Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH2:14][O:13][CH2:12][CH2:11][C:10]=2[C:15](OCC)=[O:16])=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:1]([N:4]1[C:8]([C:9]2[CH2:14][O:13][CH2:12][CH2:11][C:10]=2[CH2:15][OH:16])=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccnn2C(C)C)COCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)n1nccc1C1=C(CO)CCOC1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
To a solution of ethyl 5-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydro-2H-pyran-4-carboxylate (600 mg, 2.27 mmol) in THF (10 mL) was added LiAlH4 (1M in THF, 2.72 mL, 2.72 mmol) at −20° C., the reaction was stirred at −20° C. for 30 min, and was quenched with Sat. NH4Cl, the aqueous layer was extracted with EtOAc, the combined organics were washed with brine, dried and concentrated to give crude oil, which was purified by column (Hexanes/EtOAc=100:0 to 20:80) to give (5-(1-isopropyl-1H-pyrazol-5-yl)-3,6-dihydro-2H-pyran-4-yl)methanol (500 mg).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:26][CH3:27])=[N:19][N:20]3[CH:23]([CH3:25])[CH3:24])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][C:29]1[N:33]=[C:32]([CH2:34][C:35](OC)=[O:36])[O:31][N:30]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:26][CH3:27])=[N:19][N:20]3[CH:23]([CH3:24])[CH3:25])=[CH:16][CH:15]=2)[CH2:11][CH2:12][N:13]1[C:35](=[O:36])[CH2:34][C:32]1[O:31][N:30]=[C:29]([CH3:28])[N:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1nn(C(C)C)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc12
Reactant: COC(=O)Cc1nc(C)no1
Product: CCc1nn(C(C)C)c2cc(N3CCN(C(=O)Cc4nc(C)no4)[C@@H](Cc4ccccc4)C3)ccc12
Yield: 64 %

Procedure:
Prepared by the method outlined for Example 275 using 6-((S)-3-benzyl-piperazin-1-yl)-1-isopropyl-3-ethyl-1H-indazole and methyl (3-methyl-1,2,4-oxadiazol-5-yl)acetate as starting materials. Product was obtained as a colorless solid (64%). LC/MS (Method B) 3.95 min, [M+1]+ 487.
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH:8]=[C:7]([CH3:17])[C:6]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)C.C[O-].[Na+]>C1COCC1.CO>[CH3:16][O:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[C:5]([OH:4])=[C:6]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:7]([CH3:17])=[CH:8]2
Reactant: COc1ccc2c(OC(C)=O)c(-c3ccccc3)c(C)cc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(O)c(-c3ccccc3)c(C)cc2c1
Reaction time: 3 h
Yield: 98.2 %

Procedure:
To a solution of 3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl acetate (6) (4.00 g, 13.1 mmol) in THF and MeOH (200 mL, 1:1) was added sodium methoxide (26 mL, 0.5 M solution in MeOH) at room temperature. The reaction mixture was stirred for 3 h under N2. The reaction mixture was concentrated under reduced pressure to afford the crude product, which was purified by SiO2 column chromatography to afford 3.4 g (99%) of compound 7 as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.10 (d, J=8.0 Hz, 1H), 7.54 (dd, J1=12.0 Hz, J2=8.0 Hz, 2H), 7.45 (dd, J1=8.0 Hz, J2=8.0 Hz, 1H), 7.36 (d, J1=4.0 Hz, 2H), 7.23 (s, 1H), 7.10 and 7.08 (dd, J1=8.0 Hz, J2=4.0 Hz, 1H), 7.05 (d, J1=4.0 Hz, 1H), 5.21 (s, 1H), 3.93 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:24]=[CH:23][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:16][C:12]=2[CH:11]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:9][C:10]1[CH:24]=[CH:23][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:16][C:12]=2[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2nc(-c3ccccc3)oc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2nc(-c3ccccc3)oc2c1

