Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:12][C:13]1[O:17][N:16]=[C:15]([O:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=1)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:28][C:29]1[CH:30]=[CH:31][C:32]2[O:36][N:35]=[C:34](O)[C:33]=2[CH:38]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:12][C:13]1[O:17][N:16]=[C:15]([O:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:20])=[O:21])[CH:14]=1)[CH2:10][O:11][C:34]1[C:33]2[CH:38]=[C:29]([Cl:28])[CH:30]=[CH:31][C:32]=2[O:36][N:35]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(CO)Cc1cc(OS(=O)(=O)c2ccccc2)no1
Reactant: Oc1noc2ccc(Cl)cc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(COc1noc2ccc(Cl)cc12)Cc1cc(OS(=O)(=O)c2ccccc2)no1
Yield: 73.4 %

Procedure:
To a solution of 0.5 g of 2-tert-butoxycarbonylamino-3-(3-benzenesulfonyloxyisoxazol-5-yl)-1-propanol in 5 ml of tetrahydrofuran are added 0.21 g of 5-chloro-3-hydroxy-1,2-benzoisoxazole, 0.43 g of triphenylphosphine and 0.28 g of diethyl azodicarboxylate with ice-cooling, and they are subjected to reaction at room temperature for 24 hours. Thereafter, the solvent is removed by distillation under reduced pressure. The residue obtained is purified by a column chromatography [eluant:n-hexane:ethyl acetate=4:1], to obtain 0.5 g of oily 3-[2-tert-butoxycarbonylamino-3-(3-benzenesulfonyloxy-5-isoxazolyl)propoxy]-5-chloro-1,2-benzoisoxazole.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])([O-:3])=[O:2].[O-]CC.[Na+].[Cl:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:29]=O)[C:22](=[CH:25][C:26]=1[O:27][CH3:28])[CH:23]=O>C(O)C>[Cl:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]2[C:22]([CH:23]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:29]2)=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1cc(C=O)c(C=O)cc1OCCCl
Reactant: CCOC(=O)CC[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc2cc(OCCCl)c(OC)cc2cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
To a solution of 2.43 g of ethyl 3-nitropropionate in 15 ml of absolute ethanol cooled using an ice bath, is added 20 mL of 1N sodium ethoxide in ethanol dropwise over 10 minutes keeping the temperature at 0-5° C. A slurry of 4-(2-chloroethoxy)-5-methoxyphthalaldehyde in 5 mL of ethanol is added. The ice bath is removed and the reaction allowed to warm to room temperature and stirred for 16 hours. The reaction is transferred to a beaker with 300 mL of water and neutralized with acetic acid to pH 4. The solid is collected and washed first with water, then with 40 mL of cold ethanol. The solid is dried to provide 2.48 g (70%) of ethyl 7-(2-chloroethoxy)-6-methoxy-3-nitro-2-naphthoate and ethyl 6-(2-chloroethoxy)-7-methoxy-3-nitro-2-naphthoate (1:1 mixture) as a yellow solid, m.p. 119-29° C. dec.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:29]([NH:30][C:31](=[O:41])[C:32](=[N:39][OH:40])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:28](=[O:42])[N:10]2[C:11]=1[C:12]([O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(=[O:3])[CH3:2].N1C=CC=CC=1.[N+:49]([C:52]1[CH:60]=[CH:59][C:55]([C:56](Cl)=[O:57])=[CH:54][CH:53]=1)([O-:51])=[O:50]>C(OC(=O)C)C>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:29]([NH:30][C:31](=[O:41])[C:32](=[N:39][O:40][C:56](=[O:57])[C:55]3[CH:54]=[CH:53][C:52]([N+:49]([O-:51])=[O:50])=[CH:60][CH:59]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:28](=[O:42])[N:10]2[C:11]=1[C:12]([O:14][CH:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=NO)c3ccccc3)[C@H]2SC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=NOC(=O)c3ccc([N+](=O)[O-])cc3)c3ccccc3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
