Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[S:12]Br)=O.[NH3:14]>>[N+:9]([C:7]1[CH:6]=[CH:5][C:4]2[S:12][N:14]=[CH:1][C:3]=2[CH:8]=1)([O-:11])=[O:10]
Reactant: N
Reactant: O=Cc1cc([N+](=O)[O-])ccc1SBr
Product: O=[N+]([O-])c1ccc2sncc2c1

Procedure:
Angewandte Chemie, 36 (1923), 159 and Berichte der deutschen Chemischen Gesellschaft, 58 (1925), 2,095 disclose that thionaphthene-2,3-dione may be reacted with ammonia and hydrogen peroxide to give 3-carbamyl-1,2-benzisothiazole and that 1,2-benzisothiazole may be obtained from the latter by hydrolysis and decarboxylation. Berichte, 56 (1923), 1,630 and Liebigs Annalen der Chemie, 454 (1927), 264 describe the reaction of 2-formyl-4-nitrophenylsulfenyl bromide with ammonia to give 5-nitro-1,2-benzisothiazole. Benzisothiazoles can also be synthesized by cyclizing o-mercapto-phenyl-carbonyl compounds in the presence of polyphosphoric acid (Annali di Chimica, 53 (1963), No. 5, 577-587). German Laid-Open Application DOS No. 1,670,196 discloses the reaction of dihalomethylaryl compounds with ammonia and sulfur to give benzisothiazoles. All these processes are unsatisfactory in respect to ease of access to the starting materials, economy, and simplicity of operation coupled with a good yield of end product.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH:8]([C:19]2[CH:24]=[CH:23][C:22](Br)=[C:21]([CH2:26][C:27]3[CH:36]=[CH:35][C:30]4[O:31][CH2:32][CH2:33][O:34][C:29]=4[CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:37][O:38][C:39](=[O:41])[CH3:40])(=[O:3])[CH3:2].C1(P([CH:55]2[CH2:60][CH2:59]CCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(B(O)O)CC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH:8]([C:19]2[CH:24]=[CH:23][C:22]([CH:59]3[CH2:60][CH2:55]3)=[C:21]([CH2:26][C:27]3[CH:36]=[CH:35][C:30]4[O:31][CH2:32][CH2:33][O:34][C:29]=4[CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:37][O:38][C:39](=[O:41])[CH3:40])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1OC(c2ccc(Br)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)OC[C@H]1OC(c2ccc(C3CC3)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 193.2 %

Procedure:
To a stirred solution of acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester (10.0 g, 15.74 mmol) in toluene (100 mL) was added tricyclohexylphosphine (1.76 g, 6.29 mmol), a solution of potassium phosphate tribasic (13.3 g, 62.9 mmol) in water (15 mL), and cyclopropylboronic acid (4.06 g, 47.2 mmol). The reaction mixture was degassed for 45 min then palladium (II) acetate (529 mg, 2.3 mmol) was added. The reaction mixture was stirred at 90° C. overnight then cooled to room temperature and filtered through celite, and the celite was washed with ethyl acetate (200 mL). The organic layer of the filtrate was separated and washed with water (100 mL) followed by brine (100 mL), then dried over sodium sulfate and concentrated to give crude product which was further purified by column chromatography to furnish acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-ylmethyl ester (7.25 g, purity 98%) and this was recrystallized by absolute ethanol to give white solid (5.25 g, purity >99%).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:39])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:10](=[O:32])[C:9]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[CH:8]2)=[O:4].[NH2:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:25]([N:11]1[C:12]2[C:7](=[C:6]([OH:39])[C:5]([C:3]([NH:40][CH2:41][CH2:42][C:43]([OH:45])=[O:44])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:10]1=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)c1nc(-c2ccc(C(F)(F)F)nc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2ccc(C(F)(F)F)nc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 41.8 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-(6-trifluoromethyl-pyridin-3-yl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (67 mg, 0.13 mmol), β-alanine (674 mg, 7.6 mmol) and NaOMe solution (11 mL, 5.7 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration. The crude solid was purified by silica gel chromatography (5-50% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 32 mg of the title compound as an off-white solid. MS: (+) m/z 589.30 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:24]2[CH2:25][CH2:26][CH:21]([C:19](=[O:20])[C:16]3[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=3)[CH2:22][CH2:23]2)=[O:10])=[N:6][CH:7]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Reactant: O=C(O)c1ccc(Br)cn1
Agent: Cl
Product: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc(Br)cn2)CC1
Yield: 99.1 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 27 and using 5-bromopyridine-2-carboxylic acid (1.2 g) and (4-chlorophenyl)piperidin-4-ylmethanone hydrochloride (1.6 g), the title compound (2.4 g) was obtained.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[S:10]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11]1>>[S:10]1[CH:14]=[CH:13][C:12]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=2)=[CH:11]1
Reactant: O=Cc1ccc(Br)nc1
Reactant: OB(O)c1ccsc1
Product: O=Cc1ccc(-c2ccsc2)nc1