Procedure:
N-Bromosuccinimide (25.9 gm) was added to a cold solution of 6-methyl-2-phenylbenzoxazole (30 gm) in carbon tetrachloride (250 ml). Benzoyl peroxide (500 mg) was added and the mixture was heated under reflux for 3 hr. in the presence of u.v. light. The solid residue was filtered off. The filtrate was evaporated down slightly, treated with carbon and allowed to cool. The crystals which were formed were recrystallised from benzene to yield 6-bromomethyl-2-phenylbenzoxazole, m.p. 162° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[CH3:24][C@@H:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC#N>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:32][C@@H:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH3:24])=[C:3]([N+:21]([O-:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: COc1cc2c(Cl)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Solvent: CC#N
Product: COc1cc2c(N[C@H](C)c3ccccc3)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Temperature: 60 °C

Procedure:
A mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-nitroquinoline (for a preparation see Intermediate 18, 2.5 g, 7.5 mmol) and (R)-(+)-alpha-methylbenzylamine (2 eq, 1.82 g, Aldrich) in CH3CN (30 ml) was heated at 60° C. for 2 h. The mixture was extracted with DCM. The organic phase washed with saturated aqueous sodium hydrogen carbonate and dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue taken up in diethyl ether. The precipitate was filtered off and dried under vacuum to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-nitro-N-[(1R)-1-phenylethyl]-4-quinolinamine (2.5 g) which was used without purification in the next step.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH2:10][CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH:14]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccccc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccccc1C1=CCNCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of tert-butyl 4-[2-(trifluoromethyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate (200 mg, 0.61 mmol) in methylene chloride (5 mL) was added trifluoroacetic acid (2.5 mL). After being stirred at room temperature for 45 min, the solution was concentrated to give an oil. MS calculated for C12H12F3N: (M+H) 228; found 228.1.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[C:30]([Si:36]([CH3:39])([CH3:38])Cl)([CH:33]([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C)C=O.CCOC(C)=O>[CH3:38][Si:36]([CH3:39])([C:30]([CH3:32])([CH3:31])[CH:33]([CH3:35])[CH3:34])[O:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)c(O)c1
Reactant: CC(C)C(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)c(O[Si](C)(C)C(C)(C)C(C)C)c1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a solution of 2-hydroxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde (540 mg, 1.67 mmol) in 8 ml N,N-dimethylformamide cooled to 0° C., were added 398 mg (5.85 mol) imidazole and 1.1 ml (5.85 mmol) thexyl-dimethylchlorosilane. The reaction mixture was stirred 50 minutes at 0° C., diluted with AcOEt, washed with water/ice, HCl (1M)/ice and brine and the aqueous layer was extracted with AcOEt. The combined organic layers were dried over Na2SO4 and evaporated. Chromatography (SiO2; AcOEt/heptane) delivered 346 mg (45%) of the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([S:14][CH3:15])[N:11]3[N:16]=[CH:17][CH:18]=[C:10]3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([S:14][CH3:15])[N:11]4[N:16]=[CH:17][CH:18]=[C:10]4[CH:9]=3)[CH:3]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CSc1nc(-c2cccc(Br)c2)cc2ccnn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cccc(-c3cc4ccnn4c(SC)n3)c2)cc1
Yield: 151.1 %

Procedure:
Under an inert gas atmosphere is dissolved 5-(3bromophenyl)-7-methylsulfanyl-pyrazolo-[1,5-c]pyrimidine (compound D3)(0.25 g) and 4-methoxyphenyl boronic acid (0.45 g) in dimethoxyethane. To this solution are added bis-(triphenylphosphine)palladium(II) chloride (0.13 mmol) and an aqueous sodium carbonate solution (2M, 8 ml). The reaction mixture is heated to reflux for 18 h The mixture is diluted with ethyl acetate and filtered over silica gel. The product is partitioned between ethyl acetate and an aqueous solution of sodium bicarbonate (5%), the organic phase is dned over sodium sulfate and the crude product is purified by silica gel flash chromatography. A nearly colorless solid (0.41 g) in 60% yield is obtained,
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6](Cl)=[O:7].N1C(C)=CC=CC=1C.[H][H]>[Pd].C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[CH:6]=[O:7]
Reactant: [H][H]
Reactant: COc1cc(C(=O)Cl)ccc1C
Agent: [Pd]
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: COc1cc(C=O)ccc1C

