Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[N:16](CC=C)[C:15]([Cl:23])=[N:14][C:13]=2[N:12]([CH2:24][CH2:25][CH2:26][CH3:27])[C:11]1=[O:28])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].[C:35]1([N:41]2[C:45](=[O:46])[N:44]=[N:43][NH:42]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.N1CCOCC1>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.CO.CN(C=O)C>[CH2:24]([N:12]1[C:13]2[N:14]=[C:15]([Cl:23])[NH:16][C:17]=2[C:18](=[O:19])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:44]2[C:45](=[O:46])[N:41]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:42]=[N:43]2)[C:11]1=[O:28])[CH2:25][CH2:26][CH3:27]
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCCOS(C)(=O)=O)c(=O)n2CCCC
Reactant: O=c1nn[nH]n1-c1ccccc1
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: [Cs+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: CCCCn1c(=O)n(CCCCn2nnn(-c3ccccc3)c2=O)c(=O)c2[nH]c(Cl)nc21
Temperature: 50 °C
Reaction time: 60 h
Yield: 49 %

Procedure:
A mixture of 4-[3-butyl-8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purin-1-yl]butyl methanesulfonate (50 mg, 0.12 mmol), Cs2CO3 (45 mg, 0.14 mmol) and DMF (3 ml) was treated with 1-phenyl-1,2-dihydro-5H-tetrazol-5-one (23 mg, 0.14 mmol) and stirred for 60 h at 50° C. After cooling, the mixture was degassed by applying a vacuum and then nitrogen was introduced. Pd(PPh3)4 (20 mg, 0.017 mmol) was added and the mixture degassed once more. Morpholine (150 μl, 1.7 mmol) was added and the mixture was stirred under nitrogen for 18 h, then partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated and the aqueous layer extracted again with EtOAc. The combined extracts were concentrated, giving a yellow residue. MeOH was added and then passed down an aminopropyl column with the product eluting with 2% AcOH/MeOH. Further purification by MDAP gave the title compound as an off-white solid (27 mg, 51%). NB. ca. 10% O-alkylated material present.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[Cl:27][C:28]([O:30][CH2:31][CH2:32][CH3:33])=[O:29]>>[ClH:27].[ClH:27].[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][C:28](=[O:29])[O:30][CH2:31][CH2:32][CH3:33])[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: CCCOC(=O)Cl
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: CCCOC(=O)Nc1cccc(CCN2CCN(c3cccc4nc(C)ccc34)CC2)c1
Product: Cl
Yield: 78 %

Procedure:
The title compound was prepared in 78% yield according to the general procedure for the preparation of carbamates (Method D) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and propyl chloroformate.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl[C:31]1[C:36]([CH3:37])=[N:35][CH:34]=[CH:33][N:32]=1.C(N(CC)CC)C>C(O)CO>[CH3:37][C:36]1[C:31]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)=[N:32][CH:33]=[CH:34][N:35]=1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Reactant: Cc1nccnc1Cl
Solvent: CCN(CC)CC
Solvent: OCCO
Product: Cc1nccnc1N1CCN(C(=O)c2ccc(Nc3ccnc4cc(C(F)(F)F)ccc34)cc2)CC1

Procedure:
In the manner given in Example 6, a mixture of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine, 2-chloro-3-methylpyrazine and triethylamine is heated in ethylene glycol at 75° to 95° C. to give 1-(3-methylpyrazin-2-yl)-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[CH2:18][C:19]([O:21][CH3:22])=[O:20].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:33]1[CH2:37]OC[CH2:34]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]([CH3:17])([CH3:15])[CH3:16])[C:3]=1[CH:18]([CH2:34][CH2:33][CH3:37])[C:19]([O:21][CH3:22])=[O:20]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1C(C)(C)C)CCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1C(C)(C)C)CCC3
Yield: 46.1 %

Procedure:
This compound was prepared according to the procedure C from Methyl [2-methyl-4-(tert-butyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate (0.067 g; 0.211 mmol), LHMDS 1N in THF (0.232 mL; 0.232 mmol), 1-iodopropane (0.031 mL; 0.317 mmol) in DMF (0.85 mL) for 3 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 0.035 g (46%) of the title compound as a yellow oil.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:48])[N:20]([CH2:39][C:40]2[CH:41]=[N:42][C:43]([CH2:46][CH3:47])=[CH:44][CH:45]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:48])[N:20]([CH2:39][C:40]2[CH:41]=[N:42][C:43]([CH2:46][CH3:47])=[CH:44][CH:45]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(Cc2ccc(CC)nc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccc(CC)nc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 36.4 %