To a solution of diphenylmethyl 3-acetoxymethyl-7β-(2-hydroxyimino-2-phenylacetamido)ceph-3-em-4-carboxylate (syn-isomer) (1.5 g.) and pyridine (0.5 ml.) in ethylacetate (100 ml.) was added 4-nitrobenzoyl chloride (0.42 g) and the resulting solution was stirred at room temperature for one hour. Further portions (0.042 g 0.015 g and 0.20 g.) of the acid chloride were added, and the reaction stirred for a total of 4 hours at room temperature. Then the solution was washed with 2 N-hydrochloric acid and brine, dried, concentrated to ca. 5 ml. and added dropwise with stirring to petroleum spirit (b.p. 40°-60°). This gave a solid which was filtered and dried, yielding the title ester (1.1 g; 58%), λmax. (EtOH) 263 nm (ε 29,000), νmax. (CHBr3) 3400 (NH), 1780 (β-lactam), 1395 and 1525 (NO2), 1687 and 1515 cm.- 1 (CONH), τ (CDCl3) values include 1.70 and 2.71 (two doublets, J 8 Hz; ##STR33## 2.1-2.85 (multiplet; aromatic protons), 8.03 (singlet; OCOCH3)
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30](=[O:32])[CH3:31])=[CH:29][C:24]=2[O:23][C:22]1=[O:33].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][N:21]4[C:25]5[CH:26]=[CH:27][C:28]([C:30](=[O:32])[CH3:31])=[CH:29][C:24]=5[O:23][C:22]4=[O:33])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)c1ccc2c(c1)oc(=O)n2CCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccc2c(c1)oc(=O)n2CCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 30.5 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.0 g, 9 mmol), N-(3-chloropropyl)-6-acetyl-2-benzoxazolinone (2.4 g, 9 mmol), K2O3 (3.6 g), a few crystals of KI, and acetonitrile (50 ml) was stirred and refluxed for 13 hours. The reaction was poured into water, and a dark, brown solid that separated was collected to afford 3.3 g of crude product. The solid was chromatographed on a Waters Prep 500 HPLC. Concentration of appropriate fractions afforded 2.3 g of a yellow solid, and recrystallization from ethyl acetate yielded 1.2 g (31%) of N-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propyl]-6-acetyl-2-benzoxazolinone, m.p.=152°-154° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].[CH2:34]([O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1)[CH3:35]>>[CH2:34]([O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41]([C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[N:6]([C@@H:11]3[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]3[O:13][C:14](=[O:16])[CH3:15])[CH:5]=2)=[O:42])=[CH:39][CH:38]=1)[CH3:35]
Reactant: CCOc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CCOc1ccc(C(=O)c2cn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c3cccc(Cl)c23)cc1

Procedure:
4-Chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indole obtained in Example 1-(3) and 4-ethoxybenzoyl chloride were treated in a manner similar to Example 2-(4) to give 4-chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indol-3-yl 4-ethoxyphenyl ketone as a colorless powder. APCI-Mass m/Z 630/632 (M+H). 1H-NMR (DMSO-d6) δ 1.37 (t, J=7.0 Hz, 3H), 1.69 (s, 3H), 1.98 (s, 6H), 2.04 (s, 3H), 4.11-4.12 (m, 2H), 4.14 (q, J=7.3 Hz, 2H), 4.28-4.32 (m, 1H), 5.29 (t, J=9.7 HZ, 1H), 5.54 (t, J=9.5 Hz, 1H), 5.71 (t, J=9.2 Hz, 1H), 6.32 (d, J=9.0 Hz, 1H), 7.04 (d, J=8.8 Hz, 2H), 7.25 (d, J=7.5 Hz, 1H), 7.35 (t, J=8.0 Hz, 1H), 7.79 (d, 1H), 7.99 (d, J=8.8 Hz, 2H), 8.07 (s, 1H).