Procedure:
A mixture of 5.0 g (27.08 mmol) of 3-methoxy-4-methylbenzoyl chloride, 4.0 ml (34.34 mmol) of 2,6-lutidine and 400 mg of 10% palladium on carbon in 40 ml of THF was rapidly stirred under an atmosphere of hydrogen until no more hydrogen was taken up. Filtration and extraction with ethyl acetate gave title compound as a light yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:21][CH:20]=2)=[C:10]([CH:14]=1)[C:11](O)=[O:12])=[O:5])[CH3:2].[NH:37]1[CH2:40][CH:39]([C:41]([O:43][CH3:44])=[O:42])[CH2:38]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:23][CH:24]=2)=[C:10]([CH:14]=1)[C:11]([N:37]1[CH2:40][CH:39]([C:41]([O:43][CH3:44])=[O:42])[CH2:38]1)=[O:12])=[O:5])[CH3:2]
Reactant: COC(=O)C1CNC1
Reactant: CCOC(=O)c1ccc(OCCCc2ccc(OCCCCOc3ccccc3)cc2)c(C(=O)O)c1
Product: CCOC(=O)c1ccc(OCCCc2ccc(OCCCCOc3ccccc3)cc2)c(C(=O)N2CC(C(=O)OC)C2)c1

Procedure:
The compound is prepared in analogy to the process described in Example 6 from 5-(ethoxycarbonyl)-2-{3-[4-(4-phenoxybutoxy)phenyl]propoxy}benzoic acid and methyl 3-azetidinecarboxylate [CAS No. 343238-58-4]. The crude product is immediately reacted further without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:27]([F:30])([F:29])[F:28])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[C:19]([CH3:26])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH:65]1[CH2:69][C:68](=[O:70])[NH:67][CH2:66]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:27]([F:30])([F:28])[F:29])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:65]4[CH2:69][C:68](=[O:70])[NH:67][CH2:66]4)=[O:23])=[C:19]([CH3:26])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)O
Reactant: O=C1CNCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)N1CNC(=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round-bottom flask, was placed 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylbenzoic acid (900 mg, 1.99 mmol, 1.00 equiv), N,N-dimethylformamide (10 mL), HATU (1.1 g, 2.89 mmol, 1.45 equiv), DIEA (770 mg, 5.96 mmol, 2.99 equiv), imidazolidin-4-one hydrochloride (489 mg, 3.99 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at rt. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×20 mL of brine. The resulting organic phase was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/30-1/10). This resulted in 600 mg (58%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylphenyl)carbonyl]imidazolidin-4-one as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH3:10])[C:6]=2[CH:11]=1.[Li+].CC([N-]C(C)C)C.[I:20]CCI.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([I:20])[N:7]([CH3:10])[C:6]=2[CH:11]=1
Reactant: Cn1cnc2ccc(Cl)cc21
Reactant: ICCI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(I)nc2ccc(Cl)cc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A flask charged with a solution of 6-chloro-1-methyl-1H-benzo[d]imidazole (2 g, 12 mmol) in THF (100 mL) was cooled to −78° C. and 1.8M LDA in THF/hexanes/ethylbenzene (9.34 mL, 16.81 mmol) was added dropwise, and the mixture was stirred at −78° C. for 1 h. A solution of 1,2-diiodoethane (3.72 g, 13.2 mmol) in THF (50 mL) was added dropwise and the mixture was stirred at −78° C. for 1 h. Water (0.3 mL) was added followed by silica gel (20 g) and the mixture was concentrated in vacuo. The residue was purified by silica chromatography eluting with EtOAc in heptane (v/v, 10 to 50%) to give 6-chloro-2-iodo-1-methyl-1H-benzo[d]imidazole. 1H NMR (400 MHz, DMSO-d6) 5 ppm 3.76 (s, 3H) 7.19 (dd, J=8.59, 2.02 Hz, 1H) 7.58 (d, J=8.59 Hz, 1H) 7.78 (d, J=2.02 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([OH:10])[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH2:3]1.[CH2:11](Br)[CH:12]=[CH2:13]>>[CH2:13]([O:10][C:2]1([CH3:1])[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH2:7]1)[CH:12]=[CH2:11]
Reactant: CC1=CC(C)(O)CC(C)=C1
Reactant: C=CCBr
Product: C=CCOC1(C)C=C(C)C=C(C)C1

