Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])=[CH:17][CH:16]=2)=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:29]([N:31]=[C:32]=[S:33])[CH3:30].C(O)C>C(OCC)(=O)C>[C:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][C:3]2[C:2]([NH:1][C:32]([NH:31][CH2:29][CH3:30])=[S:33])=[CH:12][CH:11]=[CH:10][C:4]=2[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:16][CH:17]=1)#[N:28]
Reactant: CCOC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1
Reactant: CCN=C=S
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCNC(=S)Nc1cccc(C(=O)OCC)c1NCc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of ethyl 3-amino-2-[[(2′-cyanobiphenyl-4-yl)methyl]amino]benzoate (1.61 g), ethyl isothiocyanate (1.5 ml) and ethanol (1 ml) was stirred at room temperature for 3 days. The reaction mixture was dissolved in ethyl acetate and the solution was washed with water, dried and concentrated to dryness to give crystals. Recrystallization from ethyl acetate-hexane afforded pale yellow crystals (1.92 g, 91%), m.p. 108-110° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[C:9]([C:11](=[S:13])[NH2:12])[CH:8]=[C:7]([C:14]([F:17])([F:16])[F:15])[N:6]=1)([CH3:3])[CH3:2].CI.[CH3:20]C(C)=O.CCCCCC>CC(C)=O>[CH:1]([O:4][C:5]1[CH:10]=[C:9]([C:11]([S:13][CH3:20])=[NH:12])[CH:8]=[C:7]([C:14]([F:16])([F:17])[F:15])[N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cc(C(N)=S)cc(C(F)(F)F)n1
Reactant: CC(C)=O
Solvent: CI
Solvent: CCCCCC
Product: CSC(=N)c1cc(OC(C)C)nc(C(F)(F)F)c1

Procedure:
In a 100 mL capacity 3-neck round-bottomed flask attached with nitrogen bubbler & magnetic stirrer 2-isopropoxy-6-(trifluoromethyl)pyridine-4-carbothioamide (7.5 g), CH3I (10.18 g), dissolved in 75 ml acetone at RT. Reflux it for 2 h. The completion of the reaction was confirmed by TLC with 20% acetone-hexane as mobile phase. The reaction mixture was distilled & crude 2-isopropoxy-6-(trifluoromethyl)pyridine-4-carbimidothioate forwarded to next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[C:14](=[O:22])[NH:15][C:16]([CH3:21])([CH3:20])[CH2:17][C:18]=4[N:19]=3)[C:6]=2[CH:23]=1.C1C(=O)N([Br:31])C(=O)C1.O>C(Cl)Cl>[NH2:1][C:2]1[C:3]([Br:31])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[C:14](=[O:22])[NH:15][C:16]([CH3:21])([CH3:20])[CH2:17][C:18]=4[N:19]=3)[C:6]=2[CH:23]=1
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(N)cc43)sc2C(=O)N1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Product: CC1(C)Cc2nc(N3CCOc4cc(Br)c(N)cc43)sc2C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
To a stirred solution of Example 42 (0.04 g, 0.12 mmol) in DCM (1 mL) was added NBS (0.02 g, 0.12 mmol) and the reaction mixture stirred for 1 h at r.t. Water (2 mL) was added, the layers were separated and the organic fraction was concentrated in vacuo. Purification by preparative HPLC (Method 6) gave the title compound (0.006 g, 12%) as a white solid. δH (CDCl3) 7.56 (1H, s), 7.05 (1H, s), 5.30 (1H, s), 4.29-4.23 (2H, m), 4.11-4.05 (2H, m), 2.88 (2H, s), 1.40 (6H, s). LCMS (ES+) 409.2 and 411.2 (1:1 ratio) (M+H)+, RT 3.06 minutes (Method 1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH:7]([NH:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[N:18]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:31])[CH:7]([NH:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]([N:26]([CH2:27][CH3:28])[CH2:29][CH3:30])[N:18]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:41](=[O:42])[N:40]([CH3:44])[CH3:39])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)Cl
Reactant: CCN(CC)c1ncc([N+](=O)[O-])c(NC(Cc2ccc(O)cc2)C(=O)OC(C)(C)C)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)c1ncc([N+](=O)[O-])c(NC(Cc2ccc(OC(=O)N(C)C)cc2)C(=O)OC(C)(C)C)n1
Yield: 99.5 %

