Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([N:5]1[C:14]2[C:9](=[CH:10][C:11](Br)=[CH:12][CH:13]=2)[C@H:8]([NH2:16])[CH2:7][C@@H:6]1[CH3:17])(=[O:4])[CH3:3].[CH3:18][N:19]([CH2:27][CH2:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1)[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[C:2]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([C:32]3[CH:31]=[N:30][N:29]([CH2:28][CH2:27][N:19]([CH3:18])[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH:33]=3)=[CH:12][CH:13]=2)[C@H:8]([NH2:16])[CH2:7][C@@H:6]1[CH3:17])(=[O:4])[CH3:3]
Reactant: CN(CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1)C(=O)OC(C)(C)C
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](N)C[C@@H]1C
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3cnn(CCN(C)C(=O)OC(C)(C)C)c3)cc2[C@H](N)C[C@@H]1C
Temperature: 110 °C
Reaction time: 16 h
Yield: 69.6 %

Procedure:
(2S,4R)-1-Acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (for a preparation see intermediate 57) (1.219 g, 3.81 mmol) and 1,1-dimethylethyl methyl{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethyl}carbamate (for a preparation see intermediate 56) (1.608 g, 4.58 mmol) were combined in 1,4-dioxane (15 mL) and water (5.00 mL) under nitrogen to give a clear yellow solution. Potassium carbonate (1.212 g, 8.77 mmol) then [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.419 g, 0.572 mmol) were added and the resulting red mixture was stirred at 110° C. for 16 h then was cooled to room temperature and concentrated in vacuovacuo. The brown residue was suspended in DCM (20 mL) and filtered through a pad of celite (2 g). The insoluble material was washed with DCM (30 mL) and the combined filtrate and washings were concentrated in vacuovacuo. Purification of the residue on SP4 using a 10 G silica cartridge (gradient:1 to 10% MeOH in DCM) gave 1,1-dimethylethyl (2-{4-[(2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]-1H-pyrazol-1-yl}ethyl)methylcarbamate (1.195 g, 2.66 mmol, 69.6% yield) as a brown foam.
Reaction SMILES: [CH2:1]([O:3]/[C:4](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:36])[C:24]([O:26]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH:18]=2)=[CH:13][CH:12]=1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[CH2:37]([NH2:41])[CH2:38][CH2:39][CH3:40].O>CN(C)C=O>[CH2:37]([NH:41][C:24](=[O:26])[N:23]([C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11](/[CH:10]=[C:4](\[O:3][CH2:1][CH3:2])/[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:12][CH:13]=2)[CH:22]=[CH:21][CH:20]=1)[CH3:36])[CH2:38][CH2:39][CH3:40]
Reactant: CCCCN
Reactant: CCOC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)c2)cc1)OCC
Solvent: O
Solvent: CN(C)C=O
Product: CCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OCC)C(=O)OCC)cc2)c1
Yield: 62.8 %

Procedure:
A solution of 1.75 g (3 mmol) of ethyl (Z)-2-ethoxy-3-{3′-[methyl-(4-nitrophenoxycarbonyl)amino]biphenyl-4-yl}acrylate and 0.4 mL (3.7 mmol) of n-butylamine in 20 mL of dimethylformamide is heated at 80° C. for 2 hours. After addition of water, the reaction medium is extracted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a 70/30 heptane/ethyl acetate mixture. 0.8 g (63%) of ethyl (Z)-3-[3′-(3-butyl-1-methylureido)biphenyl-4-yl]-2-ethoxyacrylate is obtained in the form of a white solid after trituration from pentane.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].Br[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:7]([C:6]1[CH:9]=[C:2]([O:1][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])=[O:8]
Reactant: CCOC(=O)CCCBr
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 100 °C

Procedure:
To a solution of 5-hydroxy-2-nitrobenzaldehyde (84.0 g) and ethyl 4-bromobutyrate (86 ml) in dry dimethylformamide (500 ml) blanketed under dry nitrogen was added potassium carbonate (76.0 g). The reaction mixture was heated to 100° C. for 1 hour. This mixture was cooled, and the solvent removed by evaporation to give a dark brown syrup. This residue was partitioned between ethyl acetate and saturated sodium carbonate (500 ml each). The organic layer was washed with additional saturated sodium carbonate (3×500 ml), and with brine (2×500 ml), dried, filtered and evaporated to give a dark brown syrup. Kugelrohr distillation (180° C., 0.2 mm) afforded ethyl 4-((3-formyl-4-nitrophenyl)oxy)butyrate (95 g) as a bright yellow syrup which slowly darkened upon standing.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][S:9][C:10]2[C:15]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[CH:20]=3)=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[C:29]([O:33][C:34](=[O:37])[CH2:35]Br)([CH3:32])([CH3:31])[CH3:30]>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][S:9][C:10]2[C:15]([C:16]([N:18]([CH2:35][C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:37])[C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[CH:20]=3)=[O:17])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(N)c2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(N(CC(=O)OC(C)(C)C)C(=O)c2cccnc2SCc2ccnc(N)c2)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 69 %

