Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1)#N.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:22]1CCCC1>>[OH:9][CH:6]1[CH2:7][CH2:8][C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([CH:1]=[O:22])[CH2:4][CH2:5]1
Reactant: C1CCOC1
Reactant: N#CC1(c2ccccc2)CCC(O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: O=CC1(c2ccccc2)CCC(O)CC1

Procedure:
A thus produced 4-cyano-4-phenylcyclohexanol (b) obtained in step (1) is directly reduced, e.g., with lithium aluminum hydride (in a solvent such as tetrahydrofuran) at elevated (reflux) temperature, to give a corresponding 4-hydroxy-1-phenyl-1-cyclohexanecarboxaldehyde (c). This compound is also prepared via the tetrahydropyranyl ether of (b).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7](O)=O)([O-:3])=[O:2].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[SH:23]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]2[S:23][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=2)[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: Nc1ccccc1S
Product: O=[N+]([O-])c1cc(-c2nc3ccccc3s2)cc([N+](=O)[O-])c1
Temperature: 150 °C

Procedure:
3,5-Dinitrobenzoic acid (5.30 g) was mixed with 40 ml polyphosphoric acid and heated to 64° C. o-Aminothiophenol (2.5 ml) was added and reaction maintained to 150° C. over 0.5 hr period. The mixture was quenched with 600 ml ice-water, neutralized with KOH, cooled, and filtered. The product yield was 3.20 g, mp 73.5°-84.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([OH:12])=[O:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH2:13](N(CC)CC)C>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Cl)cc1C(=O)O
Reactant: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cc(Cl)cnc1OC

Procedure:
By the procedure of Example 1, 5-chloro-2-methoxypyridine-3-carboxylic acid [Sarges et al., J. Med. Chem. 19, 709, (1976); 10 g.] was converted to its acid chloride, which was added in one portion to 150 ml. of methanol (slight exotherm), then made basic with triethylamine (approximately 1.1 equivalents). The reaction mixture was evaporated to solids and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was washed with fresh water and then brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield title product [9.75 g., m.p. 79°-81° C., pnmr/CDCl3 /delta (ppm) 3.8 (s, 3H), 4.1 (s, 3H), 8.1 (d, 1H), 8.3 (d, 1H)].
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:13][S:12][C:11]=1[N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])=[O:9])C.Cl>O>[Cl:21][C:17]1[CH:16]=[C:15]([C:14]2[C:10]([C:8]([OH:9])=[O:7])=[C:11]([N:22]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])[S:12][CH:13]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1c(-c2cccc(Cl)c2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1c(-c2cccc(Cl)c2)csc1N1C(=O)c2ccccc2C1=O
Yield: 90 %

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) was added 4-(3-chlorophenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 4 & 5, Part C). The mixture was heated to reflux for 90 minutes, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitated was collected by filtration, washed with water, and dried, affording the desired compound as a white solid in 90% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[O:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)C=1.[C:23]1(CC(Cl)=O)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.[CH3:44][C:45](N(C)C)=[O:46]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:45](=[O:46])[CH2:44][C:25]2[CH:24]=[CH:23][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:5][C:4]=1[O:10][CH2:11][C:12]1[C:19]2[C:20](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:21]=[CH:22][CH:13]=1
Reactant: CC(=O)N(C)C
Reactant: O=C(Cl)Cc1cccc2ccccc12
Reactant: COc1ccc(N)cc1OCCc1ccc2ccccc2c1
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)Cc2ccc3ccccc3c2)cc1OCc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-[4-methoxy-3-(naphthylmethoxy)phenyl]-2-naphthylethanamide (Exemplary Compound 48) was prepared using the same experimental conditions used to prepare Exemplary Compound 52 (Scheme X, above). From 4-methoxy-3-(2-naphthylethoxy)phenylamine (350 mg, 1.25 mmol) and 1-naphthylacetyl chloride (260 mg, 1.25 mmol) in 10 mL of dimethyl acetamide containing triethylamine (1 mL, 7.17 mmol) stirred at room temperature for 16 h., was obtained 370 mg of product in (66%) yield as off white needles after recrystallization from ethyl acetate/hexane: mp 161-163° C. 1H NMR (400 MHz, Me2SO-d6) δ3.69 (s, 3H); 4.11 (s, 2H); 5.45 (s, 2H); 6.93 (d, 1H, J=8.8); 7.18 (dd, 1H, J=2.3, 8.7); 7.46-7.64 (m, 9H); 7.82-8.15 (m, 6H); 10.20 (s, 1H). Anal. Calcd for C30H25NO3: C, 80.51; H, 5.63; N, 3.13. Found: C, 80.38; H, 5.70; N, 3.12.
Reaction SMILES: [CH:1]([C:4]1[C:12]([C:13](=[O:16])[CH2:14][CH3:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[CH2:17]=O.Cl.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>CCOCC.[OH-].[Na+].CCOC(C)=O.CCCCCC>[CH2:20]([NH:27][CH2:15][CH:14]([CH3:17])[C:13]([C:12]1[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12)=[O:16])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccccc1
Reactant: CCC(=O)c1c(C(C)C)nn2ccccc12
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(CNCc1ccccc1)C(=O)c1c(C(C)C)nn2ccccc12
Yield: 9.5 %