Procedure:
A mixture of hydroxylammonium chloride (2.04 g), sodium hydrogen carbonate (3.28 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-({4-butyl-1-[(6-ethylpyridin-3-yl)methyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.93 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.38 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.32 mL) were added, and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and 1 M hydrochloric acid was added and adjusted to pH 5, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.38 g, 36%).
Reaction SMILES: [CH2:1]([O:6][CH2:7][C:8]#[C:9][CH2:10][OH:11])[CH2:2][CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C=O>C(OCC)C.O>[CH3:19][S:20]([O:11][CH2:10][C:9]#[C:8][CH2:7][O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])(=[O:22])=[O:21]
Reactant: CCCCCOCC#CCO
Reactant: CS(=O)(=O)Cl
Agent: C=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCOCC#CCOS(C)(=O)=O
Temperature: 5 °C
Yield: 9009.8 %

Procedure:
To a 300 mL 3 neck flask equipped with magnetic stirrer, addition funnel, and nitrogen inlet was charged 7.42 grams (g) of 4-(pentyloxy)but-2-yn-1-ol (0.45 mmol), 70 mL of dry ethyl ether, and 6.8 g (68 mmoles) of anhydrous triethyl amine The reaction mixture was cooled to 5° C. with stirring followed by the dropwise addition of 4.95 g (43 mmole) of methane sulfonyl chloride in 7 mls of ethyl ether. The temperature was adjusted to 0° C. and 5.4 g (180 mmole) of solid paraformaldehyde was added. The mixture was then stirred at 10-15° C. for 6 hours, then diluted with another 40 mls of ether and 70 mls of water. The organic phase was separated, and washed with water and brine, then dried over anhydrous magnesium sulfate. Filtered and concentrated under vacuum on a rotary evaporator. Isolated 9.5 g of a clear colorless liquid which was consistent with the desired structure upon analysis by 300 MHz 1H NMR.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].CC[Mg+].[Br-].[C:13](Cl)(=[O:17])[C:14](Cl)=[O:15].[CH2:19]([OH:21])[CH3:20]>C(OCC)C.C1(C)C=CC=CC=1>[CH2:19]([O:21][C:13](=[O:17])[C:14]([C:6]1[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=1[OH:5])=[O:15])[CH3:20]
Reactant: CCO
Reactant: Oc1cccc(O)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: CC[Mg+]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62 %

Procedure:
To a solution of resorcinol (5.0 g, 45.4 mmol, 1 eq) in diethyl ether (30 mL) was added 3M EtMgBr (18.5 mL, 50.0 mmol, 1.1 eq)) dropwise under argon. The reaction mixture was stirred at rt for 20 min. The ether was removed under vacuum and anhydrous toluene (80 mL) was added. A solution of oxalyl chloride (4.36 mL, 50 mmol, 1.1 eq) in toluene (20 mL) was added to the mixture dropwise under argon. The reaction mixture was stirred at rt for 15 h. Anhydrous ethanol (40 mL) was added to the mixture and the reaction mixture was stirred at rt for 1 h. Most of the solvent was evaporated and then EtOAc (60 mL) and water (40 mL) were added to the mixture. The layer was separated and the organic layer was washed with water (2×40 mL), dried over Na2SO4, filtrated, and concentrated under reduced pressure. The residue was purified by column chromatography eluted with 20% EtOAc/hexane then 50% EtOAc/hexane solution to afford white solid (5.88 g, 62%) as product. 1H-NMR (CD3CN): δ 7.62(d, J=9.0 Hz, 1H), 6.50 (dd, J=2.3, 9.0 Hz, 1H), 6.41 (d, J=2.3 Hz, 1H), 4.44 (q, 2H), 1.40 (t, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4].[C:13]([O-:16])(=[O:15])[CH3:14].[Na+]>[Na+].[I-].CN(C=O)C>[C:13]([O:16][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[F:12])=[O:4])(=[O:15])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: O=C(CCl)c1ccc(F)cc1F
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCC(=O)c1ccc(F)cc1F
Temperature: 20 °C
Reaction time: 18 h
Yield: 92.2 %

