Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([Br:17])[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[C:8]([OH:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:7]1=[O:26])[CH3:2].[OH-:29].[K+]>CC(O)(C)C>[CH2:27]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([Br:17])[CH:11]=[C:12]([C:15](=[O:29])[NH2:16])[CH:13]=2)[C:8]([OH:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:7]1=[O:26])[CH3:28]
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c(Br)cc(C#N)cc21
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCN(CC)CCN1C(=O)C(O)(c2ccccc2Cl)c2c(Br)cc(C(N)=O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To 1-(2-diethylaminoethyl)-3-hydroxy-3-(2-chlorophenyl)-4-bromo-6-cyanooxindole (462.6 mg, 1.06 mmol) dissolved in anhydrous t-BuOH (30 mL) at 50° C. was added powdered KOH (1.2 g, 20 eq). The resulting solution was stirred for 1 hour and then cooled to room temperature. Ice was added and the mixture extracted with EtOAc (3×20 mL). The extracts were combined and dried (anhydrous MgSO4). After filtration, the solvent was removed in vacuo to give a light brown solid. Purification was carried out by column chromatography (silica gel, eluting EtOAc:EtOH:Et3N, 80:20:2) to yield the title compound as a white solid (346.5 mg, 69%).
Reaction SMILES: [S:1]([NH2:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].[CH2:12]([CH:19]1[CH2:24][CH2:23][N:22]([C:25](=[O:29])[C:26](O)=[O:27])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OCC)C>[CH2:12]([CH:19]1[CH2:20][CH2:21][N:22]([C:25](=[O:29])[C:26]([NH:9][C:6]2[CH:5]=[CH:4][C:3]([S:1](=[O:10])(=[O:2])[NH2:11])=[CH:8][CH:7]=2)=[O:27])[CH2:23][CH2:24]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Solvent: CCOCC
Product: NS(=O)(=O)c1ccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)cc1

Procedure:
The title compound is prepared from sulfanilamide (Aldrich) and (4-benzyl-piperidin-1-yl)-oxo-acetic-acid (Example 5b) according to the method described in Example 1c. Melting Point: 184-187° C. (diethylether)
Reaction SMILES: O[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[CH2:3][C:4](=[O:8])[CH:5]([CH3:7])[CH3:6].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:6][CH:5]([CH3:7])[C:4](=[O:8])[CH:3]=[CH:2][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1
Reactant: CC(C)C(=O)CC(O)c1cccc([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)C(=O)C=Cc1cccc([N+](=O)[O-])c1
Yield: 97.1 %

Procedure:
A mixture of 1-hydroxy-4-methyl-1-(3-nitrophenyl)pentan-3-one (3.32 g), p-toluenesulfonic acid monohydrate (0.03 g) and toluene (50 mL) was refluxed for 1 hour under Dean-Stark conditions. The mixture was diluted with ethyl acetate, washed (sat. sodium bicarbonate, water and brine) and the solvent removed. Chromatography (hexane/ethyl acetate, 3:1) yielded 4-methyl-1-(3-nitrophenyl)-1-penten-3-one (2.98 g) as a yellow solid. NMR: 1.11 (d,6, J=6.8, CH3), 3.02 (m,1, CH), 7.27 (d,1, J=16.2, CH), 7.73 (m,2, CH,Ar), 8.24 (m,2, Ar), 8.61 (m,1, Ar), MS: m/z=219(M).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:9]([NH:16][C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]([C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1)=[O:34]>C(#N)C>[CH:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:43]=[CH:44][C:35]=1[C:33](=[O:34])[CH2:32][N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([N:16]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])=[O:5]
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(CBr)c1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)c1ccc2ccccc2c1
Yield: 80.6 %

