Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:7]([OH:12])(=[O:11])[C:8]([OH:10])=[O:9].[N:13]1([CH2:18][C:19]#[C:20][C:21]2[CH:50]=[CH:49][C:24]([CH2:25][C:26]3[C:27]4[CH:48]=[CH:47][CH:46]=[CH:45][C:28]=4[S:29][C:30]=3[C:31]3[CH:44]=[CH:43][C:34]([O:35][CH2:36][CH2:37][N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)=[CH:33][CH:32]=3)=[CH:23][CH:22]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1>N1C=CC=CC=1.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:7]([OH:12])(=[O:11])[C:8]([OH:10])=[O:9].[N:13]1([CH2:18]/[CH:19]=[CH:20]/[C:21]2[CH:22]=[CH:23][C:24]([CH2:25][C:26]3[C:27]4[CH:48]=[CH:47][CH:46]=[CH:45][C:28]=4[S:29][C:30]=3[C:31]3[CH:44]=[CH:43][C:34]([O:35][CH2:36][CH2:37][N:38]4[CH2:39][CH2:40][CH2:41][CH2:42]4)=[CH:33][CH:32]=3)=[CH:49][CH:50]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C(#Cc1ccc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1)CN1CCCC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: O=C(O)C(=O)O
Solvent: c1ccncc1
Product: C(=C/c1ccc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3ccccc23)cc1)\CN1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
A solution of 1-[2-[4-[3-[4-[3-(1-pyrrolidinyl)-1-propynyl]benzyl]benzo[b]thiophen-2-yl]phenoxy]ethyl]pyrrolidine (Example 129, Part D; 300 mg, 0.576 mmol) in 40 mL of pyridine was treated with a slurry of Lindlar catalyst (Pd/CaCO3, Pb poisoned; 100 mg) in 10 mL of pyridine. The resulting mixture was stirred under an atmospheric pressure of H2 at room temperature for 3 h. The reaction mixture was filtered through a pad of diatomaceous earth and concentrated in vacuo. Purification by radial chromatography (SiO2; 5% MeOH in CHCl3, saturated with NH4OH) gave 185 mg (0.354 mmol, 61%) of a yellow oil which was converted to the dioxalate salt according to the procedure described in Example 1, Part C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][C:21]3[S:22][C:23]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:24]=4[N:25]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([O:37]CC)=[O:36].[OH-].[Na+].C(O)C>C1COCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][C:21]3[S:22][C:23]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:24]=4[N:25]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4nc5ccc(C(F)(F)F)cc5s4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(Nc1nc2ccc(C(F)(F)F)cc2s1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 2 h
Yield: 73.6 %

Procedure:
Ethyl 6-chloro-7-(4-(6-(trifluoromethyl)benzo[d]thiazol-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (50 mg, 0.087 mmol) was diluted with THF (500 μL) followed by the addition of aqueous NaOH (433 μL, 0.43 mmol) and ethanol (100 μL). After stirring for 2 hours, the reaction was diluted with ethyl acetate and 0.5N aqueous HCl. The layers were separated and the organic layer was concentrated to yield 6-chloro-7-(4-(6-(trifluoromethyl)benzo[d]thiazol-2-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid (35 mg, 0.064 mmol, 74% yield). MS (apci, positive) m/z=548.8. 1H NMR (400 MHz, D6 DMSO) δ 13.06 (br s, 1H), 8.54 (s, 1H), 8.19 (d, 2H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.49 (s, 1H), 7.06 (d, 2H), 6.76 (s, 1H), 4.30-4.26 (m, 1H), 4.10 (dt, 1H), 3.86 (t, 1H), 2.26-2.20 (m, 1H), 2.11-2.02 (m, 1H).
Reaction SMILES: [Na][Na].[C:3]([NH:5][C:6](=[O:15])[CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]#[N:14])=[O:11])#[N:4].[N+:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)([O-:18])=[O:17]>CN(C)C=O>[C:13]([N:12]([CH2:23][C:22]1[CH:25]=[CH:26][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=1)[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]([N:5]([CH2:23][C:22]1[CH:25]=[CH:26][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=1)[C:3]#[N:4])=[O:15])#[N:14]
Reactant: N#CNC(=O)CCCC(=O)NC#N
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [Na][Na]
Solvent: CN(C)C=O
Product: N#CN(Cc1ccc([N+](=O)[O-])cc1)C(=O)CCCC(=O)N(C#N)Cc1ccc([N+](=O)[O-])cc1

