Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:14](N(CC)CC)C.N[C@@H](C(O)=O)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[O-]S([O-])(=O)=O.[Mg+2].C(=O)C1C=CC=CC=1.Cl.C(N(CC)CC)C>>[CH3:14][O:12][C:11](=[O:13])[C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[N:2]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCN(CC)CC
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O=Cc1ccccc1
Product: COC(=O)[C@@H](Cc1ccccc1)N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 1.0 eq D-phenylalanine HCl (1.6 g, 7.4 mmol) was added 1.0 eq triethylamine to dissolve the D-phenylalanine. To this solution was added 1 equiv. of MgSO4 followed by the addition of 1.0 eq benzaldehyde, the reaction was stirred overnight at room temperature under N2 atmosphere. The reaction mixture was sripped of solvent and pumped on the residue contained a good deal of triethylamine hydrochloride which was removed by dissolving the product in THF and filtering out the TEA.HCl. The crude benzylidene looked fine by NMR and was all taken on in the next step.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:20])[C:9]([S:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)([CH3:11])[CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]#[N:30].O>CN(C=O)C>[C:29]([CH2:28][O:19][C:16]1[CH:15]=[CH:14][C:13]([S:12][C:9]([CH3:11])([CH3:10])[C:8]([NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:20])=[CH:18][CH:17]=1)#[N:30]
Reactant: N#CCBr
Reactant: CC(C)(Sc1ccc(O)cc1)C(=O)NC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(Sc1ccc(OCC#N)cc1)C(=O)NC1CCCCC1
Temperature: 80 °C

Procedure:
N-Cyclohexyl-2-[(4-hydroxyphenyl)thio]-2-methylpropanamide (prepared as example 67) was dissolved in DMF and to this was added potassium carbonate and bromoacetonitrile and the resulting solution was heated to 80° C. for 2 h. The reaction mixture was poured into water and extracted with EtOAC, dried over MgSO4 and concentrated. The product was purified by flash chromatography, eluting with hexane/EtOAc, to provide 19.4 mg of the desired product. LCMS: (M+H)+=333.2.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([OH:20])=O)[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.C(N(CC)CC)C.C([Cl:36])(=O)OCC.[CH:37]([NH:40][CH2:41][CH2:42][NH2:43])([CH3:39])[CH3:38]>C1COCC1>[ClH:36].[ClH:36].[CH:37]([NH:40][CH2:41][CH2:42][NH:43][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][CH:23]=[C:15]([O:14][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:4]3[S:5][CH:6]=[C:2]([CH3:1])[N:3]=3)[CH:13]=2)[CH:16]=1)([CH3:39])[CH3:38]
Reactant: CCOC(=O)Cl
Reactant: Cc1csc(Nc2cc(Oc3cccc(C(=O)O)c3)ccn2)n1
Reactant: CC(C)NCCN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1csc(Nc2cc(Oc3cccc(C(=O)NCCNC(C)C)c3)ccn2)n1
Product: Cl
Yield: 74 %

Procedure:
Using the method of Example 32, 3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzoic acid (0.1 g, 0.3055 mmol), triethylamine (0.2129 mL, 1.527 mmol), ethyl carbonochloridate (0.03359 mL, 0.3513 mmol), N1-isopropylethane-1,2-diamine (0.1143 mL, 0.9164 mmol) were reacted in THF (2 mL) to provide N-(2-(isopropylamino)ethyl)-3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzamide dihydrochloride (0.063 g, 39.59% yield) as a light yellow solid. 1H NMR (CDCl3) δ 9.51 (bs, 1H), 8.74 (s, 1H), 8.15 (d, 1H), 7.92 (d, 1H), 7.81 (s, 1H), 7.49 (t, 1H), 7.22 (d, 1H), 6.83 (d, 1H), 6.44 (s, 1H), 3.92 (m, 2H), 3.24 (m, 2H), 3.12 (m, 1H), 2.42 (s, 3H), 1.46 (d, 6H); Mass spectrum (esi) m/z=412 (100) (M+H).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][C:9]([C:13](=[O:15])[NH2:14])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.[Cl-].[Na+]>CN(C)C=O>[C:1]1([N:7]2[C:11](=[O:12])[C:10](=[CH:21][C:20]3[CH:23]=[CH:24][C:17]([OH:16])=[CH:18][CH:19]=3)[C:9]([C:13](=[O:15])[NH2:14])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: NC(=O)C1=NN(c2ccccc2)C(=O)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)C1=NN(c2ccccc2)C(=O)C1=Cc1ccc(O)cc1

