Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26].CCN(CC)CC.O>CN(C=O)C>[CH:2]([O:15][N:16]1[C:17](=[O:26])[C:18]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:19]2[C:20]1=[O:21])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of 1-chloro-1, 1-diphenylmethane (3.42 g, 16.93 mmol), N-hydroxyphthalimide (2.30 g, 14.11 mmol) and Et3N (3.0 ml) in DMF (50 ml) was stirred at 60° C. under N2 for 8 hours. After the reaction mixture was cooled to room temperature, water (100 ml) was added. The mixture was extracted with Et2O. The combined organic phase was dried over Na2SO4. After evaporation of the solvent, the crude product was purified by chromatography(Hexane/Benzene/EtOAc=20/10/3) to give a white solid, 3.95 g (85% yield). 1H NMR (CD3Cl) δ 7.72-7.63 (1H, m), 7.56-7.53 (1H, m), 7.40-7.24 (12H, m), 5.85 (1H, s, Ph2CH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[OH:18][CH2:19][CH2:20][O:21][C:22]1[CH:31]=[CH:30][C:25]([O:26][CH2:27][CH2:28]O)=[CH:24][CH:23]=1.Cl.CN(C)CCCN=C=NCC.CCN(CC)CC>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:28][CH2:27][O:26][C:25]1[CH:30]=[CH:31][C:22]([O:21][CH2:20][CH2:19][OH:18])=[CH:23][CH:24]=1)=[O:15])[CH:7]=[CH:6]2
Reactant: OCCOc1ccc(OCCO)cc1
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2cc([C@H](C)C(=O)OCCOc3ccc(OCCO)cc3)ccc2c1
Yield: 79.1 %

Procedure:
A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 4.27 g, 18.5 mmol), hydroquinone bis(2-hydroxyethyl)ether (10.6 g, 53.3 mmol), N,N-dimethylaminopyridine (DMAP, 2.71 g, 22.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.34 g, 48.7 mmol) and NEt3 (13 mL, 93.3 mmol) in DMF (100 mL) was stirred at ambient temperature overnight. The reaction mixture was evaporated to dryness under vacuum and the residue was partitioned between HCl (3N, 100 mL) and CH2Cl2 (200 mL). The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated. The product was separated by silica gel column chromatography eluting with EtOAc/hexane (1:1, Rf=0.15) and then recrystalized from ethyl ether and hexane to give the title compound as a white solid (6.01 g, 31% yield). Mp 76-78° C. 1H NMR (CDCl3) δ 7.7-7.64 (m, 3H), 7.42-7.38 (m, 1H), 7.15-7.08 (m, 2H), 6.74-6.72 (m 4H), 4.45-4.36 (m, 2H), 4.1-3.85 (m, 7H), 3.90 (s, 3H), 2.13 (br. t, 1H), 1.58 (d, J=7.2 Hz, 3H). 13C NMR (CDCl3) δ 174.6, 157.5, 153.0, 152.8, 135.4, 133.6, 129.2, 128.8, 127.1, 126.1, 125.9, 118.8, 115.7, 115.3, 105.5, 69.7, 66.6, 63.1, 61.4, 55.2, 45.2, 18.4. MS(API) m/z 428 (M+NH4)+. Anal. calcd. for C24H26O6: C, 70.23; H, 6.38. Found: C, 70.01; H, 6.39.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][C@H:10]([OH:12])[C@@H:9]([NH:13][C:14](=[O:29])[CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:12][C@H:10]1[CH2:11][N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:8][C@@H:9]1[NH:13][C:14](=[O:29])[CH2:15][NH:16][C:17](=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CN(C2CCCCC2)C[C@@H]1O
Reactant: BrCc1ccccc1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CN(C2CCCCC2)C[C@@H]1OCc1ccccc1

