Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([O:23][CH2:24][C:25]2[C:30]([F:31])=[CH:29][C:28]([Br:32])=[CH:27][C:26]=2[F:33])=[N:7][S:8][C:9]=1[NH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:12])=O.[NH3:34]>CO.O1CCCC1>[Br:32][C:28]1[CH:29]=[C:30]([F:31])[C:25]([CH2:24][O:23][C:6]2[C:5]([C:3]([NH2:34])=[O:2])=[C:9]([NH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:12])[S:8][N:7]=2)=[C:26]([F:33])[CH:27]=1
Reactant: N
Reactant: COC(=O)c1c(OCc2c(F)cc(Br)cc2F)nsc1NC(=O)NCCCCN1CCCC1
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1c(OCc2c(F)cc(Br)cc2F)nsc1NC(=O)NCCCCN1CCCC1
Temperature: 0 °C
Yield: 76 %

Procedure:
In a 1 Liter autoclave 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid methyl ester (1.00 equiv, 27.0 g) was slurried in methanol (270 mL, 10 volumes) and tetrahydrofuran (270 mL, 10 volumes). The mixture was cooled to 0° C. and stirred at 600 rpm. Anhydrous ammonia gas was charged carefully, keeping the temperature below 10° C. Once a steady pressure of around 10 psi was maintained, the mixture was heated to 40° C. The pressure increased to about 45 psi. The pressure was adjusted to 50 psi and stirred at 600 rpm and 40° C. for 90 hours. The stir rate was then adjusted to 1000 rpm and stirred for an additional 24 hours. The ammonia was removed by vacuum, and the mixture was cooled to 20° C. and transferred out of the reactor. The mixture was filtered to remove insoluble solids (non-product related). The filtrate was diluted with 2-propanol (270 mL, 10 volumes), and the tetrahydrofuran and methanol were distilled atmospherically. Additional 2-propanol (135 mL, 5 volumes) were added, then the mixture was distilled to approximately 250 mL total volume. The slurry was cooled to 20° C. and stirred 18 hours. The solids were filtered and then dried under vacuum to give 19.9 grams of 3-(4-Bromo-2,6-difluoro-benzyloxy)-5-[3-(4-pyrrolidin-1-yl-butyl)-ureido]-isothiazole-4-carboxylic acid amide (76% yield). 1H NMR (DMSO-d6): δ 10.98 (s, 1H); 8.18 (m, 1H); 7.55 (m, 3H); 6.80 (s, 1H); 5.41 (s, 2H); 3.08 (m, 2H); 2.47 (m, 6H); 1.62 (m, 4H); 1.42 (m, 4H). MS (API-ES pos) 532/534 (M+H)+, base.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][C:8]=1[C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C1CCC(=O)O1
Reactant: c1ccc2ccccc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)CCC(=O)c1ccc2ccccc2c1
Yield: 59.3 %

