Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH2:32]([OH:36])[CH2:33][C:34]#[CH:35]>C(NCC)C.C(Cl)Cl.[Cu](I)I.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>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:35]#[C:34][CH2:33][CH2:32][OH:36])[CH:15]=[C:16]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCCO
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CC3CCOCC3)cc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: ClCCl
Solvent: CCNCC
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CC3CCOCC3)cc(C#CCCO)c21
Reaction time: 18 h

Procedure:
A solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-4-oxo-6-(tetrahydro-2H-pyran-4-ylmethyl)-1,4-dihydro-3-quinolinecarboxamide (0.074 g), copper iodide (0.013 g), Pd(PPh3)2Cl2 (0.007 g) and 3-butyn-1-ol (0.02 mL) in 7 mL diethylamine is stirred at room temperature for 3 days. The reaction is partitioned between CH2Cl2 and H20. The aqueous is extracted 3× with CH2Cl2. The organics are combined, dried over Na2SO4, filtered and concentrated. The residue is dissolved in CH2Cl2 and adsorbed onto silica. Purification by Biotage Flash 40S chromatography (eluent CH2Cl2 (1L), 0.5% MeOH/CH2Cl2 (1L), 1% MeOH/CH2Cl2 (1L), 1.5% MeOH/CH2Cl2 (1L), 2% MeOH/CH2Cl2 (1L), 3% MeOH/CH2Cl2 (1L), 5% MeOH/CH2Cl2 (1L), 7% MeOH/CH2Cl2 (1L)) affords the product as a tan residue. The residue is dissolved in a minimal amount of CH2Cl2 and hexanes are added to affect recrystallization. The solution is placed in the freezer for 18 h after which the product is collected and dried (0.037 g, 57%).
Reaction SMILES: [CH:1]([C:3]1[CH:27]=[CH:26][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1)=[O:2].B.[Na]>CO>[OH:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[CH2:10][CH2:11][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:13][CH2:14]2)=[O:8])=[CH:26][CH:27]=1
Reactant: O=Cc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Agent: B
Agent: [Na]
Solvent: CO
Product: O=C(c1ccc(CO)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Reaction time: 2 h
Yield: 77.6 %

Procedure:
1-[1-(4-Formylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (500 mg) is dissolved in methanol (10 ml) and thereto is added sodium boron hydride (63 mg) under ice cooling and the mixture is stirred for 2 hours. The solvent is concentrated and the resulting residue is purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=2:1) and recrystallized from n-hexane/ethanol to give 1-[1-(4-hydroxymethylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (390 mg) as white powder, m.p.: 138°-139° C.
Reaction SMILES: [CH3:1][C:2]([Mg]Br)=[CH:3][CH3:4].[F:7][C:8]1[N:13]=[C:12]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)[C:11]([N+:24]([O-])=O)=[CH:10][CH:9]=1.[Cl-].[NH4+]>O1CCCC1>[F:7][C:8]1[CH:9]=[C:10]2[C:3]([CH3:4])=[C:2]([CH3:1])[NH:24][C:11]2=[C:12]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)[N:13]=1
Reactant: O=[N+]([O-])c1ccc(F)nc1N1CCc2ccccc2C1
Reactant: CC=C(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1[nH]c2c(N3CCc4ccccc4C3)nc(F)cc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
1-Methyl-1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution; 138 ml, 68.9 mmol) was slowly added at −78° C. to a solution of 2-(6-fluoro-3-nitropyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline (5.38 g, 19.7 mmol) prepared in Step 2 in anhydrous tetrahydrofuran (150 ml). The reaction mixture was stirred for 1 hour at the same temperature, slowly warmed to room temperature, and then stirred overnight. 20% (w/v) Ammonium chloride solution was added to the reaction mixture, which was then extracted with ethyl acetate. The resulting organic layer was dried on anhydrous magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography. The resulting product was crystallized with ethyl ether to give the titled compound as red oil. (Yield: 32%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH:10]=[CH:14][N:15]([CH3:17])[CH3:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)cc(Cl)c1
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1cc(Cl)cc(Cl)c1
Temperature: 90 °C
Yield: 77 %

