Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[F:11][C:12]([F:21])([F:20])/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:13]([C:12]([F:11])([F:21])[F:20])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:9]=1
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)ccc2OC1C(F)(F)F
Temperature: 60 °C
Yield: 138.4 %

Procedure:
A mixture of 5-chlorosalicylaldehyde (20.02 g, 0.128 mole) and ethyl 4,4,4-trifluorocrotonate (23.68 g, 0.14 mole) was dissolved in anhydrous DMF, warmed to 60° C. and treated with anhydrous K2CO3 (17.75 g, 0.128 mole). The solution was maintained at 60° C. for 20 hours, cooled to room temperature, and diluted with water. The solution was extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford 54.32 g of an oil. The oil was dissolved in 250 mL of methanol and 100 mL of water, whereupon a white solid formed that was isolated by filtration, washed with water and dried in vacuo, to afford the ester as a yellow solid (24.31 g, 62%): mp 62–64° C. 1H NMR (CDCl3/90 MHz) 7.64 (s, 1H), 7.30–7.21 (m, 2H), 6.96 (d, 1H, J=Hz), 5.70 (q, 1H, J=Hz), 4.30 (q, 2H, J=7.2 Hz), 1.35 (t, 3H, J=7.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([N:20]1[C:28]3[C:23](=[N:24][CH:25]=[C:26]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[CH:27]=3)[C:22]3([CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH2:21]1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([N:20]1[C:28]3[C:23](=[N:24][CH:25]=[C:26]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)[CH:27]=3)[C:22]3([CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)[CH2:21]1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][N:16]([S:48]([CH3:47])(=[O:50])=[O:49])[CH2:15][CH2:14]1)=[N:7]2
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(N2CCN(S(C)(=O)=O)CC2)nc2cc(F)cc(F)c2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1′-(5,7-difluoro-3-methyl-2-(piperazin-1-yl)quinolin-4-yl)-6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (50 mg, 0.093 mmol) in DCM (5.0 mL) was treated with triethylamine (0.019 mL, 0.140 mmol) and methanesulfonyl chloride (7.3 μL, 0.093 mmol) and the reaction was stirred at rt overnight. After this time the reaction was partitioned between EtOAc and water. The separated organic layer was dried over MgSO4 and evaporated in vacuo. Purification by reverse-phase HPLC (10% to 95% acetonitrile in water) gave 1′-(5,7-difluoro-3-methyl-2-(4-(methylsulfonyl)piperazin-1-yl)quinolin-4-yl)-6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine]. 1H NMR (400 MHz, chloroform-d) δ ppm 7.57 (1H, d, J=2.3 Hz), 7.37 (1H, dt, J=9.8, 1.3 Hz), 6.78 (1H, ddd, J=11.8, 9.0, 2.4 Hz), 5.65 (1H, d, J=2.3 Hz), 4.04-4.25 (2H, m), 3.83-3.97 (2H, m), 3.69-3.78 (4H, m), 3.30-3.65 (10H, m), 2.90-3.09 (4H, m), 2.86 (3H, s), 2.26-2.39 (2H, m), 2.25 (3H, s), 1.78 (1H, d, J=13.3 Hz), 1.64-1.75 (1H, m). Mass Spectrum (ESI) m/e=615.3 (M+1).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[C@H:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=1)[C:10]1[CH:22]=[CH:21][C:13]([C:14]([N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1.[I-].[Na+].C(N(CC)CC)C.Br[CH2:40][C:41]1[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:42]=1>C(#N)C>[CH2:17]([N:16]([CH2:19][CH3:20])[C:14]([C:13]1[CH:21]=[CH:22][C:10]([C@@H:9]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)[N:3]2[C@@H:2]([CH3:1])[CH2:7][N:6]([CH2:40][C:41]3[CH:50]=[CH:49][C:44]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:42]=3)[C@H:5]([CH3:8])[CH2:4]2)=[CH:11][CH:12]=1)=[O:15])[CH3:18]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(O)c2)N2C[C@@H](C)NC[C@@H]2C)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(O)c2)N2C[C@@H](C)N(Cc3ccc(C(=O)OC)cc3)C[C@@H]2C)cc1
Reaction time: 8 h
Yield: 64.3 %

