Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[C:14]([NH2:15])=[CH:13][C:12]([CH:16]([CH3:18])[CH3:17])=[N:11]3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.N1C=CC=CC=1.[C:25](Cl)([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26]>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[C:14]([NH:15][C:25](=[O:26])[O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[CH:13][C:12]([CH:16]([CH3:18])[CH3:17])=[N:11]3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)c1cc(N)n(-c2ccc3ncsc3c2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc3ncsc3c2)n1
Reaction time: 2 h
Yield: 23.1 %

Procedure:
To a stirring solution of 1-(benzo[d]thiazol-6-yl)-3-isopropyl-1H-pyrazol-5-amine (0.80 g, 3.1 mmol) and pyridine (0.51 ml, 6.2 mmol) in CH2Cl2 (30 ml) at RT was added Troc-Cl (0.51 ml, 3.7 mmol). After 2 h, the completed reaction was washed with 10% CuSO4 (2×), H2O (1×), brine (1×), dried (MgSO4), evaporated and purified by flash column chromatography (EtOAc/hexanes) to afford 2,2,2-trichloroethyl 1-(benzo[d]thiazol-6-yl)-3-isopropyl-1H-pyrazol-5-ylcarbamate (0.31 g, 23% yield) as an oil. MS (ESI) m/z: 433.0 (M+H+), 435.0 (M+2+H+).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12]O>S(=O)(=O)(O)O>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([SH:1])=[CH:7][CH:6]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(S)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(S)cc1
Yield: 96 %

Procedure:
A solution of (4-mercapto-phenyl)-acetic acid (1.00 g, 5.94 mmol) in methanol (10 mL) was treated with a catalytic amount of concentrated sulfuric acid (2 drops). The reaction was heated under reflux for 2 h. At this time, the reaction mixture was concentrated in vacuo. The residue was re-dissolved in chloroform and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford (4-mercapto-phenyl)-acetic acid methyl ester (1.04 g, 96%) as a colorless oil: EI-HRMS m/e calcd for C9H10O2S (M+) 182.0402, found 182.0405.
Reaction SMILES: CON(C)[C:4](=[O:16])[CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][CH:7]([CH3:9])[CH3:8].[CH2:18]1COCC1>C[Mg]Br>[CH3:8][CH:7]([CH3:9])[CH2:6][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4](=[O:16])[CH3:18]
Reactant: CON(C)C(=O)C(CC(C)C)c1ccccc1
Reactant: C1CCOC1
Agent: C[Mg]Br
Product: CC(=O)C(CC(C)C)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of 75 mg (0.317 mmol) N-methoxy-N-methyl-4-methyl-2-phenylpentanamide in 1 mL dry THF, 0.45 mL 1.4 M methylmagnesium bromide was added. The reaction was stirred for 1 h, quenched with 1.2 N HCl and extracted with EtOAc. The EtOAc solution was washed with brine, dried and concentrated leaving the title compound. 1H NMR: (500 MHz, CDCl3): δ 0.95 (2d, 6H), 1.42 (m, 1H), 1.67 (m, 1H), 1.9 (m, 1H), 2.06 (s, 3H), 3.73 (m, 1H), 7.0-7.4 (m, 5H).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:14](=[O:31])[C:15]4[C:16]([O:23][C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:17][C:18]([O:21]C)=[CH:19][CH:20]=4)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4]1.CO.O>Br.CC(O)=O>[ClH:1].[NH2:2][C:3]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[C:14](=[O:31])[C:15]4[CH:20]=[CH:19][C:18](=[O:21])[NH:17][C:16]=4[O:23][C:24]=3[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: COc1ccc2c(=O)c(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)oc2n1
Agent: Br
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4[nH]c(=O)ccc4c3=O)cc2)CCC1
Yield: 91.4 %

