Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][N:10]2C(OC)=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br>>[Cl:8][C:6]1[CH:5]=[C:4]([C@H:9]2[CH2:14][C@H:13]([C:15]3[O:19][NH:18][C:17](=[O:20])[CH:16]=3)[CH2:12][CH2:11][NH:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(Cl)cc(Cl)c1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](c3cc(Cl)cc(Cl)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.9 %

Procedure:
Trans-methyl 2-(3,5-dichlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (300 mg, 0.81 mmol) was diluted with hydrogen bromide (33% in AcOH, 4.3 mL, 24.24 mmol) and stirred at ambient temperature for 48 h. Evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-(3,5-dichlorophenyl)piperidin-4-yl)isoxazol-3(2H)-one (162 mg, 64%). 1H NMR (600 MHz, CDCl3) δ 1.77-2.17 (m, 4H), 2.66-2.74 (m, 1H), 2.82-2.89 (m, 1H), 3.12-3.18 (m, 1H), 3.79 (d, 1H), 6.06 (s, 1H), 7.44-7.51 (m, 3H). HRMS Calculated for [C14H14Cl2N2O2+H]+: 313.0511. Found: 313.0513
Reaction SMILES: [CH:1]([N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10])=[CH:2][CH2:3][CH3:4].[C:11](OC)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1>CN(C)C=O>[CH:1]([N:5]1[CH2:9][CH2:8][CH:7]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=2)[C:6]1=[O:10])=[CH:2][CH2:3][CH3:4]
Reactant: CCC=CN1CCCC1=O
Reactant: COC(=O)c1cccnc1
Solvent: CN(C)C=O
Product: CCC=CN1CCC(C(=O)c2cccnc2)C1=O
Temperature: 90 °C
Yield: 94.5 %

Procedure:
Sodium hydride (8.63 g, 0.36 mol of 60% dispersion in a mineral oil) was washed with toluene to remove mineral oil. To this 20 ml of dimethylformamide (DMF), 1-(but-1-enyl) pyrrolidin-2-one (25 g, 0.1798 mol) and a solution of methyl nicotinate (20.94 g, 0.152 mol) in 15 ml of DMF were added. The reaction mixture was heated at 90° C. for 2 hrs. DMF was partially removed under reduced pressure, 50 ml water added, further cooled to 0-10° C. and pH adjusted to 7 using HCl. The reaction mixture was extracted with ethyl acetate and dried over Na2SO4. After removing the solvent under reduced pressure a yellow solid was obtained, which on recrystallisation with diisopropyl ether gave 1-(but-1-enyl)-3-nicotinoyl-pyrrolidin-2-one (II, 35.1 g, 94% yield), 95% HPLC, M.R: 65-66° C. 1H NMR (CDCl3): δ 9.3 (1H,d), 8.8 (1H,d), 8.41(1H, dt), 7.4 (1H,m), 6.76 (1H,d), 5.0 (1H,m), 4.5 (1H,m), 3.57-3.67 (2H, m), 2.7 (1H,m), 2.3 (1H, m), 2.0 (2H,m), and 1.0 (3H, t). 13C-NMR (CDCl3): δ 194.4, 167.1, 153.7, 150.4, 137.0, 134.4, 131.2, 123.3, 114.9, 51.7, 44.2, 23.2, 22.3, and 14.26. IR: 2966, 2937, 2855, 2847, 1631, 1613, 1489 Cm−1.
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15](=[O:16])[N:14]3[CH:17]=[CH:18][S:19][C:13]3=[N:12][C:11]=2[CH3:20])=[CH:6][CH:5]=1.[CH:22]1([CH2:25][O:26][C:27]2[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:28]=2[CH:29]=O)[CH2:24][CH2:23]1.[O-]CC.[Na+]>>[CH:22]1([CH2:25][O:26][C:27]2[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:28]=2/[CH:29]=[CH:20]/[C:11]2[N:12]=[C:13]3[S:19][CH:18]=[CH:17][N:14]3[C:15](=[O:16])[C:10]=2[C:7]2[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:1])[F:21])=[CH:5][CH:6]=2)[CH2:23][CH2:24]1
Reactant: COc1cccc(C=O)c1OCC1CC1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(OC(F)F)cc2)c1OCC1CC1
Yield: 39.2 %