Procedure:
The 4-[(S)-((2S,5R)-2,5-dimethylpiperazin-1-yl)(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide (0.51 g, 1.29 mmol) was dissolved in 10 mL of dry acetonitrile. Sodium iodide (20 mg, 0.13 mmol) was added and the reaction was stirred under nitrogen at room temperature during the addition of triethylamine (0.72 mL, 5.16 mmol), followed by methyl 4-(bromomethyl)benzoate (0.59 g, 2.58 mmol). The reaction mixture was stirred under nitrogen overnight. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with water, dried over Na2SO4/MgSO4 and concentrated under reduced pressure. The residual light yellow oil was purified by chromatography on silica gel (50% EtOAc in CH2Cl2) to give 0.45 g (0.83 mmol) of methyl 4-{(2R, 5S)-4-[(S)-(4-diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl]-2,5-dimethyl-1-piperazinylmethyl}-benzoate as a white amorphous solid.
Reaction SMILES: Br[C:2]1[C:11]([NH2:12])=[CH:10][C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6]C)=O.O=[C:15]1[CH2:20]C(=O)CN(C(OCC2C=CC=CC=2)=O)[CH2:16]1.[CH3:32][N:33]1[CH2:45][C:44]2NC3C=CC=C4C(=O)[NH:47][N:48]=[C:35]([C:36]=2C=34)[CH2:34]1>>[CH2:32]([N:33]1[CH2:45][C:44]2[NH:12][C:11]3[CH:10]=[C:9]([F:13])[CH:8]=[C:3]4[C:4](=[O:6])[NH:47][N:48]=[C:35]([C:36]=2[C:2]=34)[CH2:34]1)[CH2:16][CH2:15][CH3:20]
Reactant: O=C1CC(=O)CN(C(=O)OCc2ccccc2)C1
Reactant: CN1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1
Reactant: COC(=O)c1cc(F)cc(N)c1Br
Product: CCCCN1CC2=NNC(=O)c3cc(F)cc4[nH]c(c2c34)C1

Procedure:
Compound 59 was prepared from methyl 2-bromo-5-fluoro-3-aminobenzoate and benzyl 3,5-dioxopiperidine-1-carboxylate according to the procedures similar to those for Compound 44. 1H NMR (DMSO-d6) δ 11.8 (s, 1H), 10.1 (s, 1H), 7.36 (dd, 1H, J=2.4, 9.6 Hz), 7.19 (dd, 1H, J=2.4, 10.2 Hz), 3.80 (s, 2H), 3.30 (s, 2H), 2.54-2.57 (m, 2H), 1.47-1.50 (m, 2H), 1.30-1.34 (m, 2H), and 0.91 (t, 3H, J=7.2 Hz). MS (ESI) m/e [M+1]+ 301.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=O)[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.N1C=CC=CC=1.[NH2:26][N:27]1[CH2:31][CH:30]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)[CH2:29][C:28]1=[O:40]>C(O)(=O)C>[CH3:39][O:38][C:34]1[CH:33]=[C:32]([CH:30]2[CH2:31][N:27]([N:26]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:8][C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]=[CH:11][CH:10]=3)[C:28](=[O:40])[CH2:29]2)[CH:37]=[CH:36][CH:35]=1
Reactant: COc1cccc(C2CC(=O)N(N)C2)c1
Reactant: O=C(Cc1ccnc2ccccc12)c1ccccn1
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: COc1cccc(C2CC(=O)N(N=C(Cc3ccnc4ccccc34)c3ccccn3)C2)c1
Reaction time: 18 h

Procedure:
A solution of 1-pyridin-2-yl-2-quinolin-4-yl-ethanone, (0.25 g, 1 mmol) and pyridine (0.242 mL, 3 mmol) in acetic acid (2 mL) is added to 1-amino-4-(3-methoxy-phenyl)-pyrrolidin-2-one, (0.2 g, 1 mmol) at room temperature under nitrogen. The mixture is stirred 18 h and concentrated in vacuo. The residue is chromatographed on SiO2 (2% methanol/dichloromethane) to yield the title compound, 0.25 g (57%), as a yellow foam.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH2:9])[CH3:2].[CH2:10]([S:12]([C:15]1[CH:16]=[C:17]([C:25](Cl)=[O:26])[C:18]2[O:23][CH2:22][CH2:21][O:20][C:19]=2[CH:24]=1)(=[O:14])=[O:13])[CH3:11]>>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:25]([C:17]1[C:18]2[O:23][CH2:22][CH2:21][O:20][C:19]=2[CH:24]=[C:15]([S:12]([CH2:10][CH3:11])(=[O:14])=[O:13])[CH:16]=1)=[O:26])[CH3:2]
Reactant: CCN1CCCC1CN
Reactant: CCS(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2
Product: CCN1CCCC1CNC(=O)c1cc(S(=O)(=O)CC)cc2c1OCCO2
Yield: 69.8 %

