Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([S:20](Cl)(=[O:22])=[O:21])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([NH2:39])[CH:34]=1>C(Cl)Cl>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([NH:39][S:20]([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:11][CH:12]=2)(=[O:22])=[O:21])[CH:36]=[CH:37][CH:38]=1
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)c2ccccc12)c1ccccc1
Reactant: COc1cccc(N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3)c3ccccc23)c1
Yield: 47.2 %

Procedure:
To a solution of 4-benzoylamino-naphthalene-1-sulfonyl chloride (320 mg, 0.93 mmol) in CH2Cl2 (20 mL) was added triethylamine (0.26 mL, 1.85 mmol) and m-anisidine (137 mg, 1.11 mmol). The resultant solution was stirred at 25° C. overnight. The reaction mixture was quenched with water and extracted with CH2Cl2. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered and concentrated to provide the crude product as yellow viscous oil. HPLC purification of the residue gave the title compound (190 mg) as a pale white solid. 1H NMR (300 MHz, DMSO) δ 8.72 (d, 1H), 8.26 (d, 1H), 8.15 (d, 1H), 8.02 (d, 2H), 7.78 (d, 1H), 7.60 (m, 5H), 7.00 (t, 1H), 6.55 (m, 2H), 6.46 (d, 1H), 3.56 (s, 3H); LC/MS m/z 433 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[C:40]([CH3:41])=[CH:39][CH:38]=[CH:37][C:14]=1[CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:34]=[CH:35][CH:36]=1)[O:20][CH2:21][C:22]1[N:31]([CH3:32])[C:30](=[O:33])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.C(N(CC)CC)C>ClCCl>[CH3:41][C:40]1[CH:39]=[CH:38][CH:37]=[C:14]([CH2:15][O:16][C:17]2[CH:36]=[CH:35][CH:34]=[C:19]([O:20][CH2:21][C:22]3[N:31]([CH3:32])[C:30](=[O:33])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=3)[CH:18]=2)[C:13]=1[CH:12]=[O:11]
Reactant: Cc1cccc(COc2cccc(OCc3nc4ccccc4c(=O)n3C)c2)c1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(COc2cccc(OCc3nc4ccccc4c(=O)n3C)c2)c1C=O
Reaction time: 0.08 h

Procedure:
To a cooled (−78° C.) solution of oxalyl chloride (2.5 mL, 1.75 M in CH2Cl2) is added, dropwise, DMSO (80 mL). On complete addition, a solution of 2-[3-(2-hydroxymethyl-3-methyl-1 benzyloxy)-phenoxymethyl]-3-methyl-3H-quinazolin-4-one (120 mg, 0.28 mmol, example 101) in dichloromethane (1 mL) is added dropwise. This solution is stirred for 5 min then triethylamine (276 mL, 2 mmol) is added in one portion. The cold bath is removed and stirring continued for 10 min. The mixture is then diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated to give the title compound as a solid. MS (ESI) 415 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[O:4][C:5]([C:8]([OH:10])=O)=[CH:6][N:7]=1.Cl.[NH2:12][C@H:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=2)=[CH:23][CH:22]=1)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[Cl:33][C:29]1[CH:28]=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([CH2:20][C@@H:13]([NH:12][C:8]([C:5]3[O:4][C:3]([O:2][CH3:1])=[N:7][CH:6]=3)=[O:10])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:22][CH:23]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: COc1ncc(C(=O)O)o1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cnc(OC)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methoxyoxazole-5-carboxylic acid, intermediate 16, (98 mg, 0.69 mmol) and (R)-ethyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride (210 mg, 0.57 mmol) in DMF (10 mL) and CH2Cl2 (4 mL) is added HATU (272 mg, 0.72 mmol) and TEA (0.50 mL, 3.58 mmol). The crude is stirred at room temperature for 2 hrs. The crude is quenched with water and diluted in EtOAc. The organic layer is washed with water 3×, brine, dried over MgSO4, filtered, and concentrated. The crude is purified via flash chromatography using 30% EtOAc/heptane to 70% EtOAc/heptane to give (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(2-methoxyoxazole-5-carboxamido)butanoate (122 mg). HPLC retention time=1.89 minutes (condition A); MS (m+1)=443.2; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J=7.1 Hz, 3H), 2.52-2.66 (m, 2H), 2.94 (dd, 1H), 3.08 (dd, J=13.6, 6.3 Hz, 1H), 4.12 (s, 3H), 4.14-4.23 (m, 2H), 4.60-4.71 (m, 1H), 6.81 (d, J=8.8 Hz, 1H), 7.25-7.32 (m, 3H), 7.35 (t, J=7.7 Hz, 1H), 7.42 (s, 1H), 7.43-7.47 (m, 1H), 7.48-7.54 (m, 2H), 7.55 (t, J=1.6 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:12]([OH:15])([CH3:14])[CH3:13])[N:8]2[CH3:11])=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[CH:32][C:33]([NH2:36])=[N:34][CH:35]=2)O1>>[NH2:36][C:33]1[N:34]=[CH:35][C:30]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([C:12]([OH:15])([CH3:14])[CH3:13])[N:8]3[CH3:11])=[C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:3]=2)=[CH:31][CH:32]=1
Reactant: Cn1c(C(C)(C)O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cn1c(C(C)(C)O)nc2c(N3CCOCC3)nc(-c3ccc(N)nc3)nc21

