Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1.[NH2:26][C:27]1[O:31][N:30]=[C:29]([CH2:32][CH3:33])[CH:28]=1>>[CH2:32]([C:29]1[CH:28]=[C:27]([NH:26][C:23](=[O:24])[CH2:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:17][CH:18]=2)[O:31][N:30]=1)[CH3:33]
Reactant: COc1cc2ncnc(Oc3ccc(CC(=O)Cl)cc3)c2cc1OC
Reactant: CCc1cc(N)on1
Product: CCc1cc(NC(=O)Cc2ccc(Oc3ncnc4cc(OC)c(OC)cc34)cc2)on1
Yield: 55 %

Procedure:
Using an analogous procedure to that described in Example 19, 2-[4-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]acetyl chloride was reacted with 5-amino-3-ethylisoxazole. There was thus obtained the title compound in 55% yield; 1H NMR: (DMSOd6) 1.16 (t, 3H), 2.56 (q, 2H), 3.76 (s, 2H), 3.97 (s, 3H), 3.99 (s, 3H) 6.16 (s, 1H), 7.27 (d, 1H), 7.39 (s, 1H), 7.41 (d, 2H), 7.55 (s, 1H), 8.54 (s, 1H); Mass Spectrum: M+H+ 435.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[O:11][CH3:12])=[O:3]>C(Cl)Cl>[Br:10][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH3:12])=[C:4]([C@H:2]([OH:3])[CH3:1])[CH:9]=1
Reactant: COc1ccc(Br)cc1C(C)=O
Solvent: ClCCl
Product: COc1ccc(Br)cc1[C@@H](C)O
Reaction time: 0.25 h
Yield: 99.1 %

Procedure:
An oven dried 500 mL flask, was charged under nitrogen with (S)-2-methyl-CBS-oxazaborolidine 1M in toluene (2.18 mL) and dissolved in CH2Cl2 (100 mL). Me2-BH3 (13.10 mL, 26.20 mmol) was then added and cooled reaction to −30° C. then stirred for 15 minutes. 5-Bromo-2-methoxyacetophenone (5 g, 21.83 mmol) was dissolved in CH2Cl2 (10 mL) and slowly added via addition funnel to the previous solution. The resulting reaction was stirred at −30° C. for 1 hour. The solution was carefully quenched with MeOH, the solvent was removed in vacuo and the residue was purified by flash column chromatography (20% EtOAc in hexanes) to provide the desired product (5 g, 100%) as a clear oil. 1H NMR (400 MHz, CDCl3): δ 1.47 (d, J=6.41 Hz, 3H), 2.44 (d, J=5 Hz, 1H), 3.84 (s, 3H), 5.03-5.11 (m, 1H), 6.74 (d, J=8.7 Hz, 1H), 7.33 (dd, J=8.7, 2.5 Hz, 1H), 7.48 (d, J=2.5 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([OH:7])[NH:4][N:3]=1.[C:8]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:13]=CC=C[CH:9]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(O)(C)C>C(Cl)Cl>[CH:8]([O:7][C:5]1[NH:4][N:3]=[C:2]([NH2:1])[CH:6]=1)([CH3:13])[CH3:9]
Reactant: Nc1cc(O)[nH]n1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)Oc1cc(N)n[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The title compound may be prepared via the following procedure: To a suspension of 3-amino-5-hydroxypyrazole (0.50 mol) in CH2Cl2 is added triphenylphosphine (0.59 mol) and the resulting mixture is cooled to 0° C. Diisopropyl azodicarboxylate (0.59 mol) is added drop-wise over a period of 35 minutes (the temperature of the reaction mixture is kept below 2° C.) to give a suspension. The reaction mixture is then held at 0° C. for 1 hour. A precipitate may be observed after 30 minutes of the reaction. Isopropyl alcohol (1.25 mol) is then added drop-wise over a period of 30 minutes at 0° C. as the slurry thins considerably to give a suspension. The reaction mixture is then held at 0° C. for 1 hour. The reaction mixture is warmed slowly to ambient temperature and is then held at ambient temperature overnight. The reaction mixture is filtered to remove undissolved solids. The filtrate is dried (MgSO4) and concentrated under reduced pressure to give an oil. Purification by column chromatography (5%→10% MeOH in CH2Cl2) affords the title compound. (400 MHz, DMSO-d6) δ ppm 10.3 (br s, 1H), 4.84 (br s, 2H), 4.65 (s, 1H), 4.52 (m, 1H), 1.20 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH:3]=1.[OH-].[Na+].Cl>C1COCC1.O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1S(=O)(=O)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)c1cc(Br)ccc1C(=O)O
Temperature: 60 °C
Yield: 78.1 %