Procedure:
To 2-isopropyl-pyrazolo[1,5-a]pyridine (6.80 g, 42.50 mmol) in n-propionic anhydride (15 mL, 97%) at 140° C. was added concentrated H2SO4 (0.5 ml). The mixture was maintained at 140° C. overnight, cooled to room temperature basified with NaOH (aqueous 50%) until pH>11. The aqueous layer was extracted with chloroform (3×100 mL), dried (Na2SO4), filtered and concentrated. The crude product was purified by flash column chromatography (100% hexane, 9:1 hexane:ethyl acetate) to afford 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one (4.81 g, 22.27 mmol, 53%) as a yellow oil. 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one (0.500 g, 2.3 mmol), paraformaldehyde (0.069 g, 2.3 mmol), and benzylamine hydrochloride (0.329 g, 2.3 mmol) were added to a 5-mL round bottom flask. To this ethanolic hydrochloride (1 mL, 1.25% concentrated HCl in ethanol) was added and the mixture was heated to reflux for 16 hours. The mixture was then cooled and diluted with Et2O (5 mL) and 1M NaOH (aq) (10 mL). The aqueous layer was then extracted with Et2O (4×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to afford a dark brown oil. This oil was subjected to flash column chromatography (10% gradient of EtOAc/hexane ranging from 0 to 90%) which afforded 0.073 g (9.5% yield) of 3-(benzylamino)-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:7])=[CH:4][CH:3]=1.[N+:23]([O-])([OH:25])=[O:24]>C(O)(=O)C>[N+:23]([C:22]1[CH:21]=[C:5]([CH:4]=[CH:3][C:2]=1[OH:1])[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:7])([O-:25])=[O:24]
Reactant: CCCCCCCCCCCCOC(=O)c1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCOC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reaction time: 0.33 h
Yield: 95.8 %