Procedure:
Using the procedure described in example 5, treatment of L-proline-L-isoleucine benzylamide (296 mg, 0.93 mmol), with cesium carbonate (0.61 g, 1.87 mmol), and 2-bromo-2'-acetonaphthone (697 mg, 2.80 mmol, 3.0 eq) in acetonitrile (12 mL), provided 364 mg (80%) of L-isoleucine, N-[1-(2-naphth-2-yl-2-oxoethyl)-L-prolyl] benzylamide as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:11]N1C(=O)N(O)C(=O)N(O)C1=O.[C:23]([OH:26])(=[O:25])[CH3:24]>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C([O-])(=O)C.[Mn+2].C([O-])(=O)C.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:24]([C:23]([OH:26])=[O:25])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)O
Reactant: Cc1ccc([N+](=O)[O-])cc1
Reactant: O=c1n(O)c(=O)n(O)c(=O)n1O
Agent: [Co+2]
Agent: [Mn+2]
Agent: CC(=O)[O-]
Solvent: O
Product: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: O=Cc1ccc([N+](=O)[O-])cc1
Temperature: 130 °C
Reaction time: 14 h

Procedure:
In an autoclave, 0.274 g of 4-nitrotoluene, 0.011 g of hexahydro-1,3,5-trihydroxy-1,3,5-triazine-2,4,6-trione (3% by mole relative to 4-nitrotoluene), 5 g of acetic acid, 0.003 g of cobalt(II) acetate.4 H2O and 0.001 g of manganese(II) acetate .4 H2O were placed. The autoclave was charged with 1 MPa of air and placed in a heated oil bath. The mixture was stirred at 130° C. for 14 hours. After the completion of reaction, the autoclave was placed on cold water to cool down the reaction mixture quickly. The resulting mixture was analyzed by gas chromatography and was found to yield 4-nitrobenzoic acid and 4-nitrobenzaldehyde in 85% and 1% yields, respectively, at 91% conversion of 4-nitrotoluene.
Reaction SMILES: [CH:1]([NH:5][C:6]1[C:11]([CH:12]=[O:13])=[C:10](Cl)[N:9]=[C:8]([S:15][CH3:16])[N:7]=1)([CH2:3][CH3:4])[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[C:20]([CH3:27])[CH:19]=1>>[CH:1]([NH:5][C:6]1[C:11]([CH:12]=[O:13])=[C:10]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][C:20]=2[CH3:27])[N:9]=[C:8]([S:15][CH3:16])[N:7]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)Nc1nc(SC)nc(Cl)c1C=O
Reactant: Cc1cc(F)ccc1B(O)O
Product: CCC(C)Nc1nc(SC)nc(-c2ccc(F)cc2C)c1C=O