Procedure:
Add 191 g of 2-chloro-2',4'-difluoroacetophenone (Aldrich Chemical Co.) to a mixture of 246 g of sodium acetate, 3 g of NaI, and 3L of DMF. Stir the mixture at 20° C. for 18 hr. then concentrate it to 1L. Pour the residue into 6L of cold dilute aqueous HCl and extract with EtOAc. Wash the extract with brine, dry it over anhydrous Na2SO4, filter the so-formed mixture, and evaporate the filtrate to leave a residue. Chromatograph the residue on silica gel, eluting with CH2Cl-2-hexane to obtain 198 g of the title compound. ##STR100##
Reaction SMILES: O(Cl)[Cl:2].[P+5].[CH:5]1([C:10]2[NH:15][C:14](=O)[CH:13]=[C:12]([CH2:17][CH3:18])[N:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1>[OH-].[Na+]>[Cl:2][C:14]1[CH:13]=[C:12]([CH2:17][CH3:18])[N:11]=[C:10]([CH:5]2[CH2:9][CH2:8][CH2:7][CH2:6]2)[N:15]=1
Reactant: ClOCl
Reactant: CCc1cc(=O)[nH]c(C2CCCC2)n1
Agent: [Na+]
Agent: [OH-]
Agent: [P+5]
Product: CCc1cc(Cl)nc(C2CCCC2)n1
Temperature: 100 °C
Yield: 24.6 %

Procedure:
Phosphorus(V) oxychloride (150 g, 99.0 mmol) was slowly added to 2-cyclopentyl-6-ethylpyrimidin-4(3H)-one (18.9 g, 98.3 mmol) at 0° C. Then, the reaction mixture was warmed to 100° C. for 3 h. After this time, the mixture was cooled, diluted with sodium hydroxide, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/dichloromethane) to afford the title compound (5.1 g, 57%) as yellow oil. MW=210.70. 1H NMR (CDCl3, 300 MHz) δ 7.01 (s, 1H), 3.36-3.20 (m, 1H), 2.74 (q, J=7.5 Hz, 2H), 2.14-1.99 (m, 2H), 1.98-1.76 (m, 4H), 1.75-1.63 (m, 2H), 1.29 (t, J=7.5 Hz, 3H); APCI MS m/z 211 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[C:5]2[C:18]([O:20]CC)=O.B(Br)(Br)Br.C(Cl)Cl.[CH3:30][NH2:31].C1COCC1>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[C:5]2[C:18]([NH:31][CH3:30])=[O:20]
Reactant: CN
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)[nH]c2ccc(Br)cc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)[nH]c2ccc(Br)cc12
Temperature: 25 °C
Yield: 70 %

Procedure:
A suspension of ethyl 5-bromo-2-(4-fluorophenyl)-1H-indole-3-carboxylate (90 mg, 0.25 mmol) in 1,2-dichloroethane (3 mL) was cooled in an ice bath under an atmosphere of N2. A solution of boron tribromide in CH2Cl2 (1 M, 0.75 mL, 0.75 mmol) was added the reaction was allowed warm to r.t. under N2 over 4 h. Then the reaction was then quenched by the addition of a solution of methylamine in THF (2 M, 5 mL, 10 mmol). The reaction was partitioned between EtOAc and water, the organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated to give a colorless oil. Et2O/hexanes was added and a white precipitate formed. The powder was collected by filtration, washed with Et2O, and air dried to give the title compound (60 mg, 70% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.93 (s, 1H) 7.82 (d, J=1.83 Hz, 1H) 7.71-7.78 (m, 3H) 7.32-7.41 (m, 3H) 7.29 (dd, J=8.55, 1.83 Hz, 1H) 2.75 (d, J=4.58 Hz, 3H). LC/MS was performed on a Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=5% CH3CN/95% H2O/10 mM NH4OAc, solvent B=95% CH3CN/5% H2O/10 nM NH4OAc, start % B=0, final % B=100, gradient time=2 min, stop time=3 mM, flow rate=5 ml/min, column: XBridge C18 5 μm 4.6×50 mm; HPLC Rt=1.26, (ES+) m/z (MH+)=347, 349 (1:1 ratio).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:10]([CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH:5]=[CH:6][CH:7]=1.[Cl:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30].C([O-])([O-])=O.[K+].[K+].[I-].[K+]>CN(C)C=O>[ClH:22].[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:10]([CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)CN(CCc1cccc(O)c1)Cc1ccco1
Reactant: Fc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)CN(CCc1cccc(OCc2ccccc2F)c1)Cc1ccco1
Product: Cl
Yield: 71.5 %