Procedure:
22.4 g (0.1 mol) of the disodium salt of glutaric acid bis-(N-cyanamide) and 51.85 g (0.2 mol+20% excess) of 4-nitrobenzyl bromide are reacted in 120 ml of dimethylformamide at 36°-40° C. for 1 hour and the mixture is worked up in a manner similar to that in Example 2. 44.3 g (98.4% of theory) of a yellowish crystalline crude product are obtained, and are recrystallised from 440 ml of ethyl acetate. 31.5 g (70.0% of theory) of a colourless, crystalline product of a melting point 146.2°-148.2° C. are obtained.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2C=CC=CC=2)[CH2:4]1.CC([O:19]C(OC(OC(C)(C)C)=O)=O)(C)C.C(Cl)(C)=O.CCN(C(C)C)C(C)C.C(C(O)=O)(F)(F)F>[Pd].C(Cl)Cl.CCO.CO>[CH3:1][NH:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8](=[O:19])[CH3:9])[CH2:4]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CNC1CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)Cl
Solvent: CO
Product: CNC1CCN(C(C)=O)C1

Procedure:
3-(Methylamino)-1-acetylpyrrolidine was prepared from 3-(methylamino)-1-benzylpyrrolidine (TCI America) after four steps: i) (Boc)2O, MeOH, rt; ii) H2 (1 atm), 10% Pd/C, EtOH; iii) AcCl, i-Pr2NEt, CH2Cl2; iv) CF3CO2H, CH2Cl2. (m/z): [M+H]+ calcd for C7H14N2O: 143.12; found, 143.0.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH:8]1[CH2:10][O:9]1)([O-:3])=[O:2].C(O)(=O)C(O)=[O:17].O1CCOCC1>O>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH:8]([OH:17])[CH2:10][OH:9])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1OCC1CO1
Reactant: O=C(O)C(=O)O
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccccc1OCC(O)CO
Yield: 13 %

Procedure:
To a stirred solution of 38 parts of 2-(2-nitrophenoxymethyl)-oxirane in 10 parts of ethanedioic acid and 300 parts of 1,4-dioxane are added 100 parts of water. The whole is stirred and refluxed for 2 days. The reaction mixture is evaporated and the residue is crystallized from a mixture of 2,2'-oxybispropane and petroleumether. The product is filtered off and recrystallized from 2,2'-oxybispropane, yielding 29.5 parts (13%) of 3-(2-nitrophenoxy)-1,2-propanediol; mp. 96° C..
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:15][NH:16][C:17]3[C:18]([CH3:32])=[C:19]([CH:28]=[CH:29][C:30]=3[CH3:31])[O:20][CH2:21][C:22]([O:24]C(C)C)=[O:23])[CH:11]=[C:12]([OH:14])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:15][NH:16][C:17]3[C:18]([CH3:32])=[C:19]([CH:28]=[CH:29][C:30]=3[CH3:31])[O:20][CH2:21][C:22]([OH:24])=[O:23])[CH:11]=[C:12]([OH:14])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(OCC(=O)OC(C)C)c(C)c1NCc1cc(O)cc(-c2cccc(F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(OCC(=O)O)c(C)c1NCc1cc(O)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of isopropyl 2-[3-[[3-(3-fluorophenyl)-5-hydroxy-phenyl]methylamino]-2,4-dimethyl-phenoxy]acetate (100 mg, 0.22 mmol, 1.0 eq) in THF (10 mL) at 0° C. was added NaOH (1M aqueous solution, 3 mL, 3 mmol). The reaction mixture was stirred at room temperature overnight then the THF was removed under reduced pressure. The remaining aqueous solution was poured into water and adjusted to pH 4-6 by addition of diluted HCl. The solid that precipitated was collected by filtration, washed with water and dried in vacuo to give the title compound as a yellow solid (60 mg, 66%).
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[C@@H:14]2[CH2:16][C:15]2([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=CC=1)([O-])=O.[CH3:34][C@@H:35]([NH2:45])[CH2:36][CH2:37][CH2:38][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1>O1CCCC1>[CH3:32][O:31][C:27]1[CH:26]=[C:25]([C:15]2([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[CH2:16][C@@H:14]2/[CH:13]=[CH:12]/[C:11]([NH:45][C@@H:35]([CH3:34])[CH2:36][CH2:37][CH2:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[O:10])[CH:30]=[CH:29][CH:28]=1
Reactant: C[C@@H](N)CCCc1cccnc1
Reactant: COc1cccc(C2(c3cccc(OC)c3)C[C@H]2/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Solvent: C1CCOC1
Product: COc1cccc(C2(c3cccc(OC)c3)C[C@@H]2/C=C/C(=O)N[C@@H](C)CCCc2cccnc2)c1
Yield: 60.3 %