Procedure:
The title compound was prepared by alkylation of compound of Example 1 with benzyl bromide following the procedure described in Example 2. MS calculated (M+H)+ 504, found 504.
Reaction SMILES: [Al].[CH2:2](Br)[C:3]#[CH:4].[F:6][C:7]([F:23])([F:22])[C:8](=[O:21])[CH2:9][C:10]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[CH3:20])([CH3:12])[CH3:11].O>C1COCC1.C(OCC)C.C(OCC)(=O)C>[F:19][C:17]1[CH:16]=[CH:15][C:14]([CH3:20])=[C:13]([C:10]([CH3:12])([CH3:11])[CH2:9][C:8]([C:7]([F:6])([F:22])[F:23])([OH:21])[CH2:4][C:3]#[CH:2])[CH:18]=1
Reactant: Cc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Reactant: C#CCBr
Agent: [Al]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: C#CCC(O)(CC(C)(C)c1cc(F)ccc1C)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
Aluminum foil (324 mg, 12 mmol) and mercuric chloride (5.0 g, 0.02 mmol) were added to THF (6 mL) and vigorously stirred for 1 hour. Propargyl bromide (1.34 mL, 80% in toluene, 12 mmol) in 6 mL of THF was added slowly and the mixture heated up. After completion of the addition, the mixture was stirred for 2 hours at 40° C. and for 3 hours at room temperature. Half of the generated suspension was added via syringe to a solution of 1,1,1-trifluoro-4-(5-fluoro-2-methylphenyl)-4-methylpentan-2-one (500 mg, 1.91 mmol) in 20 mL of diethyl ether at −78° C. The reaction mixture was warmed up slowly to room temperature overnight. Water (20 mL) and ethyl acetate (20 mL) were added slowly. The organic phase was separated and the aqueous layer was extracted with two 10 mL portions of ethyl acetate. The combined organic phases were dried over magnesium sulfate. The solvent was removed to give 6-(5-fluoro-2-methylphenyl)-6-methyl-4-trifluoromethylhept-1-yn-4-ol (580 mg, 100%) as a colorless oil.
Reaction SMILES: O[Li].O.C([O:6][C:7](=[O:18])[CH2:8][NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C.C1COCC1.O>CO>[C:10]([NH:9][CH2:8][C:7]([OH:18])=[O:6])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)CNC(=O)c1ccccc1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
LiOH.H2O (73 mg, 1.74 mmol) was added to a solution of benzoylamino-acetic acid ethyl ester (90 mg, 0.43 mmol) in a mixture of MeOH (5 mL), THF (2 mL) and H2O (2 mL). The resulting mixture was stirred for 3 hrs at room temperature. The MeOH and THF were evaporated and the resulting residue was diluted with water (2 mL), acidified with citric acid and extracted with EtOAc. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford benzoylamino-acetic acid in 77% yield. LC-MS purity: 92%
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][C:4]=2[NH:5][N:6]=1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH:5]1[C:4]2[CH2:7][NH:8][CH2:9][C:3]=2[C:2]([NH2:1])=[N:6]1
Reactant: CC(C)(C)OC(=O)N1Cc2[nH]nc(N)c2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1n[nH]c2c1CNC2

Procedure:
tert-Butyl 3-amino-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (3670 mg, 16.36 mmol) was treated with TFA/CH2Cl2 (v/v=1/1) for 1 h. The reaction mixture was concentrated and the residue was treated with CH2Cl2/hexanes and then concentrated to give a solid. The product was passed through ion-exchange resin Strata X—C™ to give the title product (LC-MS: 125.05 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36].C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([N:26]([S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:35](=[O:36])[O:37][CH2:38][CH3:39])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)N(C(=O)OCC)c1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.1 %