Procedure:
In a similar manner 64.5 g of dextrorotary-1-ethyl-2-aminomethylpyrrolidine was reacted with 146 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride to give, after treatment and purification, 133.5 g of dextrorotatory N-(1-ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide (M.P.: 111°-112° C.; yield: 69.8%); (α)D20 =55.5° (in 5% solution in dimethylformamide).
Reaction SMILES: [C:1](=[C:4]([C:10]([O:12]C)=O)[C:5]([O:7][CH2:8]Br)=[O:6])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH3:8][O:7][C:5]([C:4]1[C:10](=[O:12])[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:2][C:1]=1[CH3:3])=[O:6]
Reactant: Nc1ccccc1
Reactant: COC(=O)C(C(=O)OCBr)=C(C)C
Solvent: CCO
Product: COC(=O)C1=C(C)CN(c2ccccc2)C1=O
Yield: 52.4 %

Procedure:
A solution of 20.6 grams (82 mmol) of impure bromomethyl methyl isopropylidenemalonate and 15.2 grams (0.169 mol) of aniline in 25 mL of absolute ethanol were stirred at room temperature. Initially a homogeneous solution formed. After a mildly exothermic reaction a precipitate formed. The reaction was refluxed for 1 hour, cooled, and filtered. The collected product was washed with ethanol and water to give 10.0 grams (43 mmol, 52% yield) of crude product. An analytical sample was prepared by recrystallizing from methanol, m. p.=143°-145° C., Elemental Analysis: Calculated: C=67.5, H=5.7, N=6.1; Found: C=67.7, H=5.9, N=6.2.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:9])[C:6](Cl)=[O:7])#[N:2].[CH:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12]([OH:19])[CH:11]=1.CN(C)C1C=CC=CC=1>C(Cl)Cl>[C:1]([CH2:3][NH:4][C:5](=[O:9])[C:6]([O:19][C:12]1[CH:11]=[CH:10][C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=1)=[O:7])#[N:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: N#CCNC(=O)C(=O)Cl
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: N#CCNC(=O)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
50 mM of [(cyanomethyl)amino]oxoacetyl chloride dissolved in methylene chloride is added dropwise at 0° to a solution of 40 mM of p-nitrophenol and 40 mM of dimethylaniline in methylene chloride. After stirring for one hour, the reaction mixture is extracted once with dilute hydrochloric acid and twice with water. The dried methylene chloride phase is concentrated under vacuum and yields 4.2 g. of [(cyanomethyl)amino]-oxoacetic acid, 4-nitrophenyl ester as a brown oil which crystallizes upon trituration with ether. Recrystallization from toluene gives white crystals, m.p. 123-124°.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[K].C([O:8][CH:9](OCC)[CH:10]([CH:13]=O)[C:11]#[N:12])C.C[O-].[Na+].CO>CCO>[NH2:12][C:11]1[C:10]([CH:9]=[O:8])=[CH:13][N:4]=[C:2]([SH:3])[N:1]=1
Reactant: CCOC(OCC)C(C#N)C=O
Reactant: NC(N)=S
Agent: C[O-]
Agent: [K]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: Nc1nc(S)ncc1C=O
Temperature: 50 °C
Yield: 72.3 %

