Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Li])=[CH2:2].[O:4]1[CH2:9][CH2:8][CH:7]=[CH:6][C:5]1=[O:10]>O1CCCC1.C1(C)C=CC=CC=1>[CH:1]([CH:7]1[CH2:8][CH2:9][O:4][C:5](=[O:10])[CH2:6]1)=[CH2:2]
Reactant: [Li]C=C
Reactant: O=C1C=CCCO1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CC1CCOC(=O)C1
Reaction time: 0.25 h

Procedure:
A stream of nitrogen gas is passed through a mixture of 19.6 ml (41.2 mmol) of 2.1M vinyllithium in tetrahydrofuran and 21 ml toluene to evaporate tetrahydrofuran. The resulting pale yellow suspension is diluted with 21 ml ether and cooled to -78°. To this solution is added 1.87 g (20.9 mmol) cuprous cyanide and the reaction mixture is then warmed to 0° for 2 min. The resulting gray suspension is cooled to -78° and 0.9 ml (10.4 mmol) of 5,6-dihydro-2H-pyran-2-one is added. The reaction mixture is stirred at -78° for 30 min and at -20° for 15 min. The reaction is quenched by the addition of saturated aqueous ammonium chloride and stirred for 1 h at room temperature. The insoluble salts are filtered off and washed with water (1×20 ml) and ether (2×20 ml). The layers are separated and the aqueous phase is extracted with ether (2×30 ml). Combined organic extracts are dried (MgSO4), filtered and evaporated to give a yellow oil which is purified by flash chromatography to obtain 4-ethenyltetrahydro-2H-pyran-2-one as a pale yellow oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([NH2:15])=[O:14])=[N:11][CH:12]=2)[CH2:3]1.[C:16](Cl)(=[O:27])[O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C>N1C=CC=CC=1>[C:16](=[O:27])([O:17][C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)[O:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[N:11][C:10]([C:13](=[O:14])[NH2:15])=[CH:9][CH:8]=2)[CH2:3]1
Reactant: NC(=O)c1ccc(N2CCC(O)C2)cn1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc(N2CCC(OC(=O)Oc3ccc([N+](=O)[O-])cc3)C2)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.6 %

Procedure:
To a solution of 5-(3-hydroxypyrrolidin-1-yl)picolinamide (1 g, 4.83 mmol) and 4-nitrophenyl carbonochloridate (1.46 g, 8.3 mmol) in pyridine (30 mL) was added DIPEA (1.25 g, 11 mmol) and the resulting mixture was stirred at rt for 3 days. The precipitate was collected by filtration and the cake was washed with DCM (20 mL) to give the desired compound (1.0 g, 56%) as a pale yellow solid. [LCMS: RtA=1.48 min, m/z 373.2 [M+H]+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[C:7]([CH:12]=[CH:13][O:14]CC)[CH:6]=2.C(O)=O>ClCCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH2:12][CH:13]=[O:14])[CH:8]=[N:9]2)=[N:4][CH:3]=1
Reactant: CCOC=Cc1cnc2cc(Br)cnc2c1
Solvent: O=CO
Solvent: ClCCCl
Product: O=CCc1cnc2cc(Br)cnc2c1

Procedure:
1,5-Naphthyridines of formula (53), wherein L2, R4, R5 and R6 are as defined in formula (I), can be prepared as described in Scheme 10. 3,7-Dibromo-[1,5]naphthyridine, prepared as described by W. W. Paudler, J. Org. Chem., 33:1384 (1968), can be treated with (2-ethoxyvinyl)tributylstannane, a halide source, such as, but not limited to, tetraethylammonium chloride, and a palladium source, such as, but not limited to, dichlorobis(triphenylphosphine)palladium (II) in a solvent, such as, but not limited to, N,N-dimethylformamide with heat (about 50° C. to about 150° C.) to provide 3-bromo-7-[2-ethoxyvinyl]-1,5-naphthyridine. 3-Bromo-7-[2-ethoxyvinyl]-1,5-naphthyridine can be treated with an acid, such as, but not limited to, formic acid at about 0° C. to about 60° C. in a solvent, such as, but not limited to, 1,2-dichloroethane to provide (7-bromo-1,5-naphthyridin-3-yl)acetaldehyde. Alternatively, 3-bromo-7-[2-ethoxyvinyl]-1,5-naphthyridine in a solvent, such as, but not limited to, tetrahydrofuran can be treated with an aqueous acid, such as, but not limited to, hydrochloric acid at about 0° C. to about 60° C. to provide (7-bromo-1,5-naphthyridin-3-yl)acetaldehyde. (7-Bromo-1,5-naphthyridin-3-yl)acetaldehyde can be treated with an amine of formula (5) under reductive amination conditions, such as, but not limited to, sodium triacetoxyborohydride and an acid, such as, but not limited to, acetic acid in a solvent, such as, but not limited to, 1,2-dichloroethane at about 0° C. to about 50° C. to provide amines of formula (52). Amines of formula (52) can be processed as described in Schemes 1–3 to provide 1,5-naphthyridines of formula (53).
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4]([CH3:10])=C1.[CH2:11]([OH:13])[CH3:12].S(=O)(=O)(O)[OH:15].[OH-].[Na+]>C(OC(=O)C)C>[CH2:11]([O:13][C:2](=[O:1])[CH2:9][C:6]([CH3:7])([CH3:8])[CH2:5][C:4](=[O:15])[CH3:10])[CH3:12]
Reactant: O=S(=O)(O)O
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(C)(C)CC(C)=O
Reaction time: 8 h
Yield: 85.9 %

