Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][C:11]1[S:12][C:13]([NH2:16])=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([N:30]=[C:31]=[S:32])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CC(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][C:11]1[S:12][C:13]([NH:16][C:31]([NH:30][C:22](=[O:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[S:32])=[CH:14][CH:15]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(N)s1)NC(=O)OC(C)(C)C
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: CCOC(=O)C(Cc1ccc(NC(=S)NC(=O)c2ccccc2)s1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 76.7 %

Procedure:
To a stirred solution of Ethyl N-(tert-butoxycarbonyl)-3-(5-amino-2-thienyl)-DL-alaninate (4.21 g, 13.4 mmol) in acetone (75 ml) at 0° C. was added benzoyl isothiocyanate (2.55 g 15.6 mmol). The mixture was stirred for 5 minutes at 0° C., warmed to room temperature and stirred for 2 hours. The solvent was removed at reduced pressure and the resulting oil dissolved in ethyl acetate, washed with 1N aqueous hydrochloric acid, brine and dried over magnesium sulphate. The solvent was removed at reduced pressure to give a dark green viscous oil. The crude product was purified by chromatography on silica gel eluting with 1:3 ethyl acetate/hexane to yield Ethyl N-(tert-butoxycarbonyl)-3-(5-(3-benzoylthioureido)-2-thienyl)-DL-alaninate (4.91 g, 77%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:60][CH2:61][C:62]1[CH:73]=[CH:72][C:65]2[B:66]([OH:71])[O:67][C:68]([CH3:70])([CH3:69])[C:64]=2[CH:63]=1.Cl>C(#N)C.CC(=O)OCC>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:24]([F:26])([F:27])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:60][CH2:61][C:62]4[CH:73]=[CH:72][C:65]5[B:66]([OH:71])[O:67][C:68]([CH3:70])([CH3:69])[C:64]=5[CH:63]=4)=[O:20])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC1(C)OB(O)c2ccc(CN)cc21
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCc1ccc2c(c1)C(C)(C)OB2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.8 %

Procedure:
To a solution of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (300 mg, 0.72 mmol) in acetonitrile (5 ml) at 0° C. was added Et3N (291.1 mg, 2.88 mmol), HATU (546.76 mg, 1.44 mmol) and 5-(aminomethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (194.2 mg, 0.86 mmol). The reaction mixture was stirred overnight at rt. The mixture was poured into 1N HCl solution and extracted with EA (20 ml×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluted with PE:EA (1:1 with 2 drops of HOAc) and prep-HPLC to give the final title compound (80 mg, yield 18.8%) as white solid: 1H NMR (300 MHz, DMSO-d6): δ 8.99 (s, 1H), 8.95 (m, 1H), 7.81-7.82 (m, 1H), 7.62-7.64 (m, 5H), 7.49-7.60 (m, 1H), 7.29-7.46 (m, 2H) 4.50-4.52 (d, J=6.0 Hz, 2H), 4.33-4.36 (m, J=9 Hz, 2H), 2.42 (s, 3H), 1.20 (s, 6H); HPLC purity: 97.1% at 214 nm and 98.3% at 254 nm; MS: 591 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27][C@H:28](C)[C:29]([O:31]C)=O)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[C@@H]1(N)C2C(=CC=CC=2)CC1.S(Cl)(Cl)(=O)=[O:45]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@H:22]4[NH:27][C:28](=[O:45])[CH2:29][OH:31])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:11])[CH3:12])#[N:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)[C@@H](C)N[C@@H]1CCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Agent: N[C@H]1CCc2ccccc21
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4NC(=O)CO)no2)cc1C#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (R)- or (S)-indane amine (1 eq) in DCM (0.05M) was added TEA (2 eq) and the appropriate sulfonyl chloride (2 eq.) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated and the pure product isolated after preparative HPLC purification.
Reaction SMILES: O1CCCCC1O[CH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[CH2:10][CH2:9]1.[NH:24]1C2C(=CC(OC3CCC(O)CC3)=CC=2)C=N1>>[NH:20]1[C:21]2[C:17](=[CH:16][C:15]([O:14][C@H:11]3[CH2:12][CH2:13][CH2:8][C@H:9]([NH2:24])[CH2:10]3)=[CH:23][CH:22]=2)[CH:18]=[N:19]1
Reactant: OC1CCC(Oc2ccc3[nH]ncc3c2)CC1
Reactant: c1cc2[nH]ncc2cc1OC1CCC(OC2CCCCO2)CC1
Product: N[C@H]1CCC[C@H](Oc2ccc3[nH]ncc3c2)C1