Procedure:
10 g (0.053 mol) of 3', 5'-dichloroacetophenone are dissolved, at room temperature and with stirring, in 50 ml of N,N-dimethylformamide dimethyl acetal. Stirring is maintained and the reaction mixture is heated for 2 h at 90° C. The mixture is concentrated to dryness under reduced pressure. The residue is taken up in 150 ml of heptane. The orange residue is filtered to give 10.0 g (yield 77%, melting point: 100° C.) of 1-(3,5-dichlorophenyl)-3-dimethylamino-2-propen-1-one.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[NH:17][C:18]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[C:26]([Cl:30])=[N:25][N:24]=[C:23]3Cl)=[O:19])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+].[O:34]1CCOCC1.Cl>O>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[NH:17][C:18]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[C:26]([Cl:30])=[N:25][NH:24][C:23]3=[O:34])=[O:19])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1N1CCOCC1)c1ccc2c(Cl)nnc(Cl)c2c1
Reactant: C1COCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1cc(C(F)(F)F)ccc1N1CCOCC1)c1ccc2c(Cl)n[nH]c(=O)c2c1
Temperature: 50 °C

Procedure:
A mixture of 1,4-dichloro-phthalazine-6-carboxylic acid (2-morpholin-4-yl-5-trifluoromethyl-phenyl)-amide (322 mg, 0.683 mmol), 2N NaOH (3.4 mL, 6.83 mmol) and dioxane (5 mL) was heated to 50° C. for 1 h. The reaction was diluted with water, acidified with conc. HCl to ˜pH 6. The reaction mixture was concentrated to low volume and filtered through celite. Chromatography (Hex/EtOAc) afforded 1-chloro-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid (2-morpholin-4-yl-5-trifluoromethyl-phenyl)-amide (49 mg) as a yellow solid, 1H NMR (400 MHz, d6-DMSO) δ: 2.99 (m, 4H), 3.80 (m, 4H), 7.41 (d, 1H), 7.56 (dd, 1H), 8.18 (d, 1H), 8.28 (s, 1H), 8.51 (dd, 1H), 8.80 (d, 1H), 10.23 (s, 1H), 13.05 (s, 1H) ppm; m/z (M+1) 452.96; and 4-chloro-1-oxo-1,2-dihydro-phthalazine-6-carboxylic acid (2-morpholin-4-yl-5-trifluoromethyl-phenyl)-amide (40 mg) as a pale yellow solid. 1H NMR (400 MHz, d6-DMSO) δ: 2.99 (m, 4H), 3.80 (m, 4H), 7.41 (d, 1H), 7.58 (dd, 1H), 8.29 (s, 1H), 8.43 (s, 2H), 8.46 (s, 1H), 10.23 (s, 1H), 13.02 (s, 1H) ppm; m/z (M+1) 452.96.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[N:12]1[CH:17]=[C:16]([CH2:18][CH2:19][CH2:20][OH:21])[CH:15]=[N:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)([O:21][CH2:20][CH2:19][CH2:18][C:16]1[CH:17]=[N:12][CH:13]=[N:14][CH:15]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCc1cncnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCc2cncnc2)cc1
Yield: 104.9 %

