Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:28]1[CH:29]=[CH:30][C:31]([C:34]([NH2:36])=[O:35])=[N:32][CH:33]=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:24])[N:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:28]2[CH:33]=[N:32][C:31]([C:34](=[O:35])[NH2:36])=[CH:30][CH:29]=2)=[CH:19][CH:18]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NC(=O)c1ccc(F)cn1
Reactant: CC(C)(C)OC(=O)N(CCc1ccccc1)Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCc1ccccc1)Cc1ccc(Oc2ccc(C(N)=O)nc2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
Dissolve (4-hydroxybenzyl)phenethylcarbamic acid tert-butyl ester (0.0915 g, 0.279 mol) in DMF (0.090 mL). Add NaH (80% in mineral oil) (0.0092 g, 0.307 mmol). Stir for 30 minutes before adding 5-fluoropyridine-2-carboxamide (0.0391 g, 0.279 mmol). Heat at 80° C. for 3 days. Load the reaction mixture directly onto a flash 40 column and elute with 35% ethyl acetate, 3% 2.0 M NH3 in methanol and 62% hexanes to give the title compound (0.103 g, 82.4%): MS ES+ 448.5 (M+H)+, base peak ES+ 392.3 (M+2H—C(CH3)3); HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 5-95% over 19 min, 95% over 19.01-25 min], tR=19.5 min, 100% purity.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([C:18]3[N:23]4[N:24]=[C:25]([NH:27]C(=O)C)[N:26]=[C:22]4[CH:21]=[CH:20][N:19]=3)[CH:15]=[CH:16][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[NH2:27][C:25]1[N:26]=[C:22]2[N:23]([C:18]([C:14]3[CH:13]=[C:12]([NH:11][S:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=4)(=[O:10])=[O:9])[CH:17]=[CH:16][CH:15]=3)=[N:19][CH:20]=[CH:21]2)[N:24]=1
Reactant: CC(=O)Nc1nc2ccnc(-c3cccc(NS(=O)(=O)c4ccc(C)cc4)c3)n2n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)Nc2cccc(-c3nccc4nc(N)nn34)c2)cc1
Reaction time: 22 h

Procedure:
A 250 mg portion of N-[5-[3-[[(4-methylphenyl) sulfonyl]amino]phenyl][1,2,4]triazolo[1,5-c]pyrimidin-2-yl]acetamide was dissolved in 30 ml of dioxane. A 15 ml portion of 1N hydrochloric acid was added, the mixture was allowed to stand 22 hours, concentrated, neutralized with aqueous potassium bicarbonate and extracted with ethyl acetate. The organic extract was evaporated and the residue taken up in 1% methanol in chloroform and filtered through hydrous magnesium silicate. The filtrate was evaporated and the residue crystallized from ethyl acetatecyclohexane giving 15 mg of the desired product as white crystals, mp 205°-208° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]([CH3:20])([CH3:19])[O:10][C:9]2=[O:21])=[CH:4][CH:3]=1.[NH:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1.CC1C=NC2C(C=1C)=CC=C1C=2N=CC(C)=C1C.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.[Cu]I>[N:22]1([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C@@H:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:11]([CH3:20])([CH3:19])[O:10][C:9]3=[O:21])=[CH:4][CH:3]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CC1(C)OC(=O)N(c2ccc(Br)cc2)[C@H]1c1ccccc1
Agent: [Cu]I
Agent: Cc1cnc2c(ccc3c(C)c(C)cnc32)c1C
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CC1(C)OC(=O)N(c2ccc(-n3nnc4ccccc43)cc2)[C@H]1c1ccccc1
Temperature: 140 °C