Procedure:
A solution of 15.8 g of isophorone in 70.0 g of ethylacetate was ozonolized at 0° C. for 2 hours. After addition of 80.0 g of absolute ethanol and 0.91 g of concentrated sulfuric acid, the reaction solution was cooked overnight under reflux. The cooled solution was adjusted to pH 7 with an ethanolic solution of sodium hydroxide. The ethanol and the ethylacetate were distilled off. The desired 3,3-dimethyl-5-oxo-hexanoic acid ethyl ester was isolated by vacuum distillation. 18.6 g of a colorless fluid (boiling point: 104° to 105° C. at 19 mbar) was obtained which according to gas chromatography contained 98.2 percent of 3,3-dimethyl-5-oxo-hexanoic acid ethyl ester. This corresponds to 18.3 g of 100 percent ester and to a yield of 85.9 percent, calculated on the amount of isophorone used.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]O)=[CH:21][CH:20]=1.O1CCCC1>C1(C)C=CC=CC=1>[Cl:3][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([O:18][CH2:17][C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:6]=2[CH3:5])=[CH:20][CH:21]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(CO)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
A solution of thionyl chloride (1.5 mL) in toluene (5 mL) was added to a mixture of 4-(5-methyl-2-phenyl-4-thiazolylmethoxy)benzyl alcohol (4.50 g), tetrahydrofuran (50 mL) and toluene (50 mL) under ice-cooling, which was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate, which was washed with saturated aqueous sodium bicarbonate solution, then with saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and concentrated to obtain colorless crystals of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenylthiazole (4.50 g, yield 94%). Melting point: 100–101° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:6][CH:7]=1.Br[CH:16]([Si](C)(C)C)[S:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C.C1C=CC=CC=1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9](=[O:14])[C@H:10]3[C@@H:18]([Si:19]([CH3:22])([CH3:21])[CH3:20])[S:17][CH2:16][C@H:11]3[C:12]2=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=CC(=O)N1c1cccc(Br)c1
Reactant: C[Si](C)(C)CSC(Br)[Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)[C@H]1SC[C@H]2C(=O)N(c3cccc(Br)c3)C(=O)[C@H]21
Temperature: 110 °C

Procedure:
A flask was charged with 1-(3-bromo-phenyl)-pyrrole-2,5-dione (800 mg, 3.17 mmol) and bromo-trimethylsilanyl-trimethylsilanylmethylsulfanyl-methane (1.36 g, 4.76 mmol, [literature compound)) in dry DMF (3 ml) under nitrogen atmosphere. The material was heated at 110° C. (oil bath) for 2 hours and then cooled to ambient. The solvent was stripped (rotovap/pump) and the remainder taken up in benzene (30 ml) and brine (30 ml). The material was shaken and the organic phase collected. The aqueous phase was back-extracted with benzene (2×20 ml) and the organic phases combined, dried (MgSO4), filtered and stripped. The crude was purified by chromatography on silica gel eluting with 5% to 40% EtOAc in hexanes, providing 1.04 g of (3S,3aS,6aR)-5-(3-bromo-phenyl)-3-trimethylsilanyl-tetrahydro-thieno[3,4-c]pyrrole-4,6-dione as a light white-yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:10][C@@H:9]2[C@@H:4]([CH2:5][O:6][C@@:7]3([CH2:16][OH:17])[O:13][C:12]([CH3:15])([CH3:14])[O:11][C@H:8]32)[O:3]1.[N:19]1C=CC=CC=1.[S:25](Cl)(Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:1][C:2]1([CH3:18])[O:10][C@@H:9]2[C@@H:4]([CH2:5][O:6][C@@:7]3([CH2:16][O:17][S:25]([NH2:19])(=[O:27])=[O:26])[O:13][C:12]([CH3:14])([CH3:15])[O:11][C@H:8]32)[O:3]1
Reactant: O=S(=O)(Cl)Cl
Reactant: c1ccncc1
Reactant: CC1(C)O[C@@H]2[C@@H](CO[C@@]3(CO)OC(C)(C)O[C@@H]23)O1
Solvent: ClCCl
Product: CC1(C)O[C@@H]2[C@@H](CO[C@@]3(COS(N)(=O)=O)OC(C)(C)O[C@@H]23)O1
Yield: 244 %

