Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1(N2C3N=CN=C(O)C=3N=C2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H:21]1[OH:22].N[C@H](C(O)=[O:43])C>>[OH:22][CH2:21][C:7]([C@H:6]([C@@H:4]([C@@H:2]([CH2:1][OH:9])[OH:3])[OH:5])[OH:43])=[O:8]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Reactant: C[C@H](N)C(=O)O
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 37 °C

Procedure:
FIGS. 4 and 5 show that in the organ preservation model, at 4° C., inosine, adenosine, alanine, and fructose provide substantial protection even up to 24 hours. When the cells are warmed to 37° C., inosine, adenosine, and alanine still afford substantial protection for an extended period of time, while the protection afforded by fructose is diminishing.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[Cl-].[NH4+].O1CCCC1.O>C(O)C.[Fe]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:11]2[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13][N:12]=2)=[CH:3][C:2]=1[CH3:1]
Reactant: CCOC(=O)c1cc(-c2ccc([N+](=O)[O-])c(C)c2)no1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(N)c(C)c2)no1
Temperature: 80 °C
Yield: 81 %

Procedure:
Ethyl 3-(3-methyl-4-nitrophenyl)isoxazole-5-carboxylate (1.0 equiv.), iron powder (2.0 equiv.), and ammonium chloride (3.0 equiv.) in a mixture of ethanol, tetrahydrofuran and water (4:2:1) were heated to 80° C. for 9 hours. Reaction mixture was cooled and filtered through celite. The filtrate was evaporated to dryness under vacuum and the residue was diluted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 0-2% acetone in chloroform, to provide the title compound as a pale green solid (81%); 1H NMR (300 MHz, DMSO-d6) δ: 1.28-1.33 (t, J=7.2 Hz, 3H), 2.07 (s, 3H), 4.31-4.38 (q, 2H), 5.38 (s, 2H), 6.62-6.65 (d, J=8.4 Hz, 1H), 7.45-7.48 (dd, J=8.1 Hz, 1.8 Hz, 1H), 7.52 (s, 1H), 7.63 (s, 1H); IR (KBr) 3490, 3381, 3135, 2975, 2905, 1725, 1628, 1606, 1471, 1417, 1381, 1279, 1134, 1027, 924, 828, 769 cm−1.
Reaction SMILES: [C:1]([C:5]1[CH:35]=[CH:34][C:8]([CH2:9][O:10][C:11]([C:13]2[CH:14]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N+:31]([O-:33])=[O:32])[C:15]([C:21]([O:23]C)=O)=C(C)[NH:17][C:18]=2[CH3:19])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C>[CH3:9][O:10][C:11]([CH2:13][C:21](/[CH:15]=[CH:14]/[C:25]1[C:26]([N+:31]([O-:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:23])=[O:12].[C:1]([C:5]1[CH:35]=[CH:34][C:8]([CH2:9][O:10][C:11](=[O:12])/[CH:13]=[C:18](\[NH2:17])/[CH3:19])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCc2ccc(C(C)(C)C)cc2)C1c1ccccc1[N+](=O)[O-]
Solvent: CCO
Product: C/C(N)=C/C(=O)OCc1ccc(C(C)(C)C)cc1
Product: COC(=O)CC(=O)/C=C/c1ccccc1[N+](=O)[O-]

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 2'-nitrobenzylideneacetoacetic acid methyl ester and 75 mmols of β-aminocrotonic acid 4-tert.-butylbenzyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-methoxycarbonyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 4-tert.-butylbenzyl ester of melting point 146° C (from ethanol).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:21]=[C:19]([OH:20])[C:17]([OH:18])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[CH2:23]([N+:27]([CH2:36][CH2:37][CH2:38][CH3:39])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH3:26]>CO>[CH2:36]([N+:27]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:37][CH2:38][CH3:39].[OH:20][C:19]1[CH:21]=[C:14]([CH2:13][C@H:9]([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:10]([O-:12])=[O:11])[CH:15]=[CH:16][C:17]=1[OH:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)[O-]
Temperature: 4 °C
Yield: 83 %