Procedure:
A glass microwave reaction vessel was charged with (S)-3-(4-bromophenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (100 mg, 0.289 mmol), benzotriazole (25.3 μL, 0.289 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.), copper (I) iodide (5.50 mg, 0.029 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.), 3,4,7,8-tetramethyl-1,10-phenanthroline (27.3 mg, 0.116 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) and cesium carbonate (188 mg, 0.578 mmol) in DMSO (578 μL). The reaction mixture was stirred and heated in a heating block at 140° C. for 4 hours. LC-MS indicated complete conversion to the desired product. After cooling to room temperature, the reaction mixture was passed through a syringe filter. The material thus obtained was purified by reverse-phase preparative HPLC using 0.1% TFA in ACN/H2O, gradient 20% to 90% over 20 minutes. The pure fractions were combined and diluted with 30% ammonium hydroxide, and the aqueous layer was extracted with DCM (3×20 mL) to provide (S)-3-(4-(1H-benzo[d][1,2,3]triazol-1-yl)phenyl)-5,5-dimethyl-4-phenyloxazolidin-2-one (10 mg, 0.026 mmol, 9.01% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.15 (d, J=8.33 Hz, 1H), 7.85 (d, J=8.33 Hz, 1H), 7.77-7.84 (m, 4H), 7.62 (dd, J=7.16, 7.91 Hz, 1H), 7.50 (d, J=7.48 Hz, 1H), 7.38-7.44 (m, J=7.60 Hz, 2H), 7.29-7.37 (m, 3H), 5.57 (s, 1H), 1.68 (s, 3H), 0.94 (s, 3H). m/z (ESI) 385.2 (M+H)+.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([S:17]Cl)=[C:13]([C:19]([Cl:22])([Cl:21])[Cl:20])[CH:12]=1)([O-:10])=[O:9]>CCOCC>[CH:1]([N:4]([CH:5]([CH3:7])[CH3:6])[S:17][C:14]1[CH:15]=[CH:16][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][C:13]=1[C:19]([Cl:20])([Cl:21])[Cl:22])([CH3:3])[CH3:2]
Reactant: CC(C)NC(C)C
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Solvent: CCOCC
Product: CC(C)N(Sc1ccc([N+](=O)[O-])cc1C(Cl)(Cl)Cl)C(C)C
Yield: 94.2 %

Procedure:
A solution of 40 g of diisopropylamine in 400 ml of ether is placed in a stirred apparatus; at 10° C., 61.4 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride in 200 ml of ether is dripped in. After the mixture has been reacted for 4 hours at 25° C., it is filtered and concentrated. There is obtained 70 g (95% of theory) of N,N-diisopropyl-4-nitro-2-trichloromethylphenylsulfenamide; m.p.: 104° C.
Reaction SMILES: N1C2C(=CC(S(N)(=O)=O)=CC=2)C=C1.[Br:14][C:15]1[CH:16]=[C:17]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:18]=[C:19]2[C:23]=1[N:22]([CH2:24][CH3:25])[CH2:21][CH2:20]2>>[Br:14][C:15]1[CH:16]=[C:17]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:18]=[C:19]2[C:23]=1[N:22]([CH2:24][CH3:25])[CH:21]=[CH:20]2
Reactant: CCN1CCc2cc(S(N)(=O)=O)cc(Br)c21
Agent: NS(=O)(=O)c1ccc2[nH]ccc2c1
Product: CCn1ccc2cc(S(N)(=O)=O)cc(Br)c21
Yield: 32.3 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 54, 7-bromo-1-ethylindoline-5-sulfonamide (Intermediate 76, 140 mg, 0.46 mmol) was converted to the title compound (45 mg, 31%). 1H NMR (DMSO-d6) δ 8.04 (d, J=1.8 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 7.63 (d, J=3.1 Hz, 1H), 7.26 (s, 2H), 6.72 (d, J=3.3 Hz, 1H), 4.60 (q, J=7.1 Hz, 2H), 1.38 (t, J=7.2 Hz, 3H); MS(ESI+) m/z 305.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C:10]([C:16]([OH:18])=O)=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH2:32]([NH:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH3:35]>C1(C)C=CC=CC=1.O>[CH2:32]([N:36]([CH2:37][CH2:38][CH2:39][CH3:40])[C:16]([C:10]1[C:11](=[O:15])[CH:12]=[C:13]([CH3:14])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]=1)=[O:18])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCNCCCC
Reactant: Cc1cc(=O)c(C(=O)O)nn1-c1ccc(Cl)cc1
Agent: CCOC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(Cl)cc2)c(C)cc1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.2 %