Procedure:
Under nitrogen, a solution of the alcohol of Example 1 (15.0 g, 0.0576 mol) and pyridine (15 mL, 0.18 mol) in methylene chloride (60 mL) was cooled to -40° C. in a dry ice/isopropanol bath. With stirring, a solution of sulfuryl chloride (16.0 g, 0.118 mol) in methylene chloride (10 mL) was added gradually (approx. 50 minutes) so that the temperature did not exceed -25° C. The ice bath was removed as soon as the addition was complete and the reaction mixture stirred for an additional 2 h. During this time the light yellow precipitate became a clumpy brown solid. Solvent was removed in vacuo to yield a sticky, brown residue. The residue was dissolved in 100 mL methylene chloride and anhydrous ammonia was bubbled through the mixture overnight at ambient temperature. The dark reaction mixture was concentrated in vacuo to give 47.7 g of the title compound as a black residue. The crude product was found to be 15.10% pure by GLC giving a corrected yield of 36.83 %.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:28][O:29][C:30]1[CH:35]=[C:34]([CH:36]([OH:39])[CH2:37][NH2:38])[CH:33]=[CH:32][C:31]=1[OH:40]>>[OH:39][CH:36]([C:34]1[CH:33]=[CH:32][C:31]([OH:40])=[C:30]([O:29][CH3:28])[CH:35]=1)[CH2:37][NH:38][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=3)(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: COc1cc(C(O)CN)ccc1O
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: COc1cc(C(O)CNC2CCN(c3ccc(NS(=O)(=O)c4ccc(NC(C)=O)cc4)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and DL-normetanephrine according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.40-1.60 (m, 2H), 1.90-2.06 (m, 2H), 2.06 (s, 3H), 2.50-3.50 (m, 5H), 3.55-3.65 (m, 2H), 3.77 (s, 3H), 4.70-4.80 (m, 1H), 5.70-5.85 (brs, 1H), 6.70-6.90 (m, 7H), 7.59 (d, J=8.7 Hz, 2H), 7.69 (d, J=8.7 Hz, 2H), 8.95 (brs, 1H), 10.37 (s, 1H); MS (ES) m/z: 555.2 (MH+); HRMS Calcd. for C28H35N4O6S(MH+): 555.2277. Found: 555.2265.
Reaction SMILES: C([O-])(=[O:3])C.[Na+].[H][H].Cl[C:9]1[C:34](=[O:35])[NH:33][C:32](=[O:36])[NH:31][C:10]=1[C:11]([NH:13][C@H:14]([C:21]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([NH2:27])=[O:26])=[O:22])[CH2:15][C:16]1[N:20]=[CH:19][NH:18][CH:17]=1)=[O:12]>[Pd].O>[OH2:3].[C:11]([NH:13][C@H:14]([C:21]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([NH2:27])=[O:26])=[O:22])[CH2:15][C:16]1[N:20]=[CH:19][NH:18][CH:17]=1)(=[O:12])[C:10]1[NH:31][C:32](=[O:36])[NH:33][C:34](=[O:35])[CH:9]=1
Reactant: CC(=O)[O-]
Reactant: [H][H]
Reactant: NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)c1[nH]c(=O)[nH]c(=O)c1Cl
Agent: [Pd]
Agent: [Na+]
Solvent: O
Product: NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)c1cc(=O)[nH]c(=O)[nH]1

