Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.C(=O)([O-])[O-].[Ca+2].[NH:24]1[CH:28]=[C:27](/[CH:29]=[CH:30]/[C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=2)[CH:26]=[N:25]1>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:24]1[CH:28]=[C:27](/[CH:29]=[CH:30]/[C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=2)[CH:26]=[N:25]1)[CH3:12]
Reactant: N#Cc1ccc(/C=C/c2cn[nH]c2)cc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Product: C[C@@H](n1cc(/C=C/c2ccc(C#N)cc2)cn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43.2 %

Procedure:
1-(((2R,3S)-2-(2,4-difluorophenyl)-3-methyl oxiran-2-yl)methyl)-1H-1,2,4-triazol obtained in step 3 (55.9 mg) was suspended in N,N-dimethylformamide (1.6 mL), and calcium carbonate (41.9 mg) and 4-((E)-2-(1H-pyrazol-4-yl)vinyl)benzonitrile (39.5 mg) were added thereto. The mixture was stirred at room temperature for 20 minutes under an argon atmosphere, and reacted by microwave irradiation at 180° C. for 15 minutes. After completion of the reaction, the resulting mixture was extracted with ethyl acetate (10 mL) and the extract was washed successively with saturated amoniumchloride (10 mL) and brine (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated by evaporation under a reduced pressure. The resulting residue was purified by silica gel chromatography to obtain the title compound (0.039 g, yield 43.5%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O[C:18]([C:20]1(CI)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][CH3:34])[CH2:21]1)=O)C>>[CH2:33]([O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]([N:22]1[CH2:23][CH2:24][CH:20]([CH2:18][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[CH2:21]1)=[O:35])[CH3:34]
Reactant: Oc1ccc(-c2ccc(F)cc2)cc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OCC)C1
Product: CCOc1ccccc1C(=O)N1CCC(COc2ccc(-c3ccc(F)cc3)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4′-fluoro-biphenyl-4-ol and 1-(2-ethoxy-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 16) to afford the racemate as a white solid (191 mg, 70%)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=2)[C:5]([F:17])=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24][C:23]=2[CH:31]=1>CO>[F:16][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:17])=[CH:4][N:3]=[C:2]([NH:18][C:19]3[CH:20]=[CH:21][C:22]4[O:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24][C:23]=4[CH:31]=3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[F:15]
Reactant: COC(=O)C1Cc2cc(N)ccc2O1
Reactant: Fc1ccc(Nc2nc(Cl)ncc2F)cc1F
Solvent: CO
Product: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(F)c(F)c4)n3)ccc2O1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of equivalent amount of 2-chloro-N4-(3,4-difluorophenyl)-5-fluoro-4-pyrimidineamine and (±)-5-amino-2,3-dihydro-2-methoxycarbonylbenzofuran in MeOH was shaken in a sealed tube at 80° C. for 48 h, cooled to room temperature and diluted with a mixture of n-hexanes:EtOAc (1:1; v/v). The resulting solid formed was filtered, washed with a mixture of EtOAc:n-hexanes (1:1; v/v), dried and analyzed to give (±)-N4-(3,4-difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.21 (bs, 1H), 9.80 (bs, 1H), 8.20 (d, 1H, J=4.8 Hz), 7.94 (bs, 1H), 7.43 (m, 3H0, 7.15 (bd, 1H, J=8.4 Hz), 6.81 (d, 1H, J=8.1 Hz), 5.35 (dd, 1H, J=6.0 and 6.3 Hz), 3.69 (s, 3H), 3.52 (dd, 1H, J=10.5), 3.22 (dd, 1H, J=9.0 and 6.0 Hz); LCMS: purity: 99%; MS (m/e): 417 (MH+).
Reaction SMILES: [F:1][C:2]1[C:3]([O:24][CH3:25])=[C:4]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=[C:6]([NH:8][C:9](=[O:17])OC2C=CC=CC=2)[CH:7]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][C:36]=1[C:37]([F:40])([F:39])[F:38])[NH:33][CH2:32][CH2:31]2>>[F:1][C:2]1[C:3]([O:24][CH3:25])=[C:4]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=[C:6]([NH:8][C:9]([N:33]2[C:34]3[C:30](=[CH:29][C:28]([O:27][CH3:26])=[C:36]([C:37]([F:39])([F:40])[F:38])[CH:35]=3)[CH2:31][CH2:32]2)=[O:17])[CH:7]=1
Reactant: COc1c(F)cc(NC(=O)Oc2ccccc2)cc1-c1cccnc1
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Product: COc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cc(F)c(OC)c(-c3cccnc3)c1)CC2
Yield: 53 %

