Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[C:5]([CH3:11])=[N:4]1)[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:18][C:19]1[CH:20]=[C:21]([CH:38]=[CH:39][C:40]=1[F:41])[O:22][C:23]1[CH:24]=[CH:25][C:26]2[N:27]([CH:29]=[C:30]([NH:32][C:33]([CH:35]3[CH2:37][CH2:36]3)=[O:34])[N:31]=2)[N:28]=1>CN(C)C=O.O1CCCC1.[OH-].[Na+]>[CH:35]1([C:33]([NH:32][C:30]2[N:31]=[C:26]3[CH:25]=[CH:24][C:23]([O:22][C:21]4[CH:38]=[CH:39][C:40]([F:41])=[C:19]([NH:18][C:8]([C:6]5[C:5]([CH3:11])=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=5)=[O:10])[CH:20]=4)=[N:28][N:27]3[CH:29]=2)=[O:34])[CH2:36][CH2:37]1
Reactant: CCn1cc(C(=O)O)c(C)n1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2F)c(C)n1
Yield: 51.6 %

Procedure:
To a solution of 1-ethyl-3-methyl-1H-pyrazole-4-carboxylic acid (2.00 g, 13.0 mmol) and N,N-dimethylformamide (3 drops) in tetrahydrofuran (30 mL) was added oxalyl chloride (2.23 mL, 26.0 mmol) with stirring under ice-cooling, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylacetamide (20 mL) with stirring under ice-cooling, N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (3.27 g, 10.0 mmol) was added thereto, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with 1N aqueous sodium hydroxide solution (50 ml) and extracted with a mixed solvent of ethyl acetate/tetrahydrofuran (1:1, 80 mL, 40 mL×2). The organic layer was washed with water (10 mL×3), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→70/30) and crystallized from ethyl acetate to give the title compound (2.39 g, yield 52%) as a white solid. melting point 199° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1C)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15][O:16][C:17]([C:19]1[CH:24]=[N:23][C:22](Cl)=[CH:21][N:20]=1)=[O:18].[C:26]([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[CH3:15][O:16][C:17]([C:19]1[N:20]=[CH:21][C:22]([N:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:9][C@H:10]2[CH3:26])=[N:23][CH:24]=1)=[O:18]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)C[C@H]2C)cn1
Temperature: 140 °C
Reaction time: 3 h

Procedure:
To (R)-1-boc-methylpiperazine (1 g, 5.0 mmol) in DMF (20 mL) is added 5-chloro-pyrazine-2-carboxylic acid methyl ester (862 mg, 5.0 mmol) and Na2CO3 (2.1 g, 20.0 mmol). The reaction mixture is stirred in a microwave reactor at 140° C. for 3 h. Then the mixture is cooled to rt and the organic solvent is removed in vacuo to afford a brown colored solid as product (1.7 g, quant.).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)[O:14][C:12](=O)[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)=O.[OH2:23]>>[CH3:7][C:6]1[O:23][C:9]([CH3:8])=[CH:10][C:11]=1[CH:12]=[O:14]
Reactant: O
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: Cc1cc(C=O)c(C)o1
Temperature: 0 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
To a solution of (2,5-dimethylfuran-3-yl)methanol (3.8 g) obtained by the above-mentioned reaction in methylene chloride (30 mL) was added a Dess-Martin reagent (15.3 g) at 0° C., and the mixture was stirred at 0° C. for 3 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane) to give the title compound (2.1 g, 56%) as an oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.C([Li])CCC.[CH:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1>[CH3:1][O:2][CH:3]([O:12][CH3:13])[CH2:4][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[C:25]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:26]
Reactant: COC(CNc1ccccn1)OC
Reactant: O=C(Cl)C1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(CN(C(=O)C1CCCCC1)c1ccccn1)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6 g of 2-[(2-pyridyl)amino]acetaldehyde dimethyl acetal (prepared as described in Beilstein E III/IV, 22, 3871) in 40 ml of tetrahydrofuran stirred at 0° C. was added dropwise 13.2 ml of butyl lithium (2.5 M solution in n-hexane) and the resulting mixture was stirred at room temperature for 1 h. Afterwards, to the solution was added dropwise in 5 min 4.46 ml of cyclohexanecarbonyl chloride. Stirring was continued for 5.5h, followed by in vacuo evaporation of the reaction mixture to dryness. The residue was purified by flash chromatography (chloroform-ethyl acetate 7:3) affording 13.3 g of the title compound.
Reaction SMILES: Cl.[CH2:2]([C:6]1[N:7]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[C:8]([CH:11]=[C:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([OH:15])=[O:14])=[CH:9][N:10]=1)[CH2:3][CH2:4][CH3:5].[CH2:28]([Li])CCC>CO.[Pt]=O>[ClH:27].[CH2:2]([C:6]1[N:7]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[C:8]([CH2:11][CH:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([O:15][CH3:28])=[O:14])=[CH:9][N:10]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=Cc1cnc(CCCC)n1Cc1ccccc1Cl)C(=O)O
Reactant: [Li]CCCC
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: CCCCc1ncc(CC(CCCC)C(=O)OC)n1Cc1ccccc1Cl
Yield: 74 %