Procedure:
A solution of 3-[4-(1-amino-cyclobutyl)-phenyl]-7-methoxy-2-phenyl-pyrano[2,3-b]pyridin-4-one hydrochloride (20 mg, 0.046 mmol) in 33% hydrogen bromide solution in AcOH (0.5 mL) was heated in a microwave oven at 100° C. for 30 minutes. The reaction mixture was added to a mixture of MeOH (10 mL) and water (5 mL) and the resultant solution passed through a 2 g SCX cartridge. The product was not retained by the cartridge. The washings containing the product were concentrated, the pH of the mixture was adjusted to ˜4 by addition of aqueous sodium hydroxide solution, and chromatographed on a 5 g C18 cartridge {gradient 20 to 70% MeOH in water+1M HCl (0.12 mL in each 10 mL of eluent)}. Fractions containing product were combined and concentrated in vacuo. The resulting residue was chromatographed on a 2 g C18 cartridge {gradient 20 to 60% MeOH in water+1M HCl (0.06 mL in each 5 mL of eluent)} to give the title compound (17.7 mg, 91%) as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.30 (d, J=9.2 Hz, 1H), 7.50-7.47 (m, 2H), 7.45-7.38 (m, 3H), 7.34-7.29 (m, 4H), 6.73 (d, J=9.0 Hz, 1H), 2.80-2.73 (m, 2H), 2.66-2.59 (m, 2H), 2.31-2.20 (m, 1H), 2.01-1.90 (m, 1H). LCMS (Method F): RT=6.97 min, [M−H]+=383.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].O.[C:8]([NH:15][C@H:16]([C:21]([OH:23])=O)[CH2:17][CH:18]([CH3:20])[CH3:19])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>>[C:8]([NH:15][C@H:16]([C:21]([NH:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])=[O:23])[CH2:17][CH:18]([CH3:19])[CH3:20])([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: CC(C)CCN
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: O
Product: CC(C)CCNC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C

Procedure:
In substantially the same manner as working Example 2, isopentylamine (2.33 ml) was condensed with Boc-L-leucine monohydrate (5.00 g, manufactured by Peptide Institute, Inc.) to give N-(Boc-L-leucyl)isopentylamine (5.73 g) as a white powdery product (yield 95%). The Boc group was deprotected with TFA, and 667 mg of thus-produced compound was condensed, in substantially the same manner as Working Example 2, with (2S,3S)-ethyl hydrogen N-Z-aziridine-2,3-dicarboxylate (Compound 1, 1.00 g) to afford the above-titled compound (Compound 11; 920 mg) as a colorless oily product (yield 58%).
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]1([C:16]2[O:22][C@H:21]3[C@H:18]([C:19](=[O:23])[NH:20]3)[N:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[N+:24](=[C:26]([C:34](=[O:37])[CH2:35][OH:36])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[N-:25].C([O-])(O)=O.[Na+]>O1CCCC1.C(Cl)Cl>[C:16]([NH:17][C@@H:18]1[C@@H:21]([O:36][CH2:35][C:34](=[O:37])[C:26](=[N+:24]=[N-:25])[C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[NH:20][C:19]1=[O:23])(=[O:22])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1N[C@H]2OC(c3ccccc3)=N[C@@H]12
Reactant: CC(C)(C)OC(=O)C(=[N+]=[N-])C(=O)CO
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(=[N+]=[N-])C(=O)CO[C@H]1NC(=O)[C@@H]1NC(=O)c1ccccc1
Yield: 73.9 %

Procedure:
90 μl of boron trifluoride etherate were added to a suspension of 564 mg (3.0 mmol) (1R,5S)-3-phenyl-4-oxa-2,6-diazabicyclo[3.2.0]hept-2-en-7-one and 1.08 g (5.4 mmol-1.8 equiv.) tert.-butyl 2-diazo-4-hydroxy-3-oxo-butanoate in 12 ml of anhydrous tetrahydrofuran at 0° C. The cooling bath was removed and after 10 minutes a clear, light yellow solution formed. After 20 minutes it was poured into a mixture of NaHCO3 solution, ice and methylene chloride. The mixture was extracted with methylene chloride (3×), washed with water and dried over magnesium sulphate. After the solvent had been evaporated off in vacuo and the residue had been crystalized from methylene chloride-ether-pentane, 861 mg (74%) of the title compound were obtained as light yellow crystals, melting point: 98° C., RF : 0.29 (toluene:ethyl acetate 2:3). Spectroscopical data identical to Example 4.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[O:15]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH2:17][CH2:16]1>>[O:15]1[CH2:16][CH2:17][N:18]([CH:21]2[CH2:26][CH2:25][N:24]([C:2]3[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=3[C:11]([F:14])([F:13])[F:12])[CH2:23][CH2:22]2)[CH2:19][CH2:20]1
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Product: Nc1ccc(N2CCC(N3CCOCC3)CC2)c(C(F)(F)F)c1