Procedure:
The title compound (0.34 g, 53%) was prepared from phenyl N-[5-fluoro-4-methoxy-3-(pyrid-3-yl)phenyl)carbamate (D24) (0.48 g, 0.0014 mole) and 5-methoxy-6-trifluoromethylindoline (D11) using the method of Example 28.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:18][CH:17]=1>CC(C)=O>[C:27]([O:26][C:25](=[O:31])[NH:24][CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:21][CH:20]=1)([CH3:28])([CH3:30])[CH3:29]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCCc1ccc(OCc2ccccc2)cc1
Yield: 87.3 %

Procedure:
To a suspension of potassium carbonate (K2CO3; 1.4 grams (g), 10.11 millimole (mmol)) in acetone (40 milliliters (mL)) was added bromomethylbenzene (1.73 g, 10.11 mmol) and tert-butyl 2-(4-hydroxyphenyl)ethylcarbamate (2 g, 8.4 mmol). The reaction mixture was heated at reflux for 15 hours (h) and then concentrated in vacuo. The residue was partitioned between diethyl ether (Et2O) and water (H2O), and the organic fraction was washed with brine, dried over sodium sulfate (Na2SO4), suction filtered, and concentrated in vacuo. The residue was purified by silica gel (SiO2) flash chromatography with 25% Et2O in hexane to afford [2-(4-benzyloxyphenyl)-ethyl]-carbamic acid tert-butyl ester as a white solid (2.4 g). This was dissolved in CH2Cl2 (50 mL) and trifluoroacetic acid (5 mL) was added. After stirring 16 h, the solvent was removed in vacuo, and the residue was redissolved in CH2Cl2, washed with 1M sodium hydroxide (NaOH), dried (Na2SO4) and filtered. The solvent was removed in vacuo to yield 2-(4-benzyloxyphenyl)-ethylamine (1.5 g). This was used without purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.Cl[C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:24]=1)[CH3:22]>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:12][OH:13])=[N:8][C:7]([S:18][C@H:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([CH3:32])(=[O:30])=[O:31])[CH:24]=3)[CH3:22])=[N:6][C:5]=2[N:19]=1
Reactant: C[C@@H](Cl)c1cccc(S(C)(=O)=O)c1
Reactant: CC(C)C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Product: CC(C)C[C@H](CO)Nc1nc(S[C@@H](C)c2cccc(S(C)(=O)=O)c2)nc2nc(N)sc12

Procedure:
The title compound was prepared from (2R)-2-[(2-amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-methylpentan-1-ol (16.5 g, 55.3 mmol) and 1-[(1R)-1-chloroethyl]-3-(methylsulfonyl)benzene (12.1 g, 55.3 mmol) using general method A.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].CCO[C:14]([S-:16])=[S:15].[K+].Cl>CN(C)C=O.O>[Cl:9][C:8]1[CH:7]=[CH:6][C:4]2[N:5]=[C:14]([SH:16])[S:15][C:3]=2[C:2]=1[Cl:1]
Reactant: CCOC(=S)[S-]
Reactant: Nc1ccc(Cl)c(Cl)c1F
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Sc1nc2ccc(Cl)c(Cl)c2s1
Temperature: 95 °C
Yield: 91.5 %

Procedure:
A mixture of 1.5 g (8.33 mmol) 3.4-dichloro-2-fluoroaniline and 1.64 g (10.00 mmol) potassium ethylxanthogenate in 8 mL dry N,N-dimethylformamide was heated in a 95° C. oil bath for 5 h. The reaction mixture was cooled to room temperature and diluted with water (25 mL). The mixture was acidified with aqueous HCl 2N. The precipitate was collected by filtration, washed with water and dried to provide 1.8 g (92%) of the title compound as a white solid. MS(m/e): 233.8 (M−H+).
Reaction SMILES: CN([CH:4]=[C:5]1[C:13](=O)[C:9]2=[N:10][O:11][N:12]=[C:8]2[CH2:7][CH2:6]1)C.[OH:15][C:16]1[CH:17]=[C:18]([NH:22][C:23]([NH2:25])=[NH:24])[CH:19]=[CH:20][CH:21]=1>CN(C=O)C>[N:10]1[O:11][N:12]=[C:8]2[CH2:7][CH2:6][C:5]3[C:13](=[N:24][C:23]([NH:22][C:18]4[CH:17]=[C:16]([OH:15])[CH:21]=[CH:20][CH:19]=4)=[N:25][CH:4]=3)[C:9]=12
Reactant: CN(C)C=C1CCc2nonc2C1=O
Reactant: N=C(N)Nc1cccc(O)c1
Solvent: CN(C)C=O
Product: Oc1cccc(Nc2ncc3c(n2)-c2nonc2CC3)c1