Procedure:
20.5 g (0.1 mole) of 1-phenyl-3-carbamoyl-2-pyrazolin-5-one and 12.2 g (0.1 mole) of p-hydroxybenzaldehyde were stirred for 1 hour in 100 ml of boiling dimethylformamide. The hot reaction mixture was poured out in 500 ml of an aqueous solution of sodium chloride (12%). After stirring and standing for a while, the yellow dye was filtered with suction, rinsed with water, and washed with hot acetone.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH2:8][CH2:7]1.C([N:18](CC)CC)C.O>C(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3]([NH2:6])=[O:4].[Cl:1][CH2:2][C:3]([NH2:18])=[O:4].[NH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH2:8][CH2:7]1
Reactant: O=C(Cl)CCl
Reactant: CCN(CC)CC
Agent: c1ccc2c(c1)NCCN2
Solvent: O
Solvent: ClC(Cl)Cl
Product: NC(=O)CCl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 1 L three-necked round bottomed flask equipped with a magnetic stir bar, reflux condenser and addition funnel, was added chloroacetyl chloride (9.6 mL, 0.120 mol) and CHCl3 (100 mL). The addition funnel was charged with a solution of tetrahydroquinoxaline (8.0 g, 0.0596 mol) and triethylamine (20.8 mL) in CHCl3 (100 mL). The flask was chilled to 0° C., and the amine was slowly added to the acid chloride. After the addition was complete, the mixture was allowed to warm to ambient temperature and stir for 1 hour. The flask was then cooled to 0° C. and H2O (50 mL) was slowly added. The mixture was diluted with CHCl3 (250 mL) and the layers were separated. The organic layer was washed with H2O (50 mL), 0.05 N NaOH (2×50 mL), H2O (50 mL), 1 N HCl (3×50 mL) and H2O (2×50 mL), and was dried over anhydrous Na2SO4. The solution was filtered and concentrated to a brown solid. The solid was collected by filtration, washed with 2-propanol (2×30 mL) and diethylether (2×40 mL) and dried to yield the title product (4.41 g, 51.5%). 1H NMR (DMSO-d6): δ3.89 (s, 4 H), 4.01 (s, 4 H), 7.25 (s, 2 H), 7.65 (br s, 2 H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH:14]3[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Cl.C(O)C.O>C(OCC)(=O)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH:14]3[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1CCc1ccc2c(c1)OCCO2
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CNCCN1CCc1ccc2c(c1)OCCO2
Reaction time: 2 h

Procedure:
To 0.60 g of 1-tert-butyl 3-ethyl 4-(2-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl)piperazine-1,3-dicarboxylate, 12 mL of 10 mol/L hydrogen chloride/ethanol was added, and the mixture was stirred for 2 hours, and then the solvent was removed under reduced pressure. The residue thus obtained was added with water and ethyl acetate. The aqueous layer was separated, ethyl acetate was added thereto, and the resultant solution was adjusted to pH 14 with a 5 mol/L aqueous sodium hydroxide solution. The organic layer was separated and dried over potassium carbonate, and the solvent was removed under reduced pressure to obtain 0.34 g of a brown oily substance, ethyl 1-(2-(2,3-dihydro-1,4-benzodioxin-6-yl)ethyl)piperazine-2-carboxylate.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(C)=O.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([CH2:7][CH2:8][CH:9]=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCC1CCCCC1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=CCCC1CCCCC1
Reaction time: 1 h
Yield: 97.5 %

