Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[C:12]([CH2:24][CH:25]([CH3:27])[CH3:26])=[N+:13]([O-:23])[C:14]([O:21][CH3:22])=[C:15]([C:17]([O:19]C)=[O:18])[N:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.O>[CH2:3]([O:10][C:11]1[N:16]=[C:15]([C:17]([OH:19])=[O:18])[C:14]([O:21][CH3:22])=[N+:13]([O-:23])[C:12]=1[CH2:24][CH:25]([CH3:27])[CH3:26])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1nc(OCc2ccccc2)c(CC(C)C)[n+]([O-])c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1c(C(=O)O)nc(OCc2ccccc2)c(CC(C)C)[n+]1[O-]
Temperature: 25 °C
Reaction time: 14 h
Yield: 91 %

Procedure:
4.1 Milliliters of 1N sodium hydroxide was added to a solution of 0.71 g of 3-benzyloxy-2-isobutyl-6-methoxy-5-methoxycarbonylpyrazine 1-oxide dissolved in 15 ml of methanol, then the mixture was stirred for 14 hours at room temperature. The reaction mixture was diluted with water, and then extracted with dichloromethane. The aqueous layer was made acidic with 6.0 ml of 1N hydrochloric acid with ice cooling, then extracted with ethyl acetate. The extract was washed with an aqueous solution saturated with NaCl twice and dried over magnesium sulfate. The solvent was removed by evaporation to obtain 0.62 g of 6-benzyloxy-5-isobutyl-3-methoxypyrazine-2-carboxylic acid 4-oxide (Compound B-22).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH:10]=O)[C:6]=2[CH:12]=1.[CH2:13]([O:15][C:16](=[O:28])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26])[CH3:14].[BH4-].[Na+].O>CC1C=CC=CC=1C.O1CCOCC1.CO>[CH2:13]([O:15][C:16](=[O:28])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH2:10][C:7]2[C:6]3[CH:12]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:9][CH:8]=2)=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26])[CH3:14]
Reactant: CCOC(=O)Nc1ccc(N)cc1[N+](=O)[O-]
Reactant: O=Cc1coc2ccc(F)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)Nc1ccc(NCc2coc3ccc(F)cc23)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
In a 3-necked round bottomed flask fitted with a Dean-Stark apparatus 5-Fluoro-benzofuran-3-carbaldehyde (3.59 g, 21.9 mmol) and (4-amino-2-nitro-phenyl)-carbamic acid ethyl ester (4.48 g, 19.9 mmol) were mixed in o-xylene (80 mL) and a catalytic amount of acidic ion exchange resin (Amberlite IRC-84, 100 mg) was added. The mixture was heated to reflux for 5 hours, filtered warm and concentrated in vacuo. This crude product was dissolved in a dioxane:methanol (4:1) mixture (90 mL) and sodiumborohydride (1.50 g, 39.8 mmol) was added portionwise over a period of 30 minutes. The reaction mixture was stirred at ambient temperature over night, then poured into water (200 mL) and extracted with ethyl acetate (3×75 mL). The combined organic fractions were washed with brine, dried (MgSO4) and evaporated to give a crude solid which was purified by chromatography on silica gel (eluent:ethyl acetate:heptane 1:2). This furnished 4.50 g (61%) of the title compound as a red crystalline material. 1H NMR (CDCl3): 1.33 (t, 3H); 4.07 (t, 1H); 4.23 (q, 2H); 4.42 (d, 2H); 6.99 (dd, 1H); 7.05 (dt, 1H); 7.25 (dd, 1H); 7.42 (t, 1H); 7.44 (d, 1H); 7.65 (s, 1H); 8.31 (d, 1H); 9.39 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[CH:29][NH:30]2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[CH:29][NH:30]2)=[CH:26][CH:25]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Reactant: Oc1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4cc[nH]c4c3)ncnc2cc1OCCCN1CCCC1
Temperature: 95 °C