Procedure:
The DMF solution of 5-dimethylaminomethylene-6,7-dihydro-5 H-benzo[1,2,5]oxadiazol-4-one 0.1 g (0.00052 mol) and 3 equivalents of N-(3-hydroxy-phenyl)-guanidine was stirred at 110° C. for overnight, the final product was purified by directly injecting the DMF reaction solution into prep HPLC.
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][CH:9]1[C:15](=[O:17])[NH2:16])=O)(C)(C)C.[ClH:18].C(OCC)C>O1CCOCC1>[ClH:18].[CH3:13][C:11]1([CH3:14])[CH2:12][NH:8][CH:9]([C:15]([NH2:16])=[O:17])[CH2:10]1
Reactant: CC1(C)CC(C(N)=O)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC1(C)CNC(C(N)=O)C1
Reaction time: 1.5 h
Yield: 95 %

Procedure:
A solution of 2-carbamoyl-4,4-dimethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.2 g, 4.95 mmol) in dioxane (5 mL) was cooled to 10° C. Hydrogen chloride dissolved in dioxane (10 mL, 6.4 N) was added and the mixture was stirred for 1.5 hours. Diethylether (50 mL) was added to completely precipitate the product, which was filtered and dried to give the title compound (0.84 g, 95%) as colorless solid; MS (ESI) 143.0 [MH+].
Reaction SMILES: [CH2:1]1[C:4]2([CH2:7][NH:6][CH2:5]2)[CH2:3][N:2]1[C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[C:20](=[O:21])[N:19]([CH3:22])[N:18]=[C:17]([C:23]3[C:24]([CH2:45][OH:46])=[C:25]([N:29]4[N:38]=[CH:37][C:36]5[C:31](=[C:32]([F:43])[CH:33]=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:35]=5)[C:30]4=[O:44])[CH:26]=[CH:27][CH:28]=3)[CH:16]=2)=[N:12][CH:13]=1.C=O.[C:49]([BH3-])#N.[Na+]>CO>[C:39]([C:34]1[CH:35]=[C:36]2[C:31](=[C:32]([F:43])[CH:33]=1)[C:30](=[O:44])[N:29]([C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:17]3[CH:16]=[C:15]([NH:14][C:11]4[CH:10]=[CH:9][C:8]([N:2]5[CH2:3][C:4]6([CH2:7][N:6]([CH3:49])[CH2:5]6)[CH2:1]5)=[CH:13][N:12]=4)[C:20](=[O:21])[N:19]([CH3:22])[N:18]=3)[C:24]=1[CH2:45][OH:46])[N:38]=[CH:37]2)([CH3:40])([CH3:41])[CH3:42]
Reactant: [BH3-]C#N
Reactant: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(N3CC4(CNC4)C3)cn2)c1=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CC2(C1)CN(c1ccc(Nc3cc(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)nn(C)c3=O)nc1)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 221.5 %

Procedure:
In a 25 mL round-bottomed flask, 2-(3-(5-(5-(2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(hydroxymethyl)phenyl)-6-tert-butyl-8-fluorophthalazin-1(2H)-one (146 mg, 234 μmol), 30% formaldehyde (42.2 mg, 38.8 μl, 1.41 mmol) and sodium cyanoborohydride (177 mg, 2.81 mmol) were combined with methanol (9 ml) to give an orange solution. The reaction mixture was stirred at 25° C. for 4 h. The crude reaction mixture was concentrated in vacuo, diluted with 10 mL 0.1 M NaOH and extracted with DCM (3×15 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 10% MeOH in DCM). The light yellow powder was dried under vacuum at 25° C. for 3 hrs to give 0.33 g (22%) of the title compound. (M+H)+=637 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ: 8.37 (s, 1H), 8.28 (d, J=2.3 Hz, 1H), 8.13 (s, 1H), 7.38-7.71 (m, 6H), 6.75-6.93 (m, 2H), 4.40 (s, 2H), 3.96 (s, 4H), 3.88 (s, 3H), 3.47 (s, 4H), 2.37 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)[CH3:2].[OH:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:17]2[CH:18]=[CH:19][C:14](=[O:13])[CH:15]=[CH:16]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: Oc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1ccc(-n2ccc(=O)cc2)cc1
Temperature: 140 °C
Reaction time: 3 h