Procedure:
A solution of methyl 4-bromo-2-(isopropylsulfonyl)benzoate (Intermediate 242; 516 mg; 1.61 mmol) in THF (10 ml) was treated with a 5 N solution of NaOH in water (4 mL) and the reaction mixture was heated at 60° C. for 1 day. The reaction mixture was acidified with aqueous HCl and the reaction mixture was extracted 3 times with EtOAc. The combined organic phases were dried over MgSO4, filtered and concentrated to dryness affording the title compound as a pale yellow solid (386 mg; 78%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:22][CH3:23])[C:8]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[N:9][C:10]=1[Cl:11])=[O:5])C.C1COCC1.[OH-].[Li+]>O>[Cl:11][C:10]1[N:9]=[C:8]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[N:7]([CH2:22][CH3:23])[C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(Cl)nc(-c2cccc3ccccc23)n1CC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(-c2cccc3ccccc23)nc(Cl)c1C(=O)O
Temperature: 50 °C

Procedure:
5-Chloro-3-ethyl-2-naphthalen-1-yl-3H-imidazole-4-carboxylic acid ethyl ester (62 g, 35 mmol) is dissolved in. THF (10 ml), and aqueous lithium hydroxide solution (2.0 N, 6.35 ml, 2.0 eq.) is added. The mixture is heated at 50° C. overnight. THF is stripped off under reduced pressure, and the residue is diluted with water (10 ml) and basified to pH=4=5. The solid precipitate is collected, washed with water and ether, and dried under high vacuum to give the title compound. LCMS 301 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[NH:4][C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:6][C:7]=1[CH3:8].O(Cl)[Cl:19].[P+5]>CN(C)C=O>[Cl:19][C:3]1[C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=[C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:4]=1
Reactant: Cc1nc(NCc2ccccn2)[nH]c(=O)c1C
Reactant: ClOCl
Agent: [P+5]
Solvent: CN(C)C=O
Product: Cc1nc(NCc2ccccn2)nc(Cl)c1C
Yield: 74 %

Procedure:
A solution of 5,6-dimethyl-2-[(pyridin-2-ylmethyl)amino]pyrimidin-4(3H)-one (7.0 g, 32.6 mmol, Step B) in phosphorus (V) oxychloride (30 mL) with addition of 1 drop of dimethylformamide was refluxed overnight under nitrogen. Then excess phosphorus (V) oxychloride was removed under reduced pressure. Toluene (30 mL) was added, and the reaction mixture was evaporated under reduced pressure. The residue was diluted with 5% aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (2×200 mL). The solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography eluted with hexane/ethyl acetate (2:1). The titled compound 6.1 g (74%) was obtained as a light-yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.10 (s, 3H), 2.39 (s, 3H), 4.54 (s, 2H), 7.20-7.30 (m, 2H), 7.68-7.76 (m, 2H), 7.76 (bs, 1H).
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[CH3:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[CH3:24])[C:17]([CH:25]=O)=[C:16]1[CH3:27].CN1C2C(=CC=CC=2)C(C)=C1C=O>>[CH3:5][NH:6][CH2:25][C:17]1[C:18]2[C:23](=[C:22]([CH3:24])[CH:21]=[CH:20][CH:19]=2)[N:15]([CH3:14])[C:16]=1[CH3:27]
Reactant: Cc1cccc2c(C=O)c(C)n(C)c12
Reactant: COC(=O)CNc1ccc(Br)cn1
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1c(C)n(C)c2c(C)cccc12
Yield: 71 %