Procedure:
Prepared as described above in Example 11 starting from 4-sec-butylamino-6-chloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 4-fluoro-2-methylphenylboronic acid to give the title compound 4-sec-butylamino-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 1.02 (in, 3H), 1.30 (m, 3H), 1.70 (m, 2H), 2.28 (m, 3H), 2.59 (s, 3H), 4.37 (m, 1H), 6.98 (m, 2H), 7.20 (m, 1H), 9.04 (br s, 1H), 9.50 (s, 1H). LC MS (m/e)=334 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([Br:25])[CH:16]=3)=[C:7]([C:13]#[N:14])[C:8](=[NH:12])[O:9]2)=[CH:4][CH:3]=1.C(ON=O)(C)(C)C.NC1C=C2C(C(C3C=C(OC)C(OC)=C(Br)C=3)=C(C#N)C(=N)O2)=CC=1>C(#N)C.CCOC(C)=O>[NH2:12][C:8]1[O:9][C:10]2[C:5]([CH:6]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([Br:25])[CH:16]=3)[C:7]=1[C:13]#[N:14])=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=2
Reactant: COc1cc(-c2c(C#N)c(=N)oc3cc(Br)ccc23)cc(Br)c1OC
Agent: CC(C)(C)ON=O
Agent: COc1cc(-c2c(C#N)c(=N)oc3cc(N)ccc23)cc(Br)c1OC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(C2C(C#N)=C(N)Oc3cc(Br)ccc32)cc(Br)c1OC
Temperature: 0 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
7-Bromo-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-2-imino-2H-chromene: To a suspension of t-butyl-nitrite (34 mg, 0.33 mmol), CuBr2 (68 mg, 0.30 mmol) in anhydrous acetonitrile (1.5 mL) at 0° C. was added 7-amino-3-cyano-2-imino-4-(3-bromo-4,5-dimethoxy-phenyl)-2H-chromene (100 mg, 0.25 mmol). The mixture was stirred at 0° C. for 4 h, then was diluted with EtOAc (50 mL), washed with saturated NaHCO3 (25 mL), brine (10 mL), dried over MgSO4, and evaporated to yield a yellow solid. The crude was purified by column chromatography (silica gel, EtOAc:hexanes, 1:2 to 1:1) to yield 50 mg (43%) of the title compound as a yellow solid. 1H NMR (CDCl3): 7.82 (brs, 1H), 7.38 (m, 1H), 7.30 (dd, J=2.1, 8.7 Hz, 1H), 7.18 (d, J=2.1 Hz, 1H), 7.09 (d, J=9.0 Hz, 1H), 6.93 (m, 1H), 3.96 (s, 3H), 3.92 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH2:4][NH2:5].[Cl:12][C:13]1[N:18]=[C:17](Cl)[CH:16]=[CH:15][N:14]=1.CCN(C(C)C)C(C)C>CC(O)C>[Cl:12][C:13]1[N:18]=[C:17]([NH:5][CH2:4][C:3]2[C:2]([F:1])=[CH:9][C:8]([F:10])=[CH:7][C:6]=2[F:11])[CH:16]=[CH:15][N:14]=1
Reactant: NCc1c(F)cc(F)cc1F
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Fc1cc(F)c(CNc2ccnc(Cl)n2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4,6-trifluorobenzylamine (5 g, 31 mmol) was added dropwise to a stirred suspension of 2,4-dichloropyrimidine (4.6 g, 31 mmol) and DIPEA (5.4 mL, 62 mmol) in IPA (100 mL) at 0° C. then the reaction mixture was warmed to room temperature and stirred overnight. The precipitate was collected and washed with diethyl ether to afford the first crop of 2-chloro-N-(2,4,6-trifluorobenzyl)pyrimidin-4-amine IV-1. The filtrate was concentrated and purified by column chromatography (0-30% v/v ethyl acetate/petrol) to afford a second crop (total yield 5.3 g, 62%). LC-MS (Method F), RT=2.27 min. (ES+) 274.
Reaction SMILES: [H-].[Na+].[CH:3]([O:6][CH2:7][CH2:8][OH:9])([CH3:5])[CH3:4].[CH2:10](Br)[C:11]#[CH:12]>O1CCCC1>[CH:3]([O:6][CH2:7][CH2:8][O:9][CH2:12][C:11]#[CH:10])([CH3:5])[CH3:4]
Reactant: C#CCBr
Reactant: CC(C)OCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCOCCOC(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 60% suspension of sodium hydride in mineral oil (2.3 g, 57.6 mmol) in tetrahydrofuran (65 mL) was added 2-isopropoxyethanol (3.0 g, 28.8 mmol) dropwise at about 0 C. The mixture was stirred for about 30 min, then propargyl bromide (3.2 mL, 28.8 mmol) was added dropwise and the mixture was stirred overnight while being allowed to warm to room temperature. The reaction was quenched by addition of water and the product was extracted with diethyl ether. The combined organic extracts were dried (MgSO4), filtered and the organic solvents were carefully distilled off at atmospheric pressure. The residue was purified by flash chromatography on silica gel using diethyl ether/n-pentane (1:6) as eluent to provide Example 613. 1H NMR (500 MHz, CDCl3): δ 1.17 (d, J=6.0 Hz, 6H), 2.42 (t, J=3.0 Hz, 1H), 3.57-3.76 (m, 5H), 4.21 (d, J=3.0 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][CH2:11][C:12]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19]C(=O)OC(C)(C)C)[CH2:15]2)=[O:13])[CH:4]=1.Cl>CO.O1CCOCC1>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][CH2:11][C:12]([N:14]2[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15]2)=[O:13])[CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)COCc2cc(C(F)(F)F)ccn2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC1CCN(C(=O)COCc2cc(C(F)(F)F)ccn2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl [(3S)-1-({[4-(trifluoromethyl)pyridin-2-yl]methoxy}acetyl)pyrrolidin-3-yl]carbamate (300 mg, 0.74 mmol) in methanol (3 mL) was added a 4.0 M solution of HCl in 1,4-dioxane (6 mL). After being stirred for 0.5 h at room temperature, the solution was concentrated under vacuum to give the title compound. MS (M+H) 304.2.
Reaction SMILES: C(OC(=O)C)C.[ClH:7].P(O[CH2:21][N:22]1[C:31]2[C:26](=[C:27]([F:36])[CH:28]=[CH:29][C:30]=2[O:32][CH2:33][CH2:34][CH3:35])[C:25](=[O:37])[C:24]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)=[CH:23]1)(OC(C)(C)C)(OC(C)(C)C)=O>C(OCC)(=O)C>[Cl:7][CH2:21][N:22]1[C:31]2[C:26](=[C:27]([F:36])[CH:28]=[CH:29][C:30]=2[O:32][CH2:33][CH2:34][CH3:35])[C:25](=[O:37])[C:24]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)=[CH:23]1
Reactant: Cl
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(COP(=O)(OC(C)(C)C)OC(C)(C)C)c12
Solvent: CCOC(C)=O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCl)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A 4N hydrogen chloride ethylacetate solution (2 ml) was added to an ethyl acetate solution (3 ml) of di-tert-butyl 5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-ylmethyl phosphate (300 mg, 0.55 mmol) while ice-cooling and the mixture was stirred at room temperature for 2 hours. The deposited insoluble matter was collected by filtration and dried, giving a white powder of 1-chloromethyl-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (18 mg, yield: 92%).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:32]=[CH:31][C:10]([O:11][C@H:12]([CH:14]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH3:13])=[CH:9][CH:8]=1.C([O:36][B:37](OC(C)C)[O:38]C(C)C)(C)C>O1CCCC1>[Si:24]([O:23][CH:14]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:12]([CH3:13])[O:11][C:10]1[CH:31]=[CH:32][C:7]([B:37]([OH:38])[OH:36])=[CH:8][CH:9]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: C[C@H](Oc1ccc(Br)cc1)C(CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(B(O)O)cc1)C(CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyllithium (2.5 ml, 1.7M in hexanes) was added over a 1 hour period to a solution of (2S,3RS)-2-(4-bromophenoxy)-3-tert-butyldimethylsilyloxy-5-pyridin-3-ylpentane (1.60 g, Example 5b)) and triisopropylborate (1.07 ml) in tetrahydrofuran (25 ml) at −78° C. The resulting solution was stirred at −78° C. for 2 hours and was then quenched by the addition of a saturated solution of ammonium chloride in water (50 ml). The mixture was poured into water (50 ml) and extracted into ethyl acetate (2×50 ml). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica eluting with ethyl acetate and then ethyl acetate:methanol (4:1) to afford the sub-title compound as a foam (1.2 g).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]1[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)=[O:4].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.CCN(CC)CC>CC(C)=O>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]([C:17]1[CH:18]=[CH:19][C:20]([O:23][S:32]([C:29]3[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=3)(=[O:34])=[O:33])=[CH:21][CH:22]=1)[N:5]([C:3](=[O:4])[C:2]([F:1])([F:24])[F:25])[CH2:14][CH2:13]2
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2c1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2c1ccc(OS(=O)(=O)c2ccc(C)cc2)cc1
Yield: 115.4 %