Procedure:
2-(2-Chloro-9-methyl-6-morpholino-9H-purin-8-yl)propan-2-ol (95 mg) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine via Procedure A and purified via reverse phase HPLC to give 89.3 mg of 131 as a white solid. MS (Q1) 370.3 (M)+
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C@H:6]([N:8]([C:13]([C:15]2[C:16]([NH:25][CH2:26][CH2:27][CH2:28][S:29][CH3:30])=[N:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[N:19][CH:20]=2)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][N:4]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:3]1.Cl[CH2:39][CH2:40][N:41]=[C:42]=[O:43].CC(C)([O-])C.[K+]>C1COCC1.O>[C:21]([C:18]1[N:17]=[C:16]([NH:25][CH2:26][CH2:27][CH2:28][S:29][CH3:30])[C:15]([C:13]([N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C@H:6]2[CH2:7][C@@H:2]([N:1]3[CH2:39][CH2:40][NH:41][C:42]3=[O:43])[CH2:3][N:4]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:5]2)=[O:14])=[CH:20][N:19]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C=NCCCl
Reactant: CSCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](N)CN(C(=O)OC(C)(C)C)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CSCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](N2CCNC2=O)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl (3R,5S)-3-amino-5-{[(2-tert-butyl-4-{[3-(methylsulfanyl)propyl]amino}pyrimidin-5-yl)carbonyl](2-methylpropyl)amino}piperidine-1-carboxylate (124 mg) was dissolved in THF (4 ml), chloroethyl isocyanate (24 μl) was added, and the mixture was stirred at room temperature for 1 hr. Potassium tert-butoxide (40 mg) was added and the reaction mixture was stirred at room temperature for 7 hr and further at 60° C. for 5 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate-hexane (10:90-100:0) and concentrated under reduced pressure to give the object compound (70.3 mg).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:12][CH2:13][C:14](OCC)=[O:15])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO.O>[C:1]1([C:7]2[N:8]=[C:9]([CH2:12][CH2:13][CH2:14][OH:15])[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCc1nc(-c2ccccc2)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCCCc1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
A solution of ethyl 3-(4-phenylthiazol-2-yl)propanoate (0.5 g, 1.91 mmol) in MeOH—H2O (10 mL, 9:1 v/v) was cooled to 0° C. and sodium borohydride (0.29 g, 7.65 mmol) was added. The reaction mixture was warmed to room temperature and further stirred for 8 h. The mixture was quenched with ice water and the organic product was extracted with EtOAc. The combined extracts were washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford 3-(4-phenylthiazol-2-yl)propan-1-ol (0.4 g, yield 95%) as colorless liquid, which was carried through without further purification. 1H NMR (400 MHz, CDCl3) δ 7.87-7.85 (m, 2H), 7.44-7.40 (m, 2H), 7.35-7.32 (m, 2H), 3.83-3.81 (t, J=5.8 Hz, 2H), 3.24-3.21 (m, 3H), 2.14-2.08 (m, 2H). MS (ESI) m/z: Calculated for C12H13NOS: 219.07. found: 220.2 (M+H)+.
Reaction SMILES: Br[CH:2]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=1)[CH:3](OCC)OCC.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25]([NH2:27])=[S:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCO.O>[CH3:17][S:16][C:12]1[N:11]=[C:10]([C:2]2[S:26][C:25]([NH:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)=[N:27][CH:3]=2)[CH:15]=[CH:14][N:13]=1
Reactant: CCOC(OCC)C(Br)c1ccnc(SC)n1
Reactant: NC(=S)Nc1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CSc1nccc(-c2cnc(Nc3ccccn3)s2)n1