Procedure:
Synthesized using compound 43c (840 mg, 4.52 mmol) and thiophen-3-ylboronic acid (867 g, 6.77 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (8:2) as eluent. Orange solid. Yield: 556 mg, 65%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=7.45 (dd, J=5.0, 2.8 Hz, 1H), 7.72-7.80 (m, 2H), 8.11 (dd, J=2.8, 1.3 Hz, 1H), 8.19 (dd, J=8.2, 2.2 Hz, 1H), 9.06 (dd, J=2.2, 0.9 Hz, 1H), 10.11 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=120.3, 126.3, 126.4, 126.9, 129.6, 136.5, 141.1, 152.6, 158.0, 190.2; (ESI): m/z=190.27 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=O)[C:3]=1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.[CH3:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH2:26][NH2:27]>C1(C)C=CC=CC=1>[CH3:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH2:26]/[N:27]=[CH:8]/[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CC(C)(C)CCN
Reactant: CC(C)(C)OC(=O)N1CCC(c2c(F)cccc2C=O)CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)CC/N=C/c1cccc(F)c1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a solution of tert-butyl 4-(2-fluoro-6-formylphenyl)piperidine-1-carboxylate (1.0 g, 4.23 mmol) in toluene (14 mL) was added 3,3 dimethylbutylamine (428.0 mg, 569.1 μL, 4.230 mmol) and 4 Å molecular sieves. The resulting solution was stirred at rt overnight. The molecular sieves were filtered off and the mixture concentrated in vacuo to give 1.5 g of tert-butyl 4-(2-((E)-(3,3-dimethylbutylimino)methyl)-6-fluorophenyl)piperidine-1-carboxylate as an off-white solid (1.5 g). The material was used without further purification for the next step. 1H-NMR in CD3CN of the crude was consistent for the product with a diagnostic peak of the imine proton @ 8.74 ppm.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23]([NH:36][C:37](=[O:39])[CH3:38])[S:24][C:25]=2[C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:17][CH:16]=1.O.NN>C(#N)C>[NH2:3][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[C:23]([NH:36][C:37](=[O:39])[CH3:38])[S:24][C:25]=2[C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:19][CH:20]=1
Reactant: CC(=O)Nc1nc(-c2ccc(CCCN3C(=O)c4ccccc4C3=O)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Agent: NN
Solvent: O
Solvent: CC#N
Product: CC(=O)Nc1nc(-c2ccc(CCCN)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-{4-{4-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]phenyl}-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide (53.2 mg) in acetonitrile (0.5 ml) was added hydrazine monohydrate (46.1 μl), and the mixture was stirred at 50° C. for 30 min. The volatiles were evaporated. To the mixture was added chloroform (1 ml), and an insoluble material was removed by filtration. The filtrate was purified by preparative thin-layer chromatography over NH silica gel with chloroform/methanol (10:1) as an eluent to give N-{4-[4-(3-aminopropyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide as a yellow solid.
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].[CH3:50][C:51]1([CH3:57])[CH2:56][O:55][CH2:54][CH2:53][NH:52]1>>[C:28]([C:32]1[N:33]=[C:34]([N:52]2[CH2:53][CH2:54][O:55][CH2:56][C:51]2([CH3:57])[CH3:50])[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC1(C)COCCN1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CCOCC2(C)C)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3,3-dimethylmorpholine and isolated as colorless gum (12.5 mg, 64%). MS (m/e): 415.4 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[NH:17][C:18](=S)[NH:19][C:20]=2[CH2:21][CH3:22])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]>[Ni].C(O)C>[C:12]([C:9]1[CH:8]=[C:7]([C:16]2[N:17]=[CH:18][NH:19][C:20]=2[CH2:21][CH3:22])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: CCc1[nH]c(=S)[nH]c1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Ni]
Solvent: CCO
Product: CCc1[nH]cnc1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 49.8 %