Procedure:
According to the procedure of Preparation 13 (c) except substituting 1,2,7-trimethyl-1H-indole-3-carboxaldehyde for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (570 mg, 71%) was obtained as an oil which slowly crystallized: MS (ES) m/e 405.4 (2M+H)+.
Reaction SMILES: [I:1][CH2:2][CH2:3][C@H:4]([OH:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:13][Si:14](Cl)([CH3:16])[CH3:15]>C(Cl)Cl>[I:1][CH2:2][CH2:3][C@H:4]([O:12][Si:14]([CH3:16])([CH3:15])[CH3:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C[Si](C)(C)Cl
Reactant: CCCCCCC[C@@H](O)CCI
Solvent: ClCCl
Product: CCCCCCC[C@H](CCI)O[Si](C)(C)C
Reaction time: 1 h

Procedure:
To a solution of 1-iodo-3(R)-decanol (490 mg) in methylene chloride (10 ml) was added trimethylsilyl chloride (336 mg) and N-ethyldiiosopropylamin (398 mg). After stirring for 1 hour, the mixture was washed with phosphate buffer (pH 6.5, 0.066M, 10 ml) and brine (10 ml), dried and evaporated in vacuo. The residue was purified by chromatography (silica gel, 20 g, methylene chloride as eluent) to give the title compound as an oil, δ (300 MHz) 0.13 (9H, s), 0.87 (3H, t), 1.15-1.50 (12H, m), 1.92 (2H, m), 3.21 (2H, m) and 3.70 (1H, m).
Reaction SMILES: COC1C=C(CC(=O)CC2C=CC=CC=2)C=CC=1.C(OCC)=O.Cl.CN.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:35]2[C:40](=[O:41])[C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:38][N:37]([CH3:48])[CH:36]=2)[CH:32]=[CH:33][CH:34]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:35]2[C:40](=[O:41])[CH:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:38][N:37]([CH3:48])[CH2:36]2)[CH:32]=[CH:33][CH:34]=1
Reactant: COc1cccc(-c2cn(C)cc(-c3ccccc3)c2=O)c1
Agent: CN
Agent: COc1cccc(CC(=O)Cc2ccccc2)c1
Agent: Cl
Solvent: CCOC=O
Product: COc1cccc(C2CN(C)CC(c3ccccc3)C2=O)c1

Procedure:
A 54 g. portion of 1-(3-methoxyphenyl)-3-phenyl-2-propanone was reacted with ethyl formate and methylamine hydrochloride as described in Examples 1-3 to prepare 10 g. of 3-(3-methoxyphenyl)-1-methyl-5-phenyl-4(1H)-pyridinone, which was reduced with 2 g. of lithium aluminum hydride. The reaction mixture was worked up as in the examples above and chromatographed over a silica gel column. About 1.4 g. of a mixture of the compounds of Examples 24 and 25 was obtained, an oil which was identified by mass spectroscopy as having a molecular weight of 293. About 1.3 g. of the piperidinone of Example 26 was recovered, which had an indicated molecular weight of 295 by mass spectroscopy.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([C:11](=[O:19])[CH2:12][N:13]([OH:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][C:4]=1[C:20]#[N:21]>>[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([CH:11]([OH:19])[CH2:12][N:13]([OH:18])[C:14]([CH3:17])([CH3:15])[CH3:16])=[CH:5][C:4]=1[C:20]#[N:21]
Reactant: CC(C)(C)N(O)CC(=O)c1cc(C#N)c(N)c(C#N)c1
Agent: Cl
Product: CC(C)(C)N(O)CC(O)c1cc(C#N)c(N)c(C#N)c1

Procedure:
m.p. of the hydrochloride: 240°-241° C. (decomp.), was prepared from 4'-amino-3',5'-dicyano-2-(hydroxy-tert.butylamino)-acetophenone analogous to Example 48.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C@@H:10]2[CH2:14][C@H:13]([S:15][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([O:23]CC3C=CC([N+]([O-])=O)=CC=3)=[O:22])[CH2:12][N:11]2[CH3:41])=[O:9])[CH2:4][CH2:3]1.O1CCCC1.[ClH:47]>O>[ClH:47].[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]([C@@H:10]2[CH2:14][C@H:13]([S:15][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([OH:23])=[O:22])[CH2:12][N:11]2[CH3:41])=[O:9])[CH2:6][CH2:7]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C)CC4)N(C)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C)CC4)N(C)C3)[C@H](C)[C@H]12