Procedure:
A solution of 2-(2-aminopyridin-4-ylmethylthio)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide (the free base of Compound No. 3-1, 50 mg, 0.14 mmol) in anhydrous N,N-dimethylformamide (2 mL) was added dropwise to a suspension of 60% sodium hydride (13 mg, 0.30 mmol) in anhydrous N,N-dimethylformamide (1.0 mL) under ice-cooling, and the mixture was stirred for 5 minutes. Bromoacetic acid tert-butyl ester (22 μL, 0.15 mmol) was added to the reaction mixture, and the mixture was stirred for 30 minutes at room temperature. The mixture was poured into ice water (15 mL), and the whole was extracted with ethyl acetate (15 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (30 mL) and brine (30 mL), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 45 mg of the target compound as a colorless amorphous. (Yield 69%)
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1.[CH3:51][O:52][CH2:53][CH2:54][O:55][CH2:56][CH2:57]O>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH:27]4[CH2:28][CH2:29][N:30]([CH2:33][C:34]([O:36][CH2:57][CH2:56][O:55][CH2:54][CH2:53][O:52][CH3:51])=[O:35])[CH2:31][CH2:32]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1
Reactant: COCCOCCO
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(CC(=O)O)CC3)CC2)cc(C)c1O
Product: COCCOCCOC(=O)CN1CCC(N2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1

Procedure:
Prepared analogously to Example 4d from 70 mg (0.10 mmol) of (R)-2-[4-(1-carboxymethyl-piperidin-4-yl)-piperazin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 13 μL (0.11 mmol) 2-(2-methoxy-ethoxy)-ethanol. The reaction solution was purified by HPLC without any further working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])=[CH:9][C:10]2[CH:15]=[CH:14][C:13](O)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.C1C=C(C2C=CC=C([OH:36])C=2)C(O)=CC=1>O1CCOCC1>[OH:1][C:2]1([OH:36])[CH:7]=[CH:6][C:5]([C:8]([CH3:17])=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH2:3]1
Reactant: Oc1cccc(-c2ccccc2O)c1
Reactant: CC(=Cc1ccc(O)cc1)c1ccc(O)cc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC(=Cc1ccccc1)C1=CCC(O)(O)C=C1
Temperature: 19 °C
Reaction time: 1.17 h

Procedure:
Trimellitic anhydride chloride (10.53 grams, 0.05 mole) and anhydrous 1,4-dioxane (400 milliliters) are added to a reactor and maintained under a nitrogen atmosphere with stirring to provide a solution. The resultant solution is cooled in an ice bath to 12° C., then a solution of 4,4'-dihydroxy-alpha-methylstilbene (5.66 grams, 0.05 hydroxyl equivalent), anhydrous 1,4-dioxane (50 milliliters) and pyridine (0.05 mole, 3.96 grams) is added dropwise to the reactor from a pressure equalizing addition funnel at a rate so as to maintain the temperature at 10°-12° C. The 4,4'-dihydroxy-alpha-methylstilbene used contains 98.8 area percent of the diphenol and 1.2 area percent of a single dimeric component as determined by high pressure liquid chromatographic analysis (uv detector set at 254 nm). After 70 minutes, addition of the solution is completed. After and additional 11 minutes, the ice bath cooling the reactor exterior is removed and the product slurry is allowed to warm to 19° C. over the next 236 minutes. The product slurry is filtered under a nitrogen atmosphere through a bed of diatomaceous earth with washing of the-filter cake using anhydrous 1,4-dioxane (250 milliliters). The clear filtrate is concentrated to approximately 100 milliliters total volume via removal of 1,4-dioxane by rotary evaporation at 90° C. under vaccuum. The resultant slurry of crystalline product is held under a nitrogen atmosphere for 24 hours followed by filtration to recover the solid product. After drying in a vacuum oven at 100° C. and 1 mm Hg the product is recovered at a constant weight of 9.3 grams of light yellow colored powder. During the drying process, a minor amount of pyridine hydrochloride sublimed out of the product. Fourier transform infrared spectrophotometric analysis of a potassium chloride pellet of the product demonstrated the presence of anhydride carbonyl group absorbances (1868 and 1782 (with 1815 as a shoulder) cm-1) and the ester carbonyl group absorbance (1742 cm-1). Proton magnetic resonance spectroscopy additionally confirms the product structure.
Reaction SMILES: C([O:5][C:6](=[O:34])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=[O:33])[C:14]2[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([C@H:21]([NH:24]C(OC(C)(C)C)=O)[CH2:22][CH3:23])[C:15]=2[F:32])[CH:8]=1)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:24][C@@H:21]([C:16]1[C:15]([F:32])=[C:14]([C:19]([Cl:20])=[CH:18][CH:17]=1)[C:13]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:6]([OH:34])=[O:5])=[O:33])[CH2:22][CH3:23]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2cccc(C(=O)OC(C)(C)C)c2)c1F
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2cccc(C(=O)O)c2)c1F
Reaction time: 18 h
Yield: 91.1 %