Procedure:
By following the same procedure as in Example 17 using 2 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethyl-2-thioxo-4-imidazoline, 50 ml of absolute ethanol, and 1 g of a Raney nickel catalyst and recrystallizing the reaction product from toluene, 0.9 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-ethylimidazole was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C1COCC1>[CH3:24][S:25]([O:16][CH2:15][CH2:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)CC1

Procedure:
A solution of 4-(2-hydroxyethyl)-piperidine-1-carboxylic acid tert-butyl ester (Aldrich, 0.50 g, 2.2 mmol), triethylamine (0.91 mL, 6.5 mmol), and methanesulfonyl chloride (0.25 mL, 3.3 mmol) in 10 mL THF were processed as described in Example 1C to give the crude title compound which was used directly in the next reaction.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O-:3])=[O:2].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[CH2:24]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1[nH]c2ccc([N+](=O)[O-])cc2c1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccccc2)c2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Temperature: 25 °C
Yield: 92.8 %

Procedure:
A solution of ethyl 5-nitro-3-phenyl-1H-indole-2-carboxylate (1.0 g, 3.23 mmol) and benzyl bromide (0.60 g, 3.5 mmol) in THF (50 mL) was treated with Cs2CO3 (3.26 g, 10 mmol) and heated to a gentle reflux for 16 h. After cooling to room temperature the reaction was quenched by addition of water and then partitioned between water and EtOAc. The organic phase was dried over MgSO4, and concentrated to yield ethyl 1-benzyl-5-nitro-3-phenyl-1H-indole-2-carboxylate as a yellowish solid (1.20 g, 93%): 1H NMR (DMSO-d6) δ 0.93 (t, J=7.0 Hz, 3H), 4.11 (q, J=7.0 Hz, 2H), 5.91 (s, 2H), 7.12 (d, J=8.3 Hz, 2H), 7.30-7.32 (m, 3H), 7.50-7.55 (m, 5H), 7.92 (d, J=9.2 Hz, 1H), 8.22 (dd, J=9.2, 2.0 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H); MS (EI) m/z 400.1 (MH+); Anal. calcd for C24H20N2O4: C, 71.99; H, 5.03; N, 7.00. Found: C, 71.77; H, 5.14; N, 6.71.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:32][CH3:33])=[C:4](/[C:17](/[CH2:30][CH3:31])=[C:18](/[F:29])\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([O:25]CC)=[O:24])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15].[OH-].[Na+]>C(O)C.C1COCC1>[Cl:1][C:2]1[C:3]([O:32][CH3:33])=[C:4](/[C:17](/[CH2:30][CH3:31])=[C:18](/[F:29])\[CH:19]=[CH:20]\[C:21](\[CH3:28])=[CH:22]\[C:23]([OH:25])=[O:24])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/CC)c1cc2c(c(Cl)c1OC)OC(C)(C)C=C2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC/C(=C(F)/C=C/C(C)=C/C(=O)O)c1cc2c(c(Cl)c1OC)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure G, a solution of ethyl 7-(8-chloro-4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-6-fluoro-3-methyl-nona-2E,4E,6E-trienoate (Compound 165, 179 mg, 0.38 mmol) in ethanol and THF was hydrolyzed with 1M NaOH to give rise to the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].[CH2:23](O)[CH3:24].S(=O)(=O)(O)O>C(Cl)CCl>[Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14](=[O:22])[C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:23][CH3:24])=[O:7]
Reactant: CCO
Reactant: O=C(O)COc1ccc(C(=O)c2ccc(O)cc2)c(Cl)c1Cl
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: CCOC(=O)COc1ccc(C(=O)c2ccc(O)cc2)c(Cl)c1Cl
Reaction time: 8 h
Yield: 93 %