Procedure:
To a solution of 2-(2-diethylamino-5-nitropyrimidin-4-ylamino)-3-(4-hydroxy-phenyl)propionic acid t-butyl ester (31.80 g, 0.074 mol) in CH2Cl2 (600 mL) was added DMAP (9.00 g, 0.074 mol). After 5 minutes triethylamine (10.23 mL, 0.074 mol) was added dropwise. N,N-dimethylcarbamyl chloride (13.83 mL, 0.110 mol) was added dropwise, and the reaction was heated to reflux overnight. The reaction mixture was concentrated in vacuo and taken up in EtOAc (1 L). The organic phase was washed with 0.5 M citric acid (3×250 mL), sat. NaHCO3 (3×250 mL), brine (1×250 mL), dried (MgSO4), filtered, and concentrated in vacuo to yield 37.0 g (99%) the title compound as a white solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Br:7][C:8]1[CH:20]=[N:19][C:11]2[NH:12][C:13](=O)[C@H:14]([CH3:17])[NH:15][CH2:16][C:10]=2[CH:9]=1>C1COCC1>[Br:7][C:8]1[CH:20]=[N:19][C:11]2[NH:12][CH2:13][C@H:14]([CH3:17])[NH:15][CH2:16][C:10]=2[CH:9]=1
Reactant: C[C@@H]1NCc2cc(Br)cnc2NC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1CNc2ncc(Br)cc2CN1
Temperature: 25 °C

Procedure:
To a solution of LAH (2.5 mL, 2.52 mmol) was added a solution of (S)-7-bromo-3-methyl-4,5-dihydro-1H-pyrido[2,3-e][1,4]diazepin-2(3H)-one (375 mg, 1.26 mmol) in THF (10 mL) at 0° C. The reaction was warmed to room temperature and stirred over night. Once the reaction was complete, it was cooled to 0° C. and carefully quenched with water (10 mL), and extracted with ethyl acetate (4×15 mL), dried over sodium sulfate and concentrated. Preparative HPLC was used to purify the title compound as a white solid (166 mg, 55%): 1H NMR (400 MHz, CDCl3) δ8.10 (d, J=2.4 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H), 4.36 (2s, 2H), 4.21 (d, J=14.3 Hz, 1H), 6.33-3.61 (m, 2H), 3.26-3.13 (m, 1H), 1.36 (d, J=6.4 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([F:10])[F:9])[CH:5]=[C:4]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[N:3]=1.[I:21][C:22]1[N:23]=[CH:24][NH:25][CH:26]=1>>[F:9][CH:8]([F:10])[C:6]1[CH:5]=[C:4]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[N:3]=[C:2]([N:25]2[CH:26]=[C:22]([I:21])[N:23]=[CH:24]2)[N:7]=1
Reactant: Ic1c[nH]cn1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)nc2)nc(Cl)n1
Product: FC(F)c1cc(-c2ccc(C(F)(F)F)nc2)nc(-n2cnc(I)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example A.3) (1.24 g, 4.0 mmol) and commercially available 4-iodo-imidazole (0.85 g, 4.4 mmol) according to the general procedure Ia. Obtained as a light brown solid (1.77 g, 95%). MS (ISP) 468.0 [(M+H)+]; mp 173° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:13]1[O:14][C:15]2[C:20]([C:21](=[O:23])[CH:22]=1)=[C:19]([O:24]C)[CH:18]=[C:17]([O:26]C)[C:16]=2[C@@H:28]1[CH2:32][CH2:31][N:30]([CH3:33])[C@H:29]1[CH2:34][OH:35].Cl.N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[Cl:1][C:2]1[C:7]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:13]1[O:14][C:15]2[C:20]([C:21](=[O:23])[CH:22]=1)=[C:19]([OH:24])[CH:18]=[C:17]([OH:26])[C:16]=2[C@@H:28]1[CH2:32][CH2:31][N:30]([CH3:33])[C@H:29]1[CH2:34][OH:35]
Reactant: COc1cc(OC)c2c(=O)cc(-c3cccc(N4CCCC4)c3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4cccc(N5CCCC5)c4Cl)oc23)[C@@H]1CO
Temperature: 180 °C