Procedure:
4-(1-Bromo-2,2-diethoxy-ethyl)-2-methylsulfanyl-pyrimidine (18-3, 0.050 g, 0.156 mmol) and 2-pyridylthiourea (0.024 g, 0.16 mmol) were stirred in 1 mL EtOH and 0.10 mL water. p-Toluenesulfonic acid monohydrate (5 mg, 0.03 mmol) was added and the reaction was heated to reflux. After 8 h an addional 30 mg (0.156 mmol) p-toluenesulfonic acid monohydrate and the reaction was refluxed an additional 16 h. The reaction was concentrated and purified by flash column chromatography (elute with a gradient: 3-6% MeOH in DCM). 1H NMR (DMSO-d6) δ 11.75 (s, 1H), 8.50 (d, 1H, J=5.4 Hz), 8.49 (m, 2H), 7.77 (t, 1H, J=6.7 Hz), 7.60 d, 1H, J=5.5 Hz), 7.13 (d, 1H, 8.2 Hz), 7.02 (t, 1H, J=6.6 Hz), 2.55 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([CH3:14])[N:11]([CH3:15])[N:10]=2)=[CH:5][C:4]=1[CH3:16].[Br:17]N1C(=O)CCC1=O.C(Cl)(Cl)Cl>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([Br:17])=[C:12]([CH3:14])[N:11]([CH3:15])[N:10]=2)=[CH:5][C:4]=1[CH3:16]
Reactant: COc1ccc(-c2cc(C)n(C)n2)cc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc(-c2nn(C)c(C)c2Br)cc1C
Yield: 49.7 %

Procedure:
At room temperature, a mixture of 3-(4-methoxy-3-methyl-phenyl)-1,5-dimethyl-1H-pyrazole (described in Reference Preparation example 43) 5.9 g, N-bromosuccinimide 5.8 g and chloroform 100 ml was stirred for seventeen hours. To the reaction mixture was added water and the resulting mixture was extracted with chloroform. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 3-(4-methoxy-3-methyl-phenyl)-4-bromo-1,5-dimethyl-1H-pyrazole 4.0 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:12][O:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[CH2:21][CH:22]([F:24])[F:23])(=O)=O>>[C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]1[CH2:12][O:11][N:10]([CH2:21][CH:22]([F:24])[F:23])[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CONC1=O
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)N[C@@H]1CON(CC(F)F)C1=O
Yield: 34.9 %

Procedure:
As described in Example 4, Step A, (3-oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester (0.30 g) was alkylated with 2,2-difluoroethyl trifluoromethanesulfonate (0.35 g). to afford the title product as a white solid (138 mg); 1H-NMR (CDCl3, 400 MHz): 6.05 (tt, 1H), 5.10 (m, 1H), 4.90 (m, 1H), 4.35 (dt, 2H), 4.20 (dd, 1H), 1.50 (s, 9H); along with the O-alkylated product (179 mg): 1H-NMR (CDCl3, 400 MHz): 5.95 (tt, 1H), 4.80 (m, 1H), 4.60 (m, 1H), 3.80-4.10 (m, 3H), 1.50 (s, 9H).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]([N:6]=[C:7]([N:10]([CH3:19])[N:11]=CC1C=CC=CC=1)SC)=O.[N:20]1([CH2:26][C:27]2[CH:37]=[CH:36][C:30]([O:31][CH2:32][CH2:33][CH2:34][NH2:35])=[CH:29][CH:28]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1.Cl>[CH3:19][N:10]1[C:7]([NH:35][CH2:34][CH2:33][CH2:32][O:31][C:30]2[CH:36]=[CH:37][C:27]([CH2:26][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:28][CH:29]=2)=[N:6][C:4]([CH2:3][S:2][CH3:1])=[N:11]1
Reactant: CSCC(=O)N=C(SC)N(C)N=Cc1ccccc1
Reactant: NCCCOc1ccc(CN2CCCCC2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CSCc1nc(NCCCOc2ccc(CN3CCCCC3)cc2)n(C)n1
Yield: 73.7 %