Procedure:
The 5-(4-allyloxy-2,3,6-trimethyl-phenyl)-3-methyl-penta-2,4-diene-1-triphenylphosphonium bromide employed as the starting material can be prepared by the procedure of Example 3. This procedure is carried out by alkylation of 1,3,5-trimethylphenol with allyl bromide to give 1,3,5-trimethyl-phenyl allyl ether (boiling point 76°-80° C./0.05 mmHg), by formylation of the ether obtained to give 4-allyloxy-2,3,6-trimethyl-benzaldehyde (boiling point 90°-102° C./0.15 mmHg), by condensation of the aldehyde obtained with acetone to give 4-(4-allyloxy-2,3,6-trimethyl-phenyl)-but-3-en-1-al (boiling point 135°-138° C./0.05 mmHg), by reaction of the ketone obtained with acetylene to give 5-(4-allyloxy-2,3,6-trimethyl-phenyl)-3-methyl-3-hydroxy-penta-4-en-1-yne, by partial hydrogenation of the tertiary acetylene carbinol obtained to give 5-(4-allyloxy-2,3,6-trimethyl-phenyl)-3-methyl-3-hydroxy-penta-1,4-diene and by reaction of the tertiary ethylene carbinol obtained with triphenylphosphine hydrobromide. There is obtained 5-(4-allyloxy-2,3,6-trimethyl-phenyl)-3-methyl-penta-2,4-diene-triphenylphosphonium bromide which melts at 114°-116° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]#[N:22])=[C:4]([SH:23])[N:3]=1.Br[CH:25]([C:27]1[CH:28]=[C:29]([C:33]([O:35][CH3:36])=[O:34])[CH:30]=[CH:31][CH:32]=1)[CH3:26].C(=O)(O)[O-].[Na+].O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:23][CH:25]([C:27]2[CH:28]=[C:29]([C:33]([O:35][CH3:36])=[O:34])[CH:30]=[CH:31][CH:32]=2)[CH3:26])[C:5]([C:21]#[N:22])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[C:7]=1[C:8]#[N:9]
Reactant: COCCOc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1
Reactant: COC(=O)c1cccc(C(C)Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc(-c2c(C#N)c(N)nc(SC(C)c3cccc(C(=O)OC)c3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
300 mg (0.919 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulfanylpyridine-3,5-dicarbonitrile (Example 15A), 245 mg (1.01 mmol) of methyl 3-(1-bromoethyl)benzenecarboxylate (Example 61A) and 231 mg (2.76 mmol) of sodium bicarbonate were dissolved in 3 ml of DMF and the mixture was stirred at RT overnight. Water was added to the reaction mixture until a clear solution had formed. The solution was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid).
Reaction SMILES: Cl[CH2:2][O:3][CH3:4].CC#N.[Cl:8][C:9]1[CH:10]=[C:11]([OH:19])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(OCC)C>[Cl:8][C:9]1[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[C:11]([O:19][CH2:2][O:3][CH3:4])[CH:10]=1
Reactant: Oc1cc(Cl)cc(C(F)(F)F)c1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CC#N
Product: COCOc1cc(Cl)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
Neat chloro(methoxy)methane (1.8 mL, 23.8 mmol) was added to a MeCN solution (20 mL) of 3-chloro-5-(trifluoromethyl)phenol (3.6 g, 18.3 mmol) and Cs2CO3 and the resulting mixture was stirred at room temperature. After 5 h the resulting mixture was diluted with diethyl ether, filtered and concentrated. The resulting material was filtered through a short pad of silica gel, followed by concentration to yield 1-chloro-3-(methoxymethoxy)-5-(trifluoromethyl)benzene.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([NH2:19])=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[CH:23][CH:22]=1>N1C=CC=CC=1>[CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[NH:19][S:26]([C:24]3[S:25][C:21]([Cl:20])=[CH:22][CH:23]=3)(=[O:28])=[O:27])[N:10]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: Cc1ccc(CNc2ccc3c(N)cccc3n2)o1
Solvent: c1ccncc1
Product: Cc1ccc(CNc2ccc3c(NS(=O)(=O)c4ccc(Cl)s4)cccc3n2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N2-(5-Methyl-furan-2-ylmethyl)-quinoline-2,5-diamine (200 mg, 0.791 mmol) was dissolved in 2 mL pyridine and 5-chlorothiophene-2-sulfonylchloride (175 mg, 0.806 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched by addition of 50 mL water and 1.2 mL acetic acid. The mixture was extracted three times with ethyl acetate (50 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->50:50 gradient). The title compound was obtained as a brown solid (192 mg, 56%), MS: m/e=434.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][C:3]=1[F:11].[C:12](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[CH:9]=[CH:10][C:5]2=[CH:4][C:3]=1[F:11]
Reactant: O=C([O-])[O-]
Reactant: Fc1cc2cc[nH]c2nc1Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccc2cc(F)c(Cl)nc21
Temperature: 70 °C
Yield: 28.4 %