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthesis Example 40 using 4-chloro-3-trifluoromethylnitrobenzene and 4-morpholinopiperidine, the title compound was obtained, melting point: 118–120° C.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[N:23]=[C:22]([N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[N:23]=[C:22]([N:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N[C@H]3CCN(Cc4ccccc4)C3)nc3ccccc23)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2nc(N[C@H]3CCNC3)nc3ccccc23)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
t-Butyl 4-(2-((S)-1-benzylpyrrolidin-3-ylamino)quinazolin-4-yl)piperazine-1-carboxylate (26 g) was dissolved in methanol (260 mL), followed by addition of 20% Pd(OH)2/C (5.2 g), and the mixture was stirred under hydrogen atmosphere at room temperature for 16 h and at 50° C. for 8 h. 20% Pd(OH)2/C (5.2 g) was further added, and the mixture was stirred under hydrogen atmosphere for 3 days. The catalyst was removed by filtration, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/a solution of 1 M ammonium in methanol=9:1) to obtain the title compound (6.3 g).
Reaction SMILES: [OH:1][NH:2][C:3]([CH:5]1[CH2:7][CH2:6]1)=[O:4].[CH2:8]([N:11]=[C:12]=[O:13])[CH2:9][CH3:10]>C(N(CC)CC)C.C(Cl)Cl>[CH2:8]([NH:11][C:12]([N:2]([O:1][C:12]([NH:11][CH2:8][CH2:9][CH3:10])=[O:13])[C:3]([CH:5]1[CH2:7][CH2:6]1)=[O:4])=[O:13])[CH2:9][CH3:10]
Reactant: CCCN=C=O
Reactant: O=C(NO)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCNC(=O)ON(C(=O)NCCC)C(=O)C1CC1

Procedure:
N-hydroxycyclopropanecarboxamide (5.0 grams), n-propyl isocyanate (9.3 grams) and 5 drops of triethylamine were stirred at room temperature in about 100 ml of methylene chloride for about 12 hours. The reaction mixture was then concentrated leaving an oily residue which crystallized upon scratching. This solid was then recrystallized from a mixture of cyclohexane and isopropanol and dried. Upon drying, the desired N-((propylamino)carbonyl)-N-(((propylamino)carbonyl)-oxy)cyclopropanecarboxamide was obtained as a white solid, m.p. 76°-78° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12][CH2:11]2)[S:8][CH:9]=1)([CH3:4])[CH3:3].C([O-])([O-])=O.[K+].[K+].C(OC(Cl)=O)=C>ClCCCl>[CH3:4][C:2]([C:5]1[N:6]=[C:7]([CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[S:8][CH:9]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1csc(C2CCN(Cc3ccccc3)CC2)n1
Agent: C=COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: CC(C)(C)c1csc(C2CCNCC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.8 g 4-(4-(1,1-Dimethylethyl)-2-thiazolyl)-1-phenylmethyl-piperidine, 2 g K2CO3 and 50 ml 1,2-dichloroethane are treated dropwise at -5° under stirring with 3.2 g chloroformic acid vinyl ester. The mixture is stirred 2 hours at room temperature and evaporated. The residue is partitioned between ethyl ether and water. The ether phase is evaporated and the residue dissolved in 30 ml methanol and 30 ml 20% aqueous hydrochloric acid. The mixture is heated 1 hour at 60° and evaporated. The residue is partitioned between aqueous NaOH and ether. The ether phase is treated with maleic acid to yield the hydrogenmaleinate of the title compound, m.p. 141°-142° (ethanol/ether).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.[C:14]([C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[C:25]([C:28]1[N:32]3[CH:33]=[C:34]([C:37](=O)[CH3:38])[CH:35]=[CH:36][C:31]3=[N:30][N:29]=1)[CH:24]=[CH:23]2)([CH3:17])([CH3:16])[CH3:15].[BH4-].[Na+].[OH-].[NH4+]>C1COCC1.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C.C(OCC)(=O)C.O.C(O)C>[C:14]([C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[C:25]([C:28]1[N:32]3[CH:33]=[C:34]([CH:37]([N:1]4[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]4)[CH3:38])[CH:35]=[CH:36][C:31]3=[N:30][N:29]=1)[CH:24]=[CH:23]2)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: CC(=O)c1ccc2nnc(-c3ccc4cccc(C(C)(C)C)c4n3)n2c1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(c1ccc2nnc(-c3ccc4cccc(C(C)(C)C)c4n3)n2c1)N1CC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.8 %