Procedure:
As in example 141, (S)-(E)-3-[2,2-bis(3-methoxyphenyl)cyclopropyl]-2-propenoic acid 4-nitrophenyl ester (2.2 g) was reacted with (R)-alpha-methyl-3-pyridinebutanamine (0.81 g) in tetrahydrofuran (15 mL) at ambient temperature overnight. The crude product, isolated in the usual manner, was purified by HPLC (ethyl acetate) and then crystallized from ethyl acetate-hexane to give 1.4 g of (S,R*)-(E)-3-[2,2-bis(3-methoxyphenyl)-cyclopropyl]-N-[1-methyl-4-(3-pyridinyl)butyl]-2-propenamide, mp 104°-106° C.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[C:10]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:18][C:8]=2[C:7]=1[OH:25])=[O:5])C.[NH2:26][CH2:27][C:28]([OH:30])=[O:29]>C[O-].[Na+].CO>[OH:25][C:7]1[C:8]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:16][C:9]=2[C:10]([CH2:12][CH:13]([CH3:15])[CH3:14])=[N:11][C:6]=1[C:4]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:5]
Reactant: CCOC(=O)c1nc(CC(C)C)c2nc(-c3ccccc3)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)Cc1nc(C(=O)NCC(=O)O)c(O)c2sc(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 77.8 %

Procedure:
A mixture of 7-hydroxy-4-isobutyl-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (35 mg, 0.10 mmole) and glycine (146 mg, 1.95 mmole) in 0.5 M sodium methoxide/methanol (3.7 ml) was refluxed for 4 days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (12 ml) and extracted three times with methyl t-butyl ether. The remaining aqueous layer was acidified to pH=3 with 1N HCl (2.5 ml). The solid precipitate was filtered, washed with water and dried in vacuo to give the title compound as a white solid (30 mg). 1H NMR (DMSO-d6, 200 MHz): δ=9.18 (br s, 1H), 8.15 (m, 2H), 7.62 (m, 3H), 4.02 (d, J=5.9 Hz, 2H), 3.12 (d, 2H, J=7.4 Hz), 2.41 (m, 1H), 0.93 (d, 2H, J=6.6 Hz); MS: (+) m/z 385.98 (M+1); (−) m/z 383.99 (M−1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([OH:22])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.ClC(OCC)=O.C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:22][C:14]3[C:15]([CH2:19][CH2:20][CH3:21])=[CH:16][C:17]([Cl:18])=[C:10]([OH:9])[C:11]=3[C:12]=2[CH3:13])=[CH:23][CH:24]=1
Reactant: CCCc1cc(Cl)c2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCc1cc(Cl)c(O)c2c(C)c(Cc3ccc(OC)cc3)oc12
Yield: 100 %

