Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.Cl.[CH3:18]O>>[CH3:18][O:9][C:8](=[O:10])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a solution of 4-biphenylacetic acid (10 g, 47 mmol) in methanol (150 mL) was added concentrated HCl (3 mL). The mixture was heated under reflux for 16 hours, cooled to rt, and the solvent was evaporated. Chromatography of the residue over silica gel (petroleum ether followed by ethyl acetate/petroleum ether 1/4) gave 4-biphenylacetic acid methyl ester (10.4 g, 98%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH2:31][CH:32]=[O:33])[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[NH2:34][C@H:35]([CH2:40]O)[C:36]([CH3:39])([CH3:38])[CH3:37].C(O)(=O)C>ClCCl>[CH3:37][C:36]([C@@H:35]1[N:34]2[C:3](=[O:4])[C:5]3[N:6]([CH:7]=[C:8]([C:20]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[O:30])[C:9](=[O:19])[C:10]=3[O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:31][C@H:32]2[O:33][CH2:40]1)([CH3:39])[CH3:38]
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Reactant: CC(C)(C)[C@H](N)CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4)c(=O)c(OCc4ccccc4)c3C(=O)N21
Yield: 85.5 %

Procedure:
The title compound was made in two steps using a similar process to that described in example Z-2. 16 (41 mg, 0.09 mmol) and freebased L-tert-leucinol (59 mg, 0.50 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (3S,11aR)-3-(1,1-dimethylethyl)-N-[(4-fluorophenyl)methyl]-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (40 mg, 85%). This material was hydrogenated in a second step as described in example Z-2 to give (3S,11aR)-3-(1,1-Dimethylethyl)-N-[(4-fluorophenyl)methyl]-6-hydroxy-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (32 mg, 97%) as a tinted white solid. 1H NMR (CDCl3) δ 11.15 (br, 1H), 10.32 (s, 1H), 8.38 (s, 1H), 7.29 (m, 2H), 6.98 (m, 2H), 5.43 (m, 1H), 4.58 (m, 2H), 4.36 (m, 2H), 4.21 (m, 1H), 3.99 (m, 1H), 3.79 (m, 1H), 1.02 (s, 9H); ES+MS: 430 (M+1).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[OH:13][CH:12]([C:9]1[CH:10]=[CH:11][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCBr
Reactant: O=Cc1ccn(-c2ccccc2)c1
Agent: [Mg]
Product: CCCCCC(O)c1ccn(-c2ccccc2)c1
Yield: 95.9 %

Procedure:
This compound was synthesized according to the procedure described in Example 3. Thus, starting from 2.2 g of 1-phenylpyrrole-3-aldehyde, 1.2 g of magnesium and 3.8 g of 1-bromopentane, 3 g of pure product was obtained as an oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#N.[CH2:11](I)[CH3:12].[C:14]([NH:18][OH:19])([CH3:17])([CH3:16])[CH3:15]>>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[N+:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[O-:19]
Reactant: N#Cc1ccc(O)cc1F
Reactant: CCI
Reactant: CC(C)(C)NO
Product: CCOc1ccc(C=[N+]([O-])C(C)(C)C)c(F)c1

Procedure:
The title compound was prepared according to the procedure described in Example 29 using 2-fluoro-4-hydroxybenzonitrile, ethyl iodide and N-tert-butylhydroxylamine. The title compound was isolated in 64.7% overall yield as slightly yellowish crystals. m.p. 82.5° C. (Rf=0.16 on a silica gel plate using hexanes/ethyl acetate, 4:1, v:v, as the eluant).
Reaction SMILES: N1C=CC=CC=1.[Br:7][C:8]1[C:13](=O)[N:12]2[N:15]=[C:16]([CH3:18])[CH:17]=[C:11]2[NH:10][C:9]=1[CH3:19].P(Cl)(Cl)([Cl:22])=O.C(=O)(O)[O-].[Na+]>ClCCCl.ClCCl>[Br:7][C:8]1[C:9]([CH3:19])=[N:10][C:11]2[N:12]([N:15]=[C:16]([CH3:18])[CH:17]=2)[C:13]=1[Cl:22]
Reactant: Cc1cc2[nH]c(C)c(Br)c(=O)n2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1cc2nc(C)c(Br)c(Cl)n2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.8 %