Procedure:
A solution of 2,2,2-trifluoro-1-[1-(4-hydroxyphenyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]ethanone (3.387 g, 9.64 mmol), p-toluenesulfonyl chloride (2.206 g, 11.6 mmol) and Et3N (1.6 ml, 11.6 mmol) in acetone (50 ml) was refluxed under N2 for 5 hr, then concentrated in vacuo. The remaining residue was suspended in H2O (100 ml) and extracted with CHCl3 (4×75 ml). The combined extracts were dried over MgSO4 and concentrated in vacuo to give 5.622 g of orange oil. Purification by flash chromatography, eluting with hexane:EtOAc (8:2) gave 4.383 g (90% yield) of white solid.
Reaction SMILES: C([O:3][C:4](=[O:33])/[C:5](/[CH3:32])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:16]=[C:17]([CH:29]3[CH2:31][CH2:30]3)[C:18]3[O:25][C:22]4([CH2:24][CH2:23]4)[C:21]([CH3:26])=[C:20]([CH3:27])[C:19]=3[CH:28]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH:29]1([C:17]2[C:18]3[O:25][C:22]4([CH2:24][CH2:23]4)[C:21]([CH3:26])=[C:20]([CH3:27])[C:19]=3[CH:28]=[C:15]([C:14]#[C:13][C:10]3[CH:9]=[CH:8][C:7](/[CH:6]=[C:5](\[CH3:32])/[C:4]([OH:33])=[O:3])=[CH:12][CH:11]=3)[CH:16]=2)[CH2:30][CH2:31]1
Reactant: CCOC(=O)/C(C)=C/c1ccc(C#Cc2cc3c(c(C4CC4)c2)OC2(CC2)C(C)=C3C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1=C(C)C2(CC2)Oc2c1cc(C#Cc1ccc(/C=C(\C)C(=O)O)cc1)cc2C1CC1
Temperature: 55 °C