Procedure:
To 15 ml of water are added 165 mg of anhydrous sodium acetate and 100 mg of 5% palladium on charcoal. On a shaking apparatus the mixture is treated with hydrogen until the absorption stops. Then a solution of 850 mg of 5-chloro orotyl-L-histidyl-L-prolinamide in 30 ml of water is added and shaking in a hydrogen atmosphere is continued at normal pressure and room temperature until 2m moles (about 50 ml) of hydrogen are consumed. The catalyst is filtered off, the filtrate is extracted two times with ether and then the aqueous layer is evaporated at room temperature under reduced pressure to a volume of about 2 to 3 ml and diluted with two times it volume of methanol. This solution is poured on a column of 150 g of basic aluminium oxide, followed by elution with methanol/water (2:1), controlled by measuring the ultraviolet absorption spectrum at 254 nm. The fractions containing the main product are combined, evaporated under reduced pressure and finally lyophylized. Thus 780 mg (96 % of the theoretical yield) of orotyl-L-histidyl-L-prolinamide hydrate (i.e., the same product as prepared in Example 2) are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5](C(OCC)=O)=[N:6][CH:7]=1.BrN1C(=O)CCC1=O.O.[NH2:23][NH2:24].[C:25]([Cl:29])(Cl)(Cl)Cl>C(O)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[N:6][C:5]2=[C:25]([Cl:29])[N:23]=[N:24][CH:13]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)c1ncc(Br)cc1C
Reactant: ClC(Cl)(Cl)Cl
Reactant: NN
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CCO
Product: Clc1nncc2cc(Br)cnc12
Temperature: 60 °C
Reaction time: 7 h

Procedure:
To a solution of ethyl 5-bromo-3-methylpyridine-2-carboxylate (1.6 g; 6.95 mmol) and benzoyl peroxide (84.23 mg; 0.347 mmol) in carbon tetrachloride (20 mL) was added N-bromosuccinimide (2.47 g; 13.91 mmol). The reaction mixture was heated at reflux for 3 h. Another equivalent of N-bromosuccinimide and benzoyl peroxide (85 mg) was added and refluxing was continued for a further 7 h. Reaction was monitored by MS. After 10 h the product was the major peak. The reaction mixture was allowed to cool, filtered through celite washed with carbon tetrachloride. The filtrate was evaporated under reduced pressure to give an oil, 2.7 g. The oil (2.7 g; 6.9615 mmol) and hydrazine hydrate (2.4 mL) in ethanol was heated at reflux overnight. The solvent was evaporated under reduced pressure, the residue was taken-up in water acidified with 2N HCl the solid obtained was collected by filtration washed with water and dried by azeotroping with toluene. Yield=0.9 g. The crude product and phosphorus oxychloride were heated at 60° C. for 1 h. The excess phosphorus oxychloride was evaporated under reduced pressure to give 3-bromo-8-chloropyrido[2,3-d]pyridazine (0.97 g) as solid. This material was azeotroped with toluene and then treated with 4-aminobenzotrifluoride (0.64 g, 0.495 mL; 3.97 mmol) in 1,4-dioxane (20ml) and heated at 40° C. for 1 h. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate and sodium carbonate solution. The ethyl acetate extracts were combined, washed with brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give an oil. The oil was purified by flash chromatography using a gradient of (90->50%) iso-hexane/ethyl acetate. The appropriate fractions were combined and evaporated under reduced pressure to give 3-bromo-N-(4-(trifluoromethyl)phenyl)pyrido[2,3-d]pyridazin-8-amine (100 mg). 1H NMR (500 MHz, DMSO-d6) δ: 7.73 (2H, d, J 8.6 Hz), 8.41 (2H, d, J 8.8 Hz), 8.91 (1H, d, J 2.2 Hz), 9.25 (1H, s), 9.33 (1H, d, J 2.2 Hz), 10.05 (1H, s).
Reaction SMILES: [Br:1][CH2:2][CH2:3][NH:4][C:5](=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13].[C:16]1([N:22]2[C:26]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:25](=[O:32])[NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[BrH:1].[N+:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[C:5]([NH:4][CH2:3][CH2:2][N:29]1[CH2:28][CH2:27][C:26]2([N:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][NH:24][C:25]2=[O:32])[CH2:31][CH2:30]1)=[O:15])([O-:14])=[O:13]
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: O=C(NCCBr)c1ccccc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: Br
Product: O=C(NCCN1CCC2(CC1)C(=O)NCN2c1ccccc1)c1ccccc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
A mixture of 1.2 parts of N-(2-bromoethyl)-2-nitrobenzamide, 1.15 parts of 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one and 45 parts of N,N-dimethylformamide is stirred and refluxed for 3 hours. After stirring is continued overnight at room temperature, N,N-dimethylformamide is evaporated in vacuo at 80° C. The residue is boiled in a mixture of 2-propanone and water and the unreacted starting material is filtered off. The filtrate is concentrated to half its volume and 2-propanol is added to the concentrate. The precipitated product is filtered off and dried, yielding 7 parts of 2-nitro-N-[2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)-ethyl]benzamide hydrobromide; mp. 259.4° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:16][CH3:17])[CH:9]=[CH:8][CH:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C.O.Cl>C1COCC1>[CH2:16]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:6]([CH2:4][OH:3])=[CH:7][CH:8]=[CH:9]2)[CH3:17]
Reactant: CCOC(=O)c1cccc2cccc(CC)c12
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cccc2cccc(CO)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
A solution of 8-ethyl-naphthalene-1-carboxylic acid ethyl ester (1.04 g) in THF (30 ml) was cooled to 0° C. and treated with diisobutyl aluminium hydride solution (11.4 ml; 1.2 M in toluene). The reaction mixture was stirred for 2 hrs at r.t., then again cooled to 0° C. and treated with H2O (50 ml) and 0.1N HCl (50 ml). The mixture was extracted with EtOAc. The organics were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient cyclohexane→cyclohexane/EtOAc 4:1) to give (8-ethyl-naphthalen-1-yl)-methanol (769 mg) as white solid. MS (ISP): 187.3 ((M+H)+.).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C1COCC1.O.[OH-].[Na+]>[CH2:20]([O:19][C:17]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)OCc2ccccc2)CC1
Reaction time: 12 h
Yield: 93 %