Procedure:
Pyridine (0.179 mL, 2.22 mmol) was added dropwise to a solution of 6-bromo-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7(4H)-one (0.179 g, 0.739 mmol) in phosphoryl chloride (1.85 mL, 19.8 mmol) and 1,2-dichloroethane (1.85 mL). The resultant reaction mixture was stirred at RT for 15 min, then warmed to 80° C. and stirred at that temperature for 15 h. The reaction mixture was concentrated in vacuo to yield a crude residue which was diluted with dichloromethane and the resultant solution was added dropwise to a saturated solution of sodium bicarbonate (40 mL) at 0° C. Additional dichloromethane (50 mL) was added, layers were separated and the organic layer was dried with sodium sulfate, filtered, and concentrated in vacuo to give a crude residue. Purification by flash column chromatography (100% hexanes to 30% EtOAc/hexanes) gave the desired product (171 mg, 89%) as a white solid. LCMS calculated for C8H8BrClN3 (M+H)+: m/z=260.0, 262.0. found: 259.9, 261.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH:10]2[CH2:23]OS(C)(=O)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[C-:29]#[N:30].[Na+]>CN(C=O)C>[C:29]([CH2:23][CH:10]1[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:11]1)#[N:30]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(COS(C)(=O)=O)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CC#N)C1
Temperature: 80 °C
Reaction time: 18 h
Yield: 92.7 %

Procedure:
To a solution of tert-butyl (6RS,7SR)-7-(3,4-dichlorophenyl)-6-{[(methylsulfonyl)oxy]methyl}-1,4-oxazepane-4-carboxylate (1.26 g) in DMF (10 mL) was added sodium cyanide (204 mg), and the mixture was stirred at 80° C. for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (990 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:18]=1.Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:18]=1
Reactant: ClCCN1CCOCC1
Reactant: O=C1c2ccc(Cl)cc2CCc2c(O)cccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1c2ccc(Cl)cc2CCc2c(OCCN3CCOCC3)cccc21

Procedure:
For the synthesis of the title compound, 0.44 g (1.69 mmol) of 8-chloro-1-hydroxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 0.345 g (1.86 mmol) of 4-(2-chloroethyl)morpholine hydrochloride and 0.93 g (6.75 mmol) of K2CO3 in 15 ml of acetonitrile are reacted by method Q. C21H21ClNO3 (Mr=371.87); GC 29.7 min
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:11]1[N:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:19](=[O:27])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[F:28])[N:12]=1)[CH2:9][CH3:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@H:8]([C:11]1[N:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:19](=[O:27])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[F:28])[N:12]=1)[CH2:9][CH3:10]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(F)c2c(=O)n1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1ccccc1
Reaction time: 1 h
Yield: 87.1 %

Procedure:
A solution of compound 110 (85 mmol) in dichloromethane (60 mL) was treated with trifluoroacetic acid (60 mL). The reaction mixture was stirred for 1 h, concentrated in vacuo, and partitioned between dichloromethane (150 mL) and 10% K2CO3 (sufficient amount to keep the pH greated than 10). The aqueous layer was extracted with additional dichloromethane (100 mL), and the combined organic layers were washed with water (50 mL) and brine (50 mL). After drying with Mg SO4, the solution was concentrated to provide compound 111 as an off-white solid (22 g, 88%). 1H NMR (300 MHz, CDCl3) δ 7.73-7.65 (m, 1H), 7.62-7.49 (m, 4H), 7.32-7.22, (m, 2H), 7.13-7.06 (m, 1H), 3.42 (dd, J=7.5, 5.2 Hz, 1H), 1.87-1.70 (m, 1H), 1.58-1.43 (m, 1H), 0.80 (t, J=7.4 Hz, 3H), ESI-MS m/z 298.2 (MH+). The reaction described above and compound 111 are shown below.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[O:16])[CH2:11][CH2:10]2)[N:3]=1.C(#N)C.C[O:31][CH2:32][CH2:33][NH2:34].CCN(C(C)C)C(C)C>CS(C)=O>[Cl:26][C:20]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=1[CH2:18][NH:17][C:15]([CH:12]1[CH2:11][CH2:10][N:9]([C:4]2[N:3]=[C:2]([NH:34][CH2:33][CH2:32][OH:31])[N:7]=[C:6]([CH3:8])[N:5]=2)[CH2:14][CH2:13]1)=[O:16]
Reactant: COCCN
Reactant: Cc1nc(Cl)nc(N2CCC(C(=O)NCc3ccc(Cl)cc3Cl)CC2)n1
Solvent: CS(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(NCCO)nc(N2CCC(C(=O)NCc3ccc(Cl)cc3Cl)CC2)n1
Temperature: 80 °C
Yield: 64.5 %