Procedure:
The following compound of Example 384 was synthesized by carrying out reactions according to the methods described in Example 372, (b) and Example 381, except for using the cis-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione obtained in Example 323, (c), as a starting material.
Reaction SMILES: [CH3:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][C@H:6]1[C:10](=[O:11])[CH2:9][CH2:8][C@@H:7]1[CH2:12][C:13](O)=[O:14].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:5]([C@H:6]1[CH:10]([OH:11])[CH2:9][CH2:8][C@@H:7]1[CH2:12][CH2:13][OH:14])/[CH:4]=[CH:3]\[CH2:2][CH3:1]
Reactant: CC/C=C\C[C@H]1C(=O)CC[C@@H]1CC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC/C=C\C[C@H]1C(O)CC[C@@H]1CCO
Temperature: 50 °C
Reaction time: 4 h

Procedure:
In a 50 ml three-necked flask equipped with a condenser, a thermometer and a magnetic stirrer, 1 g (4.5 mmol) of methyl (+/−)-jasmonate was dissolved in 15 ml of tetrahydrofuran. 430 mg (11.3 mmol) of lithium aluminium hydride, LiAlH4, were added. The mixture was stirred at 50° C. for 4 hours. When the reaction was finished, 5 ml of water were added slowly. The precipitate formed was filtered off and the filtrate was acidified to pH=5 with hydrochloric acid and then extracted with ethyl acetate (3×30 ml). The organic phase was dried over sodium sulphate, filtered on filter paper, and then concentrated. The colourless oil obtained was purified by chromatography on silica gel (eluent: dichloromethane/methanol). The colourless oil obtained was dried under vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([C:19]([OH:21])=[O:20])=[CH:18][C:12]=3[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([N:31]4[CH2:35][CH:34]=[CH:33][CH2:32]4)=[O:30])=[CH:25][CH:24]=3)[C:10](=[O:36])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH2:39](O)[CH3:40].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([C:19]([OH:21])=[O:20])=[CH:18][C:12]=3[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([N:31]4[CH2:32][CH:33]=[CH:34][CH2:35]4)=[O:30])=[CH:25][CH:24]=3)[C:10](=[O:36])[CH2:9]2)=[O:7])=[CH:37][CH:38]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([C:19]([O:21][CH2:39][CH3:40])=[O:20])=[CH:18][C:12]=3[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([N:31]4[CH2:32][CH:33]=[CH:34][CH2:35]4)=[O:30])=[CH:25][CH:24]=3)[C:10](=[O:36])[CH2:9]2)=[O:7])=[CH:37][CH:38]=1
Reactant: CCO
Agent: O=C(O)c1ccc2c(c1)N(Cc1ccc(C(=O)N3CC=CC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)N(Cc1ccc(C(=O)N3CC=CC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Reaction time: 8 h

Procedure:
10 mg (0.019 mmol) of 4-(4-chlorobenzoyl)-2-oxo-1-[4-(2,5-dihydro-1H-pyrrol-1-ylcarbonyl)benzyl]-2,3,4,5-tetrahydro-1H-benzo[e][1,4]-diazepine-8-carboxylic acid was dissolved in 2 ml of dichloromethane. 0.022 ml (0.38 mmol) of ethanol, 4 mg (0.023 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.005 ml (0.038 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OC([NH:20][C@@H:21]([C:23](O)=[O:24])[CH3:22])=O)C1C=CC=CC=1.Cl.C(N=C=NCCCN(C)C)C.C1C2C(=CC(S(Cl)(=O)=O)=CC=2)C=CN=1>ClCCl.[C].[Pd]>[NH2:20][C@H:21]([CH3:22])[C:23]([NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:24]
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NCCc1ccccc1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C[C@@H](N)C(=O)NCCc1ccccc1
Yield: 45.7 %