Yield: 69.4 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (100 mg, 0.31 mmol), (prepared as described for the starting material in Example 9), 6-hydroxyindole (50 mg, 0.37 mmol) and potassium carbonate (64 mg, 0.466 mmol) in DMF (1 ml) was heated at 95° C. for 4 hours. After cooling, the mixture was diluted with methylene chloride and poured onto a silica column. The product was eluted with methylene chloride, followed by methylene chloride/methanol (80/20 followed by 70/30 and 50/50). After removal of the solvent by evaporation, the precipitate was triturated with ether, filtered and dried under vacuum to give 6-methoxy-4-(indol-6-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (90 mg, 69%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:15]([O:22][C:23](=[O:29])[C@@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>O1CCCC1>[CH2:15]([O:22][C:23](=[O:29])[C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:11](=[O:13])[C@H:9]([CH3:10])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: -15 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
N-t-butyloxycarbonyl-L-alanine (3.8 g, 20 m mole), L-proline benzyl ester hydrochloride (5 g, 20.6 m mole) and 1-hydroxy benzotriazole, which is hereinafter referred to as HOBt (2.7 g, 20 m mole) were suspended in tetrahydrofuran, which is hereinafter referred to as THF (50 ml). N,N'-dimethylaminopropylethylcarbodiimide, which is hereinafter referred to as WSC (3.8 ml) in THF (10 ml) solution was added dropwisely to the above suspended solution while cooling with coolant of -15° C. and stirring. The reaction was carried for 3 hours at a temperature of less than 0° C. and thereafter at room temperature overnight. The solvent was removed by distillation under reduced pressure. The residue was dissolved in ethyl acetate and washed with 1N hydrochloric acid, water, 5% aqueous sodium bicarbonate and water in order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized in ether-n-hexan to give N-t-butyloxycarbonyl-L-alanyl-L-proline benzyl ester (6.7 g, yield: 89%) having melting point of 71° to 72° C. This product gave one spot by thin layer chromatography (developing solvent; chloroform:methanol:acetic acid=95:5:3, colour forming method; spraying with 0.1% ninhydrin and heating).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].C(N(CC)CC)C>C(Cl)Cl>[SH:8][C:4]1[CH:3]=[C:2]([NH:1][C:9](=[O:11])[CH3:10])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(S)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(S)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
3-Aminothiophenol (1.0 g, 7.99 mmol), acetic anhydride (0.83 mL) and triethyl amine (1.7 mL) were dissolved in methylene chloride, and the solution was stirred at room temperature for 2 hours. It was then purified by silica gel chromatography (hexane:ethyl acetate=3:1) to yield the title compound (1.16 g, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[S:29]([C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][C:40]=1[F:41])[N:37](CC1C=CC=C3C=1CN(C(OC(C)(C)C)=O)CC3)[N:36]=[CH:35]2)(=[O:31])=[O:30]>C1COCC1>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:11][N:10]=[CH:9][N:8]=1)[S:29]([C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][C:40]=1[F:41])[NH:37][N:36]=[CH:35]2)(=[O:30])=[O:31]
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(Cn3ncc4cc(S(=O)(=O)Cl)c(F)cc43)c2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3cn[nH]c3cc2F)c(OC)c1
Reaction time: 0.5 h