Procedure:
A solution of 60 mg (0.21 mmol) of 2-[[2-(3-hydroxy-phenyl)-ethyl]-(furan-2-ylmethyl)-amino]-N-methyl-acetamide, 36 mg (0.25 mmol) of 1-chloromethyl-2-fluoro-benzene, 44 mg of K2CO3 (0.32 mmol) and 3 mg of potassium iodide in 4 ml of dimethylformamide was refluxed overnight. The solvent was removed under vacuum and the crude product was purified by preparative HPLC. The isolated product was dissolved in ethyl acetate/hydrochloric acid. The solvent was removed under vacuum and the residue was triturated with diethyl ether. 65 mg (72% yield) of the title compound were isolated as a white solid.
Reaction SMILES: [CH3:1][Mg]Cl.[CH3:4][Si:5]1([CH3:12])[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:8]1([OH:11])[CH2:9][CH2:10][Si:5]([CH3:12])([CH3:4])[CH2:6][CH2:7]1
Reactant: C[Mg]Cl
Reactant: C[Si]1(C)CCC(=O)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)CC[Si](C)(C)CC1
Reaction time: 2 h
Yield: 90 %

Procedure:
To a tetrahydrofuran solution of 1.0M methylmagnesium chloride under ice cooling was added dropwise 14.2 g of 4,4-dimethyl-4-silacyclohexanone (which is synthesized by the disclosure of JP-A 7-309878). After two hours of agitation, an aqueous solution of ammonium chloride was added for hydrolysis. After ordinary post-treatments including extraction, washing and concentration, the product was purified by sublimation, obtaining 14.2 g (yield 90%) of 1,4,4-trimethyl-4-silacyclohexanol.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([N+:23]([O-:25])=[O:24])=[C:6]([C:8]([C:21]#[N:22])([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)C(OCC)=O)[N:7]=1.Cl>[OH-].[Na+]>[NH2:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([N+:23]([O-:25])=[O:24])=[C:6]([CH:8]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]#[N:22])[N:7]=1
Reactant: CCOC(=O)C(C#N)(Cc1ccccc1)c1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#CC(Cc1ccccc1)c1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
A solution of 2-Amino-α-cyano-1,6-dihydro-5-nitro-α-(phenylmethyl)-6-oxo-4-pyrimidine-acetic acid, ethyl ester as prepared above (2.0 g) in 1N NaOH (100 mL) is stirred at room temperature for 1 h and is acidified with 4N HCl (30 mL). The precipitate is collected by filtration and dried under vacuum to give 2-Amino-1,6-dihydro-5-nitro-6-oxo-α-(phenylmethyl)-4-pyrimidineacetonitrile (600 mg, 36%). ##STR13##
Reaction SMILES: [S:1]([O:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH:16]=[CH:15][O:14]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][OH:25])=[CH:22][CH:21]=1>C(OCC)C.O=P(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:25][C@@H:15]2[O:14][C@@H:13]([CH2:12][O:11][S:1]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=3)(=[O:3])=[O:2])[CH2:18][CH2:17][CH2:16]2)=[CH:22][CH:21]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC=CO2)cc1
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@H](OCc3ccc(Cl)cc3)O2)cc1
Yield: 74.9 %

Procedure:
3 g of 2-tosyloxymethyl-3,4-dihydro-2H-pyran and 1.91 g of p-chlorobenzyl alcohol were dissolved in 40 ml of diethyl ether, and 2-3 drops of phosphorus oxytrichloride were added to the resulting solution. The mixture was then allowed to react at room temperature for 1.5 days, after which 2 drops of triethylamine were added and the mixture was concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel, eluted with a 8:1 by volume mixture of hexane and ethyl acetate, to give 3.44 g of trans-6-(4-chlorobenzyloxy)-2-tosyloxymethyltetrahydropyran (having the lesser polarity), 0.59 g of cis-6-(4-chlorobenzyloxy)-2-tosyloxymethyltetrahydropyran (having the greater polarity) and 0.86 g of an approximately 1:1 cis/trans mixture.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH2:9]1)C1C=CC=CC=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[C:33](Cl)=[O:34]>>[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([C:33]([N:8]2[CH2:13][CH2:12][C@H:11]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C@H:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[CH2:9]2)=[O:34])[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C1COCCN1
Reactant: O=C1CCN(Cc2ccccc2)CC1c1ccccc1Cl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCOCC2)[C@H](c2ccccc2Cl)C1