Procedure:
Phenethylamine (285 mg) and N-(benzyloxycarbonyl)-D-alanine (500 mg) were condensed (618 mg, 85%) using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (472 mg) in dichloromethane. (R)-2-amino-N-phenethylpropanamide (197 mg) obtained by further hydrogenation reaction in the presence of 10% palladium-carbon, and isoquinoline-6-sulfonyl chloride prepared in Reference Example 1 were condensed (237 mg, 60%) in the presence of triethylamine (0.284 mL) in dichloromethane. Subsequently, 40 mg of the title compound was obtained as a pale yellow solid (13%) with reference to the method of Step 3 of Example 1.
Reaction SMILES: [OH:1][CH:2]([NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[N:11][CH:10]=1)[C:3]([Cl:6])([Cl:5])[Cl:4].S(Cl)(Cl)=O.Cl[CH:21](NC(=O)C1C=CC=NC=1)C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>C(N(CC)CC)C.CO.C1C=CC=CC=1>[CH3:21][O:1][CH:2]([NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[N:11][CH:10]=1)[C:3]([Cl:4])([Cl:5])[Cl:6]
Reactant: O=C(NC(O)C(Cl)(Cl)Cl)c1cccnc1
Reactant: O=C(NC(Cl)C(Cl)(Cl)Cl)c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: COC(NC(=O)c1cccnc1)C(Cl)(Cl)Cl
Reaction time: 8 h

Procedure:
150 ml of benzene was added to 10.0 g of N-(1-hydroxy-2,2,2-trichloroethyl)nicotinamide. 5.3 g of thionyl chloride was added dropwise thereto and the mixture was heated under reflux (60° to 80° C.) for about 5 h under stirring to complete the production of N-(1,2,2,2-tetrachloroethyl)nicotinamide. The reaction liquid was cooled to 30° C. or below. 20 ml of methanol was added to the liquid. 4.0 g of triethylamine was added dropwise to the liquid mixture while it was kept at 5° C. and the obtained mixture was stirred at room temperature for 3 h. Then, the mixture was kept at room temperature overnight. The reaction liquid was poured in an aqueous sodium bicarbonate solution and a benzene layer thus separated was washed with saturated aqueous common salt solution and water and dried over anhydrous sodium sulfate. After concentration, the residue was recrystallized from methanol to obtain 4.8 g of N-(1-methoxy-2,2,2-trichloroethyl)nicotinamide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH3:24])[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15](Cl)=[CH:16][C:17]=3[Cl:21])[NH:12][C:11]2=[O:23])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>N1C=CC=CC=1>[Cl:21][C:17]1[CH:16]=[C:15]([N:29]2[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]2)[CH:14]=[C:13]2[C:18]=1[C:19](=[O:20])[C:10]([CH3:24])([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[C:11](=[O:23])[NH:12]2
Reactant: CC1(c2ccc([N+](=O)[O-])cc2)C(=O)Nc2cc(Cl)cc(Cl)c2C1=O
Reactant: CN1CCNCC1
Solvent: c1ccncc1
Product: CN1CCN(c2cc(Cl)c3c(c2)NC(=O)C(C)(c2ccc([N+](=O)[O-])cc2)C3=O)CC1
Yield: 45.5 %