Procedure:
A mixture of methyl (E and Z)-3-[2-n-butyl-1-{(2chlorophenyl)methyl}-1H-imidazol-5-yl]-2-n-butyl-propenoate hydrochloride salt (prepared by the method in Example 6, replacing methyl lithium with butyl lithium) (245 mg, 0.578 mmol) in methanol (15 mL) and platinum oxide (30 mg) was stirred under an atmosphere of hydrogen for 0.5 hours. The catalyst was filtered, the filtrate was concentrated, and the residue was triturated with diethyl ether to afford 181 mg (74%) of methyl 3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-n-butylpropanoate hydrochloride; mp 123°-125° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]3[C:17]=1[CH:16]=[C:15]([C:18](OCC)=[O:19])[C:14]3=[C:23]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:29][CH:28]=1)[C:24]=2[CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(OCC)C>O1CCCC1>[CH2:1]([O:8][C:9]1[C:17]2[N:13]3[C:12](=[CH:11][CH:10]=1)[C:24]([CH2:25][CH3:26])=[C:23]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:29][CH:28]=1)[C:14]3=[C:15]([CH2:18][OH:19])[CH:16]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)ccc3c(CC)c(-c4ccc(OCc5ccccc5)cc4)c1n23
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCc1c(-c2ccc(OCc3ccccc3)cc2)c2c(CO)cc3c(OCc4ccccc4)ccc1n32
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 7-benzyloxy-3-(4-benzyloxyphenyl)-4-ethylpyrrolo[2,1,5-cd]indolizine-2-carboxylate (15.79 g, 30 mmol) was dissolved in 250 ml of dry tetrahydrofuran under a nitrogen atmosphere. Lithium aluminium hydride (1.8 g, 50 mmol) was added in small portions, and the mixture was stirred at room temperature for 21/2 hours. Water was added until effervescence terminated and solid potassium carbonate was added until a white suspension was formed. Diethyl ether (200 ml) was added and the reaction mixture was stirred vigorously. The reaction mixture was filtered through celite and the organic material was extracted into 3×100 ml of diethyl ether and 3×100 ml of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and the solvent was evaporated. The crude product was recrystallized from hot ethyl acetate and petroleum ether. This gave 13.06 g (89%) of 5-benzyloxy-2-(4-benzyloxyphenyl)-1-ethyl-3-hydroxymethyl-pyrrolo[2,1,5-cd]indolizine as yellow crystals. M.p. 133-134° C. MS(SP): m/z 487 (M+). 1H-NMR (DMSO-d6, 400 MHz) δ: 1.34 (t, 3H); 3.04 (q, 2H); 4.81 (s, 2H); 5.18 (m, 3H); 5.57 (s, 2H); 7.20 (d, 2H); 7.31-7.64 (m, 14H); 7.92 (d, 1H). The structure has been proven by COSY, ROESY and NOESY, 400 MHz.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([CH3:7])([OH:6])[CH3:5].C(N(CC)CC)C.[Cl:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[C:18]([CH2:23][O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[N:17]=1>CO.C(#N)C>[Cl:15][C:16]1[N:21]=[C:20]([NH:2][CH2:3][C:4]([CH3:7])([OH:6])[CH3:5])[CH:19]=[C:18]([CH2:23][O:24][CH2:25][C:26]([F:29])([F:27])[F:28])[N:17]=1
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Reactant: CC(C)(O)CN
Agent: Cl
Solvent: CO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(O)CNc1cc(COCC(F)(F)F)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
1-Amino-2-methylpropan-2-ol hydrochloride (221 mg, 1.76 mmol) was suspended in MeOH (2 mL). Triethylamine (0.147 mL, 1.06 mmol) was added and the suspension was filtered. The filtrate was added to an ice-cold solution of 2,4-dichloro-6-((2,2,2-trifluoroethoxy)methyl)-pyrimidine (92 mg, 0.35 mmol) in acetonitrile (2 mL). The mixture was stirred for 1 h at rt. The mixture was purified by preparative HPLC to give the title compound (35 mg, 32%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([N:13]1[CH2:17][C:16](=[O:18])[NH:15][C:14]1([CH3:20])[CH3:19])=[O:12])=[O:8])=[O:4].[CH:21](=O)[CH:22]([CH3:24])[CH3:23]>CO>[CH3:19][C:14]1([CH3:20])[NH:15][C:16](=[O:18])[CH2:17][N:13]1[C:11](=[O:12])[CH2:10][NH:9][C:7](=[O:8])[CH2:6][N:5]1[C:3](=[O:4])[CH2:2][NH:1][CH:21]1[CH:22]([CH3:24])[CH3:23]
Reactant: CC1(C)NC(=O)CN1C(=O)CNC(=O)CNC(=O)CN
Reactant: CC(C)C=O
Solvent: CO
Product: CC(C)C1NCC(=O)N1CC(=O)NCC(=O)N1CC(=O)NC1(C)C