Procedure:
To a 10 mL reaction vial was added the 1-(4-chloro-6-methyl-1,3,5-triazin-2-yl)-N-[(2,4-dichlorophenyl)methyl]-4-piperidinecarboxamide (50 mg, 0.121 mmol) and acetonitrile (0.754 mL) to give a white suspension. Then, [2-(methyloxy)ethyl]amine (0.105 mL, 1.206 mmol) and DIEA (0.063 mL, 0.362 mmol) were added. The reaction was heated for 1 h at 80° C. The reaction mixture was diluted with DMSO and purified by preparative HPLC to provide N-[(2,4-dichlorophenyl)methyl]-1-{4-[(2-hydroxyethyl)amino]-6-methyl-1,3,5-triazin-2-yl}-4-piperidinecarboxamide (46 mg, 0.078 mmol, 65%) as a white solid. MS (ES) m/e 439, 441 [M+H]+. 1H NMR (400 MHz, DMSO-D6) 8.5 (bs, 1H), □ 8.3 (bs, 1H), 7.7 (s, 1H), 7.4 (m, 1H), 7.3 (m, 1H), 4.7 (m, 2H), 4.3 (m, 2H), 3.8-3.3 (3H under H2O peak), 3.1 (m, 4H), 2.6 (m, 1H), 2.3 (s, 3H), 1.8 (m, 2H), 1.5 (m, 2H)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]=O)=[C:10]([O:17][CH:18]([CH3:20])[CH3:19])[CH:9]=2)[CH2:4][CH2:3]1.CC(N=P(N1CCCC1)(N1CCCC1)N1CCCC1)(C)C.[CH3:42][O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:50]1[C:54]2[N:55]=C(S(C)(=O)=O)[N:57]=[CH:58][C:53]=2[S:52][C:51]=1[C:63]([O:65][CH3:66])=[O:64]>CN(C=O)C.C(OCC)(=O)C>[CH3:42][O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:50]1[C:54]2[N:55]=[C:15]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([CH:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:9][C:10]=3[O:17][CH:18]([CH3:20])[CH3:19])[N:57]=[CH:58][C:53]=2[S:52][C:51]=1[C:63]([O:65][CH3:66])=[O:64]
Reactant: CC(C)Oc1cc(C2CCN(C)CC2)ccc1NC=O
Reactant: COC(=O)c1sc2cnc(S(C)(=O)=O)nc2c1-c1ccccc1OC
Agent: CC(C)(C)N=P(N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1sc2cnc(Nc3ccc(C4CCN(C)CC4)cc3OC(C)C)nc2c1-c1ccccc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
A mixture of 527 mg of N-[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]formamide and 953 mg of 1-[N-(2-methylpropan-2-yl)-P,P-di(pyrrolidin-1-yl)phosphorimidoyl]-pyrrolidine (BTPP) in 10 ml of anhydrous DMF is stirred at ambient temperature for 30 min, and then a solution of 577 mg of methyl 7-(2-methoxyphenyl)-2-(methylsulfonyl)thieno[3,2-d]pyrimidine-6-carboxylate in 15 ml of anhydrous DMF is slowly added. The mixture is stirred at ambient temperature for 48 h, and then diluted with ethyl acetate and washed three times with water. The organic phase is dried over magnesium sulfate, filtered and concentrated under vacuum. The crude product is purified on 80 g of silica, elution being carried out with 5-10% of methanol in dichloromethane, so as to obtain 615 mg of methyl 7-(2-methoxyphenyl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxylate in the form of a yellow solid. The crude product is diluted with 600 ml of 7N ammoniacal methanol and the solution is stirred at ambient temperature for 48 h, and then concentrated under vacuum. The residue is solubilized with 100 ml of hot ethyl acetate and the solution is left to cool in order to obtain a suspension. The suspension is cooled in an ice bath and filtered. The solid is washed with ethyl ether and dried under vacuum, so as to obtain 477 mg of 7-(2-methoxyphenyl)-2-{[4-(1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]amino}thieno[3,2-d]pyrimidine-6-carboxamide in the form of a yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]=1[OH:15])[C:7]([O:9][CH2:10]C)=[O:8])(=[O:3])[CH3:2].[N+:16]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O)([O-:18])=[O:17].N1CCCCC1.Cl>C(O)C.O>[C:7]([C:6]1[CH:5]=[C:4]2[C:14](=[CH:13][CH:12]=1)[O:15][CH:21]([C:20]1[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=1[N+:16]([O-:18])=[O:17])[CH2:2][C:1]2=[O:3])([O:9][CH3:10])=[O:8]
Reactant: CCOC(=O)c1ccc(O)c(C(C)=O)c1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: C1CCNCC1
Solvent: O
Product: COC(=O)c1ccc2c(c1)C(=O)CC(c1ccccc1[N+](=O)[O-])O2