Procedure:
In a 500 ml round bottom flask with stirbar was place 4-fluorobenzoic acid ethyl ester (16.8 g, 100 mmol), 4-hydroxypyridine (14.26 g, 150 mmol), potassium carbonate (20.7 g, 150 mmol) and N-methylpyrrolidinone (75 ml). This mixture was gradually warmed to 140° C. and kept at this temperature for three hours after which time all the starting aryl fluoride was consumed. The mixture was cooled to room temperature and with stirring ice and water was added in porions to bring the volume up to 500 ml. The precipitated product was isolated by suction filtration, washed well with water and air dried. This directly isolated material was very pure and suitable for further use. Material recrystallized from toluene had Mp 178°-180°.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]([O:27]CC)=O)=[O:22])[CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[CH3:32][NH2:33]>O1CCCC1>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]([NH:33][CH3:32])=[O:27])=[O:22])[CH2:17][CH2:16]3)=[N:13][CH:14]=2)=[CH:7][CH:8]=1
Reactant: CN
Reactant: CCOC(=O)COC(=O)N1CCN(c2ccc(-c3ccc(C(F)(F)F)cc3)cn2)CC1
Solvent: C1CCOC1
Product: CNC(=O)COC(=O)N1CCN(c2ccc(-c3ccc(C(F)(F)F)cc3)cn2)CC1

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.4.). Starting with 2.77 g (6.33 mmol) of 2-(ethyloxy)-2-oxoethyl 4-{5-[4-(trifluoromethyl)phenyl]-2-pyridyl}-1-piperazinecarboxylate, obtained in step 4.1, and 15.80 ml (31.67 mmol) of a solution of methylamine (2M) in tetrahydrofuran, and after chromatography on silica gel, eluting with a 97/3 mixture of dichloromethane and methanol, followed by recrystallization from ethyl acetate, 1.69 g of product are obtained in the form of a white solid.
Reaction SMILES: [CH2:1]=[O:2].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[OH:11].[OH-].[Na+]>O>[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:1][OH:2])[C:5]=1[OH:11]
Reactant: Cc1ccc(O)c(C)c1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C)c(O)c(CO)c1
Temperature: 50 °C

Procedure:
A 38% solution of formaldehyde (32.0 grams, 0.4 mol) was added to a stirred solution of 2,4-dimethylphenol (36.6 grams, 0.3 mol) in water (100 ml) containing sodium hydroxide (14 gr., 0.35 mol) and heated at 50° C. for 4 to 5 hours. The reaction was cooled and solid sodium hydroxide added to precipitate the salt of the product. The solid was removed by filtration and dissolved in water. This solution was neutralized with carbon dioxide (dry ice) and the resulting mixture was extracted with methylene chloride. The organic layer was removed, dried, and evaporated to yield a light brown solid. This solid was washed in hexane containing a small amount of toluene to afford a tan solid. The NMR1 and FD/MS2 data support the structure
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31](=[O:51])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[C:42]([CH2:43][O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)=[CH:41][N:40]=[N:39]2)[CH:33]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:17][CH2:16][CH2:15]2)[C:11]([C:18]([F:20])([F:21])[F:19])=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31](=[O:51])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[C:42]([CH2:43][O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)=[CH:41][N:40]=[N:39]2)[CH:33]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCC2)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: CC(C)(C)OC(=O)Nc1cc(N2CCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1

Procedure:
The title compound was prepared from (2-amino-5-azetidin-1-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J17) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert.-butyl ester (Example K5) according to the general procedure M. Obtained as a yellow foam (450 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]2[N:18]=[C:17]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:16][C:15](=[O:31])[C:14]=2[C:32]=1[CH3:33])=[O:8].N1(C(N)=O)CCC[CH2:35]1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]2[N:18]=[C:17]([NH:19][C@H:20]([C:28]([O:30][CH3:35])=[O:29])[CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:16][C:15](=[O:31])[C:14]=2[C:32]=1[CH3:33])=[O:8]
Reactant: NC(=O)N1CCCC1
Reactant: Cc1c(NC(=O)Cc2cccs2)ccc2nc(N[C@@H](Cc3ccccc3)C(=O)O)oc(=O)c12
Product: COC(=O)[C@H](Cc1ccccc1)Nc1nc2ccc(NC(=O)Cc3cccs3)c(C)c2c(=O)o1

Procedure:
N-[6-[[(2-thienylmethyl)carbonyl]amino]-5-methyl-4-oxo-4H-3,1-benzoxazin-2-yl]-L-phenylalanine, pyrrolidineamide;
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:9]([CH3:12])([O-:11])=[O:10]>>[C:2]1([C@H:1]([OH:8])[CH2:12][N+:9]([O-:11])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: C[N+](=O)[O-]
Product: O=[N+]([O-])C[C@@H](O)c1ccccc1
Yield: 84 %