Procedure:
9.87 g (51.7 mmol) of tosyl chloride in 50 ml of dichloromethane are added dropwise at room temperature to a solution of 6.5 g (47 mmol) of 3-(pyrimidin-5-yl)propanol and 9 ml (64.6 mmol) of triethylamine in 100 ml dichloromethane that is being stirred under nitrogen. The mixture is stirred for 16 hours at room temperature, then washed with water and saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated by evaporation under reduced pressure. 14.42 g of 3-(pyrimidin-5-yl)propyl tosylate are obtained, which can be processed further without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18](OC)=[O:19])[CH:8]=[C:7]2[Cl:22])(=[O:3])[CH3:2].[NH3:23]>Cl>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([NH2:23])=[O:19])[CH:8]=[C:7]2[Cl:22])(=[O:3])[CH3:2]
Reactant: CCCc1c(O)c(C(C)=O)cc2c(Cl)cc(C(=O)OC)nc12
Reactant: N
Agent: Cl
Product: CCCc1c(O)c(C(C)=O)cc2c(Cl)cc(C(N)=O)nc12

Procedure:
Methyl 6-acetyl-4-chloro-7-hydroxy-8-propylquinoline-2-carboxylate (2 g) was treated with ammonia saturated methanol in an autoclave at 100° C. for 24 hours. Removal of solvent afforded a solid which was boiled with 2 N HCl (100 ml) for 10 minutes, then cooled, and the precipitate was collected and identified as the sub-title compound by NMR.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11].CCN(C(C)C)C(C)C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:8][C:5]1[N:6]=[CH:7][C:2](/[CH:11]=[CH:10]/[C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:4]=1
Reactant: C=CC(=O)OCC
Reactant: Nc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1ccc(N)nc1
Temperature: 100 °C
Yield: 36 %

Procedure:
To a glass bomb were charged with 5-bromopyridin-2-amine (10.0 g, 57.8 mmol), ethyl acrylate (8.14 mL, 75 mmol) and DIEA (25.2 mL, 144 mmol) in DMF (40 mL). The mixture was purged with argon, followed by addition of Pd(OAc)2 (0.649 g, 2.89 mmol) and (o-Tol)3P (3.87 g, 12.72 mmol), and finally purged thoroughly with argon. The mixture was sealed, and heated with 100° C. oil bath overnight. The reaction mixture was cooled down to room temperature, and the precipitates were removed by filtering through a thin layer of Celite. The filtrate was concentrated as much as possible via rotavap, and the residue was partitioned between EtOAc/water (150 mL/100 mL). EtOAc layer was washed with water (2×100 mL), dried over Na2SO4, and concentrated. A brown slid was obtained as crude product. The crude product was triturated with EtOAc (40 mL) and the yellow solid was collected via filtration. The filter cake was rinsed with small amount of EtOAc and dried under vacuum as the first crop of product (5.0 g). The mother liquor from trituration was stripped by dilute aqueous 1 N HCl (30 mL) and water (70 mL). Aqueous layer was transferred to a clean separate funnel, basicified with 20 mL sat. Na2CO3, and extracted with EtOAc (60 mL). EtOAc layer was dried over Na2SO4, concentrated and provided the second portion of product (4.0 g). The two crops of product were combined to afford 81% yield. LCMS (m/z) 193.2 (MH+), 0.39 min.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>>[Br:1][C:2]1[N:7]=[C:6]([C:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: C1CCNC1
Product: O=C(c1cccc(Br)n1)N1CCCC1