Procedure:
To a solution of 6-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine (4.15 g, 24.33 mmol) in DMF (50 mL), under a nitrogen atmosphere, is added potassium carbonate (6.73 g, 48.66 mmol), followed by methyl iodide (2.27 mL, 36.49 mmol), and reaction heated to 70° C. for 2 h. The reaction is cooled, poured onto brine (ca. 50 mL) and the product extracted with CHCl3 (ca. 2×30 mL). The combined organic extracts are dried over magnesium sulphate, filtered, and concentrated in vacuo to give a brown solid. This is purified by column chromatography on silica, eluting with 0 to 50% DCM in hexane, to give the title compound as a white solid (1.274 g, 6.90 mmol). MS (m/z): 185/187 (M+1).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[C:7]1[S:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([Cl:12])[N:11]=1>O1CCOCC1>[CH2:1]([N:3]([CH2:4][CH3:5])[C:7]1[S:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([Cl:12])[N:11]=1)[CH3:2]
Reactant: O=[N+]([O-])c1sc(Cl)nc1Cl
Reactant: CCNCC
Solvent: C1COCCO1
Product: CCN(CC)c1nc(Cl)c([N+](=O)[O-])s1
Reaction time: 8 h
Yield: 91.6 %

Procedure:
146 g (2 mols) of diethylamine are added dropwise to a solution of 199 g (1 mol) of 2,4-dichloro-5-nitrothiazole in 1 l of dioxane at 20° C. to 30° C. in the course of about 2 hours. After the mixture has been left to stand overnight at room temperature, it is stirred in 8 l of icewater and the precipitate is filtered off, washed with water and dried. 216 g (91.7% of theory) of 2-diethylamino-4-chloro-5-nitrothiazole of melting point 85° C. (from cyclohexane) are obtained.
Reaction SMILES: [NH2:1][CH:2]([CH3:16])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1.Br[CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:28][CH3:29]>CN(C)C=O>[CH3:29][CH2:28][O:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][CH2:19][CH2:18][NH:1][C@@H:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)[CH3:16]
Reactant: CCOc1ccccc1OCCBr
Reactant: COc1ccc(CC(C)N)cc1S(N)(=O)=O
Solvent: CN(C)C=O
Product: CCOc1ccccc1OCCN[C@H](C)Cc1ccc(OC)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
5-(−2-aminopropyl]-2-methoxybenzenesulfonamide (200 g) was dissolved in dimethylformamide (950 ml) and 1-(2-Bromoethoxy)-2-ethoxybenzene (100.3 g) was added. The reaction mixture was heated to 80–85° C. for 4 hours. Dimethylformamide was then distilled off under vacuum. Water (1000 ml) was added to solid residue and the mixture was heated to 80–90° C. under stirring for 2 hours. The mixture was cooled to room temperature. Formed crystals were filtered off and were suspended in water (900 ml). Suspension was heated to 80–90° C. under stirring for 2 hours. Crystals were filtered, washed with water (200 ml) and dried to give tamsulosin base (150 g, 89.8%).
Reaction SMILES: [H][H].[N+:3]([C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1)([O-])=O.[ClH:17]>[Pd].CO>[ClH:17].[NH2:3][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=1
Reactant: CC(=O)COc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(=O)COc1ccc(N)cc1

Procedure:
A stream of hydrogen was passed through a mixture comprising 19.6 g of 1-(4-nitrophenoxy)propan-2-one, 300 ml of methanol, 30 ml of concentrated aqueous hydrochloric acid and 4 g of 10% w/v palladium-on-charcoal at room temperature for 5 hours. At the end of this time, the catalyst was filtered off, and the filtrate was concentrated by evaporation under reduced pressure, to give 20 g of the title compound. This compound was used directly and without further purification in the next step.