Procedure:
A solution of 10 g of dodecyl 4-hydroxybenzoate and 60 ml of acetic acid was heated at 30° to 35° C. and a solution of 2 ml of fuming nitric acid and 10 ml of acetic acid was added dropwise thereto over a 20 minute period with stirring. After the completion of the addition, the mixture was stirred for 1 hour. The crystals deposited in the reaction mixture were collected by filtration, washed with water and recrystallized from ethanol to obtain 11.0 g (yield 95.8%) of the desired compound having a melting point of 70° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[CH:13])=[CH:9][CH:10]=2)[NH:5][CH:4]([O:14][CH:15]([CH3:17])[CH3:16])[CH2:3]1.[Li+].[OH-:20].[CH3:21][OH:22]>O1CCCC1>[CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][C:6]3[CH:11]=[CH:10][C:9]([C:21]([OH:22])=[O:20])=[CH:8][CH:7]=3)=[CH:9][CH:10]=2)[N:5]=[C:4]([O:14][CH:15]([CH3:16])[CH3:17])[CH2:3]1
Reactant: [OH-]
Reactant: C#Cc1ccc2c(c1)NC(OC(C)C)CC2(C)C
Reactant: CO
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)OC1=Nc2cc(C#Cc3ccc(C(=O)O)cc3)ccc2C(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.0586 g (0.15 mmol) of 4,4-dimethyl-2-iso-propoxy-1,2,3,4-tetrahydro-7-ethynylquinoline (Compound 27) in 3.0 ml of tetrahydrofuran were added 1.0 ml (1.1 mmol) of 1.1M aqueous LiOH and 1.0 ml of methanol. The resulting solution was stirred at room temperature for 2 h. The reaction mixture was then concentrated and water was added to the residue. The aqueous layer was acidified to pH=1 with 10% HCl, and extracted with diethyl ether (2×). The organic layers were dried (MgSO4), filtered and concentrated to give the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]([C@H:4]1[CH2:8][CH2:7][C@@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[N:5]1C(OC(C)(C)C)=O)=[O:3].C([Cl:33])(=O)C>C(OCC)(=O)C.CO>[ClH:33].[C:17]1([CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([C@H:6]3[NH:5][C@@H:4]([C:2]([NH2:1])=[O:3])[CH2:8][CH2:7]3)=[CH:10][CH:11]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1[C@@H](C(N)=O)CC[C@H]1c1ccc(OCc2ccccc2)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cl
Product: NC(=O)[C@H]1CC[C@@H](c2ccc(OCc3ccccc3)cc2)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
To a solution of 1,1-dimethylethyl (2R,5S)-2-(aminocarbonyl)-5-{4-[(phenylmethyl)oxy]phenyl}-1-pyrrolidinecarboxylate (D38, 50 mg, 0.126 mmol) in a mixture of ethyl acetate (0.9 ml) and methanol (0.1 ml) was added acetylchloride (50 μl, 0.63 mmol) at 0° C. The mixture was shaken for 2 h and slowly allowed to warm to room temperature. After evaporating the solvent, the residue was triturated with diethyl ether to afford the title compound as a white solid (35 mg, 85%); Rt (HPLC): 3.55 min; MS: (ES/+) m/z: 297 [MH+], C18H20N2O2 requires 296; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.50 (bs, 1H); 8.15 (bs, 1H); 8.05 (s, 1H); 7.73 (s, 1H); 7.42-7.49 (m, 4H); 7.40 (t, 2H); 7.30-7.36 (m, 1H); 7.08 (d, 2H); 5.15 (s, 2H); 4.60 (dd, 1H); 4.30 (dd, 1H); 2.23-2.40 (m, 2H); 2.10-2.20 (m, 1H); 1.95-2.08 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([OH:17])=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[C:23]#[N:24]>>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:17][CH2:19][C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)[C:23]#[N:24])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(N2CCCC2)c2ccc(O)cc2n1
Reactant: N#Cc1cccc(CBr)c1
Product: Cc1cc(N2CCCC2)c2ccc(OCc3cccc(C#N)c3)cc2n1

Procedure:
In analogy to example 6 there was prepared: on reaction of 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 3-bromomethyl benzonitrile, whereby the product was isolated as free base, 3-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile as a yellow solid. ISP mass spectrum, m/e: 344.4 (M+1 calculated for C22H21N3O: 344).
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:7]([NH2:8])[CH2:6][CH2:5][O:4][CH2:3]1.CCN(C(C)C)C(C)C.[Cl:18][C:19]1[N:24]=[C:23](Cl)[C:22]([N+:26]([O-:28])=[O:27])=[CH:21][N:20]=1>C1COCC1.CCOC(C)=O>[Cl:18][C:19]1[N:24]=[C:23]([NH:8][C@H:7]2[CH2:6][CH2:5][O:4][CH2:3][C@H:2]2[CH3:1])[C:22]([N+:26]([O-:28])=[O:27])=[CH:21][N:20]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: C[C@@H]1COCC[C@@H]1N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@@H]1COCC[C@@H]1Nc1nc(Cl)ncc1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
To a suspension of 0.24 g of the hydrochloride salt of cis-3-methyl-tetrahydro-2H-pyran-4-amine (WO 2004/041161) and DIEA (1.5 mL) in THF (10 mL) at −78° C. was added 2,4-dichloro-5-nitropyrimidine (0.72 g). The mixture was allowed to slowly reach room temperature and stirred for 16 hours. The mixture was diluted with EtOAc and washed 3 times with brine. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo. Column chromatography (20→40% EtOAc/hexanes) provided 289 mg of the title compound.
Reaction SMILES: [C:1]([CH:4]=[N:5][C:6]([O:8][Si:9]([CH3:12])([CH3:11])[CH3:10])=[CH2:7])([CH3:3])=[CH2:2].[Br:13][C:14]1[CH:22]=[C:21]2[C:17](/[C:18](=[CH:32]/[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=3)/[C:19](=[O:31])[N:20]2[CH2:23][O:24][CH2:25][CH2:26][Si](C)(C)C)=[CH:16][CH:15]=1.CO>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:22]=[C:21]2[NH:20][C:19](=[O:31])[C:18]3([CH:32]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[CH:34]=4)[CH2:7][C:6](=[O:8])[NH:5][CH:4]3[C:1]([CH3:3])=[CH2:2])[C:17]2=[CH:16][CH:15]=1.[CH3:23][O:24][CH:25]([Si:9]([CH3:10])([CH3:11])[CH3:12])[CH3:26]
Reactant: C=C(C)C=NC(=C)O[Si](C)(C)C
Reactant: C[Si](C)(C)CCOCN1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Br)cc21
Solvent: CO
Solvent: Cc1ccccc1
Product: C=C(C)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Br)ccc12
Product: COC(C)[Si](C)(C)C
Temperature: 25 °C
Yield: 33.6 %