Procedure:
Prepared according to the procedure described in Example 121, Step 1, using 6-bromo-pyridine-2-carboxylic acid and pyrrolidine.
Reaction SMILES: [CH:1]1([NH:4][C@H:5]2[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>C(Cl)Cl>[CH:1]1([N:4]([C@H:5]2[CH2:10][CH2:9][C@H:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:7][CH2:6]2)[C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([Cl:25])=[CH:27][CH:28]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)C[C@H]1CC[C@H](NC2CC2)CC1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C[C@H]1CC[C@H](N(C(=O)c2ccc(Cl)cc2)C2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl 2-(trans-4-(cyclopropylamino)cyclohexyl)acetate (0.150 g, 0.710 mmol) in CH2Cl2 (2.5 mL) were added diisopropylethylamine (0.173 ml, 0.994 mmol), 4-chlorobenzoic acid (0.0866 ml, 0.852 mmol), and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.470 g, 1.85 mmol) sequentially. The mixture was stirred at room temperature overnight, diluted with CH2Cl2 (50 mL), and then washed with 10% Na2CO3 and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified through silica gel chromatography eluting with 18%-25% EtOAc-hexane. The desired amide product was obtained as a colorless oil (0.199 g). MS: 350 (M+1), C19H24ClNO3.
Reaction SMILES: [CH3:1][C@@:2]([NH2:15])([C:12]([OH:14])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([OH:11])[CH:5]=1.[CH3:16][C:17]([O:20][C:21](OC1C(Cl)=CC(Cl)=C(Cl)C=1)=[O:22])([CH3:19])[CH3:18]>CN(C)C=O>[C:17]([O:20][C:21]([NH:15][C@:2]([CH3:1])([C:12]([OH:14])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([OH:11])[CH:5]=1)=[O:22])([CH3:19])([CH3:18])[CH3:16]
Reactant: C[C@](N)(Cc1ccc(O)c(O)c1)C(=O)O
Reactant: CC(C)(C)OC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@](C)(Cc1ccc(O)c(O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 127 %

Procedure:
A mixture of 1.19 g (5.00 m moles) L-3-(3,4-dihydroxyphenyl)-2-methylalanine, 1.49 g (5.00 m moles) t-butyl 2,4,5-trichlorophenylcarbonate and 6 ml dimethylformamide is flushed with nitrogen and 1.39 ml (10.0 m moles) triethylamine is added. After stirring at room temperature for 24 hours, 60 ml H2O and 4 ml 2.5 N HCl is added. The solution is extracted 3 times with 50 ml of ethyl acetate and the extract is washed 3 times with 50 ml of water and 1 time with 50 ml of saturated sodium chloride solution and is dried (MgSO4). The solvent is removed in vacuum to give 1.98 g of a blue oil.
Reaction SMILES: F[C:2]1[CH:3]=C(C2C=CC(OCCCCCCCC)=C(F)C=2)C=C[C:7]=1O.[CH2:25]([C@H:30]1[CH2:33][C@H:32]([C:34]([Cl:36])=[O:35])[CH2:31]1)[CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:25]([CH:30]1[CH2:31][CH:32]([C:34]([Cl:36])=[O:35])[CH2:33]1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:7][CH2:2][CH3:3]
Reactant: CCCCC[C@H]1C[C@H](C(=O)Cl)C1
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)c(F)c2)cc1F
Product: CCCCCCCCC1CC(C(=O)Cl)C1
Yield: 120.8 %

Procedure:
Except that 0.60 g of the crude 3,3 '-difluoro-4-hydroxy-4'-octyloxybiphenyl obtained in Example 5- (c) was used in place of 0.7 g of the crude 3,3'-difluoro-4-hydroxy-4'-decyloxybiphenyl and 0.4 g of the crude trans-3-pentylcyclobutanecarboxylic acid chloride obtained in (d) above in place of 0.5 g of the 3-octylcyclobutanecarboxylic acid chloride used in Example 9-(g) and purification was carried out by way of column chromatography on silica gel (eluent: hexane/benzene=2/1), the operation was performed in the same manner as in Example 9-(g) to obtain 0.84 g (yield 91.1%) of 3,3'-difluoro-4-octyloxybiphenyl-4'-yl trans-3-pentylcyclobutanecarboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6]([F:8])[CH:7]=1.C([Li])(C)(C)C.[F:18][C:19]([F:26])([F:25])[C:20](OCC)=[O:21].O>CCOCC>[F:18][C:19]([F:26])([F:25])[C:20]([C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6]([F:8])[CH:7]=1)=[O:21]
Reactant: CCOC(=O)C(F)(F)F
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: O
Product: O=C(c1cc(F)cc(C(F)(F)F)c1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 75.9 %