Procedure:
To 900 ml of dichloromethane contained in a 3 liter, 3-neck flask equipped with a mechanical stirrer, drying tube and thermometer and surrounded by an ice water bath was added 290.0 g (2.26 moles) naphthalene. To the stirred suspension was added 145.2 g (1.44 moles) of succinic anhydride. A total of 400 g of aluminum chloride was then added in small increments over the next 41/2 hours while stirring and cooling in an ice water bath. The resulting amber brown-yellow reaction mixture was stirred at room temperature overnight. Next morning it was poured on crushed ice and acidified with conc. hydrochloric acid. The aqueous portion was decanted and the organic layer was filtered to collect white solids. The solids were washed with dichloromethane containing 20% hexanes and slurried in 700 ml of boiling ethyl acetate. After cooling in a cold water bath, the solids were collected by filtration and washed with fresh ethyl acetate. Then the solids were recrystallized from 500 ml of glacial acetic acid and dried under vacuum to give 195.0 g (59.4% yield) of 4-(2naphthyl)-4-oxobutyric acid as an off-white solid. M.P. 171°-175° C.; M/e 229; λmax 282 nm (7,260) in ethanol.
Reaction SMILES: [NH:1]=[C:2]([NH:4][NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[CH3:3]>O>[CH3:3][C:2]1[NH:1][C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N+:13]([O-:15])=[O:14])=[N:5][N:4]=1
Reactant: CC(=N)NNC(=O)c1ccccc1[N+](=O)[O-]
Solvent: O
Product: Cc1nnc(-c2ccccc2[N+](=O)[O-])[nH]1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
A suspension of 2-nitro-benzoic acid N′-(1-imino-ethyl)-hydrazide (4.3 g) in xylenes (50 mL) was refluxed in a flask fitted with a Dean-Stark trap. After 45 minutes of heating, the reaction suspension became a solution with a rapid condensation of water in the trap. The solution was cooled to −5° C. and stirred for 30 minute. The precipitated product was collected by filtration, washed with ice cold xylene twice, and dried in vacuo to provide 3.6 g of 3-methyl-5-(2-nitro-phenyl)-4H-[1,2,4]triazole: 1H NMR (300 MHz, CDCl3) δ 7.9-7.5 (m, 4H), 2.5 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1Br.[CH3:17][C:18]1([CH3:27])[CH2:23][CH2:22][C:21](B(O)O)=[CH:20][CH2:19]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:21]1[CH2:22][CH2:23][C:18]([CH3:27])([CH3:17])[CH2:19][CH:20]=1
Reactant: CC1(C)CC=C(B(O)O)CC1
Reactant: N#CC1(c2ccc(N)c(Br)c2)CCCCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC1(C)CC=C(c2cc(C3(C#N)CCCCC3)ccc2N)CC1
Temperature: 80 °C
Yield: 30 %

Procedure:
A solution of 1-(4-amino-3-bromo-phenyl)-cyclohexane carbonitrile (136 mg, 0.487 mmol, as prepared in the previous step) in DMF (10 mL) was treated with 4,4-dimethyl-cyclohex-1-enylboronic acid (90.0 mg, 0.585 mmol) and Na2CO3 (1.95 mL, 3.90 mmol, 2 M aq). The mixture was degassed via sonication, placed under Ar, treated with Pd(dppf)Cl2 (35.6 mg, 0.0487 mmol), and heated to 80° C. overnight. The cooled mixture was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers was dried over MgSO4 and concentrated in vacuo. Silica gel chromatography of the residue on a 20-g Isolute SPE column with 10-15% EtOAc-hexane afforded the title compound (45.9 mg, 30%) as a colorless glassy solid. Mass spectrum (ESI, m/z): Calcd. for C21H28N2, 309.2 (M+H). found 309.2.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([C:19]2[N:28]=[C:27](Cl)[C:26]3[C:21](=[CH:22][C:23]([O:32][CH3:33])=[CH:24][C:25]=3[O:30][CH3:31])[N:20]=2)=[CH:14][C:13]=1[CH3:34])C1C=CC=CC=1.CO.C([O-])=O.[NH4+]>C1COCC1.[Pd]>[CH3:31][O:30][C:25]1[CH:24]=[C:23]([O:32][CH3:33])[CH:22]=[C:21]2[C:26]=1[CH:27]=[N:28][C:19]([C:15]1[CH:16]=[C:17]([CH3:18])[C:12]([O:11][CH2:10][CH2:9][OH:8])=[C:13]([CH3:34])[CH:14]=1)=[N:20]2
Reactant: COc1cc(OC)c2c(Cl)nc(-c3cc(C)c(OCCOCc4ccccc4)c(C)c3)nc2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(OC)c2cnc(-c3cc(C)c(OCCO)c(C)c3)nc2c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 25.4 %