Procedure:
To an ice cooled suspension of 5.29 g (0.02 mol) 1-(4-chlorophenyl)-1,4-dihydro-4-oxo-6-methyl pyridazine-3-carboxylic Acid (see Example 12) and 2.02 g (0.02 mol) of triethylamine in 100 ml of toluene there is added dropwise 2.17 g (0.02 mol) of ethyl chloroformate. The suspension formed is stirred at room temperature for 15 min. and is cooled to 5° C. To the suspension is added 2.59 g (0.02 mol) di-n-butylamine and the mixture is stirred at room temperature for 18 hrs. To the mixture is added 100 ml of water and the suspension formed is stirred at room temperature for 1 hr. The toluene layer is isolated, dried over magnesium sulfate and concentrated in vacuo. The residue oil is dissolved in 25 ml of ether and to it there is added 25 ml of hexane. The mixture is allowed to stand at room temperature for 30 minutes and is vacuum filtered. The filter cake is washed with hexane and air dried to afford 5.5 g (73% yield) of product, mp 101°-105° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[NH2:12])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>C(Cl)Cl.CO.C(Cl)Cl>[CH2:23]([O:22][C:20](=[O:21])[NH:11][C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[C:6]([NH2:12])[CH:7]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)c1ccc(N)cc1N
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(NC(=O)OCc2ccccc2)cc1N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90.3 %

Procedure:
A solution of 4-tert-butylbenzene-1,3-diamine (D-9) (657 mg, 4 mmol) and pyridine (0.39 mL, 4.8 mmol) in CH2Cl2/MeOH (12/1, 8 mL) was cooled to 0° C., and a solution of benzyl chloroformate (0.51 mL, 3.6 mmol) in CH2Cl2 (8 mL) was added dropwise over 10 min. The mixture was stirred at 0° C. for 15 min, then warmed to room temperature. After 1 h, the mixture was washed with 1M citric acid (2×20 mL), saturated aqueous sodium bicarbonate (20 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford the crude (3-amino-4-tert-butyl-phenyl)-carbamic acid benzyl ester as a brown viscous gum (0.97 g), which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.41-7.32 (m, 6H,), 7.12 (d, J=8.5 Hz, 1H), 6.89 (br s, 1H), 6.57 (dd, J=2.3, 8.5 Hz, 1H), 5.17 (s, 2H), 3.85 (br s, 2H), 1.38 (s, 9H); 13C NMR (100 MHz, CDCl3, rotameric) δ 153.3 (br), 145.3, 136.56, 136.18, 129.2, 128.73, 128.59, 128.29, 128.25, 127.14, 108.63 (br), 107.61 (br), 66.86, 33.9, 29.7; ESI-MS 299.1 m/z (MH+).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[F:5][C:6]1[CH:15]=[C:14]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[CH3:21])[C:13]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:12][C:7]=1[C:8](OC)=[O:9]>>[NH2:3][C:2]([NH2:4])=[N:1][C:8](=[O:9])[C:7]1[CH:12]=[C:13]([S:22]([CH3:25])(=[O:24])=[O:23])[C:14]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[CH3:21])=[CH:15][C:6]=1[F:5]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(-n2ccnc2C)cc1F
Reactant: N=C(N)N
Product: Cc1nccn1-c1cc(F)c(C(=O)N=C(N)N)cc1S(C)(=O)=O

Procedure:
In analogy to Example 1, by reaction of guanidine with methyl 2-fluoro-4-(2-methyl-1-imidazolyl) -5-methylsulfonylbenzoate [obtainable by reacting 2-fluoro-4-chloro-5-methylsulfonylbenzoic acid with 2-methylimidazole followed by esterification] , N-diaminomethylene-2-fluoro-4- (2-methyl-1-imidazolyl) -5-methylsulfonylbenzamide is obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[NH:9][C:8]2=[O:18])[CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([C:26]([C:28]2[CH:38]=[C:37]([CH3:39])[C:31]3[N:32]([CH3:36])[C:33](=[O:35])[O:34][C:30]=3[CH:29]=2)=[O:27])[CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[CH3:36][N:32]1[C:31]2[C:37]([CH3:39])=[CH:38][C:28]([C:26]([C:22]3[N:23]=[CH:24][N:25]=[C:20]([N:1]4[CH2:2][CH2:3][CH:4]([N:7]5[CH2:13][CH2:12][C:11]6[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=6[NH:9][C:8]5=[O:18])[CH2:5][CH2:6]4)[CH:21]=3)=[O:27])=[CH:29][C:30]=2[O:34][C:33]1=[O:35]
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(N3CCC(N4CCc5ccccc5NC4=O)CC3)ncn2)cc2oc(=O)n(C)c12