Procedure:
A solution of 720 mg of 4-nitrobenzyl (1R,5S,6S)-2-[(2S,4S)-2-(4-methyl-1-piperazinylcarbonyl)-1-methyl-pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] in 60 ml of a 1:1 by volume mixture of tetrahydrofuran and water was mixed with 1.2 ml of 1N aqueous hydrochloric acid, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 800 mg of 10% w/w palladium-on-charcoal. The catalyst was then removed by filtration and the filtrate was washed with diethyl ether. The aqueous solution was concentrated by evaporation under reduced pressure, the residue was subjected to column chromatography using a Lobar column (Merck, LiChroprep RP-8, size B) and the column was eluted with 3% by volume aqueous methanol. Those fractions containing the title compound were combined and concentrated by evaporation under reduced pressure, to give 326 mg of the title compound as a colorless powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:9][CH2:8]2)=[N:3][CH:2]=1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([N:18]2[CH2:19][CH2:20][CH:15]([C:13]([N:10]3[CH2:9][CH2:8][N:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][N:3]=4)[CH2:12][CH2:11]3)=[O:14])[CH2:16][CH2:17]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: O=C(C1CCNCC1)N1CCN(c2ccncn2)CC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1)N1CCN(c2ccncn2)CC1
Reaction time: 20 h
Yield: 30 %

Procedure:
4-[1-(4-Pyrimidinyl)piperazin-4-ylcarbonyl]piperidine (385 mg) in dichloromethane (20 ml) was stirred at room temperature as a solid suspension and treated dropwise with 4-bromophenylsulphonyl chloride (385 mg) and triethylamine (0.4 ml) in dichloromethane (15 ml). The resulting clear yellow solution was stirred at the same temperature for a further 20 h and treated with saturated NaHCO3 solution (40 ml). The mixture was extracted twice with dichloromethane and the combined organic extracts washed twice each with water and brine dried over anhydrous MgSO4, filtered and evaporated under reduced pressure to a yellow solid. The solid was chromatographed through a 10 g silica bond elut prepacked column, eluting with 1% methanol, 1% ammonium hydroxide and 98% dichloromethane to give 1-(4-bromophenylsulphonyl)-4-[1-(4-pyrimidinyl)piperazin-4-ylcarbonyl]piperidine (209 mg; 30% yield based on the amine), as a colourless solid, mp 171-174° C.;
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:8]([CH3:10])[CH3:9].[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([NH:22][C:23]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:25][CH:24]=2)=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19]>CN(C=O)C>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([NH:22][C:23]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:25][CH:24]=2)=[C:17]([CH:21]=1)[C:18]([O:20][CH:8]([CH3:10])[CH3:9])=[O:19]
Reactant: CC(C)I
Reactant: COc1ccc(Nc2ccnn2-c2ccccc2)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Nc2ccnn2-c2ccccc2)c(C(=O)OC(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.9 %