Procedure:
To a 100 mL round bottom flask was added 2-amino-4,6-dimethoxy-benzamide (318 mg, 1.6 mmol), 4-(2-benzyloxy-ethoxy)-3,5-dimethyl-benzaldehyde (461 mg, 1.6 mmol), p-toluenesulfonic acid monohydrate (32 mg, 0.16 mmol), sodium hydrogensulfite (318 mg, 1.8 mmol) and dimethylacetamide (5 mL). The mixture was stirred in a 150° C. oil bath under nitrogen overnight. Water (40 mL) and ether (30 mL) were added. The precipitate was filtered off, washed with water then ether, and air-dried. The intermediate 2-[4-(2-benzyloxyethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one was obtained as light brown/beige solid. Yield 474 mg (64%). 2-[4-(2-Benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (474 mg, 1.03 mmol) was stirred in phosphorus oxychloride (10 mL) at 100° C. for 4 h. Excess phosphorus oxychloride was removed under reduced pressure. Ice was added and the solid was collected. The solid was washed with water and ether, and air-dried. 2-[4-(2-benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-4-chloro-5,7-dimethoxy-quinazoline was obtained as a light brown solid (yield: 356 mg, 72%). 2-[4-(2-Benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-4-chloro-5,7-dimethoxy-quinazoline (192 mg, 0.4 mmol) was dissolved in a small amount of THF and 10% Pd/C (dry) (66 mg) was added. Anhydrous methanol (20 mL) and ammonium formate (955 mg) were added. The mixture was stirred in a 80° C. oil bath for 5 h. The mixture was filtered through Celite, washed with MeOH/DCM, purified by column chromatography to give 2-(4-(5,7-dimethoxyquinazolin-2-yl)-2,6-dimethylphenoxy)ethanol (36 mg, 25%) as an off-white solid. Selected data: MS (ES) m/z: 355.04; mp 169-170° C.
Reaction SMILES: C(OC1C=CC([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=2)=CC=1)(=O)CCCCCCCC.[CH2:27]([C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][C:44]([C:47]([OH:49])=[O:48])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[CH2:27]([C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][C:44]([C:47]([O:49][C:18]3[CH:19]=[CH:20][C:21]([C:24]([O:26][CH:35]([CH3:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:25])=[CH:22][CH:23]=3)=[O:48])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: CCCCCCCCC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Product: CCCCCCCCc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)OC(C)CCCCCC)cc3)cc2)cc1

Procedure:
The titled optically active compound was synthesized in the same manner as in Example 1, except for replacing 4'-nonanoyloxybiphenyl-4-carboxylic acid as used in Example 1-(3) with 4'-octylbiphenyl-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[OH:9][C:10]1[CH:11]=[N:12][CH:13]=[N:14][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Oc1cncnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Brc1ccc(Oc2cncnc2)nc1

Procedure:
Educts: 2,5-dibromo-pyridine/5-hydroxypyrimidine using cesium carbonate as base and DMA as solvent
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[C:10]1(B2OC(C)(C)C(C)(C)O2)[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:9][C:5]1[CH:6]=[C:7]([NH2:8])[C:2]([C:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=2)=[N:3][CH:4]=1
Reactant: Nc1cc(Br)cnc1Br
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Nc1cc(Br)cnc1C1=CCCCC1
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
A stirred mixture of 2,5-dibromopyridin-3-amine (0.2135 g, 0.848 mmol), 1-cyclohexen-1-yl-boronic acid pinacol ester (0.30 mL, 1.40 mmol), tetrakis(triphenylphosphine)palladium (0.098 g, 0.084 mmol), and 2.0M sodium carbonate (2.0 mL, 4.00 mmol) in toluene (1.5 mL) and ethanol (0.5 mL) was heated to 90° C. After 2.5 h, the reaction was cooled to rt then diluted with water. After extraction with EtOAc, the organic extraction was dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified on silica gel (0-35% EtOAc in hexanes) to afford a white solid as 5-bromo-2-cyclohexenylpyridin-3-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.01 (1H, d, J=2.0 Hz), 7.10 (1H, d, J=2.3 Hz), 6.00 (1H, tt, J=3.7, 2.0 Hz), 3.96 (2H, br. s.), 2.45 (2H, m), 2.26 (2H, m), 1.87 (4H, m). 2,5-Dicyclohexenylpyridin-3-amine was also isolated. 1H NMR (400 MHz, CDCl3) δ ppm 8.07 (1H, d, J=2.0 Hz), 6.95 (1H, d, J=2.0 Hz), 6.16 (1H, m), 6.05 (1H, m), 3.81 (2H, br. s.), 2.48 (4H, m), 2.27 (4H, m), 1.87 (8H, m).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.S(Cl)([Cl:16])(=O)=O>>[Cl:16][C:6]1[CH:5]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: O=S(=O)(Cl)Cl
Product: Oc1ccc(OC(F)(F)F)cc1Cl
Yield: 94.1 %