Procedure:
A slurry of thiourea (92.8 g, 1.22 moles) in EtOH (90 mL) was heated under reflux and vigorously stirred. To this slurry was added a suspension of 3,3-diethoxy-2-formylpropionitrile potassium salt (P-5A) (222.20 g, 1.06 moles) in 25% sodium methoxide/MeOH (85.5 mL, 0.37 mole) and EtOH (285 mL) in five aliquots over a 10 minute period, while maintaining reflux conditions (alternatively, the latter slurry may be heated to 50° C. to give a homogenous solution for the addition). An additional portion of EtOH (150 mL) was added to facilitate stirring. The thick slurry became a bright yellow color following the addition and was held under reflux for an additional 1 hour. The mixture was then cooled and evaporated to near dryness on a rotoevaporator. The residue was dissolved in water (940 mL). Crude product was precipitated from solution by the addition of 30% acetic acid (280 mL) and isolated via filtration using a medium frit sintered glass filtration funnel. The cake was washed with water (800 mL). Purification via trituration in hot water (1 L) for 30 minutes, followed by cooling and filtration gave 118.9 grams (72.3%) of product as a bright yellow solid after drying overnight at 60° C. in a vacuum oven (subsequent preparations have demonstrated that this trituration is unnecessary). An HPLC gave purity as 98.67%. 1H-NMR (DMSO-d6) was consistent with the above desired structure (P-5B).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[CH3:18][O:19][C:20]1([NH3+:23])[CH2:22][CH2:21]1>O1CCCC1>[CH3:18][O:19][C:20]1([NH:23][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:22][CH2:21]1
Reactant: COC1([NH3+])CC1
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC1(NC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (3.1 g, 30.5 mmol) is added dropwise (30 min) at 0° to a solution of benzoyl chloride (1.5 g, 12.2 mmol) in tetrahydrofuran (25 ml) containing suspended 1-methoxycyclopropylammonium chloride (1.82 g, 13.0 mmol). The mixture is then stirred at room temperature for 30 min. The precipitate is filtered off and washed thoroughly with tetrahydrofuran. The filtrate is evaporated in vacuo yielding a crystalline residue. Recrystallisation from methanol gives pure N-(-methoxycyclopropyl)-benzamide, mp 190°-191° (1.2 g, 55%); NMR (60 MHz)=δCDCl 3=1.00-1.30 (m, 4H), 3.40 (s, 3H), 7.0 (br. s, 1H), 7.35-7.95 (m, 5H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][N:4]=1.[SH:13][C:14]1[NH:15][C:16]2[CH:22]=[C:21]([O:23][CH:24]([F:26])[F:25])[CH:20]=[CH:19][C:17]=2[N:18]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>>[CH3:12][O:11][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][S+:13]([O-:35])[C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH:24]([F:25])[F:26])=[CH:22][C:16]=3[N:15]=2)[C:8]=1[O:9][CH3:10].[Cl:1][CH2:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][N:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)Oc1ccc2nc(S)[nH]c2c1
Agent: COc1ccnc(CCl)c1OC
Product: COc1ccnc(C[S+]([O-])c2nc3cc(OC(F)F)ccc3[nH]2)c1OC

Procedure:
In one of the processes described in this patent application, 2-chloromethyl-3,4-dimethoxy pyridine was reacted with 2-mercapto-5-difluoromethoxy benzimidazole to prepare a precursor sulfide, which was isolated and oxidized by using metachloroperbenzoic acid to yield pantoprazole base in a yield of 102% by weight with respect to 2-chloromethyl-3,4 dimethoxy pyridine.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+].Cl>C(O)C.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[N:24][OH:25])=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(C=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.1 %

Procedure:
In to a solution of 4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzaldehyde (6.5 g, 22.2 mmol) in ethanol (300 mL) were added hydroxylamine hydrochloride (4.62 g, 66.55 mmol) and a solution of sodium acetate (7.27 g, 82.7 mmol) in H2O (40 mL). The mixture was stirred at room temperature for 12 h, then poured into H2O, acidified with 1N HCl and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and crystallization from acetone/ether/hexane, gave a white solid (6.1 g, 89% yield, m.p. 192°-193° C.). Analysis for: C18H16N2O3Calc'd: C, 70.12; H, 5.23; N, 9.09 Found: C, 70.31; H, 5.27; N, 8.82
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:15][CH2:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: COC(=O)c1ccc([N+](=O)[O-])cc1CBr
Yield: 82.4 %