Procedure:
A mixture of 3-(4-nitro-phenyl)-5,7-dichloro-3-methyl-1H-quinoline-2,4-dione (0.3 g, 0.82 mmol) and 1-methylpiperazine (123 mL, 1.23 mmol) in dry pyridine (5.0 mL) was heated at reflux temperature for 5 hours. After evaporation of the solvent in vacuo, the residue was diluted with water (100 mL), and the resulting suspension was extracted with ethyl acetate (100 mL×3). The organic layer was washed with brine (100 mL×2), dried over anhydrous MgSO4 concentrated under reduced pressure. The pure objective compound (0.16 g, 46%) was obtained as yellow solid by a flash column chromatography (CH2Cl2:MeOH=20:1): 1H NMR (200 MHz, CDCl3) δ 1.90 (s, 3H, CH3), 2.34 (s, 3H, NCH3), 2.54-2.59 (m, 4H, NCH2), 2.88-3.07 (m, 4H, NCH2), 6.43 (d, J=1.8 Hz, 1H, ArH), 6.64 (d, J=2.0 Hz, 1H, ArH), 7.46 (d, J=9.0 Hz, 2H, ArH), 8.17 (d, J=9.0 Hz, 2H, ArH), 8.64 (br s, 1H, NH).
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:8]=1[O:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[CH3:23][C:24]([CH3:26])=O.C([BH3-])#N.[Na+]>CO>[CH:24]([N:13]1[CH2:14][CH2:15][CH:10]([O:9][C:8]2[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:7]=2[O:6][CH3:5])[CH2:11][CH2:12]1)([CH3:26])[CH3:23]
Reactant: COc1cc([N+](=O)[O-])ccc1OC1CCNCC1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc([N+](=O)[O-])ccc1OC1CCN(C(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97 %

Procedure:
To a solution of 10% acetic acid in methanol was added 4-(2-methoxy-4-nitrophenoxy)piperidine (148 mg, 0.59 mmol, 1 eq), anhydrous acetone (5 eq), and sodium cyanoborohydride (1.5 eq). The solution was stirred at room temperature for 24 h. Reaction is 85% complete. Charged additional anhydrous acetone (5 eq) and sodium cyanoborohydride (1.5 eq) and stirred for 24 h. The solvent was evaporated, the residue brought to pH=10 with sodium carbonate and extracted with EtOAc. The organic layer was washed with water, brine, dried with magnesium sulfate and evaporated to afford 1-isopropyl-4-(2-methoxy-4-nitrophenoxy)piperidine as a yellow oil (163 mg, 97%). LC/MS (m/z): 295.2 (MH+), Rt 1.96 minutes.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][C:6]([CH3:8])=[N:5][N:4]([CH3:9])[C:3]1=[O:10].[C:11]1([C:17]2[N:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][N:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.CCOC(C)=O>[CH3:9][N:4]1[C:3](=[O:10])[N:2]([NH:1][C:23]([C:20]2[CH:19]=[N:18][C:17]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:22][CH:21]=2)=[O:24])[CH2:7][C:6]([CH3:8])=[N:5]1
Reactant: O=C(O)c1cnc(-c2ccccc2)nc1
Reactant: CC1=NN(C)C(=O)N(N)C1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1=NN(C)C(=O)N(NC(=O)c2cnc(-c3ccccc3)nc2)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 54.6 %

Procedure:
To a solution of 4-amino-2,6-dimethyl-4,5-dihydro-2H-1,2,4-triazin-3-one (0.219 g, 1.58 mmol) and 2-phenyl-pyrimidine-5-carboxylic acid (0.317 g, 1.58 mmol) in dry DMF (10 mL) under N2 is added DMTMM (0.46 g, 1.66 mmol). The mixture is stirred at rt for 22 h, then diluted with EtOAc (70 mL), and washed successively with saturated aqueous NaHCO3 solution (2×10 mL) and brine (10 mL). The organic phase is dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with heptane:EtOAc gradient to afford 2-phenyl-pyrimidine-5-carboxylic acid (2,6-dimethyl-3-oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl)-amide as a solid (0.28 g, 55%). MS: 325 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 9.24 (s, 2H), 8.45 (dd, J=7.7, 2.0 Hz, 2 H), 7.52-7.62 (m, 3H), 4.25 (s, 2H), 3.18 (s, 3H), 1.95 (s, 3H).
Reaction SMILES: [C:1]([N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:12]([N:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29]C)=[CH:25][CH:24]=2)[C:20](=[O:22])[CH3:21])[CH2:11][C@@H:10]1[CH3:31])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[C:1]([N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:12]([N:19]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[C:20](=[O:22])[CH3:21])[CH2:11][C@@H:10]1[CH3:31])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N(C(C)=O)[C@@H]2C[C@H](C)N(C(=O)c3ccccc3)c3ccccc32)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)N(c1ccc(O)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccccc2)c2ccccc21
Temperature: -78 °C