Procedure:
A solution of 1-[2-[2-(2-aminoacetamido)acetamido]acetyl]-2,2-dimethyl-4-imidazolidinone (0.5 g) and isobutyraldehyde (0.18 ml) in methanol (5 ml) was refluxed for 0.5 hours.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][CH:8]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)[CH2:9][CH3:10].Br[C:21]1[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=1>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:7][CH:8]([C:11]1[CH:16]=[CH:15][C:14]([C:21]2[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: Nc1ncccc1Br
Reactant: CCC(C)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCC(C)c1ccc(-c2cccnc2N)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A mixture of sodium carbonate (412 mg), tetrakis(triphenylphosphine)palladium(0) (112 mg), 4-(1-methylpropyl)phenylboronic acid (450 mg) and 3-bromopyridin-2-amine (336 mg) in 1,2-dimethoxyethane (15 mL) and water (3 mL) was stirred under a nitrogen atmosphere at 80° C. overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (392 mg) as a pale-yellow solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]([N:15]3[C:24]4[N:20]([C:21]([C:25]5[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=5)=[N:22][N:23]=4)[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:31][N:32](C=O)C>[C-]#N.[Zn+2].[C-]#N>[N:28]1[CH:29]=[CH:30][C:25]([C:21]2[N:20]3[C:24]([N:15]([CH:13]([C:10]4[N:11]=[N:12][N:8]([C:4]5[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=5)[C:31]#[N:32])[N:9]=4)[CH3:14])[CH2:16][CH2:17][CH2:18][CH2:19]3)=[N:23][N:22]=2)=[CH:26][CH:27]=1
Reactant: CC(c1nnn(-c2cccc(I)c2)n1)N1CCCCn2c(-c3ccncc3)nnc21
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(c1nnn(-c2cccc(C#N)c2)n1)N1CCCCn2c(-c3ccncc3)nnc21