Procedure:
To a solution of 1-isopropenyl-3-trimethylsilyoxy-2-aza-1,3-butadiene (13 mmol) prepared in Example 87a in toluene was added E/Z-6-bromo-3-(3-chloro-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one prepared in Example 161a (1.0 g, 2.16 mmol). The reaction mixture was refluxed under Argon for overnight. The mixture was cooled to room temperature, methanol (30 mL) was added, and then the mixture was concentrated. The residue was purified by chromatography (CH2Cl2:CH3OH=50:1) to give crude product (0.42 g).
Reaction SMILES: N1C=[CH:5][C:4]([CH:7]=[C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([C:17]4[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=4)[CH:15]=3)[NH:10][C:9]2=[O:29])=[CH:3][CH:2]=1.[CH:30]([O-])=O.[NH4+:33]>CO.[Pd]>[N:33]1[CH:30]=[CH:2][CH:3]=[C:4]([CH2:7][CH:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([C:17]4[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=4)[CH:15]=3)[NH:10][C:9]2=[O:29])[CH:5]=1
Reactant: O=C[O-]
Reactant: COc1cc(-c2cnc3c(c2)C(=Cc2ccncc2)C(=O)N3)cc(OC)c1OC
Reactant: [NH4+]
Agent: [Pd]
Solvent: CO
Product: COc1cc(-c2cnc3c(c2)C(Cc2cccnc2)C(=O)N3)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.9 %

Procedure:
To a solution of 3-pyridin-4-ylmethylene-5-(3,4,5-trimethoxy-phenyl)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (50 mg, 0.128 mmol) in MeOH (4 ml) was added ammonium formate (245 mg, 3.85 mmol) and Pd/C (10%, 30 mg). The mixture was stirred at room temperature for 3 hrs after which it was filtered, evaporated, and partitioned between water and DCM. The title compound (33 mg, 66%) was obtained after silica gel chromatography eluting with 0-10% MeOH:DCM. 1H NMR (CDCl3, 300 MHz): δ 10.05 (s, 1H), 8.60 (d, J=2.6 Hz, 1H), 8.45 (d, J=1.1 Hz, 1H), 8.38 (d, J=1.2 Hz, 1H), 7.62 (d, J=4.7 Hz, 1H), 7.35 (dd, J=2.9, 4.7 Hz, 1H), 6.53 (d, J=1.2 Hz, 1H), 6.38 (s, 1H), 3.95 (m, 1H), 3.90 (m, 1H), 3.85 (s, 6H), 3.84 (s, 3H), 3.84 (m, 1H).
Reaction SMILES: [C:1](=[O:4])([O-])O.[K+].[CH3:6][OH:7].[N:8]1[C:15](Cl)=[N:14][C:12](Cl)=[N:11][C:9]=1[Cl:10]>C(OCC)(=O)C>[Cl:10][C:9]1[N:11]=[C:12]([O:7][CH3:6])[N:14]=[C:15]([O:4][CH3:1])[N:8]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: O=C([O-])O
Reactant: CO
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1nc(Cl)nc(OC)n1
Temperature: 10 °C
Yield: 87.5 %