Procedure:
To a solution of Cis-N-(1-Benzoyl-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-(4-methoxy-phenyl)-acetamide (0.1 g) in dichloromethane (5 ml), boron tribromide (0.18 g) was added under stirring and under cooling at −78° C. in an acetone-dry ice bath.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[O-]CC.[Na+].Cl[CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1>>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][CH:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH:17]=1
Reactant: ClCc1cccnc1
Reactant: CCOC(=O)CC(C)=O
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(Cc1cccnc1)C(C)=O

Procedure:
Reaction of ethyl acetoacetate with sodium ethoxide and 3-(chloromethyl)pyridine gives ethyl α-(3-pyridylmethyl)acetoacetate which gives 5-(3-pyridylmethyl)-6-methyl-2-thiouracil m.p. 332°-335° when treated with thiourea and sodium ethoxide. Substitution of 5-(3-pyridylmethyl)-6-methyl-2-thiouracil for 5-(4-pyridylmethyl)-2-thiouracil in the general procedure of Example 1 gives 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-5-(3-pyridylmethyl)-6-methyl-4-pyrimidone, m.p. 128°-131°. 5-(3-Pyridylmethyl)-6-methyl-2-methylthio-4-pyrimidone and m.p. 208°-211°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]#[N:19])[CH:15]=2)[NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[C:1]([O:5][C:6](=[O:20])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]#[N:19])[CH:15]=2)[N:10]([CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[C:22]([Cl:21])[CH:23]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NC1CNc2ccc(C#N)cc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NC1Cc2cc(C#N)ccc2N(Cc2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.8 %

Procedure:
To a solution of (6-cyano-1,2,3,4-tetrahydroquinolin-3-yl)-carbamic acid tert-butyl ester (820 mg, 3 mmol), prepared as described in Example 1C, and 3-chloro benzaldehyde (0.34 mL, 3 mmol) in DCE (10 mL) was added NaBH(OAc)3 (1.78 g, 8.4 mmol), followed by acetic acid (0-34 mL, 6 mmol). The reaction was stirred at RT for 16 h, then quenched with saturated aqueous NaHCO3, extracted with CH2Cl2 (30 mL×3). The organic extracts were washed with water, saturated aqueous NaCl, dried (Na2SO4), and concentrated. The resulting residue was chromatographed (silica gel) eluting with EtOAc (10-50%) in hexanes to give the title compound (571 mg, 48%) as a foam.
Reaction SMILES: Cl.C[NH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)=[CH:6][CH:5]=1.N1C=CC=CC=1.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>O>[C:28]([NH:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]23[CH2:12][CH:13]4[CH2:19][CH:17]([CH2:16][CH:15]([CH2:14]4)[CH2:20]2)[CH2:18]3)=[CH:8][CH:9]=1)([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CNc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1
Reaction time: 18 h