Procedure:
To a solution of N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5-amine (1.6 g, 6.39 mmol, 1.5 equiv) in THF (32.0 mL) at −78° C. was added LHMDS (10.65 mL, 10.65 mmol, 2.5 equiv) and the system was stirred for 30 min followed by the slow addition of 6-fluoro-1H-indazole-5-sulfonyl chloride (1-4, 1.0 g, 4.26 mmol, 1.0 equiv) in THF (10.65 mL) and stirred overnight as the system approached ambient temperature. The reaction was quenched with ammonium chloride and extracted with EtOAc. The organic phase was dried over Na2SO4, filtered and concentrated and the residue was purified by normal phase chromatography and used directly in the next step.
Reaction SMILES: [C:1]([O-:4])([O-])=[O:2].[Na+].[Na+].C[C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][CH:15]=[N:16][C:9]=12.[O-][Mn](=O)(=O)=O.[K+]>O>[N:16]1[C:9]2[C:10](=[N:11][CH:12]=[CH:13][C:8]=2[C:1]([OH:4])=[O:2])[NH:14][CH:15]=1
Reactant: Cc1ccnc2[nH]cnc12
Reactant: O=C([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccnc2[nH]cnc12
Temperature: 55 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Na2CO3 (3.3 g, 1 eq, 31.5 mmol) and water (200 ml) are added to product 7-methyl-3H-imidazo[4,5-b]pyridine x176 (4.2 g, 31.5 mmol). The reaction mixture is heated until boiled, which caused its transformation into a solution. KMnO4 (12.5 g, 2.5 eq, 78.9 mmol) is added in small portions to the obtained boiling solution. After KMnO4 is added completely, the reaction mixture is additionally kept at 100° C. for 1 h and cooled to 50-60° C. MnO2 is filtered off, and the residue is additionally washed with hot water (2×50 ml) on a filter. The obtained aqueous solution is evaporated in vacuum to a volume of 50 ml, cooled to 5° C., and acidified with 10% HCl to pH 2-3. The obtained suspension is kept at 5° C. for 1 h. The formed precipitate is separated by filtration, washed with ice-cold water (2×10 ml), and vacuum-dried (1 mm Hg) over P2O5 overnight to give 2.06 g of 3H-imidazo[4,5-b]pyridine-7-carboxylic acid x177.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:38][C:39]1[CH:47]=[C:46]2[C:42]([CH:43]=[N:44][NH:45]2)=[CH:41][C:40]=1[C:48](O)=[O:49].C(=O)([O-])O.[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:38][C:39]1[CH:47]=[C:46]2[C:42]([CH:43]=[N:44][NH:45]2)=[CH:41][C:40]=1[C:48]([NH:8][CH:5]1[CH2:6][CH2:7][O:2][CH2:3][CH2:4]1)=[O:49]
Reactant: NC1CCOCC1
Reactant: Cc1cc2[nH]ncc2cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc2[nH]ncc2cc1C(=O)NC1CCOCC1
Reaction time: 8 h
Yield: 91.3 %

Procedure:
Tetrahydro-2H-pyran-4-ylamine monohydrochloride (0.0402 g, 0.292 mmol), triethylamine (0.07 ml, 0.5 mmol), 1-hydroxybenztriazole (0.0460 g, 0.340 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide monohydrochloride (0.0606 g, 0.316 mmol) were added to a solution of 6-methyl-1H-indazole-5-carboxylic acid (0.0437 g, 0.248 mmol) in N,N-dimethylformamide (2 ml) and stirred overnight. A saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with chloroform (×3), and the extract solution was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, followed by replacement with toluene (three times), whereby a solid was precipitated. The solid obtained was suspended in ethyl acetate and stirred to be washed, and then it was collected by filtration and dried under reduced pressure to obtain 6-methyl-N-tetrahydro-2H-pyran-4-yl-1H-indazole-5-carboxamide (0.0587 g, 91%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[C:5]([C:7]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=O.C(=O)([O-])[O-].[K+].[K+].Br[CH:34](C(OCC)=O)[C:35]([O:37]CC)=[O:36]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[C:7]3[C:8](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:16][CH3:17])[CH:15]=3)[C:9](=[O:10])[O:11][C:34]=2[C:35]([OH:37])=[O:36])[CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24]
Reactant: COc1cc(C(=O)O)c(C(=O)c2cc(Br)c(OC)c(OC)c2)cc1OC
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(-c3cc(Br)c(OC)c(OC)c3)c(C(=O)O)oc(=O)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.7 %