Procedure:
A solution of 4-trifluoromethoxyphenol (20 g, 0.11 mole) and sulfuryl chloride (18.20 mL, 0.22 mole) was stirred at room temperature for five hours. The excess of sulfuryl chloride was evaporated by rotary evaporator. The residue was dissolved in 50 mL of dichloromethane and washed with 50 mL of H2O. The organic layer was separated, dried over MgSO4, filtered and concentrated to yield 22 g of the product. The crude product was purified over a silica gel column using 10% ethyl acetate in hexane to yield 16.4 g of the product. 1H-NMR (DMSO, 500-MHz), δ 10.59 (s, 1H), 7.43 (d, J=2.75 Hz, 1H), 7.18 (dd, J1=2.75 Hz, J2=7.16 Hz, 1H), 7.03 (d, J=7.16 Hz, 1H). MS (electro-spray) [M−H] 211.4.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][NH:22][O:23][CH3:24].N1C=CC=CC=1.CCN=C=NCCCN(C)C.Cl>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[C:18]([N:22]([O:23][CH3:24])[CH3:21])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1n[nH]c2ccc(OCc3ccccc3)cc12
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)c1n[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
The title compound was prepared in a similar manner as described by F. Crestey et al., Tetrahedron 2007, 63, 419-428. To 5-(benzyloxy)-1H-indazole-3-carboxylic acid [177941-16-1](3.50 g, 13.1 mmol) in THF (70 mL) was added N,O-dimethylhydroxylamine (1.40 g, 14.4 mmol). The mixture was cooled to 0° C. before the addition of pyridine (2.30 mL, 28.7 mmol). The solution was stirred at 0° C. for 1.5 h, and then at RT for 1 h. Pyridine (2.10 mL, 26.1 mmol) and EDCl (5.00 g, 26.1 mmol) were added and the mixture was stirred at RT overnight. Water was added to the reaction mixture followed by extraction (×3) with CH2Cl2. The combined organics were washed with saturated aqueous NaHCO3 solution, dried (Phase separator) and concentrated to give the title compound. MS (LC/MS): 312.0 [M+H]+, 334.0 [M+Na]+, 645.1 [2M+Na]+, 310.0 [M−H]−; tR (HPLC conditions e): 4.44 min.
Reaction SMILES: C([O:5][C:6](=[O:45])[C:7]([O:10]/[N:11]=[C:12](/[C:32]1[N:33]=[C:34]([NH:37]C(OC(C)(C)C)=O)[S:35][CH:36]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[C:30]([CH3:31])=[N:29][N:28]=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:37][C:34]1[S:35][CH:36]=[C:32](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:45])=[O:5])/[C:13]([NH:15][C@@H:16]2[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:22])=[O:23])[C@@H:17]2[CH2:25][N:26]2[C:30]([CH3:31])=[N:29][N:28]=[N:27]2)=[O:14])[N:33]=1
Reactant: Cc1nnnn1C[C@@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c2csc(NC(=O)OC(C)(C)C)n2)C(=O)N1S(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nnnn1C[C@@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c2csc(N)n2)C(=O)N1S(=O)(=O)O
Yield: 12.4 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((5-methyl-1H-tetrazol-1-yl)methyl)-4-oxoazetidine-1-sulfonic acid (151 mg, 0.224 mmol), DCM (2.24 mL) and TFA (1.04 mL, 13.45 mmol) for 2 h. The crude residue purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (14.4 mg, 11%) as a white powder. LCMS: Rt=0.55 min, m/z=518.1 (M+1) Method 2m_acidic_polar; 1H NMR (400 MHz, D2O) δ 7.04 (s, 1H), 5.37 (d, J=5.5 Hz, 1H), 4.83-4.77 (m, 1H), 4.76-4.54 (m, 2H assumed; obscured by solvent), 2.48 (s, 3H), 1.35 (s, 3H), 1.33 (s, 3H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1([NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1.[C:24](Cl)(=[O:26])[CH3:25]>[N+](C)([O-])=O>[C:24]([C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[CH2:14][C:6]([NH:15][C:16](=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:5])[CH2:7]2)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CC1(NC(=O)c2ccccc2)Cc2ccccc2C1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CC(=O)c1ccc2c(c1)CC(C)(NC(=O)c1ccccc1)C2