Procedure:
A degassed solution of methyl 2-methyl-4-nitrobenzoate (3.5 g, 18.19 mmol), N-bromosuccinimide (3.9 g, 21.91 mmol, 1.2 eq) and benzoyl peroxide (3.63 mmol, 0.2 eq.) in 100 ml 0014 was heated at reflux for 4 hr. It was concentrated to dryness, dissolved in ether, washed 2× with water, aq. Na2S2O3, brine, dried over MgSO4, filtered, concentrated and purified by chromatography using 15% ethyl acetate in hexanes to provide 4.11 g of methyl 2-bromomethyl-4-nitrobenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=O)[C:10]([CH3:13])(C)C)[CH:5]=[C:4]([Cl:15])[N:3]=1.C([Li])CCC.CN(C)/C=C/C=O.C(OCC)C>C1COCC1.C1CCCCC1>[Cl:15][C:4]1[N:3]=[C:2]([Cl:1])[CH:7]=[C:6]2[C:5]=1[CH:13]=[CH:10][CH:9]=[N:8]2
Reactant: CC(C)(C)C(=O)Nc1cc(Cl)nc(Cl)c1
Agent: CN(C)/C=C/C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Clc1cc2ncccc2c(Cl)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.1 %

Procedure:
N-(2,6-Dichloro-4-pyridinyl)-2,2-dimethylpropanamide (1 g, 4.05 mmol) was taken up in THF (10 ml) under nitrogen and cooled to <−70° C. n-Butyl lithium (4.05 ml, 10.12 mmol, 2.5M solution in hexanes) was added over 30 min keeping the temperature below −60° C. and then stirred at below −70° C. for 1 h. (2E)-3-(dimethylamino)-2-propenal (0.607 ml, 6.07 mmol) in THF (2 ml) was added over 30 min keeping the temperature below −60° C. The reaction was stirred at below −70° C. for 20 min and then allowed to warm to room temperature. LCMS showed that no starting material remained so the reaction was quenched with 5M HCl (5 ml) and refluxed overnight. LCMS showed good conversion to product so the reaction was cooled to room temperature. The reaction mixture was basified with solid K2CO3 and extracted with EtOAc (4×25 ml). The combined organics were dried with Na2SO4, filtered and concentrated to yield a brown solid. The crude product was applied to a samplet and columned using a 40+M eluting with 12% diethyl ether in cyclohexane for 2 CVs, then with 12%-63% diethyl ether in cyclohexane over 10 CVs then held at 63% for SCVs. Appropriate fractions were combined and evaporated to give the title compound as a yellow solid (0.42 g).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)(O)=[O:6]>>[ClH:3].[Cl:3][C:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:9]=1)=[O:6]
Reactant: O=C(O)c1cn(-c2ccnc3ccc(C(F)(F)F)cc23)c2ccccc12
Reactant: O=S(Cl)Cl
Product: Cl
Product: O=C(Cl)c1cn(-c2ccnc3ccc(C(F)(F)F)cc23)c2ccccc12