Procedure:
3-Cyclohexyl-1-propanol (3.96 g, 27.8 mmol) was dissolved in DCM (90 mL) at 0° C. and treated sequentially with dimethyl sulfoxide (3.25 g, 41.7 mmol), N,N-diisopropylethylamine (8.98 g, 69.6 mmol) and sulfur trioxide pyridine complex (11 g, 69.6 mmol). After one hour, the reaction mixture was diluted with DCM (100 mL) and washed with 1N aqueous HCl (3×50 mL), saturated sodium bicarbonate (3×50 mL), and brine. The organic layer was dried over MgSO4, filtered, and concentrated to yield the title intermediate as a light yellow oil (3.8 g). 1H NMR (d6-DMSO, 300 MHz) δ (ppm): 9.72 (s, 1H), 3.65-3.72 (m, 2H), 2.46 (t, 2H), 1.65-1.73 (m, 3H), 1.51-1.56 (m, 2H), 1.14-1.48 (m, 4H), 0.85-0.96 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.[CH:19]1(B(O)O)[CH2:21][CH2:20]1.CCN(CC)CC.N1C=CC=CC=1>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH:19]1([N:8]2[CH2:7][CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:3][C:2]2=[O:1])[CH2:21][CH2:20]1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCCN1
Reactant: OB(O)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCCN(C2CC2)C(=O)C1
Temperature: 25 °C

Procedure:
A mixture of benzyl 3-oxo-1,4-diazepane-1-carboxylate (prepared according to Polish J. Chem. 1989, 63, 265-71), cyclopropylboronic acid (6 eq.), Et3N (10 eq.), pyridine (16 eq.) and Cu(OAc)2 (4 eq.) in dry THF (0.24 M) was heated for 10 min. to 140° C. in a microwave oven. After cooling to RT the mixture was filtered through celite, the solvents were removed under reduced pressure and the product was purified by chromatography on silica gel, eluenting with EtOAc/petroleum ether. The product was obtained as a white solid. 1H-NMR (300 MHz, CDCl3) δ: 7.45-7.22 (5H, m), 5.15 (2H, s), 4.22-4.07 (2H, m), 3.70-3.37 (4H, m), 2.75-2.60 (1H, m), 1.90-1.65 (2H, m), 0.85-0.72 (2H, m), 0.60-0.41 (2H, m). MS (ES) C16H20N2O3 requires: 288, found: 289 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:25][CH2:24]2)[CH2:10][N:11]([CH3:20])[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[C:43](OC(=O)C)(=[O:45])[CH3:44]>ClCCl.[OH-].[Na+]>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([N:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:43](=[O:45])[CH3:44])[CH2:27][CH2:28]2)[CH2:10][N:11]([CH3:20])[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCNC1CCN(CCC(CN(C)C(=O)c2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCN(C(C)=O)C1CCN(CCC(CN(C)C(=O)c2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Product: Cl
Reaction time: 2 h