Procedure:
Cesium carbonate (105 mg, 0.19 mmol) and 2-iodopropane (18 mg, 0.11 mmol) were added to a solution of the intermediate 5-methoxy-2-[(1-phenyl-1H-pyrazol-5-yl)amino] benzoic acid (30 mg, 0.10 mmol) in DMF (4 mL). The mixture was stirred at rt for 16 h. The reaction was quenched with water (5 mL) and then extracted with dichloromethane (3×5 mL). The combined organic layers were washed with water (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. HPLC purification of the residue (YMC propack C18 column, 150×20 mm ID, 30%-80% acetonitrile in water gradient) afforded the desired product as a white solid (20 mg, 59%). 1H NMR (300 MHz, DMSO-d6) δ 9.07 (s, 1H), 7.65 (d, 1H), 6.96-7.56 (m, 9H), 6.29 (dd, 1H), 5.06 (q, 1H), 3.69 (s, 3H), 1.24 (d, 6H); ES-MS m/z 352.1 (MH+); HPLC RT (min) 3.53.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[Cl:15][C:12]([F:13])([F:14])[C:6]1[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([NH:29][C:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CC(C)(C)N
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1NC(C)(C)C
Yield: 19.9 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 3.9 ml (0.036 mol) of t-butylamine in 30 ml of DMF were reacted affording a residue which was kugelrohr distilled at 133 Pa, pot temperature 126° C., giving 4.49 g. Purification by HPLC using 5% ethyl acetate/cyclohexane as eluting solvent afforded 1.12 g (19.9%) of product as a white solid; mp 51.5°-53° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:9]=2)[C:4](=[O:16])[NH:3]1.Br[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.O1CCOCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CCCCCC.[Cu](I)I.C(OC(=O)C)C>[CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([C:12]([F:13])([F:15])[F:14])=[CH:8][CH:9]=2)[C:4](=[O:16])[N:3]1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC1Cc2ccc(C(F)(F)F)cc2C(=O)N1
Reactant: Brc1cccnc1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC1Cc2ccc(C(F)(F)F)cc2C(=O)N1c1cccnc1
Yield: 61.8 %

Procedure:
3-Methyl-7-trifluoromethyl-3,4-dihydro-2H-isoquinolin-1-one (I-43d: 40 mg, 0.1745 mmol) was reacted with 3-bromo-pyridine (19 mg, 0.1163 mmol), 1,4-dioxane (5 mL), copper iodide (4 mg), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (8 mg) and potassium phosphate (93 mg, 0.4363 mmol). The reaction was monitored by TLC (50% ethylacetate in hexane). The reaction mass was concentrated under reduced pressure and partitioned between ethylacetate and water. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated. Purification by column chromatography on silica gel (100% ethylacetate in hexane) followed by washing with hexane and ether afforded 22 mg of the product (41.15% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]2[O:20][C:19]([C@@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[N:18][N:17]=2)=[N:4][C:5]([O:14][CH3:15])=[C:6]([C:10]([F:13])([F:12])[F:11])[C:7]=1[CH:8]=[CH2:9].C([O-])=O.[NH4+]>CCO.[OH-].[OH-].[Pd+2]>[NH2:1][C:2]1[C:3]([C:16]2[O:20][C:19]([C@@:21]([OH:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[N:18][N:17]=2)=[N:4][C:5]([O:14][CH3:15])=[C:6]([C:10]([F:12])([F:13])[F:11])[C:7]=1[CH2:8][CH3:9]
Reactant: C=Cc1c(N)c(-c2nnc([C@](C)(O)C(F)(F)F)o2)nc(OC)c1C(F)(F)F
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCc1c(N)c(-c2nnc([C@](C)(O)C(F)(F)F)o2)nc(OC)c1C(F)(F)F
Reaction time: 0.5 h