Procedure:
Step 2 To a solution of 3-[3-((R)-1-tert-Butoxycarbonylamino-propyl)-6-chloro-2-fluoro-benzoyl]-benzoic acid tert-butyl ester (219 mg, 0.45 mmol) in DCM (5 mL) was added 4M HCl in dioxane (0.445 mL, 1.78 mmol, 4 eq) and the reaction stirred for 18 h. Complete conversion. Mixture was concentrated and then triturated with diethyl ether (˜1 mL) and the solid filtered off to give 3-[3-((R)-1-amino-propyl)-6-chloro-2-fluoro-benzoyl]-benzoic acid (154 mg, 0.41 mmol, 92%). [M+H]+ 336
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][C:20]([SH:22])=[N:19][N:18]=3)=[CH:13][C:12]=12.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][C:26]=1[C:33]([F:36])([F:35])[F:34]>>[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][S:22][C:20]2[O:21][C:17]([C:14]3[CH:15]=[CH:16][N:11]4[N:10]=[CH:9][N:8]=[C:12]4[CH:13]=3)=[N:18][N:19]=2)=[CH:27][C:26]=1[C:33]([F:34])([F:36])[F:35]
Reactant: COc1ccc(CBr)cc1C(F)(F)F
Reactant: Sc1nnc(-c2ccn3ncnc3c2)o1
Solvent: CCN(CC)CC
Product: COc1ccc(CSc2nnc(-c3ccn4ncnc4c3)o2)cc1C(F)(F)F
Yield: 62 %

Procedure:
In the same manner as in Example 1 and using 5-(1,2,4-triazolo[1,5-a]pyridin-7-yl)-1,3,4-oxadiazole-2-thiol triethylamine salt instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 4-methoxy-3-(trifluoromethyl)benzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 62%) was obtained as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH2:5][OH:6].N1C=CC=CC=1.[N+:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])([O-:19])=[O:18].CCO>C1COCC1>[OH:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([CH3:10])=[C:2]([NH:1][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=2)[CH:3]=1
Reactant: Cc1ccc(CO)cc1N
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(CO)cc1NC(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a stirred, cooled (0° C.) mixture of 3-amino-4-methylbenzyl alcohol (10.0 g, 0.072 mol) and pyridine (5.8 g, 0.072 mol) in THF (100 ML) was added 3-nitrobenzoyl chloride (13.5 g, 0.072 mol). After 2 h, the mixture was concentrated, suspended in water and filtered to give a brown solid. Trituration with hot EtOH gave 18.8 g (90%) of product as a white solid, mp 198°-200° C.; 1H NMR (DMSO-d6) δ 2.20 (s, 3 H), 4.46 (s, 2 H), 7.12 (dd, J=7.8 Hz, 1.5 Hz, 1 H), 7.25 (dd, J=7.8, 1.5 Hz, 1 H), 7.82 (m, 1 H), 8.41 (m, 2 H), 8.78 (s, 1 H), 10.26 (s, 1 H).
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(O)=CC=C(C)C=1.ClC1C=CC=CC=1O.ClC1C=C(O)C=CC=1.FC(F)(F)C1C=C(O)C=CC=1.C1C(O)=CC=C(Br)C=1.FC1C=CC(O)=CC=1.FC1C=C(O)C=CC=1.C(C1C=CC(O)=CC=1)(=O)C.C(C1C=CC(O)=CC=1)#N.COC1C=CC(O)=CC=1.C(OC([NH:100][C:101](=[N:104]C(OCC)=O)SC)=O)C.C(OC(NC(=NC(OCCC)=O)SC)=O)CC.C(OC(NC(=NC(OCCCC)=O)SC)=O)CCC.COC(NC(=NC(OC)=O)SC)=O>>[N:100]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:104][CH:101]=1
Reactant: Oc1ccccc1
Reactant: CCOC(=O)N=C(NC(=O)OCC)SC
Agent: CC(=O)c1ccc(O)cc1
Agent: CCCCOC(=O)N=C(NC(=O)OCCCC)SC
Agent: CCCOC(=O)N=C(NC(=O)OCCC)SC
Product: c1ccc2[nH]cnc2c1

