Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](=[O:8])[CH2:3][O:4]C(=O)C.[O:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[C:18]1[C:19]([NH2:38])=[N:20][CH:21]=[C:22]([C:24]2[C:25]([CH2:35][O:36][CH3:37])=[N:26][N:27]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH:28]=2)[CH:23]=1.C(N(CC)CC)C>C(Cl)Cl>[NH2:38][C:19]1[N:20]=[CH:21][C:22]([C:24]2[C:25]([CH2:35][O:36][CH3:37])=[N:26][N:27]([CH:29]3[CH2:34][CH2:33][N:32]([C:3](=[O:4])[CH2:2][OH:8])[CH2:31][CH2:30]3)[CH:28]=2)=[CH:23][C:18]=1[C:10]1[O:9][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=1
Reactant: COCc1nn(C2CCNCC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCc1nn(C2CCN(C(=O)CO)CC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
(2-chloro-2-oxo-ethyl)acetate (0.029 ml) was added in one portion to a stirred mixture of 3-(1,3-benzoxazol-2-yl)-5-[3-(methoxymethyl)-1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (90 mg) and triethylamine (0.062 ml) in CH2Cl2 (5 ml) at 23° C. The resulting mixture was stirred at 23° C. for 2 hours and concentrated to dryness. Methanol (20 ml) and water (1 ml) were added to the residue followed by lithium hydroxide hydrateaqueous solution (0.334 g, 2M). The resulting solution was stirred at 23° C. After 4 hours the reaction mixture was concentrated and the crude product was purified by flash chromatography on silica gel eluting with 0 to 5% methanolic ammonia (7 N) in dichloromethane. The fractions were evaporated to dryness to afford 1-[4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-(methoxymethyl)pyrazol-1-yl]-1-piperidyl]-2-hydroxy-ethanone (42.0 mg) as a solid. NMR Spectrum: (DMSOd6): 1.77-1.87 (m, 1H), 1.88-2.00 (m, 1H), 2.05-2.14 (m, 2H), 2.79-2.89 (m, 1H), 3.11-3.21 (m, 1H), 3.41 (s, 3H), 3.78-3.88 (m, 1H), 4.08-4.21 (m, 2H), 4.40 (s, 2H), 4.41-4.51 (m, 2H), 4.58 (t, 1H), 7.40-7.48 (m, 2H), 7.66 (bs, 2H), 7.78 (dd, 1H), 7.84 (dd, 1H), 8.23 (s, 1H), 8.42 (d, 1H), 8.50 (d, 1H); Mass spectrum: M+H+ 463.
Reaction SMILES: [Li][CH2:2]CCC.[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([CH3:16])[CH:8]=1.CI.O>C1COCC1>[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([CH2:16][CH3:2])[CH:8]=1
Reactant: [Li]CCCC
Reactant: Cc1cc(Cl)ccc1C(=O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CCc1cc(Cl)ccc1C(=O)O
Temperature: 25 °C
Yield: 46 %