Procedure:
To a stirring solution of (S)-2-(5-(3-amino-6-methoxy-5-(trifluoromethyl)-4-vinylpyridin-2-yl)-1,3,4-oxadiazol-2-yl)-1,1,1-trifluoropropan-2-ol (step 1)(153 mg, 0.384 mmol) in EtOH (10 ml) was added palladium hydroxide on carbon (43.2 mg, 0.307 mmol) followed by ammonium formate (969 mg, 15.37 mmol). The reaction mixture was heated at relux for 30 minutes. The mixture was filtered through Celite® and diluted with EtOAc. The filtrate and washed with sat.NaHCO3, water, brine and dried over MgSO4. Isolute Si-TMT (2,4,6-trimercaptotriazine silica, palladium scavenger) was added the mixture was stirred for 30 mins and filtered. The solvent was removed in vacuo and purification of the crude product by chromatography on silica eluting with 0-30% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [CH3:1][C:2](=[O:5])[CH:3]=[CH2:4].[C:6]1([CH3:22])[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[CH:13]=O)[CH:7]=1.[OH-].[K+]>C(OCC)C.C(O)C.C(OCC)(=O)C.O>[C:17]1([CH3:21])[CH:18]=[CH:19][CH:20]=[C:15]([C:12]2([C:8]3[CH:7]=[C:6]([CH3:22])[CH:11]=[CH:10][CH:9]=3)[CH2:13][CH2:1][C:2](=[O:5])[CH:3]=[CH:4]2)[CH:16]=1
Reactant: C=CC(C)=O
Reactant: Cc1cccc(C(C=O)c2cccc(C)c2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: Cc1cccc(C2(c3cccc(C)c3)C=CC(=O)CC2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Butenone (7.23 cc) is added to a solution of bis-(3-tolyl)acetaldehyde (20.4 g) in ethyl ether (110 cc) and then, after cooling to 0° C., a solution of potassium hydroxide (2 g) in ethanol (12.7 cc) is added dropwise. The reaction mixture is stirred for 2 hours at 0° C. and then for 16 hours at 25° C. and diluted with ethyl acetate (200 cc) and water (200 cc). The aqueous phase is washed with ethyl acetate (2×250 cc). The combined organic phases are washed with water (2×250 cc) and then with saturated sodium chloride solution (250 cc), dried over magnesium sulphate and concentrated under reduced pressure (2.7 kPa). The residue is chromatographed on silica gel (particle size 0.04-0.063 mm, column 5.4 cm in diameter and 40 cm high), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (85/15 by volume). 4,4 -bis-(3-Tolyl)-cyclohexenone (16.7 g) is obtained in the form of yellow oil.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[CH:18](C(OCC)=O)[C:19]([O:21][C:22](C)(C)[CH3:23])=[O:20])([O-:4])=[O:3]>CCOC(C)=O>[N+:2]([C:5]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])([O-:4])=[O:3]
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)c1c([N+](=O)[O-])cc([N+](=O)[O-])c2ccccc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1c([N+](=O)[O-])cc([N+](=O)[O-])c2ccccc12
Reaction time: 8 h
Yield: 68.8 %

Procedure:
Concentrated HCl (1.5 mL) was added to a solution of t-butyl ethyl (2,4-dinitronaphthalen-1-yl)malonate (0.60 g, 1.48 mmol) in AcOEt (6 mL), and the mixture was stirred overnight. The mixture was diluted with AcOEt (30 mL), washed with H2O (10 mL), saturated aqueous NaHCO3 (10 mL) and saturated aqueous NaCl (10 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Recrystallization (Ether) afforded ethyl (2,4-dinitronaphthalen-1-yl)acetate (0.31 g, 69%) as a pale orange solid. M.p. 132-134° C.; 1H NMR (CDCl3, 500 MHz) δ 8.71 (s, 1H), 8.61 (d, 8.5, 1H), 8.30 (d, 8.5, 1H), 7.92 (dt, 1.0, 8.5, 1H), 7.86 (dt, 1.5, 8.5, 1H), 4.51 (s, 2H), 4.22 (q, 7.5, 2H), 1.27 (t, 7.5, 3H); 304 (M−); IR (neat) 3087, 2989, 1732, 1528, 1422, 1355, 1204, 1169, 1027, 889, 832, 779 cm−1. FABMS (NBA) m/z 305 (M+H+).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=2I)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([CH:24]1[CH2:28][CH2:27][CH2:26][O:25]1)#[CH:23].C(N(CC)CC)C.O>O1CCOCC1>[O:25]1[CH2:26][CH2:27][CH2:28][CH:24]1[C:22]1[N:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[C:11]2[C:12]([CH:23]=1)=[CH:13][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][CH:16]=2
Reactant: C#CC1CCCO1
Reactant: CS(=O)(=O)c1ccc(NS(=O)(=O)c2ccccc2)c(I)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc2c(c1)cc(C1CCCO1)n2S(=O)(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 91.8 %

Procedure:
To a solution of 1-benzenesulfonylamino-2-iodo-4-methanesulfonylbenzene (256 mg) in 1,4-dioxane (6 ml), 2-ethynyltetrahydrofuran (169 mg), bistriphenylphosphine palladium dichloride (21 mg), cuprous iodide (11 mg) and triethylamine (89 mg) were added successively and the mixture was stirred in a sealed tube at 60° C. for 3 hours. After cooling the reaction solution was poured into water, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (hexane:ethyl acetate=1:1) to obtain 218 mg of the desired product in a white amorphous form.