Procedure:
A mixture of compound of example 48 (0.650 g, 1.30 mmol) and pyridine hydrochloride (1.5 g, 12.90 mmol) was heated at 180° C. for a period of 2.5 hours. The reaction mixture was diluted with methanol (60 mL) and basified with solid Na2CO3 to pH 10. The reaction mixture was filtered, and washed with methanol. The organic layer was concentrated and the residue purified by column chromatography using 0.01% ammonia and 4.5% methanol in chloroform as eluent to yield the title compound as a yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:11]=2[CH:29]=1.[Cl:30][C:31]1[CH:32]=[C:33]([SH:38])[CH:34]=[CH:35][C:36]=1[Cl:37]>>[Cl:30][C:31]1[CH:32]=[C:33]([S:38][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[C:11]=3[CH:29]=2)[CH:34]=[CH:35][C:36]=1[Cl:37]
Reactant: O=C1Nc2ccc(OCCCCCl)cc2C(C2CCCCC2)(C2CCCCC2)O1
Reactant: Sc1ccc(Cl)c(Cl)c1
Product: O=C1Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc2C(C2CCCCC2)(C2CCCCC2)O1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dicyclohexyl-4H-3,1-benzoxazin-2-one and 3,4-dichloro-thiophenol.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[N:4]=[N:5][C:6](Cl)=[CH:7][C:8]=1[CH3:9]>C(O)C>[Cl:2][C:3]1[N:4]=[N:5][C:6]([NH2:1])=[CH:7][C:8]=1[CH3:9]
Reactant: N
Reactant: Cc1cc(Cl)nnc1Cl
Solvent: CCO
Product: Cc1cc(N)nnc1Cl
Temperature: 100 °C
Reaction time: 70 h
Yield: 57 %

Procedure:
Ammonia (32% solution in water, 54 mL) was added to a solution of 3,6-dichloro-4-methylpyridazine (5.0 g, 30.67 mmol) in ethanol (25 mL) in a sealed tube. The resulting mixture was stirred at 100° C. for 70 hours, cooled down and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (3:2 hexanes/ethyl acetate to 100% ethyl acetate) to yield the title compound (3.8 g, 57%) as a mixture of two isomers which was used in the next step without further purification.
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21]>>[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:23]([NH:22][CH2:20][CH3:21])=[O:24])#[N:3]
Reactant: N#Cc1c(OC[C@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Reactant: CCN=C=O
Agent: [Cl-]
Product: CCNC(=O)N1CCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N
Yield: 95 %