Procedure:
To a solution of (S)-tert-butyl pyrrolidin-3-ylcarbamate (0.502 g, 2.69 mmol), 1-(3-(8-tert-butylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone (0.464 g, 1.35 mmol) in THF (20 mL) was added tetraisopropoxytitanium (0.79 mL, 2.69 mmol) and the reaction mixture was stirred at ambient temperature for 18 hours. Ethanol (2 mL) and NaBH4 (0.204 g, 5.39 mmol) were added and the mixture was stirred at ambient temperature for 2 hours. Water (10 mL), concentrated ammonium hydroxide (2 mL) and ethyl acetate (20 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 0-90% CH3CN/water gradient; 25 CV) to give tert-butyl (3S)-1-(1-(3-(8-tert-butylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (0.485 g, 69.9%) as solid.
Reaction SMILES: CCC[CH2:4][CH2:5][CH3:6].C[Si](C#C)(C)C.[Li+].CCC[CH2-].[CH:18]([SiH:21](Cl)[CH:22]([CH3:24])[CH3:23])(C)[CH3:19]>O.O1CCCC1>[CH:22]([SiH:21]([C:18]#[CH:19])[CH:5]([CH3:4])[CH3:6])([CH3:24])[CH3:23]
Reactant: CC(C)[SiH](Cl)C(C)C
Reactant: CCCCCC
Agent: C#C[Si](C)(C)C
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C#C[SiH](C(C)C)C(C)C
Temperature: 25 °C
Yield: 54 %

Procedure:
An oven dried 500 mL round bottom flask with nitrogen atmosphere was charged with hexane (100 mL), tetrahydrofuran (20 mL), and trimethylsilylacetylene (4.8 g, 48.9 mmol) and cooled with an ice bath. N-butyllithium (2.5 M in hexane, 19.4 mL) was added dropwise and the reaction mixture was allowed to warm to room temperature. The reaction product (20.0 g) from the previously described step, “Synthesis of 3-(N-methylnonafluorobutanesulfonamido)propyl) diisopropylsilyl chloride,” was slowly added and the contents allowed to stir for sixteen hours. Water was added slowly (100 mL) and the mixture was stirred vigorously. The organic layer was separated, and the water layer extracted with 100 mL of hexane. The organic layers were combined and concentrated under reduced pressure to a brown oil. The oil was purified using chromatography on silica gel with hexane as an eluant, resulting in 23.9 g of the trimethylsilyl-protected acetylene as a clear oil. The oil (23.9 g, 42.2 mmol) was charged to an oven dried 500 mL round bottom flask. Methanol (50 mL), tetrahydrofuran (50 mL), and 5% aqueous NaOH (1 mL) were added to the flask and then stirred for one hour. Water (100 mL) was then added, and stirred vigorously. The organic layer was separated, and the aqueous layer was extracted two times with hexane (2×100 mL). The organic layers were combined and concentrated under reduced pressure to yield 3-(N-methylnonafluorobutanesulfonamido)propyl)diisopropylsilyl acetylene as a clear oil (11.2 g, 54%).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8](Br)[S:7][C:6]=1[C:11]([NH2:13])=[O:12])=[O:3].[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16](B(O)O)=[CH:15]1>COCCOC>[NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:16]2[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[S:14][CH:15]=2)[S:7][C:6]=1[C:11]([NH2:13])=[O:12])=[O:3]
Reactant: OB(O)c1csc2ccccc12
Reactant: NC(=O)Nc1cc(Br)sc1C(N)=O
Solvent: COCCOC
Product: NC(=O)Nc1cc(-c2csc3ccccc23)sc1C(N)=O
Reaction time: 4.5 h