Procedure:
The title compound was synthesized by condensation of Intermediate 14 (250 mg, 0.811 mmol) with 2-cyclopropylmethoxy-3-methoxybenzaldehyde (234 mg, 1.136 mmol) in presence of sodium ethoxide (110 mg, 1.623 mmol) according to the procedure of Example 23 to give 158 mg of the desired product; 1H NMR (300 MHz, DMSO-d6) δ 0.26-0.28 (m, 2H), 0.49-0.51 (m, 2H), 1.02-1.04 (m, 1H), 3.69 (m, 2H), 3.77 (s, 3H), 6.93-7.08 (m, 4H), 7.27-7.57 (m, 6H), 7.99 (br s, 1H), 8.15 (d, J=16.2 Hz, 1H); ESI-MS (m/z) 497.28 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:16]([C:41]([OH:43])=O)[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]([NH:32][S:33]([C:36]2[S:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1C([N+:50]([O-])=O)=CC=C(O)C=1.C1CCC(N=C=NC2CCCCC2)CC1.N>CCOC(C)=O.C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:16]([C:41]([NH2:50])=[O:43])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]([NH:32][S:33]([C:36]2[S:40][CH:39]=[CH:38][CH:37]=2)(=[O:34])=[O:35])[CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2cccs2)C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2cccs2)C(N)=O)cc1
Reaction time: 8 h
Yield: 0.4 %

Procedure:
A solution of Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-[N′α-(2-thiophenesulfonyl)-L-phenylalanyl]-L-lysine (650 mg, 1.0 mmol, example 24) dissolved in EtOAc (10 mL) was treated with p-nitrophenol (139 mg, 1.0 mmol) and DCC (206 mg, 1.0 mmol) and was left in a refrigerator overnight. Afterwards, the precipitate was filtered off through celite and the solvent evaporated. The crude intermediate was used without further purification in the next step. A portion of the intermediate (25 mg, 0.03 mmol) was added to a solution of ammonia in ethanol (1M, 10 mL). The resulting solution was stirred for 3 h before evaporation of the solvent. The residue was purified by preparative HPLC to yield 2.6 mg, 11% of the desired material.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[Cu](C#N)[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+].COCCl>CN(C)C=O>[C:14]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6])#[N:15]
Reactant: COC(=O)c1ccc(O)c(Br)c1
Reactant: N#C[Cu]C#N
Agent: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(O)c(C#N)c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 22.5 %

Procedure:
Methyl 3-bromo-4-hydroxybenzoate (37.81 g) was dissolved in N,N-dimethylformamide (250 mL), and copper cyanide (22.03 g) was added to the solution. After stirring the mixture at 150° C. for 16 hours, potassium carbonate (68.00 g) and chloromethyl methyl ether (14.8 mL) were added to the solution under ice cooling, and then the mixture was stirred for 2 hours. The reaction solution was filtered and water was added, and then the reaction mixture was extracted with ethyl acetate. After the operation of adding water to the organic layer, stirring the mixture, filtering the mixture and separating the organic layer was repeated three times, the organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was dissolved in chloroform (30 mL). Trifluoroacetic acid (30 mL) was added to the solution, and then the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure and the obtained residue was washed with a mixture of n-hexane and ethyl acetate in a mixing ratio of 2:1 to obtain the title compound (6.53 g) as a pale yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[CH:10](O)=[O:11]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH:10]=[O:11])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: O=CO
Reactant: Nc1ccc(F)c(Cl)c1
Product: O=CNc1ccc(F)c(Cl)c1
Temperature: 106 °C

Procedure:
A mixture of 100 g of 3-chloro-4-fluoroaniline and 400 ml of 97% formic acid was refluxed (106° C.) for three hours. The mixture then was poured into ice water and the resulting mixture was filtered. The solid was washed with water and dried to give N-(3-chloro-4-fluorophenyl)formamide (J. Org. Chem., 26, 2563 (1961)) (1A), as a colorless crystalline solid, mp: 94°-97° C.
Reaction SMILES: [NH:1]1[C:62](=[O:63])[C@H:51]([CH2:52][C:53]2[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[NH:55][CH:54]=2)[NH:50][C:48](=[O:49])[C@@H:46]([CH3:47])[NH:45][C:43](=[O:44])[C@H:35]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[NH:34][C:32](=[O:33])[C@@H:14]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:31])[NH:20]S(C2C=CC(C)=CC=2)(=O)=O)[NH:13][C:11](=[O:12])[C@@H:2]1[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.C1C(O)=CC=C(C)C=1>C(S)(S)C>[NH:1]1[C:62](=[O:63])[C@H:51]([CH2:52][C:53]2[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[NH:55][CH:54]=2)[NH:50][C:48](=[O:49])[C@@H:46]([CH3:47])[NH:45][C:43](=[O:44])[C@H:35]([CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:34][C:32](=[O:33])[C@@H:14]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[NH:20])[NH2:31])[NH:13][C:11](=[O:12])[C@@H:2]1[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H]2NC(=O)[C@H](Cc3ccc(Cl)cc3)NC(=O)[C@H](Cc3c[nH]c4ccccc34)NC(=O)[C@@H](C)NC(=O)[C@H](Cc3ccccc3)NC2=O)cc1
Agent: CC(S)S
Agent: Cc1ccc(O)cc1
Product: C[C@H]1NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@@H](CCCNC(=N)N)NC(=O)[C@H](Cc2ccc(Cl)cc2)NC(=O)[C@H](Cc2c[nH]c3ccccc23)NC1=O