Procedure:
Prepared as in Example 176b from (R)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example 176c) and ethyl isocyanate in 95% yield as a light yellow solid. MS 319 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:26])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[O:34]1[CH2:39][CH2:38][CH:37]([C:40](Cl)=[O:41])[CH2:36][CH2:35]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:40]([CH:37]4[CH2:38][CH2:39][O:34][CH2:35][CH2:36]4)=[O:41])[CH2:29][CH2:28]3)=[O:26])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCNCC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)C1CCOCC1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCN(C(=O)C3CCOCC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 73, the title compound rac-{(3R,4S)-4-(3,4-dichloro-phenyl)-1-[1-(tetrahydro-pyran-4-carbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using tetrahydro-2H-pyran-4-carbonyl chloride instead of propionyl chloride and was obtained as a white foam. MS m/e: 606.3 [M]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C:10]23[C:16]([CH3:18])([CH3:17])[C:13]([CH3:19])([CH2:14][CH2:15]2)[C:12](=[O:20])[CH2:11]3)[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][N:23]1[CH:27]=[C:26]([CH:28]=O)[CH:25]=[N:24]1.C([O-])(=O)C.[NH4+]>CCO>[Cl:21][C:5]1[C:6]([NH:9][C:10]23[C:16]([CH3:17])([CH3:18])[C:13]([CH3:19])([CH2:14][CH2:15]2)[C:12](=[O:20])[CH2:11]3)=[C:7]2[N:8]=[C:28]([C:26]3[CH:25]=[N:24][N:23]([CH3:22])[CH:27]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CC12CCC(Nc3c(Cl)cnc(N)c3N)(CC1=O)C2(C)C
Reactant: Cn1cc(C=O)cn1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cn1cc(-c2nc3c(NC45CCC(C)(C(=O)C4)C5(C)C)c(Cl)cnc3[nH]2)cn1
Temperature: 70 °C

Procedure:
4-(2,3-diamino-5-chloropyridin-4-ylamino)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (10) (380 mg, 1.23 mmol), 1-methyl-1H-pyrazole-4-carbaldehyde (135 mg, 1.23 mmol) were taken in EtOH (15 ml) to which ammonium acetate (112 mg) was added and the reaction mixture was heated at 70° C. for 48 h. Crude LCMS showed the desired product along with trace of starting material. The reaction mixture was allowed to come to rt and the precipitated was filtered and washed well with ethanol to afford the desired product (478 mg, 25%) as an off white solid. NMR: δ (1H, 400M Hz, DMSO-d6): 0.90 (3H, s), 0.91 (3H, s), 1.09 (3H, s), 1.40-1.80 (3H, m), 2.30-2.60 (1H, m), 3.00-3.10 (1H, m), 3.51-3.70 (1H, m), 3.93 (3H, s), 5.36 (1H, s), 8.00 (1H, s), 8.04 (1H, s), 8.31 (1H, s), 13.09 (1H, s). LCMS (254 nm): [M+H]+ 399.00 (96.43%). HPLC: 254 nm (94.06%)
Reaction SMILES: [CH:1]([CH:4]([CH:8]=[C:9]([Cl:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].[O:17]([C:24]1[N:29]=[C:28]([CH2:30]O)[CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:1]([CH:4]([CH:8]=[C:9]([Cl:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:5]([O:7][CH2:30][C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:29]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)C(C=C(Cl)c1ccccc1)C(=O)O
Reactant: OCc1cccc(Oc2ccccc2)n1
Product: CC(C)C(C=C(Cl)c1ccccc1)C(=O)OCc1cccc(Oc2ccccc2)n1

Procedure:
The acid chloride of 2-isopropyl-4-chloro-4-phenyl-3-butenoic acid is reacted with (6-phenoxy-2-pyridyl)methanol using the procedure of Example 1 to give (6-phenoxy-2-pyridyl)methyl 2-isopropyl-4-chloro-4-phenyl-3-butenoate.
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[I:12]Cl>C(Cl)Cl>[Cl:11][C:2]([Cl:1])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[C:8]([I:12])[CH:9]=1)=[O:4]
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: ClI
Solvent: ClCCl
Product: O=C(c1cc(I)c[nH]1)C(Cl)(Cl)Cl