Procedure:
To a solution of 2-(3-bromo-4,5-dimethoxybenzoyl)-4,5-dimethoxy-benzoic acid (6 g) in dimethylformamide (110 ml) are added potassium carbonate (4.29 g) and diethyl bromomalonate (3.71 g), and the mixture is stirred at room temperature overnight. The reaction mixture is evaporated to remove dimethylformamide, and to the residue are added ethyl acetate and water. The ethyl acetate layer is separated, washed, dried, and concentrated under reduced pressure. To the residue are added dioxane (35 ml) and conc. hydrochloric acid (35 ml), and the mixture is heated under reflux for five hours. The reaction mixture is cooled, and thereto are added chloroform and water. The chloroform layer is separated, washed, dried, and concentrated under reduced pressure. The residue is crystallized from ether to give 4-(3-bromo-4,5-dimethoxyphenyl)-6,7-dimethoxyisocoumarin-3-carboxylic acid (2.54 g) as listed in Table 58.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1>[Pd].C1COCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(C=Cc1ccc(O)cc1)c1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(CCc1ccc(O)cc1)c1ccccc1

Procedure:
The title compound was prepared as described in General Method 3 from 3-(4-hydroxy-phenyl)-1-phenyl-prop-2-en-1-one (25.5 g, 113.6 mmol), 5% Pd on BaSO4 (1.0 g), and THF (400 mL). The catalyst was filtered, and the filtrate was concentrated. The residue was recrystallized from 50% EtOH, to give the title compound, m.p. 118-119° C.
Reaction SMILES: CNC(=O)C1C=CC=C([C:10]2[CH:15]=[CH:14][C:13]([O:16][C@@H:17]3[C@@H:22]([OH:23])[C@@H:21]([OH:24])[C@H:20]([OH:25])[C@@H:19]([CH2:26][OH:27])[O:18]3)=[C:12]([CH3:28])[CH:11]=2)C=1.C(O[C@@H]1[C@@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H](OC2C=CC(Br)=CC=2C)[C@H]1CC([O-])=O)(=O)C.[CH3:62][O:63][C:64]([C:66]1[CH:67]=[C:68](B(O)O)[CH:69]=[CH:70][CH:71]=1)=[O:65]>>[CH3:28][C:12]1[CH:11]=[C:10]([C:68]2[CH:67]=[C:66]([CH:71]=[CH:70][CH:69]=2)[C:64]([O:63][CH3:62])=[O:65])[CH:15]=[CH:14][C:13]=1[O:16][C@@H:17]1[C@@H:22]([OH:23])[C@@H:21]([OH:24])[C@H:20]([OH:25])[C@@H:19]([CH2:26][OH:27])[O:18]1
Reactant: CNC(=O)c1cccc(-c2ccc(O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)c(C)c2)c1
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: CC(=O)OC[C@H]1O[C@H](Oc2ccc(Br)cc2C)[C@@H](CC(=O)[O-])[C@H](OC(C)=O)[C@H]1OC(C)=O
Product: COC(=O)c1cccc(-c2ccc(O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)c(C)c2)c1
Yield: 54 %

Procedure:
4c was prepared using the same procedure as for 5b with [(2R,3S,4S,5R,6R)-4,5-diacetoxy-6-(acetoxymethyl)-2-(4-bromo-2-methyl-phenoxy)tetrahydropyran-3-yl]acetate and 3-methoxycarbonylphenyl boronic acid as the reactants. Yield: 54%. 1H NMR (300 MHz, METHANOL-d4) δ ppm 8.20 (t, J=1.51 Hz, 1H), 7.94 (td, J=1.41, 7.90 Hz, 1H), 7.77-7.87 (m, 1H), 7.52 (t, J=7.55 Hz, 1H), 7.39-7.48 (m, 2H), 7.27-7.38 (m, 1H), 5.56 (d, J=1.65 Hz, 1H), 4.08 (dd, J=1.92, 3.30 Hz, 1H), 3.94-4.01 (m, 1H), 3.90-3.94 (m, 3H), 3.68-3.83 (m, 3H), 3.55-3.65 (m, 1H), 2.31 (s, 3H). MS (ESI): found [M+Na]+, 427.1
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([N:21]=[C:22]([N:25]([CH3:34])[N:26]=CC1C=CC=CC=1)SC)#[N:20].Cl>CC(C)=O>[CH3:34][N:25]1[C:22]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:16]=[CH:17][CH:18]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)=[N:21][C:19]([NH2:20])=[N:26]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CSC(=NC#N)N(C)N=Cc1ccccc1
Agent: Cl
Solvent: CC(C)=O
Product: Cn1nc(N)nc1NCCCOc1cccc(CN2CCCCC2)c1
Yield: 28.5 %