Procedure:
The crude cyclo(-pClPhe-D-Arg(Tos)-Phe-D-Ala-Trp-) (100 mg) as obtained in Example 38 was treated with HF in the presence of p-cresol (100 mg) and ethanedithiol (100 ml) for 2 hours, while cooling with ice. After HF was removed by distillation, ether was added to the residue and the precipitate formed was collected by filtration. This was purified by gel chromatography (G-25; 2 cm×80 cm). Finally, 1/5 of the product was further purified by HPLC using a column for partitioning purification of D-ODS-5-ST (2 cm×15 cm; produced by YMC Co.) to obtain cyclo(-pClPhe-D-Arg-Phe-D-Ala-Trp-).
Reaction SMILES: Cl.C[O:3][C:4](=[O:9])[C@H:5](CO)N.[C:10](=[NH:20])([O:17][CH2:18][CH3:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O.ClCCl>[C:11]1([C:10]2[O:17][CH2:18][CH:19]([CH2:5][C:4]([OH:9])=[O:3])[N:20]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=N)c1ccccc1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(O)CC1COC(c2ccccc2)=N1

Procedure:
567 mg (3.6 mmol) of L-serine methyl ester hydrochloride are dissolved in 0.5 ml of water, and 610 mg (3.6 mmol) of ethyl benzimidate in 10 ml of dichloromethane are added thereto. After 48 h at reflux, the mixture is concentrated to a volume of 50 ml of dichloromethane and washed with NaHCO3 (3×10 ml), and the aqueous phase is extracted with ethyl acetate (2×10 ml). Column chromatography (15×5 cm, hexane/ethyl acetate 1:1) yields 3.0 g of A2a (91% of theory).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[N:11]([CH3:16])[C:12](Cl)=[N:13][CH:14]=2)[OH:9])[CH:5]=[CH:6][CH:7]=1.[N:17]1([CH2:23][CH2:24][CH2:25][NH2:26])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(C(C)C)CC)(C)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[N:11]([CH3:16])[C:12]([NH:26][CH2:25][CH2:24][CH2:23][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[N:13][CH:14]=2)[OH:9])[CH:5]=[CH:6][CH:7]=1
Reactant: NCCCN1CCCCC1
Reactant: Cn1c(C(O)c2cccc(F)c2)cnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1c(C(O)c2cccc(F)c2)cnc1NCCCN1CCCCC1
Temperature: 25 °C

Procedure:
To a solution of (3-fluoro-phenyl)-(2-chloro-3-methyl-3H-imidazol-4-yl)-methanol (1 equivalent) in THF (0.2 M) is added 3-piperidin-1-ylpropylamine (1.5 equivalents) and diisopropylethylamine (1.5 equivalents). The mixture is heated at reflux until HPLC analysis shows consumption of the starting material. The reaction mixture is cooled to rt, quenched with satd. aq. NH4Cl, and extracted with EtOAc (2×). The combined organic extracts are washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude material is purified by chromatography or recrystallization to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:18])[C:5]([O:15][CH2:16][CH3:17])=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][C:12]([OH:14])=[O:13].O=S(Cl)Cl.[CH3:23]O>>[Cl:1][C:2]1[CH:3]=[C:4]([F:18])[C:5]([O:15][CH2:16][CH3:17])=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][C:12]([O:14][CH3:23])=[O:13]
Reactant: CCOc1c(F)cc(Cl)c2[nH]cc(CC(=O)O)c12
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CCOc1c(F)cc(Cl)c2[nH]cc(CC(=O)OC)c12
Temperature: 25 °C
Yield: 82 %