Procedure:
A solution of the free base from 2.82 g. of the N-methyl-4-(1-adamantyloxy)aniline hydrochloride in 20 ml. pyridine was treated dropwise with 1.64 ml. ClCO2C2H5. Following 18 hours standing in the cold the mixture was poured into ice:H2O. This was extracted with Et2O and the organic layer washed in turn with H2O, cold 2.5 N HCl, H2O NaHCO3 and brine. The extract was then taken to dryness to leave behind N-methyl, N-carbethoxy-4-(1-adamantyloxy)aniline as an oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH2:16])[N:7]=1)(=[O:3])[CH3:2].[F:17][C:18]1[CH:19]=[CH:20][C:21]([O:36][CH3:37])=[C:22]([C:24]([CH3:35])([CH3:34])[CH2:25][C:26]([OH:33])([C:29]([F:32])([F:31])[F:30])[CH:27]=O)[CH:23]=1.C(O)(=O)C.CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N:16]=[CH:27][C:26]([C:29]([F:30])([F:32])[F:31])([OH:33])[CH2:25][C:24]([C:22]2[CH:23]=[C:18]([F:17])[CH:19]=[CH:20][C:21]=2[O:36][CH3:37])([CH3:34])[CH3:35])[N:7]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: CC(=O)OCc1ccc2c(N)cccc2n1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(C=Nc1cccc2nc(COC(C)=O)ccc12)C(F)(F)F

Procedure:
Analogously to Example 37, 230 mg (1.06 mmol) of 2-(acetoxymethyl)-5-aminoquinoline is reacted with 273 mg (0.88 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 1.20 ml of concentrated acetic acid in 20.0 ml of toluene. After chromatography on silica gel with hexane-ethyl acetate (0-100%), 360 mg (81% of theory) of the product is obtained.
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[C:43]([CH3:44])=[CH:42][C:37]([C:38]([NH:40][NH2:41])=[O:39])=[CH:36][C:35]=5[CH3:45])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)[N:21]=3)[C@H:14]2[CH3:52])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1N=CN([C:60](N2C=NC=C2)=[O:61])C=1>C1COCC1>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[C:35]([CH3:45])=[CH:36][C:37]([C:38]6[O:39][C:60](=[O:61])[NH:41][N:40]=6)=[CH:42][C:43]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:46]4[CH2:47][CH2:48][O:49][CH2:50][CH2:51]4)[N:21]=3)[C@H:14]2[CH3:52])[CH:4]=[C:3]([C:2]([F:1])([F:53])[F:54])[CH:8]=1
Reactant: COc1ncc(-c2c(C)cc(C(=O)NN)cc2C)cc1-c1cnc(N2CCOCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ncc(-c2c(C)cc(-c3n[nH]c(=O)o3)cc2C)cc1-c1cnc(N2CCOCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-{5-[4-({(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(morpholin-4-yl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3,5-dimethylbenzohydrazide (Step A, 45.4 mg, 0.060 mmol) was dissolved in THF (600 μl) and treated with N,N-carbonyldiimidazole (58.6 mg, 0.361 mmol). The reaction was stirred at room temperature overnight. The reaction was purified directly by silica gel chromatography, eluting with a gradient of 25-100% ethyl acetate/hexanes to give the title compound. 1H NMR (CDCl3, 500 MHz): δ 8.97 (s, 1H), 8.17 (s, 1H), 8.02 (d, 1H), 7.89 (s, 1H), 7.73 (s, 2H), 7.62 (d, 2H), 7.29 (d, 1H), 5.67 (d, 1H), 4.72 (d, 1H), 4.35 (m, 1H), 4.01 (m, s, 4H), 3.86 (m, 4H), 3.80 (m, 4H), 2.16 (s, 3H), 2.14 (s, 3H), 0.73 (d, 3H). RTA IC50: 10 nM.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])=[CH:6][CH:5]=1)([O-])=O.O1CCCC1>[C].[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])=[CH:18][CH:19]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
A mixture of ethyl 3-[(4-nitrobenzoyl)amino]propanoate (26.6 g) synthesized above, 5% palladium-carbon (8.9 g), tetrahydrofuran (150 mL) and ethanol (150 mL) was stirred under a hydrogen atmosphere at room temperature overnight. 5% Palladium-carbon was filtered off, and the filtrate was concentrated under reduced pressure to give a white solid. Recrystallization from ethyl acetate-diisopropyl ether gave the title compound (22.6 g, 95%) as a white crystal.