Procedure:
3-[(Aminocarbonyl)amino-5-bromothiophene-2-carboxamide (0.222 g) and 1-benzothien-3-ylboronic acid (0.449 g) were sonicated in 1,2-dimethoxyethane (15 ml) and saturated aqueous sodium hydrogen carbonate solution (3.5 ml) and purged with argon. Tetrakis(triphenylphosphine)-palladium (95 mg) was added and the mixture was heated at reflux with stirring for 4.5 h, then allowed to cool and stirred at room temperature overnight. The solution was filtered and washed through with 1,2-dimethoxyethane and water. The filtrate was concentrated in vacuo and taken up in dichloromethane (20 ml) and saturated aqueous sodium hydrogen carbonate solution (20 ml). The solid product was collected by filtration, washed with dichloromethane, water, diethyl ether and dried (226 mg).
Reaction SMILES: [F:1][CH:2]([F:30])[O:3][CH:4]=[C:5]([C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=1)=[O:7].Cl[CH2:32][C:33]#[CH:34].CN(C)C=O.[H-].[Na+]>O>[F:1][CH:2]([F:30])[O:3][CH:4]=[C:5]([C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:34][C:33]#[CH:32])=[C:13]([O:18][CH3:19])[CH:12]=1)=[O:7]
Reactant: COc1cc(CCNC(=O)C(=COC(F)F)c2ccc3c(c2)CCCC3)ccc1O
Reactant: C#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1ccc(CCNC(=O)C(=COC(F)F)c2ccc3c(c2)CCCC3)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.4 %

Procedure:
239 mg of 3-difluoromethoxy-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (0.572 mmol), 128 mg (1.72 mmol) of 3-chloropropyne, 3 ml of anhydrous N,N-dimethylformamide and 20 mg (0.50 mmol) of 60% sodium hydride were mixed and stirred at room temperature for 4 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid, saturated aqueous sodium bicarbonate solution and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 225 mg of 3-difluoromethoxy-N-[2-{3-methoxy-4-(2-propynyloxy)phenyl}ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (the present compound 1268).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[C:16]([Si:20]([O:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17].CN([CH:36]=[O:37])C>C1COCC1>[Si:20]([O:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([CH:27]=1)[CH:36]=[O:37])([C:16]([CH3:19])([CH3:17])[CH3:18])([CH3:21])[CH3:22]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(F)cc1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(F)c(C=O)c1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (10.77 g) in THF (200 mL) at 0° C. was added over 25 minutes butyllithium (1.6M in hexanes, 48 mL). The mixture was cooled to −78° C. and a solution of tert-butyl(4-fluorophenethoxy)dimethylsilane [Aromatic Intermediate 3, step a] (9.7 g) in THF (50 mL) was added dropwise over 25 minutes. The reaction mixture was stirred at −78° C. for 90 minutes. DMF (9.3 mL) was then added dropwise over 10 minutes. The reaction mixture was stirred at 0° C. for 1 hour and then poured into ice-cold aqueous HCl (0.5 M, 500 mL). The mixture was extracted with ethyl acetate and the organic layer washed twice with water, dried, filtered and the solvent concentrated under reduced pressure to give the subtitled compound. Yield 10.00 g.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:14]=[C:15]([C:19](=[O:21])[CH3:20])[CH:16]=[CH:17][CH:18]=2)=[N:11][CH:12]=1.C(O)C.[BH4-].[Na+].O>ClCCl>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[N:11][C:10]([C:13]2[CH:14]=[C:15]([CH:19]([OH:21])[CH3:20])[CH:16]=[CH:17][CH:18]=2)=[N:9][CH:8]=1
Reactant: CC(=O)c1cccc(-c2ncc(OCCCN(C)C)cn2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CC(O)c1cccc(-c2ncc(OCCCN(C)C)cn2)c1
Temperature: 0 °C