Procedure:
To a solution of 30-9 (582 mg, 6.4 mmol) in CH3OH (20 mL) was added SOCl2 (1 mL). The mixture was refluxed for 2 h before it was cooled to room temperature, the solvent was removed under reduce pressure. The resulting residue was partitioned between water (30 mL) and ethyl acetate (30 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were combined, washed with brine (3×20 mL), dried over Na2SO4, filtered and concentrated to afford 30-10 (500 mg, 82%) as a light yellow solid. LRMS: calc 285.0 and found: 286.1 [M+1].
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:50][C:51]1[CH:52]=[C:53]([C:57]2[N:66]=[C:65]([NH:67][C:68]3[CH:69]=[C:70]4[C:74](=[CH:75][CH:76]=3)[N:73]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[N:72]=[CH:71]4)[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[N:58]=2)[CH:54]=[CH:55][CH:56]=1>C(Cl)Cl>[CH3:1][N:2]([CH3:7])[CH2:3][C:4]([NH:50][C:51]1[CH:52]=[C:53]([C:57]2[N:66]=[C:65]([NH:67][C:68]3[CH:69]=[C:70]4[C:74](=[CH:75][CH:76]=3)[N:73]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[N:72]=[CH:71]4)[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[N:58]=2)[CH:54]=[CH:55][CH:56]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Reactant: CN(C)CC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
A suspension of 2-(dimethylamino)acetic acid (57 mg, 0.55 mmol), PyBOP® (286 mg, 0.55 mmol), DIEA (240 μL, 1.38 mmol) in CH2Cl2 (2 mL) was stirred at RT for 10-15 minutes. This solution of activated acid was added to a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (500 mg, 1.10 mmol) and CH2Cl2 (4 mL). The reaction mixture was stirred at RT for 1.5 h. Activated another 1.5 equivalent of the acid as described above and stirred for 16 h. Diluted with more CH2Cl2 and extracted with H2O (3×). Organic layer was dried under Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica (9:1 CH2Cl2:MeOH) to give the desired product tert-butyl 5-(2-(3-(2-(dimethylamino)acetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate. (570 mg, 1.06 mmol, 96%).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](Cl)=[N:16][OH:17])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([C:21]1[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=1)#[CH:20].C(N(CC)CC)C>O1CCCC1>[CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[CH:20]=[C:19]([C:21]4[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=4)[O:17][N:16]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(OC2CCCCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(OC4CCCCC4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.8 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-cyclohexyloxy-phenyl)-acetohydroximoyl chloride (150 mg, 0.56 mmol) described in Manufacturing Example 79-1-4 and 3-ethynyl-pyridine-2,6-diamine (47.6 mg, 0.357 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (195 μL, 1.4 mmol). This reaction mixture was stirred for 4 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried with anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane: ethyl acetate=1:1˜ethyl acetate) to obtain the title compound (83 mg, 41%).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][CH2:13][CH2:14][S:15]([OH:18])(=[O:17])=[O:16].C([O-])(=O)C.[K+:23]>C(O)(=O)C>[K+:23].[C:4]1(=[O:6])[N:12]([CH2:13][CH2:14][S:15]([O-:18])(=[O:17])=[O:16])[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)[O-]
Yield: 77.6 %

Procedure:
Following the method described by Winterbottom, R. et al., J. Am. Chem. Soc., 69, 1393-1401 (1947), 21.4 g of phthalic anhydride (0.145 mol) were added to a suspension of taurine (17 g, 0.137 mol) and potassium acetate (14.2 g, 0.145 mol) in glacial acetic acid (48 mL), heated under reflux. Heating was continued to obtain the complete dissolution of the reagents (2.5 h); after cooling to 0°-5° C., a precipitate formed which was separated by filtration, washed with glacial acetic acid and absolute ethanol, dried in the air and under vacuum (50° C.), to give 31.2 g of 2-phthalimidoethanesulfonic acid potassium salt [m.p. >300° C.; 1H-NMR (D2O) d 7.85 (m, 4H), 4.05 (t, 3H, J=8 Hz), 3.25 (t, 2H, J=8 Hz). A suspension of 5 g of the salt in benzene (50 mL), dried by azeotropical distillation, was added with 2.56 g of phosphorous pentachloride (0.015 mol) and refluxed for 1 h. Then a second aliquot of phosphorous pentachloride (2.56 g, 0.015 mol) was added. The mixture was refluxed for a further 90 min, then solvents and reagents were evaporated off under vacuum and reduced pressure. The mixture was refluxed for a further 1.30 hours; cooled to r.t. and the solvents were evaporated under reduced pressure. The residue was taken up into 30 g of finely triturated ice to form a fine solid (which was filtered, washed with water and dried) of 2-phthalimidoethanesulfonyl chloride (3.71 g; m.p. =158-159° C.).
Reaction SMILES: [CH:1](I)([CH3:3])[CH3:2].[CH2:5]([O:12][C:13](=[O:42])[C@@H:14]([NH:23][C:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1)(=[O:34])=[O:33])=[O:25])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:5]([O:12][C:13](=[O:42])[C@@H:14]([NH:23][C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1)(=[O:34])=[O:33])=[O:25])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH:1]([CH3:3])[CH3:2])=[CH:18][CH:17]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(C)I
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccccc1)C1CCCCN1S(=O)(=O)c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C[C@H](NC(=O)[C@@H]2CCCCN2S(=O)(=O)c2cccc(F)c2)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.8 %