Reaction SMILES: [C:1](Cl)(=O)[C:2](Cl)=O.[Cl:7][C:8]1[CH:17]=[CH:16][C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]=1[C:18]([OH:20])=O>ClCCl.CN(C)C=O>[Cl:7][C:8]1[CH:17]=[CH:16][C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]=1[C:18]([NH:14][CH2:13][CH2:12][CH:2]1[CH2:1][CH2:10][CH2:9][CH2:8][CH2:17]1)=[O:20]
Reactant: O=C(O)c1c(Cl)ccc2ncccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCCC1CCCCC1)c1c(Cl)ccc2ncccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (0.3 mL) was added to a suspension of 6-chloro-5-quinolinecarboxylic acid (example 94(a)) (0.3 g) in dichloromethane and 2 drops of N,N-dimethylformamide. The reaction mixture was stirred at room temperature for 1 hour then evaporated to an oil. The residue was added to cyclohexylethylamine hydrochloride (0.33 g) and triethylamine (0.6 mL) in dichloromethane and then stirred at room temperature for 1 hour. Water was added and the reaction mixture was extracted with dichloromethane. The combined organics were dried and concentrated. Purification (SiO2, ethyl acetate:isohexane 50:50) gave the sub titled compound as a solid (0.115 g).
Reaction SMILES: C[O:2][C:3]1[C:4](=[O:16])[NH:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:7]=2[C:8](=[O:10])[CH:9]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+].[K+].[Br-]>C(Cl)Cl>[OH:2][C:3]1[C:4](=[O:16])[NH:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:7]=2[C:8](=[O:10])[CH:9]=1
Reactant: COc1cc(=O)c2c(C)cccc2[nH]c1=O
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Product: Cc1cccc2[nH]c(=O)c(O)cc(=O)c12
Temperature: 25 °C
Reaction time: 1.08 h

Procedure:
To a stirred solution of 3-methoxy-6-methyl-1H-1-benzazepine-2,5-dione (350 mg, 1.61 mmol) in dry CH2Cl2 (25 mL, distilled from CaH2) under N2, there was added a solution of BBr3 in CH2Cl2 (5 mL, 1M, Aldrich) in one portion over 30 seconds at rt. The reaction solution immediately became orange, then an orange precipitate formed during the addition. The reaction was allowed to stir under N2 at rt for 65 min. The reaction was added to saturated NaHCO3 (50 mL) and the resulting mixture was vigorously stirred for 15 min to give biphasic system containing some solid material. The phases were separated and the aqueous portion vacuum filtered. The clear, pale yellow, aqueous portion was extracted with CH2Cl2 (1×10 mL). The aqueous portion was acidified with concd HCl (pH 2). The resulting precipitate was collected by filtration, washed to neutrality with water (6×2 mL) and dried in vacuo to yield a highly electrostatic, colorless powder (mass could not be determined). Crystallization from EtOAc (dissolved in 15 mL, hot filtered, concd to 7 mL, allowed to cool to rt) initially yielded near colorless needles, which upon standing overnight at rt, transformed into beige cubes (146 mg, 45%, pure by 1H NMR); mp 187.5°-188.5° C. (dec.); 1H NMR (DMSO-d6) δ2.34 (s, 3H), 6.30 (s, 1H), 7.09 (d, J=7.2 Hz, 1H), 7.21 (d, J=8.1 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 10.39 (s, 1H), 11.20 (s, 1H); IR (KBr) 3207 (m), 3047 (m), 1642 (s), 1607 (s), 1598 (s), 1348 (m), 789 (m); Anal. Calcd for C11H9NO3 : C, 65.02, H, 4.46, N, 6.89. Found: C, 65.26; H, 4.54; N, 6.89. Concentration of the mother liquor yielded an additional portion of orange cubes (30 mg, 9%, pure by 1H NMR); mp 184.5°-188° C. In one crystallization, the above mentioned needles were collected; mp 177°-179° C. (dec); IR (KBr) 3389 (m), 3193 (m), 1661 (s), 1646 (s), 1601 (m), 1580 (m), 1350 (m), 1204 (m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH:14]([CH3:33])[CH2:15][CH2:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[C:25]#[C:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:34]=O.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH3:34])[CH:14]([CH3:33])[CH2:15][CH2:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[C:25]#[C:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C#Cc2ccccc2)c(CCC(C)NCCc2ccc(OC)c(OC)c2)c1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C#Cc2ccccc2)c(CCC(C)N(C)CCc2ccc(OC)c(OC)c2)c1