Procedure:
To a suspension of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-propane-1-sulfonamide (0.2 g, 0.41 mmol) in dioxane (15 mL) were added ethyl chloroformate (EtOCOCl, 44 mg, 0.41 mmol) and triethylamine (0.14 g, 1.38 mmol). The reaction was stirred at rt for 1.5 h, then concentrated in vacuo. The residue was purified by a silica gel column chromatography (hexane/EtOAc (v/v)=4/1) to afford the title compound as a white solid (0.12 g, 50%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[O:26][C:25]([C:27]([N:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH:30]2[CH2:42][O:43][C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)=[O:28])=[CH:24][CH:23]=1>CO>[ClH:15].[ClH:1].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[O:26][C:25]([C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH:30]2[CH2:42][O:43][C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)=[O:28])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3ccccc3Cl)o2)C(COc2cccnc2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(-c2ccccc2Cl)o1)N1CCNCC1COc1cccnc1
Reaction time: 1 h
Yield: 59 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(5-(2-chlorophenyl)furan-2-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (66.6 mg, 0.109 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The desired chromatography fractions were concentrated under reduced pressure, dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane (6 mL). This was concentrated under reduced pressure, yielding 30 mg (59%) of the desired product as a white solid. LC-MS: RT=5.00 min, [M+H]+=398.1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.BrC1SC=CN=1.[Cl:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][CH:26]=2)[CH:22]=[CH:23][CH:24]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.O.CCOC(C)=O>[Cl:18][C:19]1[CH:20]=[C:21]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([N:9]3[CH2:8][CH2:7][N:6]([C:2]4[S:1][CH:5]=[CH:4][N:3]=4)[CH2:11][CH2:10]3)=[O:32])=[CH:27][CH:26]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)c1ccc(-c2cccc(Cl)c2)cc1
Reactant: c1csc(N2CCNCC2)n1
Agent: Brc1nccs1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=C(c1ccc(-c2cccc(Cl)c2)cc1)N1CCN(c2nccs2)CC1
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 1-(thiazol-2-yl)piperazine (ca. 0.915 mmol, prepared from 150 mg 2-bromothiazole according to the methods described in Astles et al., J. Med. Chem., 39: 1423-1432 (1996)), 3′-chloro-biphenyl-4-carboxylic acid (212.9 mg, 0.915 mmol) in CH2Cl2 (4 ml), was added EDC (209.7 mg, 1.098 mmol) and HOBt (148.2 mg, 1.098 mmol). After being stirred overnight, the mixture was treated with EtOAc (50 ml) and water (15 ml). The organic phase was washed with brine (5 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (20% acetone/hexanes) to give the title compound (225 mg, 64% for two steps) as a white solid: 1H NMR (CDCl3, 400 MHz) δ 7.64-7.23 (m, 9H), 6.65 (t, J=3.6 Hz, 1H), 4.92 (m, br, 2H), 3.57 (m, br, 6H), 3.68 (m, 2H), 2.14 (m, 2H), 1.83 (m, 2H); MS calc'd for C20H19ClN3OS [M+H]+: 384; Found: 384.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[CH:6]([NH:8][CH:9]([P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])[C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])=[S:7].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.C(Cl)Cl>[Cl:17][C:14]([Cl:15])([Cl:16])[CH2:13][O:12][C:10]([CH:9]([P:18]([O:20][CH2:21][CH3:22])([O:23][CH2:24][CH3:25])=[O:19])[N:8]=[CH:6][S:7][CH2:2][C:3](=[O:5])[CH3:4])=[O:11]
Reactant: CC(=O)CCl
Reactant: CCOP(=O)(OCC)C(NC=S)C(=O)OCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCOP(=O)(OCC)C(N=CSCC(C)=O)C(=O)OCC(Cl)(Cl)Cl

Procedure:
A solution of chloro-2-propanone (0.470 q., 5.08 mMol) in acetone (4 ml.) is added dropwise during 15 minutes to a rapidly stirring mixture of trichloroethyl α-thioformamido-diethylphosphonoacetate (1.783 g., 4.62 mMol), K2CO3 (0.702 g., 5.08 mMol), and acetone (6 ml.). After having been stirred for 15 hours at room temperature, the mixture is diluted with methylene chloride (30 ml.) and filtered to remove salts. The filtrate is evaporated under reduced pressure to yield 2-oxo-propyl N-(trichloroethoxycarbonyl-diethylphosphonomethyl)-thioformimidate.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.Cl[C:39]([O:41][CH3:42])=[O:40]>>[F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=3)[CH2:27][CH2:28][N:29]([C:39]([O:41][CH3:42])=[O:40])[CH2:30][CH2:31]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccncc5)CCNCC4)c3F)s2)c1
Reactant: COC(=O)Cl
Product: COC(=O)N1CCC(CNC(=O)c2nccc(Sc3cnc(Nc4cc(C)ccn4)s3)c2F)(c2ccncc2)CC1