Procedure:
To N-[2-(3,4-dichlorophenyl)-4-(4-hexylaminopiperidino)butyl]-N-methylbenzamide in dichloromethane (5 mL) was added triethylamine (0.39 mL) and acetic anhydride (0.39 mL). After being stirred for 2 hours, the mixture was diluted with 1N sodium hydroxide and was extracted with dichloromethane. The combined organic extracts were washed (brine), dried, and evaporated. The resulting material was chromatographed, with dichloromethane:methanol (97:3) as the eluent, to give the title compound (0.210 g) as a white solid after evaporation from methanolic hydrogen chloridel MS: m/z=560(M+1). Analysis for C31H43Cl2N3O2.1.5 HCl: Calculated: C, 60.51; H, 7.28; N, 6.82; Found: C, 60.50; H, 7.38; N, 6.85.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:15](=[O:30])[C:16]1[CH:21]=[C:20]([C:22](F)(F)F)N=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1.[CH3:36][S:37](C1C=C(C=C(C(F)(F)F)C=1)C(N(C)C1C=NC=CC=1C1C=CC=CC=1C)=O)(=[O:39])=[O:38].F[B-](F)(F)F.BrC1C=CC=C[N+]=1CC.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:31][C:32]([F:34])([F:33])[F:35])[C:15](=[O:30])[C:16]1[CH:17]=[C:18]([C:26]([F:28])([F:27])[F:29])[CH:22]=[C:20]([S:37]([CH3:36])(=[O:39])=[O:38])[CH:21]=1
Reactant: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Reactant: O=C(c1cc(C(F)(F)F)nc(C(F)(F)F)c1)N(CC(F)(F)F)c1cnccc1-c1ccccc1F
Agent: CC[n+]1ccccc1Br
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cc(C(=O)N(CC(F)(F)F)c2cnccc2-c2ccccc2F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of 4-(2-fluorophenyl)-N-(2,2,2-trifluoroethyl)pyridin-3-amine (79 mg, 292 μmol, example 151, intermediate) in CH2Cl2 (2 mL) was added 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (78.4 mg, 292 μmol, example 114, intermediate) and 2-bromo-1-ethylpyridinium tetrafluoroborate (96.1 mg, 351 μmol) and N,N-diisopropylethylamine (75.6 mg, 102 μL, 585 μmol). The reaction mixture was stirred at room temperature for 23 hours. The reaction mixture was concentrated under vacuum. The residue was dissolved in 30 mL 1N aqueous HCl and 30 mL EtOAc and the layers were separated. The aqueous layer was extracted a second time with 30 mL EtOAc. The organic layers were washed with 30 mL 1M aqueous HCl and 30 mL 10% aqueous NaHCO3 and 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography on a 10 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light yellow solid (37 mg, 24%). MS (ESI): m/z=521.076 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][CH3:14])[C:5]([OH:7])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:39]([NH:41]O)=[NH:40])[CH:37]=2)[N:32]([CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:31]=1>CN(C=O)C>[Cl:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:39]3[N:40]=[C:5]([C:4]4[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][CH3:14])=[C:2]([Cl:1])[CH:3]=4)[O:7][N:41]=3)[CH:37]=2)[N:32]([CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:31]=1
Reactant: CCOC(=O)CCn1cc(Cl)c2cc(C(=N)NO)ccc21
Reactant: CCCOc1ccc(C(=O)O)cc1Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCOc1ccc(-c2nc(-c3ccc4c(c3)c(Cl)cn4CCC(=O)OCC)no2)cc1Cl
Temperature: 80 °C

Procedure:
3-Chloro-4-(propyloxy)benzoic acid (D100) (150 mg, 0.70 mmol) stirring in DMF was treated with EDC (146 mg, 0.76 mmol) followed by HOBt (104 mg, 0.76 mmol). The resultant solution was stirred and ethyl 3-{3-chloro-5-[(hydroxyamino)(imino)methyl]-1H-indol-1-yl}propanoate (D96) (216 mg, 0.70 mmol) added. Heated mixture at 80° C. until reaction was complete. Work up obtained the title compound as 160 mg of pale cream solid. δH (400 MHz, d6-DMSO) 1.03 (3H, t), 1.10 (3H, t), 1.77-1.86 (2H, m), 2.90 (2H, t), 4.05 (2H, q), 4.18 (2H, t), 4.49 (2H, t), 7.40 (1H, d), 7.74 (1H, s), 7.81 (1H, d), 7.91 (1H, dd), 8.15 (1H, dd), 8.22-8.23 (2H, m). MS (ES) C24H2335Cl2N3O4 requires 487; found 488 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([O:14][CH2:15][CH3:16])=[C:7]([O:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[CH:6]=1)C.O.[OH-].[Na+].Cl>O1CCOCC1>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[CH2:19][CH2:18][O:17][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]=1[O:14][CH2:15][CH3:16])[C:4]([OH:28])=[O:3]
Reactant: CCOC(=O)c1cc(OCC)c(OCC)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1cc(C(=O)O)cc(OCCc2ccc(Cl)cc2Cl)c1OCC
Temperature: 60 °C
Reaction time: 16 h