Procedure:
Further, the present inventors has reported in Tetrahedron Letters (1993) Vol. 34, p. 2657 that the reaction between benzaldehyde and nitromethane under a catalyst of lanthanum-lithium-(R)-binaphthol complex at −50° C. gives (S)-1-phenyl-2-nitro ethanol in a yield of 84% (40% e.e.), and when carried out under a catalyst of samarium-lithium-(R)-binaphthol complex at −40° C., the reaction gives the same compound in a yield of 90% (62% e.e.) ((R) or (S) in the name of each compound represents R or S isomer, respectively, showing the compound's configuration).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([CH2:20][O:21][CH2:22][CH3:23])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[S:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1>>[CH2:22]([O:21][CH2:20][C:14]1[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([C:26]4[CH:27]=[CH:28][S:24][CH:25]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:12])[C:7]=2[N:13]=1)[CH3:23]
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)C
Reactant: OB(O)c1ccsc1
Product: CCOCc1nc2c(N)nc3cc(-c4ccsc4)ccc3c2n1CC(C)C

Procedure:
7-Bromo-2-ethoxymethyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and thiophene-3-boronic acid were coupled according to the general procedure described in Part J of Example 1. Recrystallization from isopropanol followed by purification on silica gel (5% methanol in CH2Cl2 to 7% methanol in CH2Cl2 gradient) afforded 2-ethoxymethyl-1-isobutyl-7-(thiophen-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a pale yellow solid, m.p. 187–189° C.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[CH:31]=[C:30]([CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:29]=[CH:28][C:20]=2[C:21]([O:23]C(C)(C)C)=[O:22])=[CH:14][CH:13]=1)(=[O:10])[CH3:9]>>[C:8]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]2[CH:31]=[C:30]([CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:29]=[CH:28][C:20]=2[C:21]([OH:23])=[O:22])=[CH:16][CH:17]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)Nc1ccc(Nc2cc(CCc3ccccc3)ccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ccc(Nc2cc(CCc3ccccc3)ccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid 7.5 mL was added to the obtained tert-butyl 2-((4-(acetamido)phenyl)amino)-4-phenethylbenzoate, and it was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, methanol was added to the obtained residue, and solid matter was filtrated to give 2-((4-(acetamido)phenyl)amino)-4-phenethylbenzoic acid 23 mg of a white solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2[nH]1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(Br)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 65.4 %

Procedure:
To a mixture of 4-(4-bromo-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine (0.7 g, 2.364 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(bromomethyl)-3-chlorobenzene (0.583 g, 2.84 mmol) and potassium carbonate (0.980 g, 7.09 mmol). The resulting reaction mixture was stirred at 90° C. for 4 h. It was cooled to room temperature and poured into water (100 mL). The aqueous mixture was extracted with DCM (100 mL×2). The combined organic phases were washed with Brine (100 mL) and concentrated. The crude material was purified on silica column (20˜70% EtOAc in Hexane) to give the product as solid (0.65 g, 65%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.57 (s, 3H) 2.90-3.16 (m, 4H) 3.69-3.95 (m, 4H) 5.25 (s, 2H) 6.60 (d, J=2.02 Hz, 1H) 6.88 (d, J=7.07 Hz, 1H) 7.07 (s, 1H) 7.16 (d, J=2.02 Hz, 1H) 7.20-7.37 (m, 2H); MS (ES+) m/e 420.0 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:43])[C@H:4]([CH2:34][S:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[NH:5][C:6](=[O:33])[C@H:7]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:8][C@H:9]([C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+].Cl>CO>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:17]([C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:8][C@@H:7]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:6]([NH:5][C@H:4]([C:3]([OH:43])=[O:2])[CH2:34][S:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:33])=[O:18]
Reactant: COC(=O)[C@H](CSCc1ccccc1)NC(=O)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)Nc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(Nc1ccccn1)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](CSCc1ccccc1)C(=O)O

Procedure:
A solution of 0.3 g of N-[4-(2-pyridylaminocarbonyl)-(S,S)-2,4-dibenzylbutyryl]-S-benzyl-(L)-cysteine methyl ester and 1 ml of 1N sodium hydroxide in 2 ml of methanol is stirred at room temperature overnight. To the solution is added 1.1 ml of 1N hydrochloric acid. The solution is concentrated, diluted with water, the solid is collected and dried under high vacuum to give N-[4-(2-pyridylaminocarbonyl)-(S,S)-2,4-dibenzylbutyryl]S-benzyl-(L)-cysteine, melting at 75-80°; [alpha]D =+22.9°.