Procedure:
A solution of (E)-3-{4-[8-cyclopropyl-3,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl]ethynyl-phenyl}-2-methyl-acrylic acid ethyl ester (Intermediate 3, 0.06 g, 0.13 mmol) in ethanol (2 mL) was treated with a 1M solution of sodium hydroxide (0.5 mL, 0.5 mmol) and the resulting reaction mixture was heated at 55° C. for 4 h. The reaction mixture was cooled to ambient temperature and the volatiles were evaporated in vacuo to a residue that was neutralized with 5% hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate; filtered and evaporated in vacuo to afford the title product as a yellow solid after flash column chromatography over silica gel (230–400 mesh) (0.044 g, 82%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][C:20]([CH3:36])([CH3:35])[CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1)(=[O:17])[CH2:13][C:14]([CH3:16])=O.[NH2:37]/[C:38](/[CH3:44])=[CH:39]\[C:40]([O:42][CH3:43])=[O:41]>C(O)(C)C>[CH3:16][C:14]1[NH:37][C:38]([CH3:44])=[C:39]([C:40]([O:42][CH3:43])=[O:41])[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:13]=1[C:12]([O:18][CH2:19][C:20]([CH3:35])([CH3:36])[CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[CH2:24][CH2:23]1)=[O:17]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)/C=C(/C)N
Reactant: CC(=O)CC(=O)OCC(C)(C)CN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)(C)CN2CCN(C(=O)OC(C)(C)C)CC2)C1c1cccc([N+](=O)[O-])c1
Yield: 44.3 %