Procedure:
A mixture consisting of ethyl 3-acetyl-4-hydroxy-benzoate (6 g) and 2-nitro-benzaldehyde (5 g) dissolved in ethanol (100 ml) and piperidine (100 ml) was kept at reflux temperature for 24 hours. The mixture was then cooled, diluted in water (800 ml), acidified with hydrochloric acid, extracted with ethylacetate, washed with water and evaporated to dryness to obtain as raw product, 6-carbomethoxy-2'-nitro-flavanone. This product (6.8 g) was dissolved in chloroform (40 ml) and treated with a solution of benzoyl peroxide (0.15 g) and N-bromosuccinimide (3.8 g) dissolved in chloroform (60 ml). The mixture was kept at reflux temperature for 4 hours, then evaporated to dryness under vacuum at low temperature; then the residue, dissolved in ethanol 95% (150 ml), was treated with sodium hydrate 4 N (25 ml) at room temperature for a night. After acidification with hydrochloric acid and filtration, 6-carboxy-2'-nitro-flavone (3.7 g) was obtained, which was subsequently treated with stannous chloride (20 g) in concentrated hydrochloric acid (15 ml) and glacial acetic acid (15 ml) at reflux temperature for 4 hours. After cooling, dilution with water, neutralisation with ammonium hydrate 28 Be, the precipitate was filtered to give, after crystallisation from dimethylformamide, 6-carboxy-2'-amino-flavone (1.8 g; m.p.> 300° C).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21](F)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:29]#[N:30].[Na+]>CS(C)=O.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]([C:29]#[N:30])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(F)c3c2CCCC3)CC1
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(C#N)c3c2CCCC3)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
4-(4-Fluoro-5,6,7,8-tetrahydro-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester (970 mg, 2.35 mmol) was dissolved in DMSO (10 mL) and sodium cyanide (577 mg, 11.77 mmol) was added. The mixture was heated overnight at 100° C. An additional 5 equivalents of sodium cyanide (577 mg, 11.77 mmol) were added and the reaction was stirred overnight at 100° C. The reaction was cooled to room temperature and diluted with dichloromethane (100 mL). The mixture was charged to a separatory funnel and extracted three times with water, brine and then dried over MgSO4. Filtration and concentration in vacuo afforded a brown color foam that was triturated with EtOAc to afford a tan solid. Wt.: 550 mg (56%) 1H NMR (300 MHz, CDCl3) δ 7.87 (d, 1H), 7.48 (d, 1H), 4.52 (d, 1H), 3.93 (m, 2H), 3.30 (m, 1H), 3.07 (m, 4H), 2.73 (m, 2H), 1.80 (m, 6H), 1.37 (s, 9H), 1.30 (m, 2H); LC/MS m/z 418 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]([F:26])([F:25])[F:24])[CH:8]=2)[N:3]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(N(CC)CC)C.Cl>CC(N(C)C)=O>[C:17]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:23]([F:26])([F:25])[F:24])[CH:8]=3)[N:3]=[C:2]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[C:11]=2[C:12]2[NH:16][N:15]=[N:14][N:13]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C1CCNCC1
Reactant: FC(F)(F)c1ccc2nc(Cl)c(-c3nnn[nH]3)c(-c3ccccc3)c2c1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccc2nc(N3CCCCC3)c(-c3nnn[nH]3)c(-c3ccccc3)c2c1
Temperature: 100 °C
Yield: 18.6 %