Procedure:
A solution of 4-aminomethyl-1-Boc-piperidine (5.00 g, 23.4 mmol) in THF (60 mL), water (14 mL) and 5 N NaOH (46 mL) was treated with benzyl chloroformate. After 12 h, the mixture was partitioned between EtOAc and water and the aqueous phase washed with EtOAc (3×). The combined extracts were washed with water, brine and concentrated to afford 7.6 g (93%) of the title compound which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:28][C:29]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=[CH:32][C:30]=1[NH2:31]>>[CH3:21][S:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:3][C:2]([C:32]4[CH:33]=[CH:34][CH:35]=[C:29]([NH2:28])[C:30]=4[NH2:31])=[N:7][C:6]=3[CH:8]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2cccc(N)c2N)OC1(C)C
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cccc(N)c4N)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in general procedure A. Purification by column chromatography yielded 3-[6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl]-benzene-1,2-diamine which was heated in formic acid at reflux for 4 h. After cooling to room temperature, the solution was poured into saturated aqueous sodiumhydrogen carbonate solution (20 mL) and extracted into dichloromethane (3×20 mL). The combined organics were washed with aqueous brine solution (2×20 mL), dried (MgSO4), reduced in vacuo and purified by column chromatography to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]([N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:4].[I-:42].[Na+].CCCCCC>CC(C)=O>[I:42][CH2:2][C:3]([N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:4]
Reactant: CCCCCCCC/C=C\CCCCCCCCN(CCCCCCCC/C=C\CCCCCCCC)C(=O)CBr
Reactant: [I-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CCCCCCCC/C=C\CCCCCCCCN(CCCCCCCC/C=C\CCCCCCCC)C(=O)CI

Procedure:
A solution of 2-bromo-N,N-dioleylacetamide (0.81 g; 1.27 mmol) and sodium iodide (0.76 g; 5.08 mmol) in acetone is refluxed overnight. Hexane (10 ml) is added and the precipitate is filtered off to give, after evaporating the filtrate under reduced pressure, 2-iodo-N,N-dioleylacetamide (0.87 g; 100%) in the form of a yellowish liquid.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])=O)=[CH:7][CH:6]=1)(=O)C.Cl.Cl.NC1C=CC(C2CC(=O)C3C(=CC=CC=3)O2)=CC=1>[Zn].C(O)(=O)C>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:12][CH2:13][C:15]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:21]2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(C=CC(=O)c2ccccc2O)cc1
Agent: Cl
Agent: Nc1ccc(C2CC(=O)c3ccccc3O2)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ccc(C2CCc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Acetylamino-2'-hydroxychalcone (7.20 g.), was boiled under reflux with acetic acid (100 ml) and concentrated hydrochloric acid (25 ml.) for 7 hrs. The clear solution of 4'-aminoflavanone hydrochloride was treated under a nitrogen atmosphere with amalgamated zinc (from zinc powder (40 g.) and mercuric chloride (0.8 g.)) and stirred at room temperature for 4 hrs. The residual zinc was filtered off and washed with acetic acid. The combined washings and filtrate were neutralised to bicarbonate solution, and the oily product extracted into dichloromethane. The solution was chromatographed on neutral alumina, eluting with dichloromethane and the first fraction evaporated giving the solid 4'-aminoflavan, which was recrystallised from boiling 60°-80° C. petroleum ether, cooling to -10° C., yielding 180 mg., m.p. 85°-87° C.