Procedure:
Isopropyl iodide (0.62 mL, 6.2 mmol) was added to a mixture of (S)-2-{[1-(3-(fluoro)-benzenesulfonyl)-piperidine-2-carbonyl]-amino}-3-(4-hydroxy-phenyl)-propionic acid benzyl ester (700 mg, 1.30 mmol) and cesium carbonate (2.4 g, 7.4 mmol) in dry DMF (5 mL). The suspension was stirred at room temperature for 4 h. The reaction mixture was then washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The resulting oil was chromatographed (ethyl acetate/n-heptane) on silica gel to produce 620 mg (82.1%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][O:1][C:2]2[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=2)=[CH:25][CH:24]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(OCc2ccc(Cl)cc2)cn1
Reaction time: 0.17 h

Procedure:
A mixture of 5-hydroxy-2-nitropyridine (7 g), K2CO3 (6.9 g) and DMF (100 ml) is stirred for about 10 minutes. To the mixture is added 4-chlorobenzyl chloride (8.1 g) in portions over about 15 minutes. The reaction mixture is stirred about 16 hours and then heated to 45° for about 30 minutes. After cooling, the reaction is diluted with CHCl3, washed with water and saturated NaCl, dried (Na2SO4) and stripped. The crystalline solid is washed with 20% ethyl acetate/hexane, giving 5-(4-chlorobenzyloxy)-2-nitropyridine.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+].CO>>[CH3:9][O:10][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: Cc1ccnc(Cl)c1
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)ccn1
Yield: 74.7 %

Procedure:
Commercially available 2-chloro-4-methylpyridine (25.5 g, 200 mmol) and a sodium methoxide-methanol solution (28.0%, 77.0 g, 399 mmol) were mixed, and the mixture was heated under reflux for 15 hours. After completion of the reaction was confirmed by thin-layer chromatography, the resulting precipitate was filtered out, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was, evaporated under reduced pressure to give 2-methoxy-4-methylpyridine (18.4 g, yield 75%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:17]=[CH:16][C:10]3[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][C:9]=3[CH:8]=2)[CH2:5][CH:4]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:3]1.[CH:23]1([N:26]2[C:35]3[C:30](=[CH:31][C:32]([F:38])=[C:33](F)[C:34]=3[F:36])[C:29](=[O:39])[C:28]([C:40]([OH:42])=[O:41])=[CH:27]2)[CH2:25][CH2:24]1>>[C:20]([NH:19][CH2:18][CH:4]1[O:3][C:2](=[O:1])[N:6]([C:7]2[CH:17]=[CH:16][C:10]3[CH2:11][N:12]([C:33]4[C:34]([F:36])=[C:35]5[C:30]([C:29](=[O:39])[C:28]([C:40]([OH:42])=[O:41])=[CH:27][N:26]5[CH:23]5[CH2:25][CH2:24]5)=[CH:31][C:32]=4[F:38])[CH2:13][CH2:14][CH2:15][C:9]=3[CH:8]=2)[CH2:5]1)(=[O:22])[CH3:21]
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC(=O)NCC1CN(c2ccc3c(c2)CCCNC3)C(=O)O1
Product: CC(=O)NCC1CN(c2ccc3c(c2)CCCN(c2c(F)cc4c(=O)c(C(=O)O)cn(C5CC5)c4c2F)C3)C(=O)O1

Procedure:
The title compound was prepared in a procedure analogous to that used in Example 6, using N-[2-Oxo-3-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yl)-oxazolidin-5-ylmethyl]-acetamide (0.25 g) and 1-Cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (0.23 g). The product was triturated with EtOH to purify. MS (APCI)AP+, 567. NMR (DMSO6)1.1-1.22 (m, 4H), 1.78 (s, 3H), 1.87 (brm, 2H), 3.0 (brs, 2H), 3.38 (t, 2H), 3.7 (m, 3H), 4.04 (t, 2H), 4.43 (s, 2H), 4.61 (m, 1H), 7.13 (d, 1H), 7.26 (d, 1H), 7.35 (s, 1H), 7.78 (d, 1H), 8.2 (t, 1H), 8.61 (s, 1H).