Procedure:
3-[3-[1-Piperidinylmethyl]phenoxy]propanamine (2.48 g) and N-cyano-1-methyl-2-(phenylmethylene)hydrazine carboximidothioic acid, methyl ester (2.32 g) were heated at 70° under water-pump vacuum for 4 hr. Acetone was added and the solution was treated with dilute hydrochloric acid for 1 hr, washed with ether, basified and extracted with ethyl acetate. Evaporation of the ethyl acetate extracts gave an oil which crystallised from toluene/ether to give the title compound as a white solid (0.98 g) m.p. 94°-5°. TLC silica, methanol/0.88 ammonia 80:1, Rf 0.5.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:6]=[CH:7][N:8]=1.[H-].[Na+].Cl[CH2:23][C:24]1[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[F:38])[O:27][CH:28]=1.O>CN(C=O)C>[F:38][C:32]1[CH:33]=[C:34]([F:37])[CH:35]=[CH:36][C:31]=1/[CH:30]=[CH:29]/[C:26]1[O:27][CH:28]=[C:24]([CH2:23][O:19][C:16]2[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][N:5]3[CH:6]=[CH:7][N:8]=[C:4]3[CH2:3][CH2:2][OH:1])=[CH:18][CH:17]=2)[N:25]=1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)c(F)c1
Reactant: OCCc1nccn1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(F)cc3F)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
To a solution of 4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl ]butyl]phenol (260 mg) in DMF (4 ml), 60% oily sodium hydride (44 mg) was added under ice cooling. After stirring at room temperature for 30 minutes, (E)-4-chloromethyl-2-[2-(2,4-difluorophenyl) ethenyl]oxazole (281 mg) was added under ice cooling. After stirring at room temperature for 3 days, water was added under ice cooling. The precipitate was collected by filtration and washed with water. The precipitate was dissolved in a mixture of ethyl acetate-THF and dried over magnesium sulfate, after which it was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to yield the titled compound (275 mg) as pale-yellow crystals.
Reaction SMILES: Cl.C[O:3][C:4](=O)[C:5]1[C:6](=[CH:8][CH:9]=[C:10]([CH:12]([OH:26])[CH2:13][NH:14][C:15]([CH3:25])([CH3:24])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1)[OH:7].C(=O)(O)[O-].[Na+].[OH-].[NH4+:34]>CO>[OH:26][CH:12]([C:10]1[CH:11]=[C:5]([C:4]([NH2:34])=[O:3])[C:6]([OH:7])=[CH:8][CH:9]=1)[CH2:13][NH:14][C:15]([CH3:25])([CH3:24])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cc(C(O)CNC(C)(C)CCc2ccccc2)ccc1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)(CCc1ccccc1)NCC(O)c1ccc(O)c(C(N)=O)c1
Reaction time: 48 h
Yield: 63 %

Procedure:
A solution of the above hydrochloride (0.6 g) in methanol (10 ml) and ammonium hydroxide (d. 0.880; 10 ml) was allowed to stand at room temperature for 48 hours. On evaporation, a residue was obtained which was neutralised with sodium bicarbonate solution and extracted with ethyl acetate. When dried and evaporated, the solution gave the amide as a white solid, m.p. 154° (63% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH:14]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CN1CCCCC1=O
Product: CN1CC=C(c2c[nH]c3ccc(Br)cc23)CC1
Yield: 100.1 %