Procedure:
5.00 g (20.57 mmol) of 3-bromo-5-fluorobenzotrifluoride were stirred in 60 ml of dry ether and admixed dropwise at −78° C. under a protective gas atmosphere (argon) with 1.33 ml (20.75 mmol) of tert-butyllithium solution [cf. also trifluoroacylation: H. K. Nair, D. M. Quinn Bioorganic & Medicinal Chemistry Letters 3(12), 2619-22 (1993); G. J. Pork et al., J. Org. Chem. 22, 993 (1957)]. Subsequently, the reaction mixture was stirred at −78° C. for 45 minutes and then added dropwise, with the aid of a syringe, in portions at −78° C., to a solution of 3.71 g (26.17 mmol) of ethyl trifluoroacetate in 40 ml of dry ether. Thereafter, the entire reaction mixture was stirred first at −78° C. for 10 minutes and then at room temperature for one hour. For workup, the entire reaction mixture was added to water and extracted with ether. The organic phase was removed and dried at 40° C. under reduced pressure (not less than 10 mbar owing to the high volatility of the compound). This gave 4.06 g (75.9% of theory) of 2,2,2-trifluoro-1-[3-fluoro-5-(trifluoromethyl)phenyl]-ethanone, which was isolated as the hydrate.
Reaction SMILES: [CH2:1]([P:3]([O-:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2].[O-]CC.[Na+].[CH2:14](Cl)[CH:15]=[CH2:16]>C(O)C>[CH2:1]([P:3]([CH:14]=[CH:15][CH3:16])(=[O:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2]
Reactant: CCCCOP([O-])CC
Reactant: C=CCCl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC=CP(=O)(CC)OCCCC
Yield: 26 %

Procedure:
At room temperature, a three-neck flask equipped with stirrer and high-performance condenser is initially charged with 400 g of ethanol and this initial charge is devolatilized by stirring and passing nitrogen through it. Then, under nitrogen, 30 g (0.2 mol) of butyl ethylphosphonite (produced as in Example 3) are added, followed by the dropwise addition of initially 14.5 g (0.25 mol) of sodium ethoxide in ethanol and thereafter 19.1 g (0.25 mol) of allyl chloride. Following a reaction time of 5 hours, the reaction solution is passed for purification through a column charged with Deloxan® THP II and the solvent is removed in vacuo. The product (butyl ethylpropenylphosphinate) is purified by column chromatography to obtain 9.9 g (26% of theory) of butyl ethylpropenylphosphinate as colorless oil.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[CH3:6][N:7]([CH3:30])[C:8]([C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([NH:21][C:22]3[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=3)[N:16]=[C:17]2Cl)=[CH:12][C:11]=1[O:28][CH3:29])=[O:9]>>[CH3:30][N:7]([CH3:6])[C:8]([C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([NH:21][C:22]3[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=3)[N:16]=[C:17]2[O:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:12][C:11]=1[O:28][CH3:29])=[O:9]
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1C(=O)N(C)C
Reactant: OC1CCC1
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(OC3CCC3)c2cc1C(=O)N(C)C

Procedure:
Similar procedure as described in example 400 was used, starting from cyclobutanol and 1-Chloro-6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-7-carboxylic acid dimethylamide to give 1-Cyclobutoxy-6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-7-carboxylic acid dimethylamide, LC-MS: m/e 396(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][CH2:13][NH2:14])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: NCCC1(c2ccc(Cl)cc2)CCC1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: Clc1ccc(C2(CCN3CCCC3)CCC2)cc1