Procedure:
A mixture of of N-[2-(3,4-dimethoxyphenyl)ethyl]-5-methoxy-α-methyl-2-(phenylethynyl)benzenepropanamine (0.3 g, 0.68 mmole), the free base of the product of Example 1e, and 37% aqueous formaldehyde (0.5 mL) were combined in absolute methanol (5 mL). With stirring, sodium borohydride (0.05 g, 1.3 mmole) was added, and the resulting reaction mixture stirred overnight. The mixture was concentrated in vacuo, the resulting residue dissolved in 5 mL of EtOAc, 5 mL of 1N sodium hydroxide was added and the resulting layers separated. The aqueous layer was extracted with EtOAc and washed with water, brine and dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated in vacuo to give 0.3 g of the title product as a golden oil. The title product is the antihypertensive pharmaceutical prepared in Example 32 of European Pat. No. 146,271.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:11][C:12]([CH3:18])([CH2:16][OH:17])[C:13]([OH:15])=[O:14]>CN(C1C=CN=CC=1)C.CCOCC>[C:1]([O:17][CH2:16][C:12]([CH3:18])([CH3:11])[C:13]([OH:15])=[O:14])(=[O:3])[CH3:2]
Reactant: CC(C)(CO)C(=O)O
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)OCC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetyl chloride (4.52, 58.2 mmol) was added dropwise to a cold (0° C.) pyridine solution (10 ml) of 2,2-dimethyl-3-hydroxypropionic acid (5.5 g, 46.5 mmol) and 4-DMAP (0.57 g, 4.65 mmol). After stirring overnight at ambient temperature, the reaction was poured into ether (200 ml). This mixture was washed with 10% HCl (2×20 ml), and saturated brine (2×25 ml) and the resulting ethereal solution was dried (MgSO4). Evaporation gave the title compound as a pale yellow solid which was used in the next step without further purification. NMR (CDCl3) δ 4.13 (2 H, s), 2.08 (3 H, s), 1.26 (6 H, s).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[NH2:34][C:35](N)=[O:36].Cl>O>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C@:4]([CH2:3][CH2:2][NH:1][C:35]([NH2:34])=[O:36])([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[O:9][C:8]2=[O:10])[CH3:12])=[CH:18][CH:17]=1
Reactant: NC(N)=O
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCN)(c2ccc(F)cc2)OC1=O
Agent: Cl
Solvent: O
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCNC(N)=O)(c2ccc(F)cc2)OC1=O
Yield: 61.8 %

Procedure:
To a solution of (R)-6-(2-aminoethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluoro-phenyl)-1,3-oxazinan-2-one (30 mg, 0.065 mmol) and urea (16 mg, 0.26 mmol) in H2O (3 mL) was added concentrated HCl (0.05 mL), and the mixture was refluxed overnight. The reaction mixture was crystallized by standing at rt. The precipitate was filtered and rinsed well with water to give 1-(2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl)urea (20 mg, 68%). LC-MS Method 3 tR=1.3, min, m/z=498; 1H NMR (CDCl3): 1.54-1.60 (d, 3H), 2.01-2.09 (m, 1H), 2.22-2.41 (m, 4H), 2.91-3.14 (m, 2H), 3.35-3.44 (m, 1H), 5.56-5.62 (s, 1H), 5.63-5.71 (m, 1H), 6.87-6.99 (m, 2H), 7.01-7.12 (m, 3H), 7.22-7.31 (m, 2H), 7.32-7.48 (m, 3H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[S:45]1[C:50]2=[C:51]3[C:55](=[CH:56][CH:57]=[C:49]2[O:48][CH2:47][CH2:46]1)[NH:54][C:53]([C:58](O)=[O:59])=[CH:52]3.CCN(C(C)C)C(C)C>CN(C=O)C.O.CCOC(C)=O>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:58]([C:53]2[NH:54][C:55]3[C:51]([CH:52]=2)=[C:50]2[S:45][CH2:46][CH2:47][O:48][C:49]2=[CH:57][CH:56]=3)=[O:59])=[C:28]([F:44])[C:29]=1[O:34][C:35]1[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=1
Reactant: O=C(O)c1cc2c3c(ccc2[nH]1)OCCS3
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4c5c(ccc4[nH]3)OCCS5)c2F)c1