Procedure:
A solution of 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (0.10 gm, 0.29 mmoles), ethyl chloroformate (0.1 mL) and triethylamine (1.0 mL) in tetrahydrofuran (15 mL) was stirred at room temperature overnight. The volatiles were removed in vacuo. The residue was purified by chromatography on silica gel and eluted with 15% ethylacetate in hexane to yield 100 mg (91%) of 2 (p-methoxybenzyl) 3 methyl 4 ethoxycarbonyloxy 5 -5-propyl 7 chlorobenzofuran, mp. 99°-100° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[N:15]([S:19]([CH2:22][CH:23](O)[CH2:24][CH2:25][CH2:26][CH3:27])(=[O:21])=[O:20])[CH:16]([CH3:18])[CH3:17].N12CCCCC1CNCC=C2.Cl>C(Cl)Cl.S(Cl)(C)(=O)=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[N:15]([S:19]([CH:22]=[CH:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:20])=[O:21])[CH:16]([CH3:18])[CH3:17]
Reactant: CCCCC(O)CS(=O)(=O)N(c1ccc(C(F)(F)F)cc1OCOC)C(C)C
Agent: C1=CN2CCCCC2CNC1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CCCCC=CS(=O)(=O)N(c1ccc(C(F)(F)F)cc1OCOC)C(C)C
Reaction time: 0.17 h
Yield: 91.3 %

Procedure:
To a solution of 2-(N-isopropyl-2-hydroxyhexylsulfonylamino)-5-trifluoromethylphenyl methoxymethyl ether (160 mg; prepared in Reference Example 31.) in methylene chloride (2.0 ml), triethylamine(104 μl) and mesylchloride (35μl) were added in a stream of argon at 0° C. The mixture was stirred for 10 minutes. To the mixture, 1,5-diazabicyclo[5,4,0]undecene (134 μl) was added. The mixture was stirred for 2 hours at room temperature. To the reaction mixture, diluted HCl was added. The mixture was extracted with ethyl acetate, washed, dried over and concentrated with the reduced pressure. The residue was purified on silica gel column chromatography (hexane:AcOEt=8:1) to give the title compound (140 mg) having the following physical data.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:20]([NH:22][CH2:23][CH2:24][C:25]1[CH:32]=[CH:31][C:29]([OH:30])=[C:27]([OH:28])[CH:26]=1)=[O:21])[C@@H:10]([CH3:19])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)(C)(C)C.[C:33]([OH:45])(=O)/[CH:34]=[CH:35]/[C:36]1[CH:43]=[CH:42][C:40]([OH:41])=[C:38]([OH:39])[CH:37]=1>>[C:33]([NH:8][C@H:9]([C:20]([NH:22][CH2:23][CH2:24][C:25]1[CH:32]=[CH:31][C:29]([OH:30])=[C:27]([OH:28])[CH:26]=1)=[O:21])[C@@H:10]([CH3:19])[O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:45])/[CH:34]=[CH:35]/[C:36]1[CH:43]=[CH:42][C:40]([OH:41])=[C:38]([OH:39])[CH:37]=1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)NCCc1ccc(O)c(O)c1
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)/C=C/c1ccc(O)c(O)c1)C(=O)NCCc1ccc(O)c(O)c1

Procedure:
The title compound was prepared from N-[Nα-(tert-butoxycarbonyl)-O-benzyl-L-threonyl]dopamine (1.0 g, 2.3 mmol, example 9, step A) as described for example 9 (step B) using caffeic acid (620 mg, 3.4 mmol) instead of 3,4-dihydroxybenzoic acid. The crude material was purified by flash chromatography using 30% EtOAc/CHCl3 and 5% MeOH/CHCl3 as the eluent. The title compound was obtained as yellow crystals (717 mg, 62%).
Reaction SMILES: C=CCCCCCC.B1[CH:14]2[CH2:15][CH2:16][CH2:17][CH:10]1[CH2:11][CH2:12][CH2:13]2.Br[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][C:28]=1[CH2:29][CH3:30])[O:25][C:24]([C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[C:33]([O:47][CH3:48])[CH:32]=1)=[C:23]([OH:49])[C:22]2=[O:50]>O1CCCC1.[OH-].[Na+]>[CH2:29]([C:28]1[CH:27]=[C:26]2[C:21]([C:22](=[O:50])[C:23]([OH:49])=[C:24]([C:31]3[CH:32]=[C:33]([O:47][CH3:48])[C:34]([O:39][CH2:40][C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)=[C:35]([O:37][CH3:38])[CH:36]=3)[O:25]2)=[CH:20][C:19]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:10])[CH3:30]
Reactant: CCc1cc2oc(-c3cc(OC)c(OCc4ccccc4)c(OC)c3)c(O)c(=O)c2cc1Br
Reactant: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C=CCCCCCC
Product: CCCCCCCCc1cc2c(=O)c(O)c(-c3cc(OC)c(OCc4ccccc4)c(OC)c3)oc2cc1CC
Reaction time: 7 h