Procedure:
The title compound, MS: m/e=521.1 (M+H+), was prepared in accordance with the general method of example 26 from 1-benzyl-3-(2-chloro-phenyl)-piperidin-4-one, morpholine and 3,5-bistrifluoromethyl-benzoyl chloride.
Reaction SMILES: C([NH:5]CC(C)C)C(C)C.C(N(CC)CC)C.[CH3:17][C:18]1[CH:31]=[C:30]2[C:21]([S:22][C:23]3[CH:24]=[C:25]([C:33](Cl)=[O:34])[CH:26]=[CH:27][C:28]=3[C:29]2=[O:32])=[CH:20][CH:19]=1>C(Cl)Cl.O>[CH3:17][C:18]1[CH:31]=[C:30]2[C:21]([S:22][C:23]3[CH:24]=[C:25]([C:33]([NH2:5])=[O:34])[CH:26]=[CH:27][C:28]=3[C:29]2=[O:32])=[CH:20][CH:19]=1
Reactant: Cc1ccc2sc3cc(C(=O)Cl)ccc3c(=O)c2c1
Reactant: CC(C)CNCC(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc2sc3cc(C(N)=O)ccc3c(=O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
A solution of 5.0 g (38.8 mmoles) of diisobutyl amine and 5.0 g (49.5 mmoles) of triethyl amine in 40 cc of CH2Cl2 is poured drop by drop in the CH2Cl2 solution containing 7.47 g (25.9 mmoles) of 7-methyl 9-oxo-thioxanthene-3-carbonyl chloride. After approximately 1 hour at room temperature under stirring, the mixture is poured in water, the organic phase is separated and washed again with water. The organic phase is then separated, dehydrated and dried after purification on a flash column (SiO2— eluent: CH2Cl2:AcOEt 9:1). 5.4 g (54.7%) of a yellow solid with the following spectral properties are obtained:
Reaction SMILES: [Br:1][C:2]1[C:16]2=[C:17]3[C:5]([NH:6][CH2:7][CH:8]3[CH2:9][C@@H:10]3[C@@H:15]2[CH2:14][C@H:13]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:12][N:11]3[CH3:26])=[CH:4][CH:3]=1.ClOC(C)(C)C.N>O1CCCC1.C(N(CC)CC)C>[Br:1][C:2]1[C:16]2=[C:17]3[C:5]([NH:6][CH:7]=[C:8]3[CH2:9][C@@H:10]3[C@@H:15]2[CH2:14][C@H:13]([NH:18][C:19](=[O:25])[N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:12][N:11]3[CH3:26])=[CH:4][CH:3]=1
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(Br)ccc4c3C(CN4)C[C@H]2N(C)C1
Agent: CC(C)(C)OCl
Agent: N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(Br)ccc4[nH]cc(c34)C[C@H]2N(C)C1
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 71.8 %

Procedure:
A solution of 4.2 g of 3-(12-bromo-2,3-dihydro-6-methyl-8α-ergolinyl)-1,1-diethylurea in a mixture of 300 ml of absolute tetrahydrofuran and 50 ml of absolute triethylamine is combined at -40° C. with a solution of 1.58 ml of tert-butyl hypochlorite in 250 ml of absolute tetrahydrofuran, and the mixture is stirred for 15 minutes at -40° C. The reaction mixture is poured on 1 liter of ice, combined with 25% strength ammonia solution until the reaction is alkaline, and extracted with dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated. The crude product is crystallized from ethyl acetate/pentane, thus obtaining 3 g of 3-(12-bromo-6-methyl-8α-ergolinyl)-1,1-diethylurea.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[CH2:35][CH2:36]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CC(N(C)C)=O>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[CH2:35][CH2:36][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCCCN2C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccccc1CCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCCCC1CCOc1ccccc1CCc1ccccc1
Yield: 75.6 %

Procedure:
Following a procedure similar to that described in Example 40(a), 0.930 g of 2-(2-phenylethyl)phenol (prepared as described in Preparation 19), 0.527 g of potassium t-butoxide and 1.66 g of 1-t-butoxycarbonyl-2-[2-(p-toluenesulfonyloxy)ethyl]piperidine were reacted in 20 ml of dimethylacetamide. The mixture was then worked lap as described in Example 40(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.34 g (yield 75%) of the title compound as a colorless oil.