Procedure:
In a similar manner, using phenol, p-cresol, o-chlorophenol, m-chlorophenol, o,p-dichlorophenol, m,p-dichlorophenol, m-trifluoromethylphenol, p-bromophenol, p-fluorophenol, m-fluorophenol, p-acetylphenol, p-cyanophenol, m-hydroxyphenol, and p-methoxyphenol in place of p-chlorophenol, the corresponding 1,2-diamino-4-phenoxy (or substituted phenoxy) benzenes and 2-carbomethoxyamino-5(6)-phenoxy (or substituted phenoxy) benzimidazole compounds are prepared. Using the 1,2-diamino compounds prepared above in this Example, and substituting 1,3-bis-ethoxycarbonyl-S-methyl isothiourea, 1,3-bis-propoxycarbonyl-S-methyl isothiourea, or 1,3-bis-butoxycarbonyl-S-methyl isothiourea for the 1,3-bis-methoxycarbonyl-S-methyl isothiourea, the corresponding 2-carbalkoxyamino-5(6)-phenoxy (or p-substituted phenoxy) benzimidazole compounds are prepared, where R is ethyl, propyl or butyl.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9]1[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[NH:11][C:10]=1C(O)=O)[CH2:2]2>CN(C)C1C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH:3]1[CH:4]2[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]2)[CH2:2]1
Reactant: COc1ccc2[nH]c(C(=O)O)c(C3CN4CCC3CC4)c2c1
Solvent: CN(C)c1ccccc1
Product: COc1ccc2[nH]cc(C3CN4CCC3CC4)c2c1

Procedure:
100 mg of 3-(3-quinuclidinyl)-5-methoxyindole-2-carboxylic acid are stirred at 180° in N,N-dimethylaniline for 8 hours. The mixture is then worked up as is customary. 3-(5-methoxy-3-indolyl)quinuclidine is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[C:14]2[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:4][C:3]=1[S:20]([NH2:23])(=[O:22])=[O:21].[F:24][C:25]1[N:30]=[C:29](F)[CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[C:14]2[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:4][C:3]=1[S:20]([NH:23][C:27]1[CH:28]=[CH:29][N:30]=[C:25]([F:24])[N:26]=1)(=[O:21])=[O:22]
Reactant: Fc1ccnc(F)n1
Reactant: Cn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(N)(=O)=O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccnc(F)n2)c(F)c1
Yield: 70.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 111d by using the 2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide (0.16 g, 0.47 mmol) prepared in Example 114c, 2,4-difluoropyrimidine (0.16 g, 1.41 mmol), potassium carbonate (0.26 g, 1.88 mmol) and DMF (4.7 mL), to yield the title compound (143.6 mg, 70%) as a colorless amorphous solid.
Reaction SMILES: C[Al](C)C.[C:5]1([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Si:18]([O:25][CH2:26][C:27]#[C:28][C:29](OCC)=[O:30])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(Cl)Cl>[C:12]1([N:11]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:29](=[O:30])[C:28]#[C:27][CH2:26][O:25][Si:18]([C:21]([CH3:23])([CH3:22])[CH3:24])([CH3:20])[CH3:19])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: CCOC(=O)C#CCO[Si](C)(C)C(C)(C)C
Agent: C[Al](C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC#CC(=O)N(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
To a solution of 1.4 mL Me3Al (2.0M in hexanes) in 3.6 mL anhydrous CH2Cl2 under N2 was added 0.49 g of diphenylamine in one portion. After stirring 30 min, 0.35 g ethyl 4-(t-butyldimethylsilyloxy)-2-butynoate in 0.4 mL CH2Cl2 was added dropwise. The reaction was stirred overnight at room temperature, then heated in an oil bath at 35° overnight. The reaction was quenched by the addition of a few drops of 1N HCl, diluted with H2O, and extracted with CH2Cl2. The combined organics were with H2O and brine and dried over Na2SO4. Filtration, evaporation, and flash chromatography with a 10-15% Et2O/hexanes gradient provided 0.31 g of product.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:15])[F:14])[NH:6]2.Br[CH2:17][C:18]([O:20][CH3:21])=[O:19].C([O-])([O-])=O.[Cs+].[Cs+]>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:14])[F:15])[N:6]2[CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CBr
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)Cn1c(C(F)F)cc2c(Cl)c(C#N)ccc21