Procedure:
Aluminium chloride (3.7 g) is dissolved in nitromethane (12 ml) under nitrogen followed by N-(2-methyl-indan-2-yl)-benzamide (3.0 g) at 0° C. Acetyl chloride (0.85 ml) is added dropwise over 30 minutes. After 4 hours at room temperature the mixture is quenched with ice and concentrated HCl, extracted with DCM. The organic layers are washed with dilute HCl and brine. Evaporation of the solvent yielded the desired product. ES+ MS m/e 294 (MH+)
Reaction SMILES: C(OC([N:8]1[CH:21]([C:22](O)=[O:23])[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=5)=[CH:28][CH:27]=4)[C:15](=[O:25])[NH:16]3)=[CH:11][C:10]=2[CH2:9]1)=O)(C)(C)C.Cl.[CH3:43][O:44][C:45](=[O:62])[C@@H:46]([NH2:61])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)=[CH:50][CH:49]=1>>[ClH:40].[CH3:43][O:44][C:45](=[O:62])[C@@H:46]([NH:61][C:22]([CH:21]1[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:26]4[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=5)=[CH:30][CH:31]=4)[C:15](=[O:25])[NH:16]3)=[CH:11][C:10]=2[CH2:9][NH:8]1)=[O:23])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][CH:55]=2)=[CH:50][CH:49]=1
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2CC1C(=O)O)NC(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C)cc2)cc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3

Procedure:
(S)-2-({(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-methyl-biphenyl-4-yl)-propionic acid methyl ester hydrochloride (74 mg, LC/MS: m/z 751) was prepared from (S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester (150 mg) and (S)-2-Amino-3-(4′-methyl-biphenyl-4-yl)-propionic acid methyl ester hydrochloride according to general procedures A and C.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]([O:17]C)=[O:16])=[CH:9]2)=[CH:3][CH:2]=1.C1COCC1.[OH-].[Na+]>CO>[C:1]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]([OH:17])=[O:16])=[CH:9]2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(=O)n(Cc2ccc(-c3ccccc3)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(=O)n(Cc2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
To a solution of methyl 1-(4-biphenylylmethyl)-1,6-dihydro-6-oxo-3-pyridinecarboxylate (4.5 g) in methanol (50 ml)/THF (50 ml) was added dropwise 1N aqueous sodium hydroxide (28 ml) at room temperature. The reaction mixture was stirred at room temperature for 3 hr and concentrated. The residue was diluted with 1 N hydrochloric acid (30 ml) and extracted with a mixed solvent of ethyl acetate and THF. The organic layer was washed with saturated aqueous sodium chloride, dried, and concentrated. Diisopropylether was added to the residue and the resulting crystals were collected by filtration to obtain the titled compound (4.2 g).
Reaction SMILES: [Cl:1][C:2]([Cl:14])([Cl:13])[CH2:3][O:4][C:5](=[O:12])[NH:6][C:7]1[S:11][N:10]=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:35]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:36]([O:38][CH3:39])=[O:37].CC(OC(/N=N/C(OC(C)C)=O)=O)C>CN(C)C=O.O>[S:11]1[C:7]([N:6]([C:5]([O:4][CH2:3][C:2]([Cl:1])([Cl:13])[Cl:14])=[O:12])[C@H:35]([C:36]([O:38][CH3:39])=[O:37])[CH2:40][CH:41]([CH3:43])[CH3:42])=[CH:8][CH:9]=[N:10]1
Reactant: COC(=O)C(O)CC(C)C
Reactant: O=C(Nc1ccns1)OCC(Cl)(Cl)Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1ccns1
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.2 %