Procedure:
5 cm3 of thionyl chloride are added to 0.713 g (2 mmol) of 3-carboxy-1-(6-(trifluoromethyl)quinol-4-yl)-1H-indole under an argon atmosphere. After stirring at reflux for 2 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), successively triturated three times with 20 cm3 of dichloromethane and then concentrated to dryness under reduced pressure (2.7 kPa) to give 0.85 g of 3-chlorocarbonyl-1-(6-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride in the form of a yellow powder which is used directly in the following step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][CH2:11][C:10]3=[N:13][CH:14]=[CH:15][N:9]3[CH2:8][C:7]=2[CH:16]=1.[CH3:17][C:18]1[CH:35]=[CH:34][CH:33]=[CH:32][C:19]=1[C:20]([NH:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)=[O:21].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]([C:27]([C:26]3[CH:25]=[CH:24][C:23]([NH:22][C:20](=[O:21])[C:19]4[CH:32]=[CH:33][CH:34]=[CH:35][C:18]=4[CH3:17])=[CH:31][CH:30]=3)=[O:28])[CH2:11][C:10]3=[N:13][CH:14]=[CH:15][N:9]3[CH2:8][C:7]=2[CH:16]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc2c(c1)Cn1ccnc1CN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)Cn1ccnc1CN2C(=O)c1ccc(NC(=O)c2ccccc2C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
As described for Example 125 a mixture of 1.0 mmol of 7-methoxy-10,11-dihydro-5H-imidazo[2,1-c][1,4]benzodiazepine, 1.1 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride and 1.5 mmol of triethylamine in 10 ml of dichloromethane is stirred for 3 hours at room temperature and worked up to give the product as a solid.
Reaction SMILES: [CH2:1]([C:3]1[CH2:4][NH:5][CH:6]=[C:7]([CH2:9][CH3:10])[CH:8]=1)[CH3:2].C(C1C(CC)=CC(CC)=CN=1)CC.[C:24]([OH:27])(=[O:26])[CH3:25]>>[C:24]([O-:27])(=[O:26])[CH3:25].[CH2:1]([C:3]1[CH:4]=[NH+:5][CH:6]=[C:7]([CH2:9][CH3:10])[CH:8]=1)[CH3:2]
Reactant: CC(=O)O
Reactant: CCC1=CNCC(CC)=C1
Agent: CCCc1ncc(CC)cc1CC
Product: CC(=O)[O-]
Product: CCc1c[nH+]cc(CC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 140 grams of 1-Butyl, 2-propyl, 3,5-diethyl 1,2-dihydropyridine and 2-propyl 3,5-diethylpyridine prepared as described in example 1 was added 18 grams of acetic acid, the mixture was stirred for 18 hours at ambient temperature in the presence of air. The resulting reaction product was extracted with water. The water insoluble fraction was identified as 2-propyl 3,5-diethylpyridine. The aqueous extract was evaporated under diminished pressure to yield 71 grams of N-Butyl, 2-propyl, 3,5-diethylpyridinium acetate, nuclear magnetic resonance spectrum, solvent CCl4. δ in ppm, 9.20 m, 1H; 8.33, m, 1H; 4.78 m, 2H; 2.95, m, 6H; 1.80 s, 3H; 1.33, m, and 0.99 m, 18H.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH:7]=[CH:8][C:9]2[CH:19]=[CH:18][C:12]([C:13](OCC)=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH:7]=[CH:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:13][OH:14])=[CH:18][CH:19]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccc(C=Cc2ccc(OC)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C=Cc2ccc(CO)cc2)cc1
Reaction time: 1 h

Procedure:
Ethyl 4-(4-methoxystyryl)benzoate (67 g.) in 600 ml. of tetrahydrofuran was gradually added to a suspension of 12 g. of lithium aluminum hydride in 300 ml. of tetrahydrofuran at such a rate to maintain gentle reflux. The reaction mixture was heated at reflux for two hours, then cooled and 24 ml. of water in 24 ml. of tetrahydrofuran added slowly. The mixture was stirred for one hour, heated to reflux temperature and filtered hot through a steam-jacketed funnel. The solvent was removed from the filtrate to give 55 g. of 4-(4-methoxystyryl)benzyl alcohol, m.p. 200°-202° C. when recrystallized from ethanol.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:18][C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=2)=[CH:6][CH:5]=1.Cl[CH2:20][C:21]([NH2:23])=[O:22]>O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([CH2:20][C:21]([NH2:23])=[O:22])[C:12]3[C:13]([N:18]=2)=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:6][CH:5]=1
Reactant: Clc1ccc(-c2nc3cccnc3[nH]2)cc1
Reactant: NC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: NC(=O)Cn1c(-c2ccc(Cl)cc2)nc2ncccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Under nitrogen flow, sodium hydride (0.96 g, 0.0234 mole, 60% in oil) was washed with hexanes (~70 ml) and decanted. Dimethylformamide was added (100 ml) and the 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine (5.0 g, 0.022 mole) was added in portions. The reaction mixture was heated at 70°-85° C. for 11/2 hours. Chloroacetamide (2.06 g, 0.022 mole) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was added to water (~600 ml) and the precipitate was collected by filtration, washed with water, and dried under high vacuum overnight at 50° C. NMR indicated at 14% yield of the isomer: 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetamide and an 86% yield of the title compound. The solid was dissolved in pyridine, filtered, and diluted with water to produce crystalline product with refrigeration. The solid was collected by filtration, washed with water and dried under high vacuum at 90° C. overnight to give 2.3 g (36.5%) of the title compound, mp 280°-283° C. with decomposition.