Procedure:
A solution of N-Boc-(L)-Dopa (175 g, 0.59 mol) in methanol (1 L) was cautiously mixed with a methanolic solution of tetrabutylammonium hydroxide (1.0 M, 0.55 L) at 0° C. for 30 min. The mixture was then concentrated under reduced pressure and dried by azeotroping with toluene twice. The residue was crystallized after cooling at 4° C. for 16 h. The resulting crystalline solid washed with acetone (400 mL×3), collected on a Buchner funnel, and then dried under high vacuum to afford 245 g (83% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6): δ 0.94 (t, J=7.6 Hz, 12H), 1.30 (m, 17H), 1.60 (m, 8H), 3.18 (m, 8H), 4.58 (m, 1H), 5.68 (d, J=5.6 Hz, 1H), 6.30 (d, J=7.6 Hz, 1H), 6.46 (d, J=8.0 Hz, 1H), 6.51 (s, 1H), 8.85 (s, 1H); 8.94 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:15][CH2:14][CH2:13][C@@:9]1([CH3:16])[C:10]([OH:12])=O)=O)(C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[F:50][C:51]1[CH:66]=[CH:65][C:54]([CH2:55][C:56]2[C:57]([CH3:64])=[C:58]([CH3:63])[C:59](=[O:62])[NH:60][N:61]=2)=[CH:53][C:52]=1[C:67]([N:69]1[CH2:74][CH2:73][NH:72][CH2:71][CH2:70]1)=[O:68]>CN(C=O)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:50][C:51]1[CH:66]=[CH:65][C:54]([CH2:55][C:56]2[C:57]([CH3:64])=[C:58]([CH3:63])[C:59](=[O:62])[NH:60][N:61]=2)=[CH:53][C:52]=1[C:67]([N:69]1[CH2:74][CH2:73][N:72]([C:10](=[O:12])[C@:9]2([CH3:16])[CH2:13][CH2:14][CH2:15][NH:8]2)[CH2:71][CH2:70]1)=[O:68]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(C)C(=O)O
Reactant: Cc1c(Cc2ccc(F)c(C(=O)N3CCNCC3)c2)n[nH]c(=O)c1C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(Cc2ccc(F)c(C(=O)N3CCN(C(=O)[C@]4(C)CCCN4)CC3)c2)n[nH]c(=O)c1C
Temperature: 60 °C

Procedure:
A mixture of 1-(tert-butoxycarbonyl)-2-methylproline (1 eq), TEA (2 eq), PyBOP (1 eq) and 6-[4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl]-4,5-dimethylpyridazin-3(2H)-one (II) in dry DMF (0.1 M) was heated at 60° C. with microwaves irradiation for 2 hours. The product was isolated by preparative-HPLC. After lyophilization of the pooled product fractions the residue was dissolved in 10% TFA/DCM and the solution was warmed to 45° C. for 1 h. The residue obtained after solvent evaporation was further purified by SCX cartridge. Lyophilization from water/MeCN afforded the title compound as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 12.67 (1H, s), 7.38-7.13 (3H, m), 3.96 (2H, s), 3.8-3.5 (5H, m), 3.3 (1H under water signal), 3.26-3.13 (2H, m), 2.92-2.78 (1H, m), 2.76-2.58 (1H, m), 2.34-2.15 (1H, m), 2.02 (3H, s), 2.00 (3H, s), 1.75-1.46 (3H, m), 1.26 (3H, s). MS (ES) C24H30FN5O3 requires: 455. found: 456 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][C@H:8]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH2:22])=[CH:17][C:16]=1[O:24][CH2:25][CH2:26][C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[CH:29]=[CH:30][CH:31]=[N:32]2)(=[O:14])=[O:13])[CH:9]=[O:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl.O>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][CH:8]([CH:9]=[O:10])[CH2:7][C:6]([OH:37])=[O:5])(=[O:14])=[O:13])=[C:16]([O:24][CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][CH:31]=[N:32]3)[CH:17]=1)(=[O:23])[NH2:22]
Reactant: CC(C)(C)OC(=O)C[C@@H](C=O)NS(=O)(=O)c1ccc(C(N)=O)cc1OCCc1cccc2ncccc12
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1ccc(S(=O)(=O)NC(C=O)CC(=O)O)c(OCCc2cccc3ncccc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.1 %