Procedure:
To a stirring solution of 1-octene (0.032 g, 0.3 mmol, 1.4 eq) in tetrahydrofuran (1 ml) under argon at 0° C. was added 9-BBN in tetrahydrofuran (0.5M, 0.6 ml, 0.3 mmol, 1.5 eq). The reaction was stirred for 7 hours then 6-bromo-7-ethyl-3-hydroxy-2-(4-benzyloxy-3,5-dimethoxy-phenyl)-chromen-4-one 57 (0.102 g, 0.2 mmol) in tetrahydrofuran (4 ml), 3M NaOH solution (0.2 ml) and dichloropalladium(dppf) (0.005 g, 0.006 mmol, 0.03 eq) were added and the reaction heated to reflux for 15 hours. The reaction was then quenched with water and diethyl ether and acidified (6 M HCl). The organic layer was collected and the aqueous layer extracted with dichloromethane. The combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to give a red oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH:16]([CH:17]([CH3:19])[CH3:18])[C:15](=[O:20])[O:14]C1=O.FC(F)(F)C1C=CC(N2C(C(C)C)C(=O)OC2=O)=CC=1.C(C1C=C(C=CC=1)C=O)(=O)C1C=CC=CC=1.[C-]#N.[K+]>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C@H:16]([C:15]([OH:20])=[O:14])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)C1C(=O)OC(=O)N1c1ccc(C(F)(F)F)cc1F
Agent: CC(C)C1C(=O)OC(=O)N1c1ccc(C(F)(F)F)cc1
Agent: O=Cc1cccc(C(=O)c2ccccc2)c1
Agent: [C-]#N
Product: CC(C)[C@H](Nc1ccc(C(F)(F)F)cc1F)C(=O)O

Procedure:
Each of 3-(2-fluoro-4-trifluoromethylphenyl)-4-isopropyloxazolidine-2,5-dione and 3-(4-trifluoromethylphenyl)-4-isopropyloxazolidine-2,5-dione, prepared by the procedure of Example 77, is reacted with m-benzoylbenzaldehyde and potassium cyanide using the procedure of Example 71 to yield the m-benzoyl α-cyanobenzyl ester of N-(2-fluoro-4-trifluoromethylphenyl)valin and the m-benzoyl-α-cyanobenzyl ester of N-(4-trifluoromethylphenyl)valine.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5])C.[OH-].[K+]>C(O)C>[CH3:24][O:23][C:20]1[N:19]=[C:18]([O:25][CH3:26])[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][N:21]=1
Reactant: CCOC(=O)c1cn(-c2cccc(-c3cnc(OC)nc3OC)c2)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ncc(-c2cccc(-n3cnc(C(=O)O)c3)c2)c(OC)n1

