reflux for 12 h. Water (50 ml) and 2 M hydrochloric acid (30 ml) were added; and the aqueous solution was washed with ether. The solution was basified to pH 10 with 2 M sodium hydroxide (30 ml) and extracted with ether. The organic extract was evaporated to give a brown oil which was distilled to afford the title compound as a colourless oil (11.8 g) b.p. 70°/0.4 mm. NMR (CDCl3) 2.9,d, (1H); 3.27,d, (1H); 6.48,s, (2H); 7.6,m, (4H); 7.83,s, (3H); ca. 8.5,m, (>6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[S:12]C(=O)N(C)C)=[O:5])[CH3:2].[H-].[Na+]>CO>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[SH:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(C)nc1SC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1sc(C)nc1S
Yield: 92.5 %

Procedure:
To a mixture of 4-[(dimethyl-carbamoyl)sulfanyl]-2-methyl-thiazole-5-carboxylic acid ethyl ester (0.84 g, 3.06 mmol) in MeOH (30 ml) is added sodium hydride (60% oil dispersion) (0.4 g, 10.1 mmol). The mixture is refluxed for 1 h under an atmosphere of nitrogen and concentrated. The residue is treated with 1M hydrochloric acid and extracted with EtOAc (3×30 ml). The combined organic layers are washed with brine (30 ml), dried over sodium sulfate and concentrated to give 4-mercapto-2-methyl-thiazole-5-carboxylic acid ethyl ester (0.58 g, 2.83 mmol, 94%), which is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]2[N:6]3[C:12](=[O:13])[CH2:11][CH:10]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:9][C:7]3=[N:8][C:4]=2[CH:3]=1.[ClH:23].C(O)(=[O:26])C>>[Cl:22][C:21]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]=[C:7]([CH2:9][CH:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][C:12]([OH:13])=[O:26])[NH:6][C:5]=2[CH:20]=1.[ClH:23]
Reactant: O=C1CC(c2ccccc2)Cc2nc3cc(Cl)c(Cl)cc3n21
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)CC(Cc1nc2cc(Cl)c(Cl)cc2[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The solution of 7,8-dichloro-3-phenyl-3,4-dihydropyrido[1,2-a]benzimidazol-1(2H)-one (96 mg) in a mixture of acetic acid (2 ml) and conc. HCl (1 ml) was heated to reflux shortly and then stirred at rt for 1 h. All volatiles were removed at the water aspirator at elevated temperature and the residue was dried by azeotropic distillation with toluene. The crude was triturated with chloroform (5 ml) to give 4-(5,6-dichloro-2-benzimidazolyl)-3-phenylbutanoic acid•HCl (102 mg) as colourless solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.CCCCC.C([Li])(C)(C)C.[CH3:21][O:22][C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1)=[O:24].[Cl-].[NH4+]>C(OCC)C>[CH3:21][O:22][C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]([C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[O:4][CH2:3][O:2][CH3:1])[OH:30])=[CH:27][CH:26]=1)=[O:24]
Reactant: COCOc1cccnc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: CCOCC
Product: COCOc1cnccc1C(O)c1ccc(C(=O)OC)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 9.4 %

Procedure:
Next, to a mixture of 3-(methoxymethoxy)pyridine (10.0 g, 71.9 mmol) and diethyl ether (1000 ml), a 1.47 mol/L t-butyllithium n-pentane solution (62 ml, 86.2 mmol) was added dropwise at −70° C. over 25 minutes. After stirring at −70° C. for 1 hour, a solution of 4-methoxycarbonylbenzaldehyde (14.0 g, 90.5 mmol) in diethyl ether (80 mL) was added over 30 minutes and stirred at −70° C. for 1.5 hours. After warming to room temperature, the reaction mixture was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:80) to give (4-methoxycarbonylphenyl)-[3-(methoxymethoxy)pyridin-4-yl]-methanol (2.06 g, 9.4%) as a yellow powder.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[C:11](Cl)=[C:10]([C:19]#[N:20])[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>ClCCl>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[C:11]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:10]([C:19]#[N:20])[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: N#Cc1c(Cl)c2cccnc2n(Cc2ccccc2)c1=O
Solvent: ClCCl
Product: N#Cc1c(N2CCNCC2)c2cccnc2n(Cc2ccccc2)c1=O
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A solution of 1-benzyl-4-chloro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (8) (530 mg, 1.79 mmol) in dichloromethane was added slowly to a stirred solution of piperazine (463 mg, 5.37 mmol) in dichloromethane at room temperature. The solution was further stirred overnight at room temperature and diluted by dichloromethane. The solution was subsequently washed with saturated NaHCO3 solution, water and brine, then dried over Na2SO4 and evaporated to yield 610 mg (98%) of 1-benzyl-2-oxo-4-piperazin-1-yl-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (9) as white solids. MP: 211° C.; 1H-NMR (DMSO-d6): δ 2.93 (m, 4H), 3.57 (m, 4H), 5.53 (s, 2H), 7.20-7.27 (m, 5H), 7.34 (dd, J=4.8, 8.0 Hz, 1H), 8.26 (dd, J=1.6, 8.0 Hz, 1H), 8.65 (dd, J=1.6, 8.0 Hz, 1H); EIMS: 296 (M+1). EIMS: 346 (M+1).