Yield: 37.6 %

Procedure:
HATU (0.061 g, 0.161 mmol) was added as a solid to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol), 2,3-dihydro-7H-[1,4]oxathiino[3,2-e]indole-8-carboxylic acid (0.038 g, 0.161 mmol) and DIPEA (0.028 mL, 0.161 mmol) in DMF (1 mL). After 2 hours the reaction mixture was poured into EtOAc and water and the organic layer separated. The organic layer was dried over MgSO4, filtered and the solvent evaporated. The residue was dissolved in MeOH and purification was accomplished by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.032 g, 38%) as a white solid. 1H NMR (400 MHz, Acetone-d6) δ ppm 10.76 (br. s., 1H), 8.36 (t, 1H), 7.64 (t, 1H), 7.42-7.52 (m, 2H), 7.39-7.42 (m, 2H), 7.20 (dd, 1H), 7.00 (dd, 1H), 6.77 (d, 1H), 4.70 (d, 2H), 4.38-4.43 (m, 2H), 3.23-3.28 (m, 2H). LCMS: m/z=528.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:18][CH3:19])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[CH:15][N:16]=1)[CH:8]=[C:7]2[OH:17].C(C1N=C(C2C=C(O[CH:39]3[CH2:57][CH:56]4[N:41]([C:42](=[O:62])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH:49]=[CH:50][CH:51]5[C:53]([C:59]([OH:61])=[O:60])([NH:54][C:55]4=[O:58])[CH2:52]5)[CH2:40]3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[Br:1][C:2]1[C:3]([O:18][CH3:19])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[CH:15][N:16]=1)[CH:8]=[C:7]2[O:17][CH:39]1[CH2:57][CH:56]2[N:41]([C:42](=[O:62])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH:49]=[CH:50][CH:51]3[C:53]([C:59]([OH:61])=[O:60])([NH:54][C:55]2=[O:58])[CH2:52]3)[CH2:40]1
Reactant: COc1ccc2c(O)cc(-c3nccs3)nc2c1Br
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nccs3)nc2c1Br

Procedure:
The title compound was prepared from 8-bromo-4-hydroxy-7-methoxy-2-(thiazol-2-yl)quinoline (40) and intermediate 7 following the procedure (Step F-H) reported for 18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid 10: m/z=670 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:16][CH:15]=3)=[N:10][CH:11]=1)=[O:5])C.[OH-].[K+].CO.Cl>O>[F:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:13]2[C:14]3[C:19](=[CH:18][C:17]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:16][CH:15]=3)[CH:20]=[C:12]2[C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH3:1])=[O:5])=[CH:11][N:10]=2)=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1ccc(-c2cc3cc(S(C)(=O)=O)ccc3n2Cc2ccc(F)cc2)nc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(-c2cc3cc(S(C)(=O)=O)ccc3n2Cc2ccc(F)cc2)nc1
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
A mixture of 2-(5-ethoxycarbonylpyridin-2-yl)-1-(4-fluorobenzyl)-5-methanesulfonylindole (0.68 g), potassium hydroxide (0.24 g) and methanol (45 ml) was stirred at 15 to 30° C. for 30 minutes under nitrogen atmosphere. To the reaction solution was added water and the mixture was neutralized with hydrochloric acid. The precipitated crystal was filtered off. The resulting crude crystal was recrystallized (methanol) to obtain 0.44 g of the desired product.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:9][O:10][CH2:11][C:12](OC)=[O:13]>C[O-].[Na+].C1(C)C=CC=CC=1>[CH3:9][O:10][CH2:11][C:12]([O:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)=[O:13]
Reactant: OCCn1ccnc1
Reactant: COCC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCC(=O)OCCn1ccnc1
Yield: 90.2 %

Procedure:
In a nitrogen atmosphere, a mixture of 112 g of 2-(1H-imidazol-1-yl)ethanol, synthesized in Synthesis Example 1, 156 g of methyl methoxyacetate, 3.0 g of sodium methoxide, and 200 g of toluene was heated under reflux for 20 hours while distilling off the methanol formed during the reaction. The solvent was distilled off in vacuo. Purification by vacuum distillation gave 166 g of 2-(1H-imidazol-1-yl)ethyl methoxyacetate (boiling point 126° C./27 Pa, yield 90%).