Procedure:
0.66 g (1.54 mmol) of 3-[2-(2,4-Dichlorophenyl)-ethoxy]-4,5-diethoxy-benzoic acid ethyl ester was dissolved in 6 ml of dioxan. 5 ml of water and 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was heated at 60° C. for 4 h and stirred at room temperature for 16 h. The reaction solution was cooled to 0° C. and concentrated hydrochloric acid was added to give a pH of 1-2, whereupon the product precipitated from solution. The suspension was stirred for 30 min, then the product was filtered off and dried under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]#N)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[H-].C([Al+]C(C)C)(C)C.CCCCCC.[OH2:25]>ClCCl>[CH3:1][O:2][C:3]1([CH:9]=[O:25])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: O
Reactant: COC1(C#N)CCOCC1
Agent: CC(C)[Al+]C(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCC
Product: COC1(C=O)CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
4-Methoxytetrahydro-2H-pyran-4-carbonitrile (1.00 g, 7.08 mmol) was dissolved in dichloromethane (20 mL). To this, a 1 mol/L solution of diisopropylaluminum hydride in hexane (10.9 mL, 10.9 mmol) was added at −78° C. and the mixture was stirred at room temperature for 30 minutes. The reaction was stopped by addition of water (10.9 mL) at 0° C. The mixture was stirred at room temperature for 1 hour and then filtered through Celite. The solvent was evaporated off under reduced pressure and the residue was dissolved in tetrahydrofuran (10 mL). To this, a 1 mol/L aqueous hydrogen chloride solution was added and the mixture was stirred at room temperature for 30 minutes. The reaction was stopped by addition of a saturated aqueous sodium bicarbonate solution to the reaction mixture, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to give 4-methoxytetrahydro-2H-pyran-4-carbaldehyde (195 mg, yield: 19%).
Reaction SMILES: [C:1]1([CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]([N:10]2[CH2:15][CH2:14][C:13]3[NH:16][CH:17]=[N:18][C:12]=3[CH:11]2[C:19]([O:21][CH3:22])=[O:20])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:31]([N:50]1[C:54]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=2[C:61]2[CH:66]=[CH:65][C:64]([CH2:67]Br)=[CH:63][CH:62]=2)=[N:53][N:52]=[N:51]1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C=O>[C:23]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([N:10]2[CH2:15][CH2:14][C:13]3[N:16]=[CH:17][N:18]([CH2:67][C:64]4[CH:63]=[CH:62][C:61]([C:56]5[CH:57]=[CH:58][CH:59]=[CH:60][C:55]=5[C:54]5[N:50]([C:31]([C:44]6[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=6)([C:38]6[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=6)[C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)[N:51]=[N:52][N:53]=5)=[CH:66][CH:65]=4)[C:12]=3[CH:11]2[C:19]([O:21][CH3:22])=[O:20])=[O:9])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)C1c2nc[nH]c2CCN1C(=O)C(c1ccccc1)c1ccccc1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1c2c(ncn2Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)CCN1C(=O)C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 11.8 %

Procedure:
Methyl 5-diphenylacetyl-4,5,6,7-tetrahydroimidazo-[4,5-c]pyridine-4-carboxylate (1.60 g) is dissolved in dimethylformamide (20 ml), and thereto is added sodium hydride (60% oil-dispersion, 176 mg) under ice-cooling. The mixture is stirred at 0° C. for 20 minutes, and thereto is added [2'-(1-trityl-1H-tetrazol-5-yl)bipheyl-4-yl]methyl bromide (2.40 g), and the mixture is stirred under ice-cooling for one hour, and further at room temperature for one hour. The reaction solution is concentrated under reduced pressure, and to the residue are added chloroform and water. The organic layer is dried, and evaporated to remove the solvent. The resulting residue is purified by silica gel column chromatography (solvent; chloroform/methanol=100:1) to give methyl 5-diphenylacetyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (430 mg) as a colorless foam.
Reaction SMILES: [CH:1](=[O:4])CC.[C:5](#[N:8])[CH2:6][CH3:7].C(#N)C=C.N.[C:14](#[N:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[CH3:1][O:4][C:18]1[CH:19]=[CH:20][C:15]([C:14]#[N:21])=[CH:16][CH:17]=1.[C:5](#[N:8])[CH2:6][CH2:7][CH2:17][CH2:16][CH2:15][CH2:20][CH3:19]
Reactant: N#Cc1ccccc1
Reactant: CCC=O
Reactant: CCC#N
Agent: N
Solvent: C=CC#N
Solvent: CC#N
Product: CCCCCCCC#N
Product: COc1ccc(C#N)cc1