Procedure:
A solution of 2,2,2-trichloroethylisothiazol-5-ylcarbamate (253 mg, 0.918 mmol), triphenylphosphine (266 mg, 1.01 mmol) and methyl 2-hydroxy-4-methylpentanoate (151 mg, 1.03 mmol) in N,N-dimethylformamide (2.0 mL) at 0° C. was treated dropwise with diisopropylazodicarboxylate (200 μL, 1.02 mmol) and stirred at rt for 5 h. The mixture was then poured into water and extracted with a 1:1 mixture of ether and ethyl acetate (3×). The combined organics were washed with water and saturated sodium chloride solution, dried (Na2SO4) and concentrated. Flash chromatography of the residue on silica gel eluting with a mixture of ethyl acetate and, hexanes (1:3) gave 260 mg of methyl N-isothiazol-5-yl-N-[(2,2,2-trichloroethoxy)carbonyl]leucinate as a faint-yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[NH2:12].[C:13](Cl)(Cl)=[O:14]>O1CCOCC1.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]2[C:6]([O:8][C:13](=[O:14])[NH:12][C:4]=12)=[O:7]
Reactant: COc1cccc(C(=O)O)c1N
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COc1cccc2c(=O)oc(=O)[nH]c12
Reaction time: 8 h
Yield: 98 %

Procedure:
To a mixture of 10.0 g (60.0 mmol) of 3-methoxyanthranilic acid in 60 mL of 1,4-dioxane was slowly added 100 mL (193 mmol) of a 1.93 molar solution of phosgene in toluene, at room temperature. The mixture was stirred overnight. The mixture was concentrated to yield a residue which was triturated with ethyl acetate-hexane (1:4), filtered, washed with hexane and dried to afford 11.33 g (98%) of the 3-methoxyisatoic anhydride as an off white solid. MS (Cl mode) m/z 176 (M-18, 100%), 194 (M+H, 53%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Br:9])=[CH:4][C:3]=1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.[C:24](C1NC=CN=1)(C1NC=CN=1)=[O:25]>O1CCCC1>[F:8][C:6]1[C:5]([Br:9])=[CH:4][C:3]2[N:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:24](=[O:25])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(Br)c(F)cc2N)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(F)c(Br)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,1-Dimethylethyl 4-[(2-amino-4-fluoro-5-bromophenyl)amino]-1-piperidinecarboxylate (D44) (0.83 g, 2.1 mmole) was dissolved in anhydrous tetrahydrofuran (20 ml) and carbonyl diimidazole (0.51 g, 3.2 mmole) was added in portions over 15 minutes. The mixture was stirred at rt for 1 hr and the at reflux temperature for 18 hrs. The cooled mixture was concentrated to dryness under vacuum and the residue purified by silica gel chromatography eluting with 15-100% ethyl acetate in n-pentane to afford the title compound as a buff solid, 0.54 g, 51% LC/MS—85% m/e 412/414 (MH−).