Procedure:
Following the procedure given for example 81, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)-N-((4-(pyridin-4-yl)piperidin-4-yl)methyl)picolinamide (compound example 45) was reacted with methyl chloroformate to give the title compound. LC/MS (M+H)+: 594. Ret. time: 1.32 min. (Condition I); analytical HPLC Ret. time: 5.23 min (Condition H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:27])=[C:9]([C:23]([Cl:26])=[CH:24][CH:25]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2)[CH3:6])=[O:4].C(N(CC)CC)C.[C:35](Cl)(=[O:42])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>ClCCl>[Cl:27][C:8]1[C:7]([N:5]([C:3](=[O:4])[CH2:2][NH:1][C:35](=[O:42])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH3:6])=[CH:25][CH:24]=[C:23]([Cl:26])[C:9]=1[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[CH:17]2
Reactant: CCCCCCC(=O)Cl
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Reaction time: 0.5 h

Procedure:
To a mixture of 8-[3-(N-glycyl-N-methylamino)2,6-dichlorobenzyloxy]-2-methylquinoline (100 mg), triethylamine (50 mg) and dichloromethane (2.0 ml) was added heptanoyl chloride (0.05 ml) in an ice-water bath. The mixture was stirred at the same temperature for 30 minutes and washed with water. The organic layer was collected and dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (dichloromethane-methanol) to give 8-[2,6-dichloro-3-[N-(heptanoylglycyl)-N-methylamino]benzyloxy]-2-methylquinoline (130 mg) as a pale yellow oil.
Reaction SMILES: CN(CCCN=C=NCC)C.[C:12]([O:16][C:17](=[O:26])[CH2:18][C@@H:19]([CH2:23][CH:24]=[CH2:25])[C:20]([OH:22])=O)([CH3:15])([CH3:14])[CH3:13].ON1C2N=CC=CC=2N=N1.Cl.[NH2:38][C@@H:39]([C:51]([CH3:54])([CH3:53])[CH3:52])[C:40]([NH:42][C@@H:43]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH3:44])=[O:41].C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:53][C:51]([CH3:52])([CH3:54])[C@H:39]([NH:38][C:20]([C@H:19]([CH2:23][CH:24]=[CH2:25])[CH2:18][C:17]([O:16][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:26])=[O:22])[C:40]([NH:42][C@@H:43]([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[CH3:44])=[O:41]
Reactant: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@@H](NC(=O)[C@@H](N)C(C)(C)C)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
N-(Dimethylaminopropyl)-N′-ethylcarbodiimide (4.21 g, 22.0 mmol) was added to a stirred mixture of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]pent-4-enoic acid (A. L. Castelhano, S. L. Bender, J. G. Deal, S. Homer, T. J. Liak, Z. Yuan, World Patent WO96/16027 (1996)) (3.80 g, 17.8 mmol) and 1-hydroxy-7-azabenzotriazole (2.49 g, 18.3 mmol) in anhydrous dimethylformamide (60 mL) under nitrogen at 4° C. After 1 h, (2S)-amino-3,3-dimethyl-N-[(1R)-1-phenylethyl]butanamide hydrochloride (Preparation 1)(5.10 g, 18.8 mmol) was added, followed by diisopropylethylamine (2.42 g, 19.2 mmol). After another 30 min, the mixture was allowed to warm to room temperature. After 17 h at room temperature, the mixture was concentrated under reduced pressure, and partitioned between ethyl acetate (400 mL) and water (400 mL). The aqueous layer was saturated with sodium bicarbonate and extracted with ethyl acetate (2×100 mL). The combined organic solutions were concentrated under reduced pressure, the residue was dissolved in ether (500 mL) and washed with water (3×200 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was triturated with pentane, filtered and dried to give tert-butyl (3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)hex-5-enoate (6.70 g, 88%), as a colourless solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][C:11]([O:16][CH3:17])=[CH:10][C:9]=2[O:18][CH3:19])[C:4](=[O:20])[CH2:3]1.[C:21]([C@:29]([C:44]([OH:46])=[O:45])([OH:43])[C@:30]([C:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([OH:34])[C:31]([OH:33])=[O:32])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[C:35]([C@:30]([C:31]([OH:33])=[O:32])([OH:34])[C@:29]([C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([OH:43])[C:44]([OH:46])=[O:45])(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[CH3:1][N:2]1[CH2:7][CH2:6][C@H:5]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][C:11]([O:16][CH3:17])=[CH:10][C:9]=2[O:18][CH3:19])[C:4](=[O:20])[CH2:3]1
Reactant: COc1cc(OC)c(C2CCN(C)CC2=O)c(OC)c1
Agent: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1
Solvent: CO
Product: COc1cc(OC)c([C@H]2CCN(C)CC2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (±)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone (1.60 g, 5.73 mmoles) and dibenzoyl-D-tartaric acid (2.28 g, 315 mmol) in 10 mL of methanol was heated at reflux temperature under argon atmosphere and it was cooled to room temperature. After stirring overnight at room temperature the precipitated solid was filtered, washed with a small amount of methanol to obtain the first crop of (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone dibenzoyl-D-tartaric acid salt (2.65 g). The filtrate solution was concentrated to a volume of ca 6 mL and was stirred at ambient temperature for one day. The second crop of the chiral salt (0.24 g) was obtained by filtering the solid and washed it with a small amount of methanol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[O:12][CH2:13][CH:14]1[CH2:16][CH:15]1[CH3:17].C(O)(=O)C>[Fe].O>[CH3:11][C:5]1[CH:4]=[C:3]([O:12][CH2:13][CH:14]2[CH2:16][CH:15]2[CH3:17])[C:2]([CH3:1])=[CH:7][C:6]=1[NH2:8]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1OCC1CC1C
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(OCC2CC2C)c(C)cc1N
Temperature: 80 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
A mixture of 0.70 g of 2,5-dimethyl-1-[(2-methylcyclopropyl)methoxy]-4-nitrobenzen e, 0.83 g of iron powder, 15 mL of acetic acid and 15 mL of water was stirred at 80° C. for 1 hour. The reaction mixture was cooled to around room temperature, and then concentrated under reduced pressure. The resulting residue was converted into basic with an aqueous 1 N sodium hydroxide solution, then ethyl acetate was added, and the mixture was filtered. The filtrate was extracted with ethyl acetate, and then the organic layer was washed with water and saturated salt water, and dried over anhydrous magnesium sulfate. The resulting residue was subjected to silica gel column chromatography to obtain 0.46 g of 2,5-dimethyl-4-[(2-methylcyclopropyl)methoxy]phenylamine.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[NH:6][N:5]=[C:4]2[CH2:9][O:10][C:11]3[CH:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:14]([CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)=[CH:13][C:12]=3[N:3]12.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(Cl)Cl>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[CH3:1][CH:2]1[C:7](=[O:8])[NH:6][N:5]=[C:4]2[CH2:9][O:10][C:11]3[CH:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:14]([CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:13][C:12]=3[N:3]12
Reactant: CC1C(=O)NN=C2COc3cc(-c4ccccc4)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1C(=O)NN=C2COc3cc(-c4ccccc4)c(C4CCNCC4)cc3N21
Yield: 78 %