Procedure:
In a 1-liter (1000-ml) four-necked flask equipped with a stirrer and a thermometer, 52.6 g (0.525 mol) of potassium hydrogencarbonate, 80.1 g (5.0 mol, water content: 530 ppm) of methanol and 100 ml of ethyl acetate were placed. With stirring at a temperature of not higher than 10° C., 46.1 g (0.25 mol) of cyanuric chloride was added, followed by stirring at 20° C. for 1 hour. Then, the reaction solution was refluxed at 62° C. for 6 hours. The weight of the reaction solution from which a salt formed had been removed was 202 g, and the water content was 46,300 ppm. Then, 150 ml of ethyl acetate and 200 ml of water were added, followed by liquid separation. The organic layer was washed with 200 ml of water and then vacuum concentrated to obtain 38.4 g of 2-chloro-4,6-dimethoxy-1,3,5-triazine as a white solid. The yield was 87.5%. From the gas chromatography analysis, the purity proved to be 93.8% (% by area).
Reaction SMILES: [Si](OC[C:20]1([C:36]#[N:37])[CH2:24][CH:23]=[CH:22][N:21]1[C:25]1[CH:30]=[CH:29][C:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:27][CH:26]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:56]1CCC[CH2:57]1>>[CH2:34]([O:33][C:31]([C:28]1[CH:27]=[CH:26][C:25]([N:21]2[C:22]([CH2:57][OH:56])=[CH:23][CH:24]=[C:20]2[C:36]#[N:37])=[CH:30][CH:29]=1)=[O:32])[CH3:35]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1ccc(N2C=CCC2(C#N)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CCOC(=O)c1ccc(-n2c(C#N)ccc2CO)cc1

Procedure:
To a solution of 2-tert-butyldiphenylsilyloxymethyl-1-(4-ethoxycarbonylphenyl)pyrrole-2-carbonitrile (1.9 g) in tetrahydrofuran (19 ml) was added tetrabutylammonium fluoride (5.6 ml, 1M tetrahydrofuran solution) through syringe at ambient temperature. The mixture was stirred for half an hour at the same temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with aqueous hydrochloric acid, water and brine, and then dried, and concentrated in vacuo. The oily residue was chromatographed on silica gel (elution by ethyl acetate/n-hexane=1/1) to give 1-(4-ethoxycarbonylphenyl)-5-hydroxymethylpyrrole-2-carbonitrile (702.5 mg) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([NH:20][C:21]([C:23]2[C:31]3[CH:30]=[C:29]([C:32]4[C:37]([Cl:38])=[CH:36][N:35]=[C:34](Cl)[N:33]=4)[S:28][C:27]=3[CH:26]=[CH:25][CH:24]=2)=[O:22])[CH2:19][CH2:18]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][C:34]2[N:33]=[C:32]([C:29]3[S:28][C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([C:21](=[O:22])[NH:20][CH:17]5[CH2:18][CH2:19]5)[C:31]=4[CH:30]=3)[C:37]([Cl:38])=[CH:36][N:35]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Temperature: 25 °C