Procedure:
A mixture of 2-chloro-4-phenyl-3-(1H-tetrazol-5-yl)-6-trifluoromethyl-quinoline (105 mg, 279 μmol), piperidine (47.6 mg, 55.3 μl, 559 μmol) and triethylamine (84.8 mg, 117 μl, 838 μmol) in DMA (2 ml) was heated to 100° C. in a sealed tube. After 4 h 0.1N HCl was added at room temperature and the mixture was extracted with EtOAc. The combined organic layers were washed with 0.1N HCl and brine and dried with Na2SO4. The remaining brown oil was purified by chromatography (silica gel, DCM/MeOH 98:2 to 95:5). The product fractions were concentrated and the remaining solid was dissolved in EtOAc, filtered through silica gel and evaporated. The remaining residue was finally purified by preparative thin-layer chromatography (DCM/MeOH 95:5) to obtain the title compound (22 mg, 18%) as light yellow solid. MS (ESI): 425.4 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[N:7]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:6][C@@H:5]1[CH3:21])(=[O:3])[CH3:2].[N+:22]([O-])([OH:24])=[O:23]>C(O)(=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[C:11]([N+:22]([O-:24])=[O:23])[CH:12]=2)[N:7]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:6][C@@H:5]1[CH3:21])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(=O)N1c2cc([N+](=O)[O-])c(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Temperature: 110 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
A reaction vial was charged with isopropyl (S)-4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.100 g, 0.282 mmol) and acetic acid (1 mL), and the reaction was heated to 110° C. Nitric acid (37.7 μL, 0.845 mmol) was added dropwise and the reaction was stirred at 110° C. for 1 h. The reaction was cooled to ambient temperature and then added dropwise to an ice/water bath. The resulting slurry was filtered, and the filter cake was dried overnight under vacuum to provide isopropyl (S)-4-acetyl-7-bromo-3-methyl-6-nitro-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.111 g, 99%) as a white solid. MS (ESI, pos. ion) m/z 428 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH2:13][CH2:14][CH2:15][NH2:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[O:27][CH2:28][CH2:29][CH2:30][CH2:31]Cl>CS(C)=O.O>[C:7]1([CH2:13][CH2:14][CH2:15][NH:16][CH2:31][CH2:30][CH2:29][CH2:28][O:27][C:18]2[CH:19]=[CH:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCCCc1ccccc1
Reactant: ClCCCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(CCCNCCCCOc2ccc3ccccc3c2)cc1
Temperature: 145 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and 3-phenylpropylamine (0.42 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 4-(2-naphthyloxy)-1-chlorobutane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 145° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(3-phenylpropyl)-(4-(naphthalen-2-yloxy)butyl)amine solid, m.p. 117° C., (yield 0.67 gm, 93.6%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][O:10][C:9]2=[O:19])[CH:5]=[CH:4][N:3]=1.[F:20][C:21]([F:26])([F:25])[CH:22]([NH2:24])[CH3:23].CCN(C(C)C)C(C)C.[OH2:36]>CS(C)=O>[C:13]1([C@H:12]2[CH2:11][O:10][C:9](=[O:19])[N:8]2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:24][CH:22]([CH3:23])[C:21]([F:26])([F:25])[F:20])[N:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:20][C:21]([F:26])([F:25])[C:22]([OH:10])=[O:36]
Reactant: O
Reactant: CC(N)C(F)(F)F
Reactant: O=C1OC[C@H](c2ccccc2)N1c1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1nccc(N2C(=O)OC[C@@H]2c2ccccc2)n1)C(F)(F)F
Product: O=C(O)C(F)(F)F
Temperature: 115 °C