Procedure:
The title compound is prepared from 8-{1-[2-(3-iodo-phenyl)-2H-tetrazol-5-yl]-ethyl}-3-pyridin-4-yl-5,6,7,8-tetrahydro-4H-1,2,3a,8-tetraaza-azulene (1 mmol), zinc cyanide (1.1 mmol), palladium (0) tetrakis-triphenylphosphine (0.05 mmol) in DMF (5 mL) at 80° C. overnight.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][C:22]3[N:26]=[CH:25][NH:24][N:23]=3)[CH:13]=2)=[O:9])=[N:5][C:4]2[S:27][CH:28]=[C:29]([CH2:30][O:31][CH2:32][C:33]3[CH:43]=[CH:42][C:36]([C:37]([O:39]CC)=[O:38])=[CH:35][CH:34]=3)[C:3]1=2.[OH-].[Na+].C1COCC1.CO>O>[O:1]=[C:2]1[NH:7][C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][C:22]3[N:26]=[CH:25][NH:24][N:23]=3)[CH:13]=2)=[O:9])=[N:5][C:4]2[S:27][CH:28]=[C:29]([CH2:30][O:31][CH2:32][C:33]3[CH:43]=[CH:42][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=3)[C:3]1=2
Reactant: CCOC(=O)c1ccc(COCc2csc3nc(C(=O)NCc4ccnc(OCCCc5nc[nH]n5)c4)[nH]c(=O)c23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(COCc2csc3nc(C(=O)NCc4ccnc(OCCCc5nc[nH]n5)c4)[nH]c(=O)c23)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A mixture of ethyl 4-[({[4-oxo-2-({[(2-{[3-(1H-1,2,4-triazol-3-yl)propyl]oxy}pyridin-4-yl)methyl]amino}carbonyl)-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl]methyl}oxy)methyl]benzoate obtained in Example 41 (309 mg, 0.512 mmol), 4N aqueous sodium hydroxide solution (0.64 mL, 2.6 mmol), THF (6 mL), methanol (6 mL) and water (6 mL) was stirred at 100° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and 1N hydrochloric acid and methanol were added to the residue. The resulting crystals were recrystallized from ethyl acetate to give the title compound as a white powder (221 mg, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:18][CH:19]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]2)[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:10](=[O:11])[NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[CH2:18][CH:19]2[CH2:23][CH2:22][CH:21]([O:24][C:25](=[O:27])[CH3:26])[CH2:20]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Nc1nccs1)C(CC1CCC(O)C1)c1ccc(Cl)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1CCC(CC(C(=O)Nc2nccs2)c2ccc(Cl)c(Cl)c2)C1
Yield: 49.8 %