Procedure:
A solution of tert-butyl 4-(1-methyl-2-oxo-8-phenyl-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)piperidine-1-carboxylate (0.020 g, 0.042 mmol) in DCM (6 mL) and TFA (1 mL) was stirred at ambient temperature for 1.5 h. The solvent was removed in vacuo to give 1-methyl-8-phenyl-9-(piperidin-4-yl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoroacetic acid (0.016 g, 78%) as a pale yellow solid. LC/MS (Table 1, Method 5) Rt=2.314 min.; MS m/z: 377 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:23][C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27]([NH2:29])=[O:28])[CH2:20][CH2:21][CH:22]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[Pd]>[C:1]1([C:7]2[N:8]=[C:9]([CH:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[CH2:23][C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27]([NH2:29])=[O:28])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)c1cccc(CC2CCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cccc(CC2CCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Yield: 71.7 %

Procedure:
3-{[2-(4,5-Diphenyloxazol-2-yl)-2-cyclopenten-1-yl]-methyl}benzamide (75 mg) was hydrogenated over 5% Pd/C (3 mg) in methanol (20 ml) at room temperature at 3 atm for 7 hours. The mixture was filtered and the filtrate was evaporated in vacuo. The residue was triturated with a mixture of ether and n-hexane to afford 3-{[2-(4,5-diphenyloxazol-2-yl)-1-cyclopentyl]methyl}benzamide (54 mg).