Procedure:
A mixture of (S)-3-(2-chloropyrimidin-4-yl)-4-phenyloxazolidin-2-one (40 mg, 0.145 mmol), 1,1,1-trifluoropropan-2-amine (82 mg, 0.725 mmol), Hunig's Base (0.038 mL, 0.218 mmol) in DMSO (0.4 mL) was heated under argon at 115° C. for ˜3 days. Then mixture was allowed to cool to room temperature. The mixture was diluted with DMSO and water (˜10 vol. % of DMSO), filtered through a syringe filter and purified by reverse phase HPLC. Selected fractions were collected and lyophilized providing (45)-4-phenyl-3-(2-(1,1,1-trifluoropropan-2-ylamino)pyrimidin-4-yl)oxazolidin-2-one (ratio of two isomers: 7/3) as white solid as its trifluoroacetic acid salt. LCMS m/z 353.2 (M+H)+, Rt 0.78 min. HRMS(A) m/z 353.1231 (M+H)+, Rt 1.92/1.96 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[CH3:11][C:12]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:13]=1[NH2:14]>O1CCOCC1>[Cl:10][C:4]1[C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=[C:2]([NH:14][C:13]2[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:12]=2[CH3:11])[N:3]=1.[Cl:1][C:2]1[N:3]=[C:4]([NH:14][C:13]2[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:12]=2[CH3:11])[C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: Clc1nc(Cl)c(Cl)c(Cl)n1
Solvent: C1COCCO1
Product: Cc1cc(C)c(Nc2nc(Cl)c(Cl)c(Cl)n2)c(C)c1
Product: Cc1cc(C)c(Nc2nc(Cl)nc(Cl)c2Cl)c(C)c1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
2,4,5,6-tetrachloropyrimidine (0.0134 mol), 1,4-dioxane (30 ml), 2,4,6-trimethyl aniline (0.0134 mol), and NN-bis(1-methylethyl)ethanamine(0.0136 mol) were added to a flask under argon and stirred at 55° C. for 16 hours. The solvent was evaporated, and the residue was dissolved in CH2Cl2, then purified by column chromatography over silica gel (eluent: CH2Cl2/hexane 1/4, and 1/2). The desired fractions were collected and their solvent was evaporated, yielding 0.15 g 4,5,6-trichloro-N-(2,4,6-trimethylphenyl)-2-pyrimidinamine (interm. 6) and 3.15 g 2,5,6-trichloro-N-(2,4,6-trimethylphenyl)-4-pyrimidinamine (interm. 7).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=3[O:29][CH3:30])[C:23](O)=[O:24])=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].[CH3:31][NH2:32]>>[CH3:31][NH:32][C:23]([C:22]1[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:20]([O:19][C:17]2[CH:16]=[CH:15][C:12]3[CH2:13][CH2:14][N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:9][CH2:10][C:11]=3[CH:18]=2)[CH:21]=1)=[O:24]
Reactant: CN
Reactant: COc1ccc(C(=O)O)cc1Oc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)CC2
Product: CNC(=O)c1ccc(OC)c(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c1

Procedure:
The title compound was prepared from 3-[(3-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-4-(methyloxy)benzoic acid (E266, Step 2) and methylamine using the method of Example 264, Step 5; MS (ES+) m/e 327 [(M+H)—CO2tBu]+.