Procedure:
Synthesized as described in Example 4 using 4-chloro-2-(difluoromethyl)-1H-indole-5-carbonitrile, methyl bromoacetate (2 eq) and Cs2CO3 (2 eq): MS (ES) m/z 299 (M+1).
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:11]([CH2:27][C:28]2[CH:29]=[N:30][C:31](=[O:34])[CH2:32][CH:33]=2)[C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)C1C=CC=CC=1>C(O)C.Cl>[Cl:25][C:23]1[CH:24]=[C:19]([S:18][C:12]2[N:11]([CH2:27][C:28]3[CH:29]=[N:30][C:31](=[O:34])[CH2:32][CH:33]=3)[C:10]([CH2:9][OH:8])=[N:14][C:13]=2[CH:15]([CH3:17])[CH3:16])[CH:20]=[C:21]([Cl:26])[CH:22]=1
Reactant: CC(C)c1nc(COCc2ccccc2)n(CC2=CCC(=O)N=C2)c1Sc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CCO
Product: CC(C)c1nc(CO)n(CC2=CCC(=O)N=C2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 24.2 %

Procedure:
In a mixture of 5 ml of ethanol and 10 ml of 36% hydrochloric acid was dissolved 50 mg of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-1-(5,6-dihydro-6-oxopyridin-3-ylmethyl)-4-isopropyl-1H-imidazole, and the mixture was stirred at 90° C. for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. An aqueous sodium hydrogen carbonate solution was added, the mixture was extracted with ethyl acetate, the extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The crystals were washed with diethyl ether, filtered, and 10 mg of 5-(3,5-dichlorophenylthio)-2-hydroxymethyl-1-(5,6-dihydro-6-oxopyridin-3-ylmethyl)-4-isopropyl-1H-imidazole (116a)was obtained (yield 24%). mp 220° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:14])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([Cl:14])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1Cl

Procedure:
23.0 g of 2,4-dichloro-3-nitrobenzoic acid and 150 ml of thionyl chloride were refluxed for 6 hours under heating. Then, thionyl chloride was distilled off to obtain crude 2,4-dichloro-3-nitrobenzoyl chloride. 200 ml of methanol was added to the crude compound and refluxed under heating. Methanol was distilled off, and then ethyl acetate was added thereto to obtain an ethyl acetate solution. The solution was washed sequentially with a 5% sodium hydroxide aqueous solution, diluted hydrochloric acid and water. After drying, the solvent was distilled off to obtain 21.8 g of the desired product. Melting point: 72°-74° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:18])[NH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH3:27].O>CN(C=O)C>[CH2:26]([N:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]1=[O:18])[CH3:27]
Reactant: O=c1[nH]cc(-c2cccc(Cl)c2)c2ncccc12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(-c2cccc(Cl)c2)c2ncccc2c1=O
Temperature: 21 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a suspension of 8-(3-chlorophenyl)-1,6-naphthyridin-5-one (128 mg, 0.5 moles) and potassium carbonate (83 mg, 0.6 moles) in 10 ml DMF was added dropwise iodoethane (0.06 ml, 0.75 moles) under an atmosphere of nitrogen. The reaction mixture was stirred overnight at 21° C. The mixture was poured into 50 ml water and after stirring for one hour a white precipitate was collected and dried. Crystallization from ether/hexanes gave 117 mg (82% yield) of the desired 6-ethyl-8-(3-chlorophenyl)-1,6-naphthyridin-5-one as a white solid. Characteristic analytical data are as follows: mp 127°-128° C.; TLC 1:4 EtOAc/Hex; 1H NMR (CDCl3, 300 MHz) δ1.42 (t, 3H, J= 7.2), 4.11 (q, 2H, J=7.2), 7.35-7.60 (m, 6H), 8.76 (dd, 1H, J=8.0, 1.9), 8.93 (dd, 1H, J=4.5, 1.8); 13C NMR (75 MHz, CDCl3) δ161.54, 154.13, 151.62, 137.15, 136.60, 134.29, 134.16, 129.96, 129.53, 128.24, 127.70, 121.95, 119.63, 108.46, 44.62, 14.67; IR (KBr) vmax 3439, 1647, 1622, 1591, 1564, 1552, 1483, 1458, 1439, 1417, 1375, 1298, 1176, 1167, 1099, 794, 729, 711, 696, 603 cm-1 ; mass spectrum (EI), m/e 284. Anal. (C16H13ClN2O .1/8 H2O) Calcd.: C, 66.96; H, 4.57; N, 9.76. Found: C, 66.82; H, 4.55; N, 9.61.