Procedure:
To a solution of (S)-3-[4-carbamoyl-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid tert-butyl ester (0.08 g, 0.15 mmol) in dichloromethane (10 mL) and water (0.1 ml) was added trifluoroacetic acid (1 mL). The reaction was stirred for 1 h at room temperature. The reaction was then concentrated under reduced pressure to yield a clear oil. The residue was purified by reverse phase high-pressure liquid chromatograph using a gradient of 0% to 30% acetonitrile containing 0.1% TFA and water containing 0.1% TFA over 140 minutes to yield 3-[4-carbamoyl-2-(2-quinolin-5-yl-ethoxy)-benzenesulfonylamino]-4-oxo-butyric acid as a white solid (0.01 g, 14%). MS(APCI) m/z 472.1 (M+1)
Reaction SMILES: [OH-:1].[NH4+:2].[NH2:3][C@:4]([CH3:60])([C:56]([CH3:59])([CH3:58])[CH3:57])[CH2:5][O:6][C@@H:7]1[C@@:14]2([CH3:39])[C@@H:15]3[CH2:16][CH2:17][C@H:18]4[C:27]([C@@:10]3([CH2:11][O:12][CH2:13]2)[CH2:9][C@H:8]1[N:40]1[C:44]([C:45]2[CH:50]=[CH:49][N:48]=[C:47]([C:51](OCC)=O)[CH:46]=2)=[N:43][CH:42]=[N:41]1)=[CH:26][CH2:25][C@:24]1([CH3:28])[C@:19]4([CH3:38])[CH2:20][CH2:21][C@@:22]([C@H:33]([CH3:37])[CH:34]([CH3:36])[CH3:35])([CH3:32])[C@H:23]1[C:29]([OH:31])=[O:30]>O1CCOCC1.CO>[NH2:2][C:51]([C:47]1[CH:46]=[C:45]([C:44]2[N:40]([C@@H:8]3[CH2:9][C@:10]45[C:27]6[C@H:18]([CH2:17][CH2:16][C@H:15]4[C@@:14]([CH3:39])([CH2:13][O:12][CH2:11]5)[C@H:7]3[O:6][CH2:5][C@@:4]([NH2:3])([CH3:60])[C:56]([CH3:57])([CH3:59])[CH3:58])[C@:19]3([CH3:38])[C@:24]([CH3:28])([C@H:23]([C:29]([OH:31])=[O:30])[C@:22]([C@H:33]([CH3:37])[CH:34]([CH3:36])[CH3:35])([CH3:32])[CH2:21][CH2:20]3)[CH2:25][CH:26]=6)[N:41]=[CH:42][N:43]=2)[CH:50]=[CH:49][N:48]=1)=[O:1]
Reactant: [NH4+]
Reactant: [OH-]
Reactant: CCOC(=O)c1cc(-c2ncnn2[C@@H]2C[C@@]34COC[C@](C)([C@@H]3CC[C@H]3C4=CC[C@@]4(C)[C@H](C(=O)O)[C@@](C)([C@H](C)C(C)C)CC[C@]34C)[C@H]2OC[C@](C)(N)C(C)(C)C)ccn1
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)[C@@H](C)[C@@]1(C)CC[C@]2(C)[C@H]3CC[C@@H]4[C@@]5(COC[C@@]4(C)[C@@H](OC[C@](C)(N)C(C)(C)C)[C@H](n4ncnc4-c4ccnc(C(N)=O)c4)C5)C3=CC[C@@]2(C)[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.1 %