Reaction SMILES: [CH2:1]([C:17]1[CH:25]=[C:21]([C:22]([OH:24])=[O:23])[C:20]([OH:26])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(O)(=O)C1C(=CC=CC=1)O.C(C1C=CC(O)=CC=1)CCCCCCCCCCCCCCC.[OH-].[Ca+2:61].[OH-]>C1(C)C(C)=CC=CC=1.O.CO>[CH2:1]([C:17]1[CH:25]=[C:21]([C:22]([O-:24])=[O:23])[C:20]([OH:26])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Ca+2:61].[CH2:1]([C:17]1[CH:25]=[C:21]([C:22]([O-:24])=[O:23])[C:20]([OH:26])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCc1ccc(O)c(C(=O)O)c1
Agent: CCCCCCCCCCCCCCCCc1ccc(O)cc1
Agent: O=C(O)c1ccccc1O
Agent: [Ca+2]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCCCCCc1ccc(O)c(C(=O)[O-])c1
Temperature: 40 °C

Procedure:
The 5-(hexadec-1-yl)salicylic acid of Example 3 (3.16 g) was mixed with a commercial lower alkyl (i.e. less than C20) salicylic acid (Infineum M7103, obtainable from Infineum UK Limited, 3.89 g), and 4-(hexadec-1-yl)phenol of Example 2 (0.34 g). The salicylic acid mixture and xylene (100 g) were mixed together at room temperature. Calcium hydroxide (2.50 g), a promoter (methanol:water (97%:3%), 25.29 ml) and further xylene (120 g) were added, nitrogen passed through the mixture (60 ml.min−1) and the resulting mixture heated in an oil bath at 40° C. for 1 hour.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].Cl.Cl[CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:18]([N:19]([CH2:22][CH3:23])[CH2:20][CH2:21][N:10]1[C:11]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:14])[CH3:17]
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
A suspension of 6-nitro-3,4-dihydroquinolin-2(1H)-one (400 mg, 2.08 mmol), 2-chloro-N,N-diethylethanamine hydrochloride (394 mg, 2.29 mmol) and potassium carbonate (862 mg, 6.24 mmol) in 10 mL DMF was stirred at room temperature overnight. After this time, the mixture was poured into 20 mL H2O then extracted with 2×50 mL CH2Cl2. The organic layer was separated, washed with brine and concentrated to give a yellow brown solid which was subjected to flash chromatography on silica gel using 5% MeOH/CH2Cl2 to give a yellow viscous oil (585 mg, 96.5%). 1H-NMR (CDCl3) δ: 8.16 (dd, J=2.5, 9 Hz, 1H), 8.06 (d, J=2.5 Hz, 1H), 7.23 (d, J=9.0 Hz, 1H), 4.07 (t, J=7.0 Hz, 2H), 3.00 (t, J=7.0 Hz, 2H), 2.73-2.55 (m, 8H), 1.01 (t, J=7.0 Hz, 6H).