Procedure:
At r.t. to a solution of 2,2,2-trichloro-1-(1H-pyrrol-2-yl)ethanone (10.0 g, 47.1 mmol) in methylene chloride (80 mL) was added dropwise a solution of iodine monochloride (8.406 g, 51.77 mmol) in methylene chloride (40 mL) with stirring. After completion of addition the mixture was stirred at r.t. for additional 2 h. The mixture was diluted with methylene chloride, quenched with saturated Na2S2O3 solution. After separation the organic solution was washed with water and brine, dried over Na2SO4, filtered, and concentrated to give the crude product which was directly used in the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].C([Li])CCC.CO[C:13](=O)[C@@H:14]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15]1.S(=O)(=O)(O)O>C1COCC1.O>[CH3:1][C:2]1[CH:3]=[C:13]([C@H:14]2[NH:15][C:16](=[O:19])[CH2:17][CH2:18]2)[O:5][N:4]=1
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Reactant: CC(C)=NO
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc([C@@H]2CCC(=O)N2)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a cooled (0°-5° C.) solution of acetone oxime (11.74 g, 160.8 mmol) in THF (200 mL) was slowly added n-butyl lithium (128.6 mL, 2.5M, 321.6 mmol) in hexanes. After being stirred at 0°-5° C. for one hour, a solution of pyroglutamic methyl ester (10.0 g, ~69.9 mmol, the product of step 13a)in THF (50 mL) was added. After stirring for 4 hr, the solution was allowed to slowly warm up to room temperature, and the stirring was continued for 16 hr. Sulfuric acid (35 g, 98%) was slowly added with cooling, followed by the addition of water (35 mL). The resulting mixture was refluxed for one hour. The organic layer was decanted and the slurry was washed with ethyl acetate (5×50 mL). To the mixture was added ethyl acetate (400 mL) and sodium carbonate until basic. Again, the organic layer was decanted and the slurry was washed with ethyl acetate (4×20 mL). The combined organics were then dried over magnesium sulfate. Evaporation of the solvents gave the title product (5.33 g, 46%), which was taken directly to the next step. HPLC (analytical Chiralark AD column) analysis indicated >99.6% ee.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:20])[C@@H:11]([CH3:28])[CH2:10]2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:38](Cl)(=[O:40])[CH3:39]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([C:19](=[O:20])[C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH:11]([CH3:28])[CH2:10]2)[C:38](=[O:40])[CH3:39])=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: C[C@H]1C[C@@H](Nc2ccc(Cl)cc2)c2ccccc2N1C(=O)c1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(c1ccc(Cl)cc1)C1CC(C)N(C(=O)c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
To a solution of (2S,4R)-[4-(4-chloro-phenylamino)-2-methyl-3,4-dihydro-2H-quinolin-1-yl]-(4-fluoro-phenyl)-methanone (250 mg, 0.636 mmol) in acetyl chloride (5 mL) was added diisopropylethylamine (120 uL, 0.70 mmol). The mixture was stirred at rt 4 h. The mixture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with sat. aqueous sodium bicarbonate, brine and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (25/75 hexanes/ethyl acetate gradient) to afford pure N-(4-chloro-phenyl)-N-[1-(4-fluoro-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (200 mg, 71%).
Reaction SMILES: [CH3:1][C:2]([CH3:30])([O:4][C:5]([NH:7][C@H:8]([C:27]([OH:29])=[O:28])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17](=[O:26])[N:18]([CH3:25])[C:19](=[O:24])[N:20]([CH3:23])[C:21]=2[CH3:22])=[CH:12][CH:11]=1)=[O:6])[CH3:3].C(=O)(O)[O-].[Na+].[C:36]([O:39][CH:40](Cl)[CH3:41])(=[O:38])[CH3:37].O>CN(C=O)C>[C:36]([O:39][CH:40]([O:28][C:27](=[O:29])[C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17](=[O:26])[N:18]([CH3:25])[C:19](=[O:24])[N:20]([CH3:23])[C:21]=2[CH3:22])=[CH:12][CH:11]=1)[NH:7][C:5]([O:4][C:2]([CH3:30])([CH3:1])[CH3:3])=[O:6])[CH3:41])(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)Cl
Reactant: Cc1c(-c2ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OC(C)OC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 77 %