Procedure:
98 mg (0.40 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.12 g (0.40 mmol) 6-(6-chloropyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.14 mL (0.80 mmol) DIPEA were stirred in 3 mL DMF for 2 h at RT. The mixture was diluted with methanol, and the precipitate formed was suction filtered, washed with MeOH and diethyl ether and dried.
Reaction SMILES: Cl.[CH2:2]1[C:6]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH2:5][CH2:4][O:3]1>CO>[CH2:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][O:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCOC2)CC1
Agent: Cl
Solvent: CO
Product: C1CC2(CCN1)CCOC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.9 %

Procedure:
Methanolic hydrogen chloride (3M, 3 mL) was added to a stirred, cooled (0° C.) solution of 1,1-dimethylethyl 2-oxa-8-azaspiro[4.5]decane-8-carboxylate (Description 25, 150 mg, 0.62 mmol) in methanol and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure and the residue was dissolved in methanol and passed through Amberlyst™ 26 ion exchange resin, eluting with methanol. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane, dried (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound (77 mg, 88%). m/z (ES+) 142 (M+1).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3I)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:34][C:35]1([CH3:41])[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O1CCOCC1>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[N:37]3[CH2:38][CH2:39][CH2:40][C:35]([CH3:41])([CH3:34])[CH2:36]3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Reactant: CC1(C)CCCNC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1N1CCCC(C)(C)C1

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (500 mg, 0.837 mmol), 3,3-dimethylpiperidine (142.5 mg, 1.26 mmol), Bis(tri-t-butylphosphine)palladium (0) (43 mg, 0.084 mmol), cesium carbonate (685 mg, 2.10 mmol) and 1,4-dioxane (5 mL) were sealed in a microwave vessel. The reaction mixture was irradiated by microwave at 170° C. for 30 minutes. Reaction crude was purified by SiO2 to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(3,3-dimethylpiperidin-1-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. LCMS calc.=582.19; found=583.44 (M+1)+. 1H NMR signals are doubled because of atropoisomerism 1H NMR (CDCl3, 500 MHz) δ 7.88 (s, 1H), 7.77 (s, 2H), 7.58 (s, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.16 (d, J=8.5 Hz, 1H), 5.72 (d, J=8.0 Hz, 1H), 4.76 (d, J=16 Hz, 1H), 4.57 (d, J=15.5 Hz, 1H), 3.94-3.87 (m, 1H), 2.84 (br s, 1H), 2.68 (br s, 1H), 2.63 (d, J=11 Hz, 1H), 2.52 (d, J=11 Hz, 1H), 1.81 (br s, 1H), 1.71 (br s, 1H), 1.38 (br s, 2H), 1.06 (s, 3H), 0.99 (s, 3H), 0.67, 0.66 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1N=CN[CH:5]=1.[OH:12][C:13]1[CH:18]=CC(NCC(O)=O)=[CH:15][CH:14]=1>>[NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[CH:15]=[CH:14][C:13]([OH:12])=[CH:18][CH:5]=1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: O=C(O)CNc1ccc(O)cc1
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
The above procedure is repeated using the methyl and ethyl esters of histidine and 4-hydroxy phenylglycine, and the ethyl ester of L-tyrosine to produce the corresponding amino acid ester derivatives.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: Cc1ccccc1CBr
Product: Cc1ccccc1COc1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 1-Bromomethyl-2-methyl-benzene using the conditions described in Example 10C to provide 1-Chloro-4-(2-methyl-benzyloxy)-2-nitro-benzene which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([C:12](=[O:17])[CH2:13][CH2:14][CH2:15]3)=[C:10]3[N:18]([CH3:25])[C:19](=[O:24])[N:20]([CH3:23])[C:21](=[O:22])[C:9]=23)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]([OH:17])[CH2:13][CH2:14][CH2:15]3)=[C:10]3[N:18]([CH3:25])[C:19](=[O:24])[N:20]([CH3:23])[C:21](=[O:22])[C:9]=23)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)C(=O)CCC3
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n3c(c2n(C)c1=O)C(O)CCC3
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 5-(3-fluorophenyl)-1,3-dimethyl-8,9-dihydropyrimido[4,5-a]indolizine-2,4,10(1H,3H,7H)-trione (step 1)(150 mg, 0.439 mmol) in MeOH (2197 μL) at 0° C. was added sodium borohydride (49.9 mg, 1.318 mmol) portionwise. The resulting yellow solution was warmed to room temperature and stirred for 15 minutes. The reaction was concentrated in vacuo. The residue was diluted with water (5 mL) and DCM (10 mL). The aqueous phase was separated and extracted with DCM (3×10 mL). The combined organic fractions were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a pale yellow solid;
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si](C(C)(C)C)(C)C)[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:28][CH2:27][C:26](=[CH:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:25][CH2:24]1)(C(C)(C)C)(C)C.O1CCCC1.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(O)(=O)C>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:28][CH2:27][C:26](=[CH:29][C:30]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[CH2:25][CH2:24]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(=CC(=O)OCc3ccccc3)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(C=C1CCC(c2ccc(O)cc2O)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To a round bottomed flask equipped with magnetic stirrer was added benzyl [4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylidene]acetate (232 mg), tetrahydrofuran (5 ml), tetrabutylammonium fluoride hydrate (429 mg) and glacial acetic acid (94 μl). After stirring at room temperature for 0.5 hr, the solvent was removed in vacuo and the residue partitioned between ethyl acetate (100 ml) and water (20 ml). The layers were separated and the aqueous phase was extracted with ethyl acetate (50 ml). The combined organic phases were washed with water (50 ml), brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash chromatography (SiO2, ethyl acetate/petroleum ether, 1:3 v/v) furnished the title compound (100 mg, 72%) as a cream solid. δH (CD3OD): 1.59-1.67 (2H, m), 1.98-2.13 (4H, m), 2.37-2.48 (2H, m), 3.14 (1H, ft), 5.16 (2H, s), 5.75 (1H, s), 6.26 (1H, dd), 6.30 (1H, d), 6.89 (1H, d), 7.30-7.44 (5H, m); m/z (ES+) 337 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:14])O[C:11](=[O:13])[CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>C(O)(=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([N:19]2[C:11](=[O:13])[CH:12]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[C:9]2=[O:14])[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cccc(C2=CC(=O)OC2=O)c1
Reactant: Nc1cccc(Cl)c1
Solvent: CC(=O)O
Product: Cc1cccc(C2=CC(=O)N(c3cccc(Cl)c3)C2=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (3-methylphenyl)-furan-2,5-dione (265 mg, 1.41 mmol) in acetic acid (5 ml) at room temperature was added 3-chloroaniline (149 μl, 1.41 mmol). The reaction mixture was heated to reflux and stirred for 3 hours. The reaction mixture was cooled to room temperature. The precipitate formed was filtered, re-suspended in water (15 ml) and recovered by filtration. The precipitate was washed with water (10 ml), heptane (10 ml) and dried under air suction followed by high vacuum.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[NH:11]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:12]1.[OH-].[Na+]>O.ClCCl>[CH:3]([C:12]1[NH:11][C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]=1[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[O:4]
Reactant: CN(C)C=O
Reactant: O=C(O)CCc1c[nH]c2c1CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Temperature: -9 °C
Yield: 84 %