Procedure:
This compound is prepared by hydrolysis of 9m using a 1:1 mixture of aqueous potassium hydroxide (2M) and ethanol.
Reaction SMILES: [CH3:1][S:2]([O-:4])=[O:3].[Na+].Br[C:7]1[C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].CCN(C(C)C)C(C)C.CS(C)=O>CCOC(C)=O.[O-]S(C(F)(F)F)(=O)=O.[Cu+2].[O-]S(C(F)(F)F)(=O)=O>[CH3:1][S:2]([C:7]1[C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10])(=[O:4])=[O:3]
Reactant: CS(=O)[O-]
Reactant: Nc1cccc(Br)c1[N+](=O)[O-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CS(=O)(=O)c1cccc(N)c1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
To a mixture of copper(II) triflate (0.83 g, 2.3 mmol), sodium methanesulfinate (2.8 g, 27.6 mmol), 3-bromo-2-nitroaniline (5.0 g, 23 mmol) under N2, was added DIEA (0.50 mL, 4.6 mmol) and DMSO (10 mL). The stirred mixture was heated in a pre-heated 110° C. oil bath for 18 h. The mixture was cooled to rt, diluted with EtOAc, and filtered through a pad of Celite™. The filtrate was washed with water, brine, dried and concentrated in vacuo. Purification of the residue by flash chromatography over silica gel, using 0 to 10% gradient of MeOH in DCM with 0.2% NH4OH as eluent gave 3-(methylsulfonyl)-2-nitroaniline: 1H NMR (400 MHz, CDCl3) δ 7.44 (1H, dd, J=8.0, 4.0 Hz), 7.35 (1H, t, J=8.0 Hz), 7.02 (1H, dd, J=8.0, 4.0 Hz), 5.04 (2H, br), 3.36 (3H, s); LC-MS (ESI) m/z 217.0 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][CH2:6]2)#N.O.O.[PH2]([O-])=[O:28].[Na+]>C(O)(=O)C.N1C=CC=CC=1.[Ni]>[CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][CH2:6]2)=[O:28]
Reactant: CCOC(=O)C1c2ccc(C#N)cc2CCN1C(=O)OC(C)(C)C
Reactant: O=[PH2][O-]
Agent: [Ni]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C1c2ccc(C=O)cc2CCN1C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
To a solution of 1-ethyl 2-tert-butyl 6-cyano-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (0.5 g, 1.51 mmol) in acetic acid (5.00 mL) and pyridine (10 mL) was added a mixture of Raney-nickel (0.5 g, 1.51 mmol) and water (5 mL), and then sodium hypophosphite monohydrate (2.5 g, 23.59 mmol) was added thereto under argon atmosphere. The mixture was stirred at 60° C. for 3 hr, and then overnight at 100° C. The reaction mixture was filtered through Celite, and the filtrate was diluted with ethyl acetate. The mixture was washed with aqueous ammonium chloride solution, aqueous sodium hydrogencarbonate solution and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5→70% ethyl acetate/hexane) to give 1-ethyl 2-tert-butyl 6-formyl-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate (0.430 g, 1.290 mmol, 85%) as a colorless oil.
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:4]([C:20]2[CH:25]=[CH:24][C:23]([S:26](=[O:29])(=[O:28])[NH2:27])=[CH:22][CH:21]=2)=[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[CH3:30][N:31]([CH:33]=O)[CH3:32].COC(OC)N(C)C>C(OCC)(=O)C>[Br:1][CH2:2][C:3]1[C:4]([C:20]2[CH:25]=[CH:24][C:23]([S:26](=[O:28])(=[O:29])[N:27]=[CH:30][N:31]([CH3:33])[CH3:32])=[CH:22][CH:21]=2)=[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1sc(-c2ccc(Cl)cc2)c(CBr)c1-c1ccc(S(N)(=O)=O)cc1
Reactant: CN(C)C=O
Agent: COC(OC)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1sc(-c2ccc(Cl)cc2)c(CBr)c1-c1ccc(S(=O)(=O)N=CN(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.7 %

Procedure:
To a stirred suspension of Ethyl 4-(bromomethyl)-5-(4-chlorophenyl)-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (compound 35a, 2.7 g, 5.24 mmol) in ethyl acetate (30 ml) were added DMF (1.91 g, 2.01 ml, 26.2 mmol) and N, N-Dimethylformamide dimethyl acetal (DMF-acetal) (0.69 g, 0.76 ml, 5.76 mmol) under a nitrogen atmosphere at room temperature (about 25° C.). The reