Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][C:22]([OH:24])=O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC(OCC)=O.[NH3:33].Cl>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][C:22]([NH2:33])=[O:24])=[O:11])=[CH:25][CH:26]=1)([O-:3])=[O:2]
Reactant: CC(=O)S[C@H]1C[C@@H](CC(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: N
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)S[C@H]1C[C@@H](CC(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.5 h

Procedure:
(2R,4S)-1-(p-Nitrobenzyloxycarbonyl)-2-carboxymethyl-4-acetylthiopyrrolidine (82 mg) was dissolved in 1.5 ml of dry tetrahydrofuran, and 33 mg of triethylamine was added thereto. Ethyl chloroformate (35 mg) was added to the mixture under nitrogen stream at -10° to -15° C., followed by stirring at the same temperature for 30 minutes. 29% (w/w) Aqueous ammonia (13 mg) was added at -40° C. to the resulting mixture, followed by stirring at -30° to -40° C. for 30 minutes. The reaction mixture was acidified with dilute hydrochloric acid, diluted with ethyl acetate, washed successively with water, a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel thin layer chromatography to obtain (2R,4S)-1-(p-nitrobenzyloxycarbonyl)-2-aminocarbonylmethyl-4-acetylthiopyrrolidine.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@H:6]2[C@H:5]([N:13]2[C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:22][CH:23]4[CH2:25][CH2:24]4)[C:16]=3[CH:15]=[CH:14]2)[CH2:4]1.[CH3:26][C:27](=O)[CH3:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:12][C:9]1([CH3:11])[O:8][C@@H:7]2[C@@H:3]([CH2:2][NH:1][CH:27]([CH3:28])[CH3:26])[CH2:4][C@@H:5]([N:13]3[C:17]4[N:18]=[CH:19][N:20]=[C:21]([NH:22][CH:23]5[CH2:25][CH2:24]5)[C:16]=4[CH:15]=[CH:14]3)[C@@H:6]2[O:10]1
Reactant: CC(C)=O
Reactant: CC1(C)O[C@@H]2[C@@H](CN)C[C@@H](n3ccc4c(NC5CC5)ncnc43)[C@@H]2O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)NC[C@H]1C[C@@H](n2ccc3c(NC4CC4)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
7-[(3aS,4R,6R,6aR)-6-(Aminomethyl)-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-N-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.900 g, 5.53 mmol) was dissolved in DCE (65 ml) and propan-2-one (0.81 ml, 11.1 mmol) was added and the reaction left for 15 mins. Sodium triacetoxyborohydride (1.642 g, 7.75 mmol) was added and the reaction left overnight. The reaction was quenched by the addition of sat. Na2CO3 solution (65 ml) and DCM (65 ml). The organic layer was separated and the aqueous layer was extracted with DCM (3×65 ml). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give the crude product. The product was purified by silica flash column chromatography using between 100% DCM and 20% 2M NH3 in MeOH:80% DCM as eluent to give the product as a pale yellow foamy solid (2.125 g, 100%): MS (ESI+) for C21H31N5O2 m/z 386.5 [M+H]+, 408.1 [M+Na]+; LC purity 100% (UV), 100% (ELS) (ret. time, 0.99 min); 1H NMR (500 MHz, CDCl3) δ 8.16 (s, 1H), 7.25 (d, J=3.63 Hz, 1H), 6.70 (br. s., 1H), 5.03 (dt, J=11.90, 6.19 Hz, 1H), 4.91-4.99 (m, 1H), 4.50-4.60 (m, 1H), 2.88 (quin, J=6.27 Hz, 2H), 2.78-2.85 (m, 1H), 2.70-2.78 (m, 1H), 2.38-2.46 (m, 1H), 2.35 (dt, J=12.37, 6.27 Hz, 1H), 2.06 (q, J=11.93 Hz, 1H), 1.55 (s, 3H), 1.31 (s, 3H), 1.11 (t, J=5.83 Hz, 6H), 0.81-0.96 (m, 2H), 0.55-0.72 (m, 2H).
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=O.[CH2:12]([NH:19][C:20]([NH2:22])=[S:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[CH2:12]([NH:19][C:20]1[S:21][CH:3]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)[N:22]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(CBr)c1ccccn1
Reactant: NC(=S)NCc1ccccc1
Agent: Br
Solvent: CCO
Product: c1ccc(CNc2nc(-c3ccccn3)cs2)cc1

Procedure:
A solution of 2-(Bromoacetyl)pyridine hydrobromide (100 mg, 0.36 mmol) in ethanol (2 mL) was treated with 1-benzyl-2-thiourea (90 mg, 0.54 mmol). The resulting yellow solution was concentrated, and the crude residue was purified on reverse phase HPLC to produce N-benzyl-4-(pyridin-2-yl)thiazol-2-amine.
Reaction SMILES: [CH2:1]([N:3]([N:11]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:13]=[CH:12]1)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].[Li+].CCC[CH2-].[Cl:27]C(Cl)(Cl)C(Cl)(Cl)Cl>O1CCCC1>[Cl:27][C:12]1[N:11]([N:3]([CH2:1][CH3:2])[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:7])[CH3:8])[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:13]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CCN(C(=O)OC(C)(C)C)n1cnc(-c2cccnc2)c1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)n1cc(-c2cccnc2)nc1Cl
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 3.4 %

Procedure:
A vacuum dried 25 mL round bottomed flask equipped with a magnetic stir bar and containing tert-butyl ethyl(4-(pyridin-3-yl)-1H-imidazol-1-yl)carbamate (77 mg, 0.267 mmol) was charged with anhydrous tetrahydrofuran (THF, 3 mL) and cooled to −78° C. N-butyllithium (0.25 mL 0.675 mmol, 2.5 M in hexanes) was added and the mixture was stirred for 15 minutes. Hexachloroethane (189 mg, 0.80 mmol) dissolved in anhydrous THF (1 mL) was added dropwise to the reaction mixture while maintaining a temperature of −78° C. After stirring for 1 hour, the reaction was allowed to warm to room temperature. The reaction mixture was loaded directly on a silica gel column and the THF was removed in a vacuum oven. The crude product was purified using silica gel chromatography (0-25% methanol/dichloromethane) to afford the title compound (3 mg, 0.009 mmol, 3.5%) as a yellow oil: 1H NMR (600 MHz, CDCl3) δ 8.92 (d, J=1.6 Hz, 1H), 8.50 (dd, J=4.8, 1.5 Hz, 1H), 8.06 (dt, J=7.9, 2.0 Hz, 1H), 7.33-7.27 (m, 2H), 3.89 (dq, J=14.5, 7.3 Hz, 1H), 3.68 (dq, J=14.3, 7.2 Hz, 1H), 1.44 (s, 9H), 1.22 (t, J=7.2 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 152.90, 148.47, 146.02, 136.07, 134.08, 131.81, 128.79, 123.36, 117.66, 83.23, 45.32, 28.04, 13.03; ESIMS m/z 323 ([M+H]+).
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]3)=[CH:9][CH:8]=2)[N:5]=[C:4]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1.[C:28](Cl)([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29].C([O-])(O)=O.[Na+]>CCOC(C)=O>[C:24]([C:4]1[CH:3]=[C:2]([C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29])[N:6]([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:14]3)=[CH:9][CH:8]=2)[N:5]=1)([CH3:26])([CH3:27])[CH3:25]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(-n3nc(C(C)(C)C)cc3N)cc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(-n3nc(C(C)(C)C)cc3C(=O)OCC(Cl)(Cl)Cl)cc2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.3 %

Procedure:
To a stirring solution of tert-butyl 7-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.50 g, 1.35 mmol) and Troc-Cl (0.19 ml, 1.38 mmol) in EtOAc (15 mL) was added satd. NaHCO3 (2.75 ml, 2.02 mmol). The resulting biphasic mixture was stirred at RT for 5 h. The layers were separated and the organic washed with sat'd. NaHCO3 (1×) and brine (1×), dried (Na2SO4) and concentrated in vacuo to obtain tert-butyl 7-(3-tert-butyl-5-((2,2,2-trichloroethoxy)carbonyl)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.69 g, 94% yield). MS (ESI) m/z: 545.0 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([NH:23][C:24](=[O:33])[CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F:40][C:41]([F:52])([F:51])[O:42][C:43]1[CH:50]=[CH:49][C:46]([CH2:47]Br)=[CH:45][CH:44]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([N:23]([C:24](=[O:33])[CH2:25][O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:47][C:46]3[CH:49]=[CH:50][C:43]([O:42][C:41]([F:40])([F:51])[F:52])=[CH:44][CH:45]=3)[CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(NC(=O)COc3ccccc3)c2)CC1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])c(N(Cc3ccc(OC(F)(F)F)cc3)C(=O)COc3ccccc3)c2)CC1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of 1 g (2.19 mmol) 4-[4-nitro-3-(2-phenoxy-acetylamino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester, 1.07 g (3.29 mmol) cesiumcarbonate and 0.79 g (3.29 mmol) 4-(trifluoromethoxy)benzyl bromide (commercially available) in 6.6 ml DMF was stirred at 110° C. for 2 h. After cooling to room temperature the precipitate was filtered of. The residue was used without further purification. The title compound was isolated as brown solid (0.39 g; 37%). MS(ISP): 631.5 (M+H)+
Reaction SMILES: [Na].[Br-].[NH2:3][C:4]1[C:9]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=[CH:6][N+:5]=1[CH2:14][C:15]([O:17]CC)=O.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH2:20]([C:14]1([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH:11]([CH3:12])[CH3:13])[C:4]2=[N:3][C:15]1=[O:17])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C[n+]1cccc(OC(C)C)c1N
Agent: [Br-]
Agent: [Na]
Solvent: CCO
Product: CC(C)OC1=CC=CN2C1=NC(=O)C2(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
Metallic sodium (81 mg) is added to 3.0 ml of absolute ethanol and is stirred for one hour at room temperature. Then, the reaction mixture was added with 586 mg (1.77 mmol) of 2-amino-3-isopropoxy-1-(ethoxy-carbonylmethyl) pyridiniumbromide and stirred at room temperature for one hour. Then, the reaction mixture was added with 605 mg (3.54 mmol) of benzylbromide at 0° C. and stirred at room temperature for 4 hours. Then, the resulting precipitates were filtrated out and dried. The obtained crystals were re-crystallized from ethanol to obtain 588 mg (yield: 92%) of the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[CH2:6]2.ClS([N:19]=[C:20]=[O:21])(=O)=O.C(#N)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([C:20]([NH2:19])=[O:21])[C:7](=[O:14])[CH2:6]2
Reactant: COc1cc2c(cc1OC)NC(=O)C2
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OC)N(C(N)=O)C(=O)C2

Procedure:
Following the procedure of Example 24, the title compound was prepared from 5,6-dimethoxy-2-oxindole (8.0 g, 0.042 mole), chlorosulfonyl isocyanate (7.08 g, 0.05 mole) and acetonitrile (75 ml). The crude product obtained upon evaporation of the ethyl acetate extract was recrystallized from acetonitrile/acetic acid (1:1). Yield=6.02 g (60%); m.p. 206.5°-209° C.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH:18]3OC(=O)[CH2:19]3)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]>CCCCCCC>[CH:18]([C@H:15]1[CH2:16][CH2:17][C@H:12]([C@H:9]2[CH2:10][CH2:11][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]2)[CH2:13][CH2:14]1)=[CH2:19]
Reactant: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C3CC(=O)O3)CC2)CC1
Solvent: CCCCCCC
Product: C=C[C@H]1CC[C@H]([C@H]2CC[C@H](CCCCC)CC2)CC1
Temperature: 170 °C

Procedure:
4-(trans-4-(trans-4-pentylcyclohexyl)cyclohexyl) -2-oxetanone obtained in Example 5 was placed in a reactor, the interior of which was then sufficiently replaced by nitrogen. The reactor was heated, and after heating to 170° C. for 3 hours, it was cooled to room temperature. The resulting solid was dissolved in heptane and purified with silica gel chromatography to provide trans-1-ethenyl -4-(trans-4-pentylcyclohexyl)-cyclohexane at a yield of 95%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C([O-])(O)=O.[Na+].Cl[CH2:15][CH:16]=O.O>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:15]=[CH:16][N:8]=[C:4]2[CH:3]=1
Reactant: O=CCCl
Reactant: Nc1cc(Cl)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Clc1ccn2ccnc2c1

Procedure:
To a solution of 4-chloro-pyridin-2-ylamine (25.0 g, 0.194 mol) in EtOH (250 mL) was added NaHCO3 (32.7 g, 0.389 mol) followed by a 50% solution of chloroacetaldehyde in water (37 mL, 0.292 mol). The mixture was refluxed for 6 h. The solvents were removed under reduced pressure and the crude mixture was diluted with water (250 mL) and extracted with EtOAc (2×125 mL). The combined organic layers were washed with brine (50 mL), dried (MgSO4) and concentrated under reduced pressure to give 7-chloro-imidazo[1,2-a]pyridine (32.7 g). 1H NMR (400 MHz, CDCl3) δ 8.06 (1H, d), 7.64 (2H, d), 7.56 (1H, s), 6.79 (1H, dd).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:16][CH2:17][C:18]3([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:12](OC)=[O:13])[CH:10]=1)[NH:7][N:6]=[CH:5]2.ClC1C=C(C(OCC2(C3C=CC(F)=CC=3)CCN(C(OC(C)(C)C)=O)CC2)CO)C2C(=CN(COCC[Si](C)(C)C)N=2)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH:11]([O:16][CH2:17][C:18]3([C:31]4[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=4)[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[CH2:12][OH:13])[CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: COC(=O)C(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn[nH]c12
Agent: CC(C)(C)OC(=O)N1CCC(COC(CO)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(COC(CO)c2cc(Cl)cc3cn[nH]c23)(c2ccc(F)cc2)CC1

Procedure:
Prepared according to the procedure used to prepare tert-butyl 4-((1-(5-chloro-1H-indazol-7-yl)-2-methoxy-2-oxoethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate using tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-hydroxyethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate as the starting material. 1H-NMR (CDCl3, 500 MHz) δ 10.20 (bs, 1H), 7.93 (s, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.25 (dd, J=8.5 Hz, 5.2, 2H), 7.06 (dd, J=8.6, 8.5 Hz, 2H), 7.02 (d, J=1.8 Hz, 1H), 4.46 (dd, J=7.0, 4.3 Hz, 1H), 3.76 (dd, J=11.9, 7.3 Hz, 1H), 3.67 (dd, J=11.9, 4.3 Hz, 1H), 3.40 (m, 2H), 3.00 (m, 2H), 2.23 (m, 1H), 2.10 (m, 1H), 1.84 (m, 1H), 1.75 (m, 1H), 1.42 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 171.2, 161.7 (d, J=247 Hz), 155.0, 137.8, 136.4, 133.9, 128.7 (d, J=7.7 Hz), 126.3, 125.6, 124.9, 122.6, 119.9, 115.8 (d, J=21 Hz), 83.0, 79.7, 79.4, 65.7, 41.4, 39.9 (br), 32.5, 32.2, 28.5.
Reaction SMILES: Br[CH:2]=[C:3]1[O:7][C:6](=[O:8])[CH:5]=[CH:4]1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.[F-].[Cs+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O.[Cl-].[Na+].O.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>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](/[CH:2]=[C:3]2/[CH:4]=[CH:5][C:6](=[O:8])[O:7]/2)=[CH:13][CH:12]=1
Reactant: O=C1C=CC(=CBr)O1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1C=C/C(=C/c2ccc(C(F)(F)F)cc2)O1

Procedure:
A mixture containing 5-bromomethylene-2(5H)furanone (0.175 g, 1 mmol), 4-trifluoromethylphenylboronic acid (0.228 g, 1.2 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (0.035 g, 0.05 mmol), tetrabutylammonium iodide (0.018 g, 0.05 mmol) and cesium fluoride (0.456 g, 3 mmol) in toluene (10 mL) and water (10 mL) were stirred at reflux for 24 hours under nitrogen. After cooling, brine (50 mL) was added and the product extracted with ethyl acetate (50 mL×3). The organic fractions were combined, washed with brine (50 mL×3), dried over anhydrous sodium sulfate and evaporated to dryness to give a brown solid. The resulting solid was chromatographed (silica gel: eluent 50:50 dichloromethane/light petroleum) giving the desired product 29 as a light yellow powder. Yield 0.133 g (55%), m.p. 92-94° C., UV-Vis λmax (MeOH) 223 (15948), 237 (10856), 323(35739) nm. 1H NMR (CDCl3) δ 7.87 (d, J=8.3 Hz, 2H, H2′ and H6′), 7.63 (d, J=8.3 Hz, 2H, H3′ and H5′), 7.52 (d, J=5.7 Hz, 1H, H4), 6.28 (d, J=4.9 Hz, 1H, H3), 6.04 (s, 1H, H6).
Reaction SMILES: Cl[Si:2]([Cl:5])([CH3:4])[CH3:3].[CH3:6][C:7]1[CH-:8][C:9]2[C:14]([CH:15]=1)=[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:12]=[CH:11][CH:10]=2.[Li+]>CCOCC>[Cl:5][Si:2]([CH3:3])([CH3:4])[CH:8]1[C:9]2[C:14](=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[CH:15]=[C:7]1[CH3:6]
Reactant: C[Si](C)(Cl)Cl
Reactant: Cc1cc2c(-c3ccccc3)cccc2[cH-]1
Agent: [Li+]
Solvent: CCOCC
Product: CC1=Cc2c(-c3ccccc3)cccc2C1[Si](C)(C)Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a colorless solution of dichlorodimethylsilane (12.90 g, 100 mmol, 3.00 eq.) in ether (30 ml) at −30° C. was added lithium (2-methyl-4-phenylindenide) (7.07 g, 33.3 mmol, 1.00 equiv.) in portions to give a cloudy yellow mixture. The reaction was allowed to warm to room temperature and stirred for 4 hours, becoming cloudy white with precipitate. The mixture was evaporated under vacuum, leaving a white solid. The solid was extracted with pentane (40 ml), and the extract was filtered to give a light yellow solution and white solid. The solution was evaporated under vacuum, leaving a white solid. Yield 9.85 g (99%). 1H NMR(C6 D6): δ7.59 (d, 2H), 7.44 (m, 1H), 7.36 (m, 3H), 7.22 (m, 2H), 6.86 (d, 1H), 3.42 (d, 1H), 2.11 (d, 3H), 0.27 (s, 3H), −0.03 (s, 3H).
Reaction SMILES: [NH:1]([C:3]1[C:4]([CH3:10])=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1)N>O.[Ni]>[CH3:10][C:4]1[C:3]([NH2:1])=[N:8][C:7]([CH3:9])=[CH:6][N:5]=1
Reactant: Cc1cnc(C)c(NN)n1
Agent: [Ni]
Solvent: O
Product: Cc1cnc(C)c(N)n1
Temperature: 50 °C

Procedure:
To a solution of 3-hydrazino-2,5-dimethylpyrazine (2.00 g, 14.5 mmol) from Step A in 75 mL of water was added approximately 1 g (wet) Raney Ni, 50% slurry in water. After stirring at reflux for 2 h, the reaction mixture was filtered hot through Celite, and subsequently washed with hot water, followed by dichloromethane. The concentrated residues were suspended in ethylenediamine and heated at 50° C. for 30 min with stirring. Concentration followed by purification by flash chromatography (silica gel, 50% ethyl acetate/hexane) yielded the title compound. LC/MS 124 (M+1).
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].CO.C[O-].[Na+].Cl[CH:13]=[CH:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([OH:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:19]=1>C(OCC)C>[OH:30][CH:24]([C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[O:17][CH2:16][CH:15]=[CH:14][CH2:13][S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCC(O)c1cccc(OCCC=CCl)c1
Reactant: O=C(O)CCS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCCCCC(O)c1cccc(OCC=CCSCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
9.15 ml. (0.105 mole) 3-mercaptopropionic acid are dissolved in 70 ml. methanol and stirred with 315 ml. 1M sodium methylate solution for 10 minutes at ambient temperature under an atmosphere of nitrogen. Subsequently, 19.79 g. (0.07 mole) 1-chloro-4-[3-(1-hydroxyhexyl)-phenoxy]-but-1-ene in 70 ml. methanol are added dropwise thereto in the course of 15 minutes. The reaction mixture is further stirred for 3 hours at ambient temperature and the solvent is then stripped off. The residue is taken up in diethyl ether and extracted several times with 2M aqueous sodium hydroxide solution. The aqueous solution is acidified with 2M hydrochloric acid and the desired compound is extracted with methylene chloride. After drying and stripping off the solvent, there are obtained 22.5 g. (91% of theory) of the title compound in the form of an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].P(OC)(OC)(O[CH3:25])=O.O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[N:12]([CH3:25])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COP(=O)(OC)OC
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ncccc12
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2cccnc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Yield: 85.1 %

Procedure:
2.8 g of 1-(m-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was dissolved in 30 ml of dry dimethylformamide. To this was added 4.2 g of trimethyl phosphate and the mixture was refluxed for 6 hours. After the reaction was complete, the solvent was distilled off from the mixture, and to the residue obtained was added water to precipitate a crude product. The product was recrystallized from acetone to yield 2.5 g of 1-(m-nitrophenyl)-3-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione as pale yellow prisms, melting at 234°-235°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH3:17])[C:15](=[O:18])[N:14]([CH3:19])[C:13](=[O:20])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:21]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:21][C:12]1[C:13](=[O:20])[N:14]([CH3:19])[C:15](=[O:18])[N:16]([CH3:17])[C:11]=1[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(-c2cc(=O)n(C)c(=O)n2C)cc1OC
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: COc1ccc(-c2c(Cl)c(=O)n(C)c(=O)n2C)cc1OC
Temperature: 100 °C
Reaction time: 5 h
Yield: 79.6 %

Procedure:
To a solution of 6-(3,4-dimethoxyphenyl)-1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (2.0 g) in acetic acid (100 ml) was added N-chlorosuccinimide (0.97 g), and the mixture was stirred at 100° C. for 5 hours. After cooling, the reaction mixture was evaporated, and dissolved in chloroform, The solution was washed with aqueous sodium bicarbonate, and dried over magnesium sulfate. After removal of the solvent, resulting mass was crystallized from ethanol, to give 5-chloro-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (1.79 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.CN(C)CCN(C)C.C([Li])CCC.[C:20]1(=[O:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1COCC1.O>[CH3:1][N:2]1[C:6]([C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1cccn1
Reactant: O=C1CCCCC1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cn1nccc1C1(O)CCCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To a solution of 1-methylpyrazole (6.0 g, 73.1 mmol) and N,N,N′,N′-tetramethylethylenediamine (10.96 mL, 73.1 mmol) in THF (125 mL), butyl lithium (2.69 M solution in hexane; 31.8 mL, 85.5 mmol) was added at −78° C. The reaction solution was stirred at −78° C. for 30 minutes. Then, cyclohexanone (9.06 mL, 87.7 mmol) was added thereto, and the mixture was stirred at room temperature for 15 hours. To the reaction solution, water (500 mL) was added, followed by extraction with ethyl acetate (250 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=3:2), to yield the title compound (11.32 g, 86%) as a colorless oil.