Procedure:
3.114 g of 1-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]phenyl}ethanone (10.4 mmol) are dissolved in 30 ml of abs. ethanol in a 100 ml one-necked flask, and 0.394 g of sodium borohydride (10.4 mmol) is subsequently added in portions with ice/water cooling and stirring, and the reaction batch is stirred at RT for a further 20 h. For work-up, the reaction mixture is diluted with 50 ml of dichloromethane and shaken 2× against water, and the dichloromethane phase is evaporated to dryness and purified by chromatography (silica gel/DCM/MeOH 9:1);
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[O:22]1[CH2:23][CH2:24][N:19]([CH2:2][CH2:3][O:4][C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:20][CH2:21]1
Reactant: ClCCOc1ccccc1C=Cc1ccccn1
Reactant: C1COCCN1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: C(=Cc1ccccc1OCCN1CCOCC1)c1ccccn1

Procedure:
2-[o-(β-Morpholino-ethoxy)-styryl]-pyridine was prepared from 2-[o-(β-chloro-ethoxy)-styryl]-pyridine (m.p. 57°-58° C.) and morpholine, and the free base was converted into its dihydrochloride, yielding 53% of theory of the compound of the formula ##STR10## which had a melting point of 248° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][C:10](=[O:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13].Cl[CH:18]([CH3:22])[C:19](=[O:21])[CH3:20]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[CH3:7][O:8][CH2:9][C:10](=[O:16])[CH:11]([CH:18]([CH3:22])[C:19]([CH3:20])=[O:21])[C:12]([O:14][CH3:15])=[O:13]
Reactant: CC(=O)C(C)Cl
Reactant: COCC(=O)CC(=O)OC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: COCC(=O)C(C(=O)OC)C(C)C(C)=O
Yield: 30.8 %

Procedure:
16.58 g (120 mmol) of potassium carbonate and 0.46 g (2 mmol) of benzyltriethylammonium chloride are suspended in 50 ml of acetonitrile. While stirring there are added thereto 14.60 g (100 mmol) of methyl 4-methoxyacetoacetate and there are added dropwise thereto within 10 minutes 15.97 g (150 mmol) of 3-chloro-2-butanone. The mixture is stirred at 20°-25° C. for a further 65 hours. The reaction mixture is poured on to 70 ml of 4N HCl/ice (pH value=1) and extracted 3 times with 100 ml of ethyl acetate each time. The combined organic phases are dried over magnesium sulphate and concentrated on a rotary evaporator. The crude product distils at 95° C./0.05 mbar and gives 6.67 g (42%) of methyl 4-methoxy-2-[1-methylacetonyl]-acetoacetate.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]1[CH:17]=[CH:18][C:19]([N+:31]([O-:33])=[O:32])=[C:20]([N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:21]=1.[H-].[Na+]>CN(C)C=O>[CH3:30][N:22]([C:20]1[CH:21]=[C:16]([O:14][C:11]2[CH:10]=[CH:9][C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:19]=1[N+:31]([O-:33])=[O:32])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27]
Reactant: Oc1ccc(Cc2ccccc2)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(Cc3ccccc3)cc2)ccc1[N+](=O)[O-]
Yield: 88 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 4-benzylphenol (7 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (9.15 g), sodium hydride (55 wt. %, 1.74 g) and anhydrous N,N-dimethylformamide (70 ml) and the reaction mixture was purified to give the title compound (12.2 g).