Procedure:
Methyl N-[2-(methylthio)acetyl]-1-methyl-2-(phenylmethylene)hydrazine carboximidothioate (1.2 g) and 3-[4-(1-piperidinylmethyl)phenoxy]propanamine (0.9 g) were heated at 55° under water vacuum for 2 h. Additional carboximidothioate (0.09 g) was then added and the mixture heated for a further 1 h. The reaction mixture was dissolved in toluene (5 ml) and 5N hydrochloric acid (4 ml), stirred at room temperature for 18 h and the phases separated. The aqueous phase was basified to pH 10 with sodium carbonate and extracted with ethyl acetate to give an oil, which was chromatographed using ethyl acetate-methanol (3:1) to give the title compound (1.04 g) as an orange brown oil.
Reaction SMILES: [H-].[Na+].[C:3](Cl)(=[O:5])[CH3:4].[F:7][C:8]1[CH:29]=[CH:28][C:11]([NH:12][C:13]2[CH:14]=[C:15]([CH:24]=[CH:25][C:26]=2[CH3:27])[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[CH:10][CH:9]=1.Cl>C(OCC)(=O)C.CN(C)C=O>[C:16]([C:15]1[CH:24]=[CH:25][C:26]([CH3:27])=[C:13]([N:12]([C:11]2[CH:10]=[CH:9][C:8]([F:7])=[CH:29][CH:28]=2)[C:3](=[O:5])[CH3:4])[CH:14]=1)(=[O:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1Nc1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N(c1ccc(F)cc1)c1cc(C(=O)c2ccccc2)ccc1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
60% sodium hydride 79 mg and acetyl chloride 0.14 mL were added to N,N-dimethylformamide 5.0 mL solution of 3-(4-fluoroanilino)-4-methylbenzophenone 0.50 g under ice cooling sequentially, and it was stirred at room temperature for 4 hours. After the reaction mixture was cooled to ice temperature,60% sodium hydride 79 mg and acetyl chloride 0.14 mL were added sequentially, and it was stirred at room temperature for 5 hours and 30 minutes. Ethyl acetate and 1.0 mol/L hydrochloric acid were added to the reaction mixture. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after sequential washing with 1.0 mol/L hydrochloric acid and saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=2:1] to give N-(5-benzoyl-2-methylphenyl)-N-(4-fluorophenyl)acetamide 82 mg of orange oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:5])[CH3:2].[O:20]=[S:21]1(=[O:35])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[NH:24][C:23]([CH2:31][C:32](O)=[O:33])=[N:22]1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[N:11]([C:32](=[O:33])[CH2:31][C:23]1[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:21](=[O:20])(=[O:35])[N:22]=1)[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)=[O:5])[CH3:2]
Reactant: O=C(O)CC1=NS(=O)(=O)c2ccccc2N1
Reactant: CCOC(=O)C1CCCC1NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)C1CCCC1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2ccccc2N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(4-Fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (prepared as described in Example 11, 133.5 mg, 0.503 mmol) was mixed with (1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (132.9 mg, 0.554 mmol) in N,N-dimethylformamide (4.6 mL). N-methylmorpholine (122 μL, 1.11 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (106.2 mg, 0.554 mmol). The reaction mixture was shaken at 25° C. for 16 h. A 1.0 M aqueous hydrochloric acid solution (4.6 mL) was added at 25° C., and the aqueous layer was extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with saturated aqueous brine solution (10 mL). The organic layer was dried over sodium sulfate, filtered, concentrated and dried in vacuo to afford the crude product, 2-[[2-(1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(4-fluoro-benzyl)-amino]-cyclopentanecarboxylic acid ethyl ester, as a pale yellow oil, which was directly used in the next step without further purification. LC-MS (ESI) calcd for C24H26FN3O5S 487.16, found 488.3 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]1[CH2:14][N:15]([C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.[Cl:42][C:43]1[CH:44]=[C:45]([CH:50]=[CH:51][C:52]=1[NH:53][C:54](OC1C=CC([N+]([O-])=O)=CC=1)=[O:55])[C:46]([O:48][CH3:49])=[O:47]>C1COCC1>[C:18]([O:17][C:16]([N:15]([CH2:14][CH:9]1[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:13][CH2:12][N:11]([C:54]([NH:53][C:52]2[CH:51]=[CH:50][C:45]([C:46]([O:48][CH3:49])=[O:47])=[CH:44][C:43]=2[Cl:42])=[O:55])[CH2:10]1)[C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1ccccc1F)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)N2CCC(c3ccccc3F)C(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.5 %