Procedure:
A mixture of 24 g of dimethylformamide and 300 mL of dichloromethane was cooled to −9° C. Phosphorus oxychloride (50 g) was rapidly added via an addition funnel. 3-(4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid (54.9 g) was added in portions with vigorous stirring. The mixture was warmed to room temperature and then refluxed for 10 minutes. It was then cooled to 5° C. and diluted with 300 mL of water. The pH was adjusted to 10 using 10N sodium hydroxide. The layers were separated. The aqueous layer was cooled to 10° C. and the pH adjusted to 2-3 with about 130 mL of 10 N hydrochloric acid. The oil which formed solidified and was collected by vacuum filtration, washed three times with water and dried under vacuum at 50° C. to give 52.8 g (93% yield) of 3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid as a dark brown solid.
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:22]([NH:24][CH3:25])=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])=O)(C)(C)C>CO>[ClH:1].[NH2:9][CH2:10][C:11]([NH:13][C@H:14]([C:22]([NH:24][CH3:25])=[O:23])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:12]
Reactant: CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: CNC(=O)[C@H](Cc1ccccc1)NC(=O)CN

Procedure:
Gaseous HCl is bubbled through a solution of t-boc-gly-phe-NHCH3 8a (9.2 g, 2.7×10-2 mole) and methanol (200 ml). After 1/2 hour the methanol is evaporated at reduced pressure leaving a clear colorless oil which, when triturated with Et2O crystallizes to give 9a as a colorless power: m.p. 220°-223° C. In a similar fashion, gly-phe-leu-NHEt.HCl is prepared from its corresponding t-boc-derivative.