Procedure:
Following the procedure described in detail in Example 1, 30.0 gm (0.153 mole) 5-bromoindole and 38 mL (0.306 mole) 1-methylpiperidone were reacted together to prepare 44.6 gm (100%) of the desired compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[CH2:6][CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9][CH2:10][C:4]=2[CH:3]=1.[C:21](Cl)(=O)[C:22]([CH3:25])([CH3:24])[CH3:23]>>[CH3:21][C:22]([C:25]1[O:20][C:19]2[C:2]([N:1]=1)=[CH:3][C:4]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=1[CH:18]=2)([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)c(O)cc2CC1
Reactant: CC(C)(C)C(=O)Cl
Product: CC(C)(C)c1nc2cc3c(cc2o1)CCNCC3

Procedure:
The title compound was prepared as described in General Procedure 2 from 1,1-dimethylethyl 7-amino-8-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate and pivaloyl chloride.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[CH3:7][C:8]([CH3:12])=[CH:9][CH:10]=O>O>[CH3:7][C:8](=[CH:9][CH2:10][CH2:1][C:2](=[CH:3][CH:4]=[O:5])[CH3:6])[CH3:12]
Reactant: CC(C)=CC=O
Reactant: CC(C)=CCO
Solvent: O
Product: CC(C)=CCCC(C)=CC=O

Procedure:
100 parts of 3-methyl-2-buten-1ol is brought to refluxing temperature (140° C) and 100 parts of 3,3-dimethylacrolein in which 2 parts of dibensoyl peroxide has been dissolved is introduced in the course of one hour while stirring. The reaction mixture is then heated for another three hours at 140° C, while the water formed is continuously removed using pentane as entrainer. Working up gives 105 parts of citral. The yield is thus 86% of theory based on 3,3-dimethylacrolein at a conversion of 67%.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:33])=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27]([OH:29])=O.[CH3:34][C:35]1[CH:40]=[C:39]([CH3:41])[N:38]=[C:37]([C:42]2([NH2:45])[CH2:44][CH2:43]2)[N:36]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:41][C:39]1[CH:40]=[C:35]([CH3:34])[N:36]=[C:37]([C:42]2([NH:45][C:27]([C:26]3[C:25]([O:31][CH3:32])=[CH:24][C:23]([CH3:33])=[C:22]([C:3]4[CH:4]=[CH:5][C:6]5[O:10][C:9]([C:11]6[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=6)=[C:8]([C:18]([NH:19][CH3:20])=[O:21])[C:7]=5[C:2]=4[F:1])[CH:30]=3)=[O:29])[CH2:43][CH2:44]2)[N:38]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)c(F)c12
Reactant: Cc1cc(C)nc(C2(N)CC2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5nc(C)cc(C)n5)CC4)c(OC)cc3C)c(F)c12
Reaction time: 8 h

Procedure:
To a mixture of 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (50 mg, 0.11 mmol), crude 1-(4,6-dimethylpyrimidin-2-yl)cyclopropanamine (100 mg) in 2 ml DMF at room temperature was added BOP (100 mg, 0.22 M, 2.0 eq.) and triethyl amine (0.046 ml 0.33 M, 3.0 eq.), and the mixture stirred overnight under an N2 atmosphere. The mixture was poured into crushed ice, and the solid precipitate was filtered and dried. The product obtained was further purified by preparative HPLC. Yield: 15 mg (24%) 1H NMR (400 MHz, CD3OD): δ 7.97-7.94 (m, 2H), 7.89 (s, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.31-7.25 (m, 3H), 7.19 (s, 1H), 7.14 (s, 1H), 4.11 (s, 3H), 2.96 (s, 3H), 2.48 (s, 6H), 2.31 (s, 3H), 1.86-1.83 (m, 2H), 1.55-1.52 (m, 2H). 19F NMR (376.57 MHz, CD3OD) δ −77.40 (TFA), −112.33, −122.75 (CFCl3 as reference).