Procedure:
85.38 g. (0.25 mole) of 2,3-dichloro 4-(4'-hydroxybenzoyl)-phenoxyacetic acid, 34.5 g. (0.75 mole) of ethanol, and 100 ml. of ethylene dichloride, using 3.5 ml. of sulfuric acid as the catalyst were mixed and refluxed with stirring overnight according to the procedure of Clinton and Laskowski, J.A.C.S. 70 3135, 1948. The acid gradually went into solution. The reaction layer was cooled, separated and the organic layer washed successively with water, twice with KHCO3 solution and finally with water. The dried ethylene dichloride was evaporated to dryness to give an oil which solidified to give 86 g. crude ester on trituration with pentane and filtering; m.p. 127°-9° (93% yield). This material was used without further purification in subsequent experiments.
Reaction SMILES: [CH2:1]([CH:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13]C)=[CH:10][CH:11]=2)[NH:6][CH2:5][CH2:4]1)[CH3:2].B(Br)(Br)Br.N#N>C(Cl)Cl>[CH2:1]([CH:3]1[C:12]2[C:7](=[CH:8][C:9]([OH:13])=[CH:10][CH:11]=2)[NH:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1CCNc2cc(OC)ccc21
Agent: BrB(Br)Br
Agent: N#N
Solvent: ClCCl
Product: CCC1CCNc2cc(O)ccc21
Temperature: 0 °C
Yield: 97.5 %

Procedure:
In a flame dried 100 mL rb flask equivuipped with a magnetic stir bar and a N2 gas inlet was dissolved (R/S)-4-ethyl-1,2,3,4-tetrahydro-7-methoxyquinoline (21 mg, 109.9 μmol) in CH2Cl2 (4 mL). The solution was cooled to 0° C. and a 1.0M solution of BBr3 in CH2Cl2 (0.33 mL, 320 μmol, 2.75 equiv) was added slowly by syringe. The solution was warmed to rt and stirred under a blanket of N2 for 9 h. The reaction was quenched by addition of sat. NaHCO3 solution (5 mL), extracted with CH2Cl2 (3×25 mL), washed with brine (2×20 mL), dried (Na2SO4) and concentrated in vacuo to give 19 mg (99%) of the desired phenolic amine as a clear yellow oil. Data for (R/S)-4-ethyl-1,2,3,4-tetrahydro-7-hydroxyquinoline: 1H NMR (400 MHz, CDCl3) 6.85 (d, J=8.1, 1H), 6.11 (dd, J=2.4, 8.3, 1H), 5.98 (d, J=2.4, 1H), 3.25 (m, 2H), 2.57 (m, 1H), 1.85 (m, 1H), 1.76 (m, 1H), 1.67 (m, 1H), 1.51 (m, 1H), 0.940 (t, J=7.4, 3H).
Reaction SMILES: Cl([O-])=O.[Na+].[F:5][CH:6]([F:18])[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][C:9]=1[O:16][CH3:17].S(=O)(=O)([OH:21])N.C(O)(=O)C>O>[F:5][CH:6]([F:18])[O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]([OH:21])=[O:13])=[CH:10][C:9]=1[O:16][CH3:17]
Reactant: NS(=O)(=O)O
Reactant: COc1cc(C=O)ccc1OC(F)F
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C(=O)O)ccc1OC(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 7.3 g of 80% strength sodium chlorite in 15 ml of water is added dropwise with continuous stirring to a mixture of 10.0 g of 4-difluoromethoxy-3-methoxybenzaldehyde, 6.5 g of sulphamic acid and 50 ml of glacial acetic acid. The internal temperature is kept between 30° and 35° C. by cooling with ice water. After dropwise addition is complete, the mixture is stirred for a further 1 h and then diluted with water. The precipitated 4-difluoromethoxy-3-methoxybenzoic acid is filtered off with suction, washed with water, dried in vacuo and crystallized from acetonitrile/petroleum ether (b.p. 40°) 2/8. Yield 7.1 g; m.p. 170° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C([O:19][C:20](=[O:34])[C@@H:21]([O:30][CH2:31][CH2:32][CH3:33])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)C.C1(C2C=CC=CC=2)C=CC(OCCOC2C=CC(C[C@H](OC)C(O)=O)=CC=2)=CC=1>>[C:8]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][O:29][C:26]2[CH:25]=[CH:24][C:23]([CH2:22][C@H:21]([O:30][CH2:31][CH2:32][CH3:33])[C:20]([OH:34])=[O:19])=[CH:28][CH:27]=2)=[CH:6][CH:7]=1
Reactant: CCCO[C@@H](Cc1ccc(O)cc1)C(=O)OCC
Reactant: BrCCOc1ccc(-c2ccccc2)cc1
Agent: CO[C@@H](Cc1ccc(OCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O
Product: CCCO[C@@H](Cc1ccc(OCCOc2ccc(-c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from 4-(2-bromo-ethoxy)-biphenyl (Example 377, Step 1) and (2S)-3-(4-hydroxy-phenyl)-2-propoxy-propionic acid ethyl ester (Example 377, Step 4) via the same procedure used for the preparation of (2S)-3-{4-[2-(biphenyl-4-yloxy)-ethoxy]-phenyl}-2-methoxy-propionic acid (Example 283, Step 3) to produce a white solid. MS (ES) for C26H28O5 [M+H]+: 421.0, [M+NH4]+: 438.0, [M+Na]+: 443.0, [M−H]−: 3239.2.
Reaction SMILES: [Cl-].[Cl:2]C=[N+](C)C.[C:7]([C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1)(O)=[O:8]>C(Cl)Cl>[CH:14]([C:13]1[CH:16]=[CH:17][C:10]([C:7]([Cl:2])=[O:8])=[CH:11][CH:12]=1)=[O:15]
Reactant: C[N+](C)=CCl
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: [Cl-]
Solvent: ClCCl
Product: O=Cc1ccc(C(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of (chloromethylene)dimethylammonium chloride (Vilsmeier Reagent; 37.7 g, 0.280 mol) in CH2Cl2 (300 mL) at 0° C. was treated with 4-carboxybenzaldehyde (40.0 g, 267 mmol) in one portion. The reaction mixture was stirred at 0° C. for 30 min, then at room temperature for 2 h. HPLC analysis of an aliquot of the reaction mixture quenched into MeOH indicated consumption of 4-carboxybenzaldehyde. The reaction mixture was filtered through a medium porosity glass frit. The filtrate, containing the title compound, was stored at 0° C., and used in the next step without further manipulation.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[CH3:19]O>>[CH3:6][O:7][C:8]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:9]=1[C:10]([O:12][CH3:19])=[O:11]
Reactant: COc1ccc(C(=O)O)c(OC)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OC)cc1OC