Procedure:
A solution of 2-(3,4-dichloro-phenyl)-3-(3-hydroxy-cyclopentyl)-N-thiazol-2-yl-propionamide (prepared as in Example 36, 147.8 mg, 0.38 mmol) and acetic anhydride (72 μL, 0.77 mmol) in pyridine (2 mL) and methylene chloride (1 mL) was stirred at 25° C. for 20 h. The resulting reaction mixture was concentrated in vacuo. Since the reaction did not go to completion, the residue was re-dissolved in pyridine (1.8 mL) and acetic anhydride (1.4 mL, 14.84 mmol) and then stirred at 25° C. for an additional 7 h. The reaction mixture was concentrated in vacuo and then diluted with ethyl acetate (50 mL). The organic layer was washed with a 1N aqueous hydrochloric acid solution 3×50 mL), water (50 mL), and a saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 35% ethyl acetate/hexanes) afforded acetic acid 3-[2-(3,4-dichloro-phenyl)-2-(thiazol-2-ylcarbamoyl)-ethyl]-cyclopentyl ester (80.8 mg, 49%) as a white solid: mp 49-52° C.; (ES)+-HRMS m/e calcd for C19H20Cl2N2O3S (M+H)+ 427.0645. found 427.0648.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].Br[CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>O>[C:18]([Si:15]([CH3:17])([CH3:16])[O:14][CH2:13][CH2:12][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[Cl:1])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=Cc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(C=O)cc1Cl
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of 3-chloro-4-hydroxy-benzaldehyde (227 mg, 1.45 mmol), (2-bromoethoxy)-tert-butyldimethylsilane (347 mg, 1.45 mmol), cesium carbonate (709 mg, 2.18 mmol) and DMSO (2 mL) was stirred at 80° C. for 17 h. The reaction mixture was cooled to room temperature and water (50 mL) was added. The resulting precipitate was filtered off, washed with water, air-dried, dissolved in a small amount of ethyl acetate and purified by column chromatography. 4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-3-chlorobenzaldehyde was obtained as a white solid (yield: 267 mg, 58%). To a 100 mL round-bottomed flask was added 2-amino-4,6-dimethoxy-benzamide (166 mg, 0.85 mmol), 4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-3-chlorobenzaldehyde (267 mg, 0.85 mmol), p-toluenesulfonic acid monohydrate (21 mg, 0.11 mmol), sodium hydrogensulfite (216 mg, 1.2 mmol) and dimethylacetamide (5 mL). The mixture was stirred in a 150° C. oil bath under nitrogen for 17 h. After cooling to room temperature, water (50 mL) was added. The precipitate was filtered off, washed with water and air-dried. The crude product was purified by column chromatography to give 2-(3-chloro-4-(2-hydroxyethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (45 mg, 23%). Selected data: MS (ES) m/z: 377.03; MP 287-288° C. (decomposed).
Reaction SMILES: CN(C)C=O.[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C-]#N.[Na+].[C:17](#[N:20])[CH:18]=[CH2:19]>O>[C:6]([CH2:19][CH2:18][C:17]#[N:20])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=CC#N
Reactant: O=Cc1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCC(=O)c1ccccc1
Temperature: 30 °C
Reaction time: 0.25 h

Procedure:
320 ml of absolute dimethylformamide, 42.5 g (0.4 mol) of freshly distilled benzaldehyde and 9.8 g (0.2 mol) of sodium cyanide are introduced into a 500 ml 4-necked flask equipped with dropping funnel, stirrer, KOH drying tube and internal thermometer. A week exothermic reaction takes place after the addition of sodium cyanide to the reaction mixture and the temperature rises from 30° to 34° C. The reaction mixture is stirred for 15 minutes at a reaction temperature of 30° C and a solution of 15.9 g (0.3 mol) of freshly distilled acrylonitrile and 80 ml of absolute dimethylformamide is introduced dropwise into the reaction mixture in the course of one hour at the same temperature. Stirring is then continued for 1/4 hours at the same temperature. The reaction mixture, which is now very creamy, is poured on to 800 ml of water and vigorously shaken. The aqueous solution is extracted twice with 200 ml of chloroform and twice with 100 ml of chloroform. The combined chloroform solutions are vigorously washed with water and dried over MgSO4 and the chloroform is distilled off. Inoculating crystals are added to the residue. β-Benzoyl-propionitrile then crystallises at once. It is suction filtered and washed with ethanol. 26.6 g of β-benzoylpropionitrile are obtained. M.p.: 69° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([O:16][CH:17]([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:7][CH:8]=1.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1.N1C=CC=CC=1>O1CCCC1>[CH:17]([O:16][CH:10]([CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][O:1][C:29]([NH:28][C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:27][CH:26]=2)=[O:30])[CH:4]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:18])[CH3:19]
Reactant: CCOC(=O)C(Cc1cccc(CO)c1)OC(C)C
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)C(Cc1cccc(COC(=O)Nc2ccc(C(F)(F)F)cc2)c1)OC(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 87.5 %