Procedure:
To a yellow solution of 2,2,6,6-TMPH (5.45 g, 38.69 mmol) in THF (6 mL) was added n-BuLi (16 mL) slowly at −78° C. under protection of nitrogen, thereto, the mixture was warmed up to room temperature, stirred at this temperature for an hour, and then cooled to −78° C. again, a solution of 4-chloro-2-methylbenzoic acid (3.0 g, 17.58 mmol) in THF (30 mL) was added slowly, kept stirring at this temperature for an hour, added MeI (5.49 g, 38.69 mmol) solution (in 20 mL THF), the mixture above was then stirred overnight at room temperature. LCMS showed the completion of the reaction, added water, the mixture was then washed with ethyl acetate, the aqueous phase was acidified to pH=1, extracted with ethyl acetate twice, and concentrated the organic phase, washed the residue with PE/EA=1/1 to give 1.5 g of the title compound (46%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH:10]=2)O1.Br[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1.C(Cl)Cl>COCCOC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[O:13]1[C:12]2([CH2:17][CH2:18][C:9]([C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=3)=[CH:10][CH2:11]2)[O:16][CH2:15][CH2:14]1
Reactant: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(C2=CCC3(CC2)OCCO3)nc1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dioxaspiro[4.5]dec-7-ene prepared as above (8.40 g, 31.56 mmol), 2-bromo-5-nitropyridine (6.0 g, 29.55 mmol) in DME (200 mL), degassed 2M potassium carbonate (40 mL) was added palladium tetrakis(triphenylphosphine) (Pd(PPh3)4; 1.8 g, 1.58 mmol). The reaction mixture was evacuated with nitrogen (3 cycles) and allowed to stir under vacuum for 5 minutes, then heated to 80° C. overnight. The reaction mixture was allowed to cool to ambient temperature, EtOAc (200 mL) was added followed by water (200 mL), the suspension was filtered and the organic phase was separated and the aqueous layer re-extracted into EtOAc (200 mL). The organic extracts were combined, washed with brine (200 mL), dried (MgSO4) and concentrated to leave crude product. DCM was added and the suspension was filtered and dried to leave the title compound (1.64 g). The filtrate was concentrated after the addition of DCM a further 1.51 g of product was obtained, the filtrate was purified on a 120 g SiliCycle cartridge eluting 20-50-70% EtOAc in isohexane to provide 1.72 g of product. Total yield is 4.85 g (18.51 mmol, 58%);
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:11][CH:10]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.[CH:19]1([NH:22][C:23]([C:25]2[C:34](=[O:35])[C:33]3[C:28](=[N:29][CH:30]=[CH:31][CH:32]=3)[N:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[C:38]([Br:43])[CH:37]=3)[CH:26]=2)=[O:24])[CH2:21][CH2:20]1.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CCOC(C)=O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:43][C:38]1[CH:39]=[C:40]([C:3]2[CH:8]=[CH:7][C:6]([CH:9]3[CH2:11][CH:10]3[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=2)[CH:41]=[C:36]([N:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][N:29]=3)[C:34](=[O:35])[C:25]([C:23]([NH:22][CH:19]3[CH2:20][CH2:21]3)=[O:24])=[CH:26]2)[CH:37]=1
Reactant: O=C(NC1CC1)c1cn(-c2cc(Br)cc(Br)c2)c2ncccc2c1=O
Reactant: CCOC(=O)C1CC1c1ccc([Sn](C)(C)C)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC1c1ccc(-c2cc(Br)cc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)cc1
Temperature: 80 °C

Procedure:
A mixture of ester from step 2 (1.7 eq), dibromo from step 1 (1 eq), Pd2(dba)3 (0.05 eq) and triphenylarsine (0.25 eq) in DMF (0.05M) was heated at 80° C. for 2 h. The mixture was cooled to rt, diluted with EtOAc and water, the organic was washed with brine, dried and solvent evaporated. The residue was purified by flash chromatography (CH2Cl2:MeOH; 99:1 to 90:10) to afford the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[C:31]([OH:32])=[CH:30][CH:29]=[C:28]([CH3:33])[CH:27]=1>C(OCCO)C>[OH:32][C:31]1[CH:30]=[CH:29][C:28]([CH3:33])=[CH:27][C:26]=1[NH:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: Cc1ccc(O)c(N)c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3cc(C)ccc3O)c2cc1OC
Yield: 93.9 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, in 15 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 147.8 mg (1.2 mmol) of 2-amino-p-cresol to give 315.0 mg (94.0%) of the product as a yellow solid, m.p. 198-200° C., mass (electrospray, m/e): M+H 335.8.
Reaction SMILES: C(N([CH2:10][C:11]1[C:19]2[C:18](=[O:20])[N:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16](=[O:27])[N:15]([CH2:28][C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])[C:14]=2[S:13][C:12]=1[C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([NH:46][O:47][CH3:48])=[O:45])=[CH:39][CH:38]=1)C)C1C=CC=CC=1.[Cl:49]C([O-])=O>C1COCC1.C(=O)(O)[O-].[Na+]>[Cl:49][CH2:10][C:11]1[C:19]2[C:18](=[O:20])[N:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16](=[O:27])[N:15]([CH2:28][C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])[C:14]=2[S:13][C:12]=1[C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([NH:46][O:47][CH3:48])=[O:45])=[CH:39][CH:38]=1
Reactant: CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(-c2ccccc2)c(=O)n3Cc2c(F)cccc2F)cc1
Reactant: O=C([O-])Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CONC(=O)Nc1ccc(-c2sc3c(c2CCl)c(=O)n(-c2ccccc2)c(=O)n3Cc2c(F)cccc2F)cc1
Reaction time: 2.5 h

Procedure:
Into a solution of N-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea (7.7 g, 11.53 mmol) in THF (200 ml) which was cooled with a dry ice-acetone bath was added α-choloroethyl chloroformate (1.7 ml, 11.64 mmol). The temperature of the mixture was elevated up to room temperature, and the mixture was stirred for 2.5 hours. The reaction mixture was diluted with saturated aqueous solution of sodium bicabonate and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure.
Reaction SMILES: CS([O:5][C:6]1[CH:7]=[C:8]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([O:17]CC)=[O:16])=[CH:11]2)(=O)=O.O1CCCC1.CO.[OH-].[K+]>O>[OH:5][C:6]1[CH:7]=[C:8]([O:20][C:21]2[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11]2
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OS(C)(=O)=O)c2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2cc(O)c3[nH]c(C(=O)O)cc3c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.5 %