Procedure:
Concentrated ammonium hydroxide (0.15 ml, 1.079 mmol) was added to a stirred solution of (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-[[(2R)-2-amino-2,3,3-trimethylbutyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-14-[5-[2-(ethoxycarbonyl)-4-pyridinyl]-1H-1,2,4-triazol-1-yl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid (Example 171, 38.1, 0.042 mmol) in 1,4-dioxane (0.42 ml). A white precipitate formed about a minute or two after the addition of ammonium hydroxide. The reaction mixture was stirred at room temperature. After 20 hours, additional 1,4-dioxane (0.15 ml) and concentrated ammonium hydroxide (0.05 ml, 0.360 mmol) were added to the reaction mixture. After 26 hours, the reaction mixture had become a colorless solution. After 44 hours, LCMS and 1H NMR showed the reaction to be complete. The reaction mixture was evaporated under reduced pressure to give a colorless residue. The residue was dissolved in methanol and purified using a single HPLC run on a 30×150 mm Sunfire Prep C18 OBD 10 μm column by eluting with acetonitrile/water+0.1% TFA. The total flow rate was 20 ml/min and the HPLC method employed a 17 minute 20%-100% acetonitrile/water gradient followed by a 2 minute acetonitrile flush. The product fractions were combined, the solvent was evaporated under reduced pressure, and the residue was lyophilized from acetonitrile and water to give the title compound (29.9 mg) as a white solid.
Reaction SMILES: [C:1]1([C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.I[CH2:31][CH2:32][CH2:33][O:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1.O>C1COCC1.CCCCCC>[C:19]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH2:31][CH2:32][CH2:33][O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2ccnc2)cc1
Reactant: ICCCOC1CCCCO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2ccnc2CCCOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 310 mg (1 mmol) of 1-triphenylmethylimidazole (K H. Buchel et al.; Drugs Made in Germany, 1972, 15, 77) in 12 ml of dry THF is cooled to 0° under nitrogen and treated with 0.647 ml (1.1 mmol) of 1.7 M solution of n-BuLi in hexane. The solution is stirred at room temperature for 1 hour, then recooled to 0° and treated with 405 mg (1.5 mmol) of 1-iodo-3-(tetrahydropyran-2-yloxy)propane dissolved in 2 ml of dry THF. The reaction mixture is allowed to warm to room temperature overnight, then poured into water and extracted with ethyl acetate. The organic extract is rinsed with brine and dried (MgSO4). Removal of solvents in vacuo affords the title A compound.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH2:8]=O.[C:10]([N:18]1[CH2:23][CH2:22][N:21]2[CH:24]=[CH:25][CH:26]=[C:20]2[CH2:19]1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N>O>[C:10]([N:18]1[CH2:23][CH2:22][N:21]2[C:24]([CH2:8][N:2]3[CH2:7][CH2:6][O:5][CH2:4][CH2:3]3)=[CH:25][CH:26]=[C:20]2[CH2:19]1)(=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C=O
Reactant: C1COCCN1
Reactant: O=C(c1ccccc1)N1CCn2cccc2C1
Agent: Cl
Agent: N
Solvent: O
Product: O=C(c1ccccc1)N1CCn2c(CN3CCOCC3)ccc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.5 %

Procedure:
A mixture of 2.05 g of morpholine hydrochloride, 1.24 g of a 40% solution of formaldehyde, and 3.4 g of 2-benzoyl-1,2,3,4-tetrahydropyrrolo-[1,2-a]-pyrazine was stirred for 4 hours at room temperature. 10 ml of water, alkalized with a 25% solution of ammonia, was added to the reaction mass and the product was extracted with benzene. The benzene solution was filtered through a column of aluminium oxide and the benzene was removed by distillation to give 2.2 g (67.5%) of 2-benzoyl-6-(morpholinomethyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine. This compound was prepared in the form of a noncrystalline oil. Nmr (CDCl3): δ2.1-2.4 (m) (4H, CH2); 3.3 (s) (2H, CH2N); 3.5-3.6 (m) (4H, CH2); 3.7-4.0 (m) (4H, 3,4-CH2); 4.6 (s) (2H, 1-CH2); 5.6-5.7 (m) (1H, 7-H); 5.8-5.9 (m) 1H, 8H); 7.3-7.4 (5H, C6H5). Anal. calculated for C19H23N3O2 : C 70.13%; H 7.12%; N 12.91% and found: C 70.36%; H 7.19%; N 12.75%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:21]#[N:22])[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17]CC)=[O:16])=[CH:7][C:6]=2[CH:20]=1.[OH-].[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:21]#[N:22])[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(C#N)c2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1cc(Cl)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 22 %