Procedure:
2.1 1 ml of conc. sulfuric acid is added to a solution of 100 g of 2,4-dimethoxybenzoic acid in 500 ml of methanol, and the mixture is refluxed for 14 hours. The mixture is cooled, the solvent is removed, the residue is dissolved in 1 litre of MTB, the solution is washed three times with 200 ml of water each time and dried, and the solvent is removed, giving 105.5 g of methyl 2,4-dimethoxybenzoate.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[SH:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]>>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([S:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[N:3][C:4]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)CCS
Reactant: Nc1ncc(Br)nc1Oc1ccccc1
Product: COC(=O)CCSc1cnc(N)c(Oc2ccccc2)n1

Procedure:
Prepared according to the method of Example from 5-Bromo-3-phenoxypyrazin-2-amine and methyl 3-mercaptopropanoate.
Reaction SMILES: C([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=O)=[CH:7][CH:6]=1)(C)(C)C.[NH2:14][CH:15]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH3:16]>>[C:8]([N:14]([CH2:9][C:8]1[CH:7]=[CH:6][CH:5]=[CH:13][CH:12]=1)[CH:15]([CH3:16])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])([CH3:12])([CH3:9])[CH3:7]
Reactant: CCCCCC(C)N
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Product: CCCCCC(C)N(Cc1ccccc1)C(C)(C)C

Procedure:
The N-t-butylbenzyl-N-(1-methylhexyl)amine was synthesized in the same manner as in Example 2, procedures 1 and 2 using 4-t-butylbenzoyl chloride and 2-aminoheptane as starting materials.