Procedure:
4-(2-aminoethyl)-piperidine-1-carboxylic acid tert-butyl ester (0.390 g, 1.72 mmol) is added to a stirred suspension of 2-(2,5-dichloro-pyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (0.250 g, 0.686 mmol) and diisopropylethylamine (0.300 mL, 1.72 mmol) in anhydrous 1,4-dioxane (4 mL) at room temperature under nitrogen. The resultant mixture is heated at 95° C. for 12 hours then cooled to room temperature and purified (silica gel chromatography, eluting with 2 M NH3/CH3OH in dichloromethane: 0 to 7%) to give 4-{2-[5-chloro-4-(4-cyclopropylcarbamoyl-benzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[CH:19]1[CH2:25][C:24](=O)[O:23][C:21](=[O:22])[CH2:20]1.[ClH:27]>ClCCl.O1CCOCC1>[ClH:27].[N:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][C:24]=1[CH2:25][CH:19]([C:10]1[CH:11]=[CH:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=1)[CH2:20][C:21]([OH:23])=[O:22]
Reactant: Nc1ccccc1N
Reactant: O=C1CC(c2ccc3ccccc3c2)CC(=O)O1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(O)CC(Cc1nc2ccccc2[nH]1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,2-Phenylenediamine (54 mg) and 3-(2-naphthyl)glutaric anhydride (120 mg) were dissolved in dichloromethane (2 ml) with heating. The solution was stirred at rt for 1 h. The precipitate formed was collected by suction filtration, washed with dichloromethane, and dried to give a mixture of regioisomeric amides (131 mg) as colourless solid. This solid was dissolved in 1,4-dioxane (1 ml) with heating, and 4M HCl in 1,4-dioxane (1 ml) was added. The solution was heated to reflux for 1 h. After removal of the solvent the residue was triturated with acetone to give 4-(2-benzimidazolyl)-3-(2-naphthyl)butanoic acid HCl (100 mg) as colourless solid.
Reaction SMILES: [OH:1][CH:2]([CH:23]=[CH2:24])[CH:3]([NH:9][C:10](=[O:22])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19])[C:4](OCC)=[O:5].[CH3:25][NH2:26]>CO>[OH:1][CH:2]([CH:23]=[CH2:24])[CH:3]([NH:9][C:10](=[O:22])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19])[C:4](=[O:5])[NH:26][CH3:25]
Reactant: CN
Reactant: C=CC(O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C(=O)OCC
Solvent: CO
Product: C=CC(O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C(=O)NC

Procedure:
4.5 g (12.9 mmol) of ethyl 3-hydroxy-2-(4-fluoro-2-trifluoromethylbenzoylamino)pent-4-enoate were dissolved in methanol. With ice cooling methylamine gas was introduced for 2 h. The reaction solution was then concentrated and washed. This gave 3.1 g (80% of theory) of the title compound as a colorless solid (diastereomer ratio 2:1).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[S:10][CH2:9][CH2:8][C:7]2([C:15](N)=[O:16])[OH:14].C([OH:21])(C)C>O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[S:10][CH2:9][CH2:8][C:7]2([C:15]([OH:16])=[O:21])[OH:14]
Reactant: NC(=O)C1(O)CCSc2ccc(Cl)cc21
Reactant: CC(C)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1(O)CCSc2ccc(Cl)cc21

Procedure:
Potassium hydroxide (5.1 g, 91 mmol) and 6-chloro-4-hydroxythiochromane-4-yl-carboxamide (1.36 g, 5.58 mmol; from step (ii) above) were dissolved in water (25 mL) and isopropanol and refluxed for 2 d. The isopropanol was removed under reduced pressure and the aqueous residue was washed with diethyl ether. Acidification with aq. HCl, extraction with ethyl acetate, and then drying and concentration in vacuo afforded the sub-title compound. Yield: 0.87 g (64%).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH3:7].C([Li])CCC.[C:13]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)#N.Cl.C([O:24]CC)C>CCCCCC>[CH3:7][C:6]1[CH:5]=[C:4]([C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[O:24])[O:3][C:2]=1[CH3:1]
Reactant: N#Cc1cccnc1
Reactant: CCOCC
Reactant: Cc1ccoc1C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: Cc1cc(C(=O)c2cccnc2)oc1C
Temperature: 0 °C
Yield: 18 %

Procedure:
2,3-Dimethylfuran (5 g) was dissolved in diethyl ether (75 ml) under an argon atmosphere, a 1.6 M hexane solution (35.7 ml) of n-butyllithium was added dropwise thereto at 0° C., and the mixture was stirred under reflux for 2.5 hr. Thereafter, the reaction solution was cooled to −78° C., a solution of 3-cyanopyridine (6.0 g) in diethyl ether (20 ml) was added dropwise thereto, and the mixture was stirred at room temperature for 3 hr. The reaction solution was poured into ice to stop the reaction solution. The reaction solution was adjusted to pH 5 by the addition of 2 M hydrochloric acid and was extracted with chloroform. The chloroform layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give (4,5-dimethylfuran-2-yl)-(3-pyridyl)-methanone (1.9 g, yield 18%).