Procedure:
To a suspension of N-[(1,1-dimethylethoxy)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine (1.006 mmol, 420 mg) and sodium bicarbonate (5.03 mmol, 422 mg) in DMF (8 mL) was added 1-chloroethyl acetate (5.03 mmol, 616 mg) at room temperature. The reaction mixture was stirred for 48 h. Then, it was poured into water (50 mL) and was extracted with ethyl acetate (3×50 mL). The combined extracts were washed with water (2×50 mL) and brine solution (100 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the filtrate gave the crude product which was purified by silica gel chromatography using a Biotage (40s) column to obtain 390 mg (77% yield) of N-[(1,1-dimethylethoxy)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine 1-(acetoxy)ethyl ester as an amorphous white solid. ES-HRMS m/e calcd for C25H33N3O8 (M+Na) 526.2160, found 526.2143.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-])=O)=[C:6]([NH:8][CH2:9][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])[CH:7]=1.[Cl-].[NH4+]>[Fe].C(O)C>[NH2:16][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[NH:8][CH2:9][CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(C)CNc1cc(Br)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)C(C)CNc1cc(Br)ccc1N
Temperature: 60 °C
Yield: 82.9 %

Procedure:
Iron powder (7 g, 0.12 mol) was added to a mixture of methyl 3-(5-bromo-2-nitrophenylamino)-2-methyl-propanoate (8 g, 25.2 mmol) in the mixed solvents of ammonium chloride aqueous (50 mL) and ethanol (100 mL). Once addition was completed, the mixture was heated to 60° C. for 2 hours. The mixture was filtered. The filtrate was concentrated, diluted with water (100 mL), extracted with ethyl acetate (150 mL×3). The organic layers were separated, combined, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3:1) to afford methyl 3-(2-amino-5-bromophenylamino)-2-methylpropanoate (6 g, 83%).
Reaction SMILES: [NH2:1][C:2]([CH3:15])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]2=[N:7]1)[C:3]#[N:4].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[S:23])=[CH:20][CH:19]=1>>[N:7]1[N:6]([CH2:5][C:2]([NH:1][C:22](=[S:23])[C:21]2[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:27])[F:28])=[CH:26][CH:25]=2)([C:3]#[N:4])[CH3:15])[N:10]=[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=12
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CC(N)(C#N)Cn1nc2ccccc2n1
Product: CC(C#N)(Cn1nc2ccccc2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(2H-benzotriazol-2-yl)-2-methylpropionitrile, described in Example 5, and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (0.12 g, 59%). Rf=0.6 (1:1 EA/heptane). MS (ES): M/Z [M+H]=406. 1H NMR: (400 MHz, DMSO-d6): 1.75 (s, 3H), 5.39-5.50 (m, 2H), 7.46 (dd, J=6.6, 3.1 Hz, 2H), 7.85-7.95 (m, 6H) and 9.01 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:5][NH:6][C:7](=[O:15])OC1C=CC=CC=1.[C:20]([NH2:29])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:22])[CH3:21].C(N(CC)CC)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:5][NH:6][C:7]([NH:29][C:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:22])[CH3:21])=[O:15]
Reactant: O=C(NOc1cc(Cl)cc(Br)c1)Oc1ccccc1
Reactant: CC(C)(N)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(NC(=O)NOc1cc(Cl)cc(Br)c1)c1ccccc1
Reaction time: 5 h
Yield: 86 %

Procedure:
3.00 g of phenyl 3-bromo-5-chlorophenoxycarbamate was dissolved in 50 ml of tetrahydrofuran. The resulting solution was added to a mixture of 1.54 g of cumylamine and 1.15 g of triethylamine, followed by stirring for 5 hours, while being heated to reflux. The reaction solvent was then distilled off under reduced pressure. The resulting residue was partially purified by silica gel column chromatography (eluent: hexane:ethyl acetate=3:1). The resulting crude crystal was washed with hexane to obtain 1-(3-Bromo-5-chlorophenoxy)-3-(2-phenylpropan-2-yl)urea (2.89 g, yield: 86%).