Procedure:
To a mixture of ethyl 7-[(methylsulfonyl)oxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (2.81 g), tetrahydrofuran (30 mL) and methanol (20 mL) was added a solution of potassium hydroxide (85%, 1.8 g) in water (20 mL). The mixture was stirred at room temperature for 15 h and then partitioned between ethyl acetate and aqueous citric acid solution. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated to give a light brown solid, which was washed with ethyl acetate-hexane to give the title compound (2.12 g, 98%) as a light orange solid.
Reaction SMILES: C(Cl)(Cl)Cl.[C:5]([O-:8])(=O)[CH3:6].[C:9]([O-:12])(=O)[CH3:10].C([O-])(=O)C.[Cl:17][C:18]1[CH:31]=[CH:30][C:21]([C:22]2[CH:27]=[C:26]([CH3:28])[C:25]([Pb+3])=[CH:24][CH:23]=2)=[CH:20][CH:19]=1.Cl.[C:33]1(C)[CH:38]=CC=[CH:35][CH:34]=1>CN(C)C1C=CN=CC=1>[Cl:17][C:18]1[CH:31]=[CH:30][C:21]([C:22]2[CH:27]=[C:26]([CH3:28])[C:25]([CH:6]3[C:5](=[O:8])[CH:34]4[CH2:35][CH:10]([CH2:38][CH2:33]4)[C:9]3=[O:12])=[CH:24][CH:23]=2)=[CH:20][CH:19]=1
Reactant: CC(=O)[O-]
Reactant: Cc1ccccc1
Reactant: Cc1cc(-c2ccc(Cl)cc2)ccc1[Pb+3]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: Cc1cc(-c2ccc(Cl)cc2)ccc1C1C(=O)C2CCC(C2)C1=O
Temperature: 80 °C

Procedure:
Bicyclo[3.2.1]-2,4-dione (0.20 g, 1.44 mmol) and 4-dimethylaminopyridine (0.88 g, 7.21_mmol) are added to a mixture of chloroform (4 ml) and toluene (1 ml), and the reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 4′-Chloro-3-methylbiphen-4-yllead triacetate (0.95 g, 1.6 mmol) is added in one portion and the reaction mixture is stirred and heated to 80° C. under an atmosphere of nitrogen for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered through a plug of diatomaceous earth and the two phases separated. The aqueous phase is extracted with dichloromethane (2×5 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 3-(4′-chloro-3-methylbiphen-4-yl)bicyclo[3.2.1]octane-2,4-dione.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1)=[CH2:2].CS(C)=O.[C-:15]#[N:16].[K+]>O>[CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][C:15]#[N:16])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C=Cc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 22.2 g 4-vinyl benzylchloride (0.131 mol), 60 mL dimethylsulfoxide, and 12.8 g potassium cyanide (0.196 mol) was stirred at room temperature for 17 hours. The mixture was poured into 500 mL water and extracted several times with ethyl acetate. The combined organic layers were washed with brine and concentrated under vacuum. The crude red oil was purified by column chromatography on silica gel using 7/93 ethyl acetate/hexane to give 4-vinylbenzylcyanide, a yellow oil (18.03 g, 96%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[CH:19]1([CH2:22][NH2:23])[CH2:21][CH2:20]1>>[CH:19]1([CH2:22][NH:23][C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: NCC1CC1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Product: Cc1c(-c2ccc(C(=O)NCC3CC3)s2)noc1C(F)(F)F
Yield: 67 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and cyclopropylmethylamine by the method described in Example 2 Method B. The reaction mixture was evaporated in vacuo, triturated and filtered with the aid of water, then washed with an aqueous 1 N hydrochloric acid solution followed by water. The crude solid was then triturated with a 25% EtOAc/hexanes solution (3×1 mL) and air dried to afford product as a colorless solid (110 mg, 67%). 1H NMR (CDCl3) 0.27-0.32 (m, 2 H), 0.55-0.61 (m, 2 H), 1.03-1.12 (m, 1 H), 2.37 (d, J=0.9, 3 H), 3.31 (d, J=5.7, 1 H), 3.33 (d, J=5.7, 1 H), 6.23 (br s, 1 H), 7.50 (d, J=4.0, 1 H), 7.56 (d, J=4.0, 1 H). 19F NMR −63.1. LC/MS 6.5 min, [M+1]+ 331.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].Br[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C>C1COCC1>[OH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: NCCOCCO
Reactant: CC(C)(C)OC(=O)CBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNCCOCCO
Temperature: 0 °C
Yield: 23.3 %