Procedure:
2-[1-(4-Chlorophenyl)cyclobutyl]ethylamine (12 g) prepared as described in Example 1, 1,4-dibromobutane (12.4 g) and anhydrous sodium carbonate (14.3 g) were mixed in xylene (100 ml) and the mixture heated under reflux with stirring for sixteen hours. The mixture was cooled, filtered and the xylene removed by evaporation to give a residue which on distillation gave N-2-[1-(4-chlorophenyl)cyclobutyl]ethylpyrrolidine (b.p. 148°-150°/1.5 mm Hg) (Formula 1 R1,R2 =H; R3 and R4 together with the nitrogen atom forming a pyrrolidine ring; R5 =4-Cl; R6, R7 and R8 =H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.Cl.[CH3:20][C:21]1[C:22]([CH2:28][NH2:29])=[N:23][CH:24]=[C:25]([CH3:27])[CH:26]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:29][CH2:28][C:22]2[C:21]([CH3:20])=[CH:26][C:25]([CH3:27])=[CH:24][N:23]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: Cc1cnc(CN)c(C)c1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1cnc(CNc2nc(N)nc(-c3ccco3)c2C#N)c(C)c1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, C-(3,5-dimethyl-pyridin-2-yl)-methylamine dihydrochloride and DBU in DME. ES-MS m/e (%): 321 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[C:27]([Cl:29])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C@H:19]3[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]3)[C:15]2=[O:26])=[C:11]([Cl:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[CH:36]([Si:39](Cl)([CH:43]([CH3:45])[CH3:44])[CH:40]([CH3:42])[CH3:41])([CH3:38])[CH3:37]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([Cl:30])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C@H:19]3[CH2:20][CH2:21][C@H:22]([O:25][Si:39]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])[CH:36]([CH3:38])[CH3:37])[CH2:23][CH2:24]3)[C:15]2=[O:26])=[C:27]([Cl:29])[CH:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1[C@H]1CC[C@H](O)CC1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C

Procedure:
Mix (R)-3-(4-Benzyloxy-2,6-dichloro-benzyl)-trans-1-(4-hydroxy-cyclohexyl)-pyrrolidin-2-one (Preparation 16) (1.37 g, 3.07 mmol) and imidazole (0.527 g, 68.08 mmol) in 10 ml of dry DMF. Add triisopropylsilylchloride (0.81 ml, 3.07 mmol) dropwise and stir at room temperature for 5 hours. Quench with 1N HCl and extract with ethyl acetate. Wash the extract with NaHCO3 and brine. Dry over magnesium sulfate, filter, and concentrate. After flash column chromatography, receive 1.83 g (99%) of the title compound: Mass spectrum (apci) m/z=604 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18].C(N=C=NCCCN(C)C)C>CN(C=O)C>[CH2:17]([N:19]([CH2:20][CH3:21])[C:14]([CH:10]1[O:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:16])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Reactant: CCNCC
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C

Procedure:
4-(t-Butoxycarbonyl)morpholine-2-carboxylic acid and diethylamine were dissolved in DMF, 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide was added thereto at room temperature, and the whole was stirred to obtain t-butyl 2-[(diethylamino)carbonyl]morpholine-4-carboxylate.
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:12]([OH:17])[CH:13]([CH2:15][CH3:16])[CH3:14].N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1>[CH3:14][CH:13]([CH2:15][CH3:16])[CH2:12][O:17][C:1]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[O:10]
Reactant: CCC(C)CO
Reactant: O=Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCC(C)COC(=O)c1ccc(C=O)cc1
Temperature: 25 °C

Procedure:
315 g of said terephthalaldehydic acid chloride dissolved in 400 ml of toluene was dropped into an ice-cooled mixed solution of commercially available S(-)-2-methylbutanol (optically active amyl alcohol) and 230 g of pyridine, and heated under reflux for 2 hours. The reaction solution was cooled to room temperature and further cooled with ice, and acidified by adding 6N hydrochloric acid thereto to remove pyridine in the organic layer. The organic layer was then washed successively with water, 2N aqueous sodium hydroxide solution, and again with water. Toluene as a solvent was distilled off in vacuum, and the remaining reaction product was distilled in vacuum to obtain p-(2-methylbutoxycarbonyl)benzaldehyde (b.p. 118°-124° C./3.5 Torr).