Procedure:
In a Group 1 process, propanal is converted into a mixture containing some propionitrile and acrylonitrile together with acetonitrile, aldehydes, and other by-products by a reaction with gaseous ammonia and air at 460° C. over Sn/Sb oxide catalyst (M. Cathala, et al., Bull. Soc. chim. France, 1979, pp. 173-178). In another example (R. J. Card and J. L. Schmitt, J. Org. Chem., 1981, vol. 46, pp. 754-757), benzonitrile, p-methoxybenzonitrile, and octanenitrile are obtained in good yields by passing a stream of gaseous ammonia containing 5 mol % of the corresponding aldehyde through a catalyst bed (3 cm of Cu/alumina) at 325° C. According to Brit. Pat. 709,337, acrolein is converted into acrylonitrile in a gas phase reaction with air/ammonia/steam/ nitrogen mixture over molybdenum catalysts at 285-445° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]1[C:11]([Cl:27])=[N:12][C:13]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)=[N:14][C:15]=1[CH3:16]>CN(C)C=O>[ClH:27].[CH3:9][C:10]1[C:11]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)=[N:12][C:13]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)=[N:14][C:15]=1[CH3:16]
Reactant: Cc1nc(N2CCc3ccccc3C2)nc(Cl)c1C
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Product: Cc1nc(N2CCc3ccccc3C2)nc(Nc2ccc(F)cc2)c1C
Product: Cl
Yield: 67.1 %

Procedure:
After 4-fluoroaniline(0.24 ml, 2.5 mmol) was added to a mixture solution of 5,6-dimethyl-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)-4-chloropyrimidine(0.33 g, 1.2 mmol) and dimethylformamide(10 ml), 0.31 g of the titled compound was obtained in accordance with the same procedure as in Step 4 of Example 57.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]=[CH:10][N+:11]([O-:13])=[O:12])[C:4]=1[OH:14].[C:15]([O-])(=[O:17])[CH3:16].[Na+]>C(OC(=O)C)(=O)C.C(O)C>[C:15]([O:14][C:4]1[C:5]([CH:9]=[CH:10][N+:11]([O-:13])=[O:12])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])(=[O:17])[CH3:16]
Reactant: CC(=O)[O-]
Reactant: COc1cccc(C=C[N+](=O)[O-])c1O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: COc1cccc(C=C[N+](=O)[O-])c1OC(C)=O
Temperature: 0 °C

Procedure:
A mixture of 2-methoxy-6-(2-nitrovinyl)phenol (29.0 grams, 0.15 mole) and sodium acetate (12.4 grams, 0.15 mole) in acetic anhydride (100 ml.) was refluxed for 4 hours and then poured into ice water. The resulting semi-solid precipitate was dissolved in hot 95% ethanol. Cooling the solution precipitated the crude product which was purified for analysis by chromatography on silica gel with methylene chloride as elutant. The purified 2-methoxy-6-(2-nitrovinyl)phenyl acetate melted at 128° C.-129° C.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[C:10]4[S:30][CH:29]=[CH:28][C:11]=4[C:12]([NH:16][C:17]4[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=4)[C:20]([O:22]CC)=[O:21])=[N:13][C:14]=3[CH:15]=2)=[N:4][N:3]=[N:2]1.C1COCC1.[OH-].[Li+].Cl>O.CO>[NH:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[C:10]4[S:30][CH:29]=[CH:28][C:11]=4[C:12]([NH:16][C:17]4[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=4)[C:20]([OH:22])=[O:21])=[N:13][C:14]=3[CH:15]=2)=[N:4][N:3]=[N:2]1
Reactant: CCOC(=O)c1cccc(Nc2nc3cc(-c4nnn[nH]4)ccc3c3sccc23)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(Nc2nc3cc(-c4nnn[nH]4)ccc3c3sccc23)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
ethyl 3-(7-(1H-tetrazol-5-yl)thieno[3,2-c]quinolin-4-ylamino)benzoate (1.0 eq, 7.6 mg, 0.018 mmol) was suspended in a 1:1:1 mixture of THF, MeOH and water. Lithium Hydroxide was added (40 mg, 1.66 mmol) and the mixture stirred at room temperature for one hour. Water and hydrochloric acid were added and the resulting solid filtered and dried to afford 3-(7-(1H-tetrazol-5-yl)thieno[3,2-c]quinolin-4-ylamino)benzoic acid as a solid. LCMS (ES): 95% pure, m/z 389 [M+1]+.