Procedure:
The ester from Step 2 (0.51 g 1.5 mmol) was dissolved in THF (5 mL) and ethanol (5 mL), treated with 2.5N sodium hydroxide (1.2 mL, 3.0 mmol), and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo, acidified with 3N HCl extracted with ethyl acetate, washed with water, brine, dried over MgSO4, concentrated in vacuo, and recrystallized from diethyl ether/hexane to give a white powder (0.10 g, 21%): mp 238.1–239.7° C. 1H NMR (acetone-d6/300 MHz) 7.97 (s, 1H), 7.92 (d, 1H, J=2.4 Hz), 7.89 (d, 1H, J=2.4 Hz), 6.14 (q, 1H, J=6.6 Hz). FABLRMS m/z 302 (M−H). ESHRMS m/z 301.9819 (M−H, Calc'd 301.9832). Anal. Calc'd for C12H5ClF3NO3: C, 47.47; H, 1.66; N, 4.61. Found: C, 47.41; H, 1.70; N, 4.55.
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[CH:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.BrCCC=C.[Cl-].[NH4+]>C1COCC1>[CH3:21][O:20][C:18]([C:13]1([CH2:11][CH2:10][CH:9]=[CH2:8])[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:19]
Reactant: COC(=O)C1CCCC1
Reactant: [Li]CCCC
Agent: C=CCCBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=CCCC1(C(=O)OC)CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
To a solution of diisopropylamine (225 mmol, 31.6 mL) in THF (150 mL) was added dropwise a solution of n-butyl lithium (217.5 mmol, 87 mL, 2.5M) in hexanes at −10° C. while maintaining the temperature below 0° C. After addition, the solution was stirred for 30 min at 0° C. To this, a solution of methyl cyclopentane carboxylate (150 mmol, 19.23 g) in THF (30 mL) was added dropwise at −70° C. maintaining the internal temperature between −60 to −70° C. After addition, the reaction mixture was stirred for 1 h at −50 to −60° C. Then, a solution of 4-bromo-1-butene (142.2 mmol, 19.2 g) in THF (30 mL) was added dropwise and the light brown suspension was stirred for 1 h at −60 to −70° C. Then, it was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into a saturated solution of ammonium chloride (250 mL) and the mixture was extracted with ether (2×150 mL). The combined extracts were washed with a saturated solution of sodium chloride (150 mL) and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the solution was concentrated under vacuum and the residue was distilled at 63-67° C./2.5 mm Hg to give 13.77 g (53%) of a colorless oil. HR MS (C11H16O2): Obs mass, 182.1311. Calcd mass, 182.1307 (M+).
Reaction SMILES: CN(C)C=O.[F:6][C:7]([F:19])([F:18])[C:8]1[CH:9]=[C:10]([CH:14](O)[CH:15]=[CH2:16])[CH:11]=[CH:12][CH:13]=1.S(Cl)([Cl:22])=O>ClCCl>[Cl:22][CH:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:7]([F:19])([F:18])[F:6])[CH:9]=1)[CH:15]=[CH2:16]
Reactant: C=CC(O)c1cccc(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CC(Cl)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
Dimethylformamide (5 mL) was added to a solution of 1-[3-(trifluoromethyl)phenyl]prop-2-en-1-ol (50 g) in dichloromethane (500 mL) at 0 to 5° C. The reaction mixture was stirred for 5-10 min at room temperature. The reaction mixture was cooled at 0 to 5° C. and thionyl chloride (44.26 g) was added slowly maintaining the temperature at 0 to 5° C. The reaction mixture was stirred at 0 to 5° C. for 1-2 hours. After completion of the reaction, the mixture was quenched slowly with ice-chilled de-ionized water (250 mL) at 0-10° C. and stirred for additional 30 minutes at 0 to 5° C. Organic Layer was separated, washed twice with a solution of sodium chloride (10%; 250 mL) and concentrated under vacuum at 40° C. to 45° C. to give 1-(1-chloroprop-2-en-1-yl)-3-(trifluoromethyl)benzene.
Reaction SMILES: C(O[CH:5]([CH2:12][CH3:13])[CH:6]([N+]([O-])=O)[CH2:7][CH3:8])(=O)C.[N+:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])#[C-:15].C1CCN2C(=NCCC2)CC1.Cl>C1COCC1>[CH2:12]([C:5]1[C:6]([CH2:7][CH3:8])=[CH:15][NH:14][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:13]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CCC(OC(C)=O)C(CC)[N+](=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1[nH]cc(CC)c1CC
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.6 %