Procedure:
2-(2-aminoethoxy)ethanol (11 g, 104.62 mmol, 1.00 equiv) was dissolved in THF (300 mL) and cooled to 0° C. To the stirring solution was added dropwise tert-butyl 2-bromoacetate (20 g, 102.54 mmol, 1.00 equiv) and then triethylamine (15.5 g, 153.18 mmol, 1.50 equiv) dropwise The solution was then stirred for 16 h at room temperature. The solvent was removed and the residue then dissolved in DCM and washed twice with brine, then dried over anhydrous sodium sulfate and solvent removed. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1) as eluent. This resulted in 5.25 g (16%) of the product as a yellow oil. MS (ES, m/z) 220 [M+H]+
Reaction SMILES: [H-].[Na+].[C:3]([C:8]1[CH:22]=[CH:21][C:11]([CH2:12]P(=O)(OCC)OCC)=[CH:10][CH:9]=1)([O:5][CH2:6][CH3:7])=[O:4].[CH:23]([C:25]1[C:34]([O:35][CH2:36][C:37]#[C:38][CH2:39][CH3:40])=[CH:33][C:32]2[C:31]([CH3:42])([CH3:41])[CH2:30][CH2:29][C:28]([CH3:44])([CH3:43])[C:27]=2[CH:26]=1)=O>CN(C=O)C>[CH2:36]([O:35][C:34]1[C:25](/[CH:23]=[CH:12]/[C:11]2[CH:10]=[CH:9][C:8]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:22][CH:21]=2)=[CH:26][C:27]2[C:28]([CH3:44])([CH3:43])[CH2:29][CH2:30][C:31]([CH3:42])([CH3:41])[C:32]=2[CH:33]=1)[C:37]#[C:38][CH2:39][CH3:40]
Reactant: CCC#CCOc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)c1ccc(CP(=O)(OCC)OCC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC#CCOc1cc2c(cc1/C=C/c1ccc(C(=O)OCC)cc1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Yield: 90.1 %

Procedure:
193 mg of NaH (55% in mineral oil) were placed in 10 ml of abs. DMF under argon and 1.66 g of diethyl (4-carbethoxybenzyl)-phosphonate were added thereto at 0° and the mixture was subsequently stirred at room temperature until the H2 evolution had finished. Then, 1.08 g of 2-formyl-3-pent-2-ynyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene without addition solvent were added at 0°. After 30 min. at room temperature the mixture was extracted with hexane and washed twice with ethanol/H2O=8/2. Drying, evaporation and direct crystallization from hexane yielded 1.45 g of ethyl (E)-4-[2-(3-pent-2-ynyloxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-vinyl]-benzoate as yellowish crystals of m.p. 80°-82°.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[I-].[Na+].[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[C:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29]Cl)[CH2:24][CH2:23]2)=[CH:17][CH:16]=1>O1CCCC1>[C:3]([CH:2]([CH2:29][CH2:28][N:25]1[CH2:24][CH2:23][C:22](=[C:21]([C:18]2[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=2)[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: Fc1ccc(C(=C2CCN(CCCl)CC2)c2ccc(F)cc2)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)C(C)=O
Temperature: 20 °C

Procedure:
0.182 mol of ethyl acetoacetate is added at 0° C. to a suspension containing 0.182 mol of sodium hydride in 800 ml c.f tetrahydrofuran. The reaction medium is maintained for one hour at 20° C. and 0.182 mol of sodium iodide is then added. The mixture is cooled to 0° C. and 0.182 mol of 4-[bis(4-fluorophenyl)methylene]-1-(chloroethyl)piperidine is added. The mixture is brought to reflux for 12 hours and then concentrated under vacuum. The residue is taken up in water and the product is extracted with dichloromethane. The oil obtained is purified by chromatography on a column of 70-230 mesh silica, eluting with a mixture of dichloromethane and methanol (99:1 V/V).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([NH2:13])[C:10]2=[N:14][C:15]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[CH:16][C:17](=[O:18])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:25][O:26][C:27]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:28]=1[C:29](O)=[O:30].ClC1C=CC(C(O)=O)=C(OC)C=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([NH:13][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[CH:35][C:27]=2[O:26][CH3:25])[C:10]2=[N:14][C:15]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)=[CH:16][C:17](=[O:18])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCn2c(nc(-c3ccncc3)cc2=O)C(N)C1
Reactant: COc1ccc(C(=O)O)c(OC)c1
Agent: COc1cc(Cl)ccc1C(=O)O
Product: CCOC(=O)N1CCn2c(nc(-c3ccncc3)cc2=O)C(NC(=O)c2ccc(OC)cc2OC)C1