Procedure:
1.6 g of m-nitrobenzaldehyde, 3.7 g of 3-[4-(tert-butyloxycarbonyl)-1-piperazinyl]-2,2-dimethylpropyl acetoacetate, and 1.3 g of methyl 3-aminocrotonate were dissolved in 10 ml of isopropanol, and the solution was subjected to heating reflux for 12 hours. Then, the solvent was concentrated under reduced pressure. Diethyl ether was added to the residue to give 2.7 g of a colorless powdery crystal (yield: 44%). The IR and NMR data of the compound thus obtained are as follows: ##STR14##
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]=[CH:12][CH2:13][OH:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](Cl)(=[O:24])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:15]([O:14][CH2:13][CH:12]=[CH:11][CH2:10][O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:24])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(OCC=CCO)c1ccccc1
Reactant: O=C(Cl)CCc1ccccc1
Product: O=C(CCc1ccccc1)OCC=CCOC(=O)c1ccccc1

Procedure:
4-Benzoyloxy-2-butenyl hydrocinnamate was prepared by the procedure of Example 1 from 19 gms. (0.1 mole) of 4-hydroxy-2-butenyl benzoate and 17 gms (0.1 mole) of hydrocinnamoyl chloride. The structure of the final product was characterized on the basis of NMR and IR spectral analyses as described in Example 1.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:12]([C@@H:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=3)[OH:28])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:40]1[CH2:45][CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH2:42][CH2:41]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F-].[Cs+]>O.O1CCCC1.C1(C)C=CC=CC=1>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:12]([C@@H:27]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:31][CH:30]=3)[OH:28])=[C:11]([C:43]3[CH2:44][CH2:45][O:40][CH2:41][CH:42]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CC1(C)Cc2nc(C3CCOCC3)c([C@H](O)c3ccc(C(C)(C)C)cc3)c(I)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)Cc2nc(C3CCOCC3)c([C@H](O)c3ccc(C(C)(C)C)cc3)c(C3=CCOCC3)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1

Procedure:
Obtained by starting from (R)—((S)-5-(tert-butyldimethylsilyloxy)-4-iodo-7,7-dimethyl-2-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydroquinolin-3-yl)(4-tert-butylphenyl)methanol and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A 2 M solution of caesium carbonate in water is used instead caesium fluoride. The reaction is run in tetrahydrofurane/toluene 4:1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([Cl:17])[N:10]=[C:9](Cl)[N:8]=1.[CH:24]1[CH:29]=[CH:28][C:27]([CH2:30][SH:31])=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([Cl:17])[N:10]=[C:9]([S:31][CH2:30][C:27]2[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=2)[N:8]=1
Reactant: COC(=O)c1c(Cl)nc(Cl)nc1NCc1ccc(OC)c(Cl)c1
Reactant: SCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1c(Cl)nc(SCc2ccccc2)nc1NCc1ccc(OC)c(Cl)c1

Procedure:
A mixture of 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-2,6-dichloropyrimidine (prepared in the above (2)) 150 mg, a 1.0M solution of benzylthiol in dimethylformamide 0.40 ml, triethylamine 40 mg and dimethylformamide 2.5 ml is stirred at room temperature for 2.5 days. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo. The residue is separated with preparative thin-layer chromatography (solvent; hexane:chloroform:ethyl acetate=30:30:4) and crystallized from isopropyl ether to give 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-chloro-2-benzylthiopyrimidine as a colorless crystalline powder 125 mg. mp 89–90° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(N(CC)CC)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>ClCCl>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: CCOC(=O)CCC(CCCCN)CCCc1cccnc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Temperature: 25 °C

Procedure:
To a solution of 2200 g of crude ethyl 8-amino-4-[3-(3-pyridyl)-propyl]-octanoate in 28.8 L of dichloromethane is added 1377 g of triethylamine. The solution is cooled to 0° and a solution of 1435 g of p-chlorophenylsulfonyl chloride in 14.3 L of dichloromethane is added over a period of 45 minutes maintaining the temperature below 5°. The reaction is allowed to slowly warm up to room temperature overnight. The reaction mixture is washed 3 times with 15 L of sodium bicarbonate and then with water, dried over sodium sulfate and evaporated to dryness to yield ethyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)-propyl]-octanoate as an oil.