Procedure:
After 4-acetoxy-3-nitrohexane (11.34 g, 60 mmol) had been added to a reaction vessel, the vessel was replaced with nitrogen, and dry-THF (150 ml) and ethyl isocyanoacetate (7.28 ml, 66 mmol) were added. Then, DBU (20.76 ml, 144 mmol) was slowly dropped while the vessel was cooled in an ice bath, and the whole was stirred at room temperature for 12 hours. After the completion of the reaction, 1 N hydrochloric acid was added, the whole was extracted with chloroform, and the extract was washed with water and a saturated salt solution. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. After that, the concentrated product was purified by means of silica gel column chromatography to yield ethyl 3,4-diethylpyrrole-2-carboxylate (10.97 g, 94% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:4]=2[N:5]=[C:6](S(C)=O)[N:7]=1.[CH2:24]([N:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][NH2:30])[CH3:25].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:4]=2[N:5]=[C:6]([NH:30][CH2:29][CH2:28][CH2:27][N:26]([CH2:31][CH3:32])[CH2:24][CH3:25])[N:7]=1
Reactant: CS(=O)c1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CCN(CC)CCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)CCCNc1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
To the compound 4-chloro-8-(2,6-difluorophenyl)-2-(methylsulfinyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (1.59 g, 4.47 mmol) in dichloromethane (89.4 mL) were added N,N-diethyl-1,3-propanediamine (0.845 mL, 5.36 mol) and triethylamine (1.26 uL, 8.94 mmol). The mixture was stirred at rt overnight. Some white precipitate was formed during the reaction. Filtration followed by wash with ethyl acetate/dichoromethane/methnol afforded the title compound (1.028 g, 60%). LC-MS m/z 383 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[N+:10]([C:3]1[CH:4]=[C:5]([CH:6]=[O:7])[CH:8]=[CH:9][C:2]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1ccc(Br)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 17 h
Yield: 81 %

Procedure:
4-Bromo-3-nitrobenzaldehyde (2.0 g) was suspended in N,N-dimethylformamide (30 mL), phenylboronic acid (1.3 g), sodium carbonate (1.8 g), water (6 mL) and tetrakis-(triphenylphosphine)palladium(0) (1.0 g) were added, and the resulting mixture was stirred at 90° C. for 17 hours. The reaction mixture was cooled to room temperature and then partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was washed successively with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1) to give the title compound (1.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19](SC)[N:20]([CH3:23])[C:21](=[O:22])[C:16]=4[C:15]([CH3:26])=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(O)(=O)C>COCCOC.C(O)C.[Ni]>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[CH:19][N:20]([CH3:23])[C:21](=[O:22])[C:16]=4[C:15]([CH3:26])=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CSc1nc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(=O)n1C
Agent: [Ni]
Solvent: CCO
Solvent: COCCOC
Solvent: CC(=O)O
Product: Cc1cn(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c2ncn(C)c(=O)c12
Temperature: 40 °C
Yield: 84.9 %

Procedure:
In a mixture of DME (120 ml) and ethanol (12 ml) was dissolved 7-[4-(4-chlorobenzoyl)benzyl]-3,5-dimethyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (800 mg) followed by addition of acetic acid (672 mg), and the mixture was warmed to 40° C. Then, Raney nickel was added until disappearance of the starting compound had been verified by TLC. The catalyst was then filtered off and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution in that order, and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was allowed to stand, whereupon crystals separated out. This crystal crop was harvested by filtration, rinsed with ethanol and hexane, and dried to provide the title compound (608 mg).