Procedure:
By analogy with the method described in example 1 (step 1.8), using 9-amino-4-oxo-2-pyridin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester and 2,4-dimethoxy-benzoic acid in place of (+/−)-9-amino-4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza benzocycloheptene-7-carboxylic acid ethyl ester hydrobromide (1:1) and 4-chloro-2-methoxy-benzoic acid, the compound, 0.103 g (76%), was obtained as a white powder.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[C:20]([CH:22]1[NH:27][CH2:26][CH2:25][NH:24][CH2:23]1)#[CH:21]>N1C=CC=CC=1>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:24]4[CH2:25][CH2:26][NH:27][CH:22]([C:20]#[CH:21])[CH2:23]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: C#CC1CNCCN1
Solvent: c1ccncc1
Product: C#CC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1
Temperature: 140 °C
Yield: 13.5 %

Procedure:
A mixture of 1.23 g of 7 -chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.95 g of 3-ethynylpiperazine and 15 ml of pyridine is heated at 140° C. in a pressure bottle for 18 hours and then purified as described in Example 101, giving 210 mg of the desired product.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.C(N(C(C)C)C=O)(C)C.[CH2:16]([C:18]1[CH:31]=[CH:30][C:21]([O:22][C:23]2[C:24](=O)[NH:25][CH:26]=[N:27][CH:28]=2)=[CH:20][CH:19]=1)[CH3:17].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:4][C:24]1[C:23]([O:22][C:21]2[CH:30]=[CH:31][C:18]([CH2:16][CH3:17])=[CH:19][CH:20]=2)=[CH:28][N:27]=[CH:26][N:25]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCc1ccc(Oc2cnc[nH]c2=O)cc1
Agent: CC(C)N(C=O)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCc1ccc(Oc2cncnc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of oxalyl chloride (Aldrich) (1.97 g, 15.2 mmoles) in dichloromethane (6 mL) was added in several portions to a stirred, ice-bath cooled solution of diisopropylformamide (Aldrich) (2.00 g, 15.17 mmoles) in dichloromethane (25 mL). The ice-bath was removed, and the solution was stirred at ambient temperature for 10 minutes. Solid 5-(4-ethylphenoxy)pyrimidin-4(3H)-one (1.00 g, 4.62 mmoles) was added, and the mixture was refluxed with stirring for 45 minutes. The solution was cooled and poured into a cold solution of vigorously stirred, saturated aqueous sodium bicarbonate (80 mL). The organic layer was washed with cold saturated aqueous sodium bicarbonate (80 mL), with cold water (80 mL) and then dried over sodium sulfate. The dry solution was spin evaporated in vacuo to give the intermediate 4-chloro-5-(4-ethylphenoxy)pyrimidine as an orange liquid. The liquid was dissolved in ethanol (50 mL) and trans-4-hydroxycyclohexylamine hydrochloride (Aldrich) (1.79 g, 11.45 mmoles) was added. A solution of sodium ethoxide, which had been prepared from sodium hydride (60% in mineral oil) (Aldrich) (0.41 g, 10.25 mmoles) and ethanol (15 mL) was added. The flask was rinsed with ethanol (10 mL), and the reaction was refluxed with stirring for 65 hours. The volatiles were removed by spin evaporate in vacuo to a small volume, and the residue was triturated with water (100 mL). The gummy residue was extracted with dichloromethane (150 mL). The solution was washed with water (80 mL), dried over sodium sulfate and spin evaporated in vacuo. This material was dissolved in ethyl acetate-hexanes and chromatographed on Silica Gel 60 (E. M. Science, 230-440 mesh) (13×4 cm column bed) using ethyl acetate as the eluent for the first 1.2 L and then with 5% ethanol in ethyl acetate. The fractions that contained homogeneous product were spin evaporated in vacuo to give a syrup. The pure 5-(4-ethylphenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine was converted to the hydrochloride by the same procedure described in Example 4. The residue was triturated under ethyl acetate to give a white solid which was collected, washed with ethyl acetate and dried in vacuo to give 1.25 g (77% yield) of 5-(4-ethylphenoxy)-4-(trans-4-hydroxycyclohexylamino)pyrimidine hydrochloride as a white solid, mp 245-243° C.