Procedure:
A suspension in tetrahydrofuran (2.0 ml) containing 100 mg of ethyl 3-[3-(hydroxymethyl)phenyl]-2-isopropoxypropanoate, 150 mg of α,α,α-trifluoro-p-tolylisocyanate and 35 μl of pyridine was stirred at room temperature for 14 hours. The solvent was removed, and the residue was treated with dichloromethane. After filtering off insoluble substances, the residue was purified by silica gel column chromatography, to give 149 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]3[CH2:16][C:15](=O)[CH2:14]3)[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C(O)C>N1C=CC=CC=1>[F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]3[CH2:16][C:15](=[N:21][OH:22])[CH2:14]3)[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C1CC(c2cccc(Oc3ccc(F)cc3)c2)C1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C1CC(c2cccc(Oc3ccc(F)cc3)c2)C1

Procedure:
A solution of 3-(3-(4-fluorophenoxy)phenyl)cyclobutanone (2.59 g, 10.1 mmol) and hydroxylamine hydrochloride (844 mg, 12.1 mmol) in 1:1 ethanol:pyridine (50 mL) was stirred for 36 hours. It was then concentrated in vacuo. The residue was taken up in brine (50 mL) and extracted with ethyl acetate (3×50 mL). The organics were combined, dried over MgSO4 and concentrated to afford 3-(3-(4-fluorophenoxy)phenyl)cyclobutanone oxime which was used as is.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](\[CH3:17])/[CH:5]=[C:6]=[C:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][C:10](=[O:15])[CH:9]=[C:8]1[CH3:16].C(N([CH2:23][CH3:24])CC)C.CNC1(NC)C=CN=CC1.[OH2:35]>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[C:23]([O:1][CH2:2]/[CH:3]=[C:4](\[CH3:17])/[CH:5]=[C:6]=[C:7]1[C:12]([CH3:13])([CH3:14])[CH2:11][C:10](=[O:15])[CH:9]=[C:8]1[CH3:16])(=[O:35])[CH3:24]
Reactant: O
Reactant: CC1=CC(=O)CC(C)(C)C1=C=C/C(C)=C/CO
Reactant: CCN(CC)CC
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: CNC1(NC)C=CN=CC1
Product: CC(=O)OC/C=C(\C)C=C=C1C(C)=CC(=O)CC1(C)C
Yield: 48 %

Procedure:
To a solution of (3E)-4-(5-hydroxy-3-methyl-1,3-pentadien-1-ylidene)-3,5,5-trimethyl-2-cyclohexen-1-one (1.2 g, 5.2 mmol) in acetic anydride (5.0 mL) and triethylamine (5.0 mL) cooled to 0° C., was added 4,4-dimethylaminopyridine (25 ng). After 15 min. water was added to the reaction mixture, and the product was extracted three times with ether. The combined ethereal extracts were washed with sodium chloride solution, and dried over anhydrous sodium sulfate. Evaporation of the solvent and chromatography over silica gel in the manner described in Example 1 above gave the desired product (680 mg, 48%).
Reaction SMILES: [C:1]1([O:11][CH2:12][C@H:13]2[O:15][CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:16]([NH2:19])([CH3:18])[CH3:17]>CO>[CH3:17][CH:16]([NH:19][CH2:14][C@H:13]([OH:15])[CH2:12][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:18]
Reactant: CC(C)N
Reactant: c1ccc2c(OC[C@@H]3CO3)cccc2c1
Solvent: CO
Product: CC(C)NC[C@H](O)COc1cccc2ccccc12
Yield: 92.6 %

Procedure:
A solution of (S)-(+)-glycidyl naphthyl ether (20 g, 0.1 m) and isopropylamine (10 g, 0.17 m) in methanol (100 mL) was refluxed for 1 hour and evaporated to dryness. The residue was taken up with ether (200 mL), washed with water and dried over MgSO4. After filtering, the filtrate was acidified with gaseous HCl. The crude solid was recrystallized from ethanol to afford 24 g (81%) of pure 1-propranolol, mp 198°-200° C., [α]D25 -26.8 (c 1, EtOH). NMR and IR were consistent with the assigned structure.