Procedure:
To a mixture of 191 mg of tert-butyl {[4-(2-fluorophenyl)piperidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate, 0.115 mL of triethylamine, and 3.0 mL of THF was added 175 mg of methyl 3-chloro-4-{[(4-nitrophenoxy)carbonyl]amino}benzoate at room temperature. After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 330 mg of methyl 4-({[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-(2-fluorophenyl)piperidin-1-yl]carbonyl}amino)-3-chlorobenzoate as a crude product. ESI+: 674
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].[CH:7]([N:10]1[CH:14]=[CH:13][C:12](O)=[N:11]1)([CH3:9])[CH3:8].CC(C)=[O:18]>C(N(CC)CC)C>[CH2:1]([NH:4][C:5](=[O:18])[O:6][C:13]1[CH:12]=[N:11][N:10]([CH:7]([CH3:9])[CH3:8])[CH:14]=1)[CH2:2][CH3:3]
Reactant: CC(C)n1ccc(O)n1
Reactant: CC(C)=O
Reactant: CCCN=C=O
Solvent: CCN(CC)CC
Product: CCCNC(=O)Oc1cnn(C(C)C)c1
Temperature: 40 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
8.5 g (0.1 mol) of n-propyl isocyanate were added dropwise to a solution of 12.6 g (0.1 mol) of 1-isopropylhydroxy-pyrazole and 3 drops of triethylamine in 50 ml of acetone. The reaction mixture was then further stirred for 4 hours at 40° C. and the solvent was distilled off in vacuo. 20 g (95% of theory) of 1-isopropyl-pyrazol-4-yl N-n-propylcarbamate were obtained as a brown oil with a refractive index of nD22 =1.4885.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[CH:12]=[CH:13][C:14]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:15]([CH:35]=1)[C:16]([NH:18][C:19]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22])=[O:17])(=O)C.CC(C)=O>C(Cl)(Cl)Cl.CO>[CH2:37]([O:36][C:14]1[CH:13]=[CH:12][C:11]([OH:10])=[CH:35][C:15]=1[C:16]([NH:18][C:19]1[CH:28]=[C:27]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22])=[O:17])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OC(C)=O)ccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
Potassium carbonate (1.6 g) was added to a solution mixture of methyl 2-(5-acetoxy-2-(benzyloxy)benzamido)-4-phenylbenzoate (3.8 g) in chloroform (5.0 mL), methanol (10 mL), and acetone (10 mL), followed by stirring at room temperature for 1 hour. The insoluble substance was removed by filtration, and then the solvent was evaporated under reduced pressure, and 1.0 mol/L hydrochloric acid and chloroform were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 3.4 g of methyl 2-(2-(benzyloxy)-5-hydroxybenzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:13][SH:14])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(N(CC)CC)C.[CH2:23](Br)[CH:24]=[CH2:25].CCOC(C)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C@@H:4]([NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])[CH2:13][S:14][CH2:25][CH:24]=[CH2:23]
Reactant: COC(=O)[C@H](CS)NC(=O)OC(C)(C)C
Reactant: C=CCBr
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCSC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C

Procedure:
N-BOC-cysteine methyl ester (obtained from Sigma-Aldrich, Auckland, New Zealand) (5.00 g, 21.2 mmol) was dissolved in anhydrous DCM (30 mL) under an atmosphere of argon. Triethylamine (3.26 mL, 23.3 mmol) and allyl bromide (2.02 mL, 23.3 mmol) were added. The reaction mixture was stirred at rt for eighteen h before being concentrated in vacuo. The residue was partitioned between EtOAc and 1M hydrochloric acid. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica using a gradient of EtOAc and (50/70) petroleum ether to yield a white solid, 3.22 g, 55%. Rf=0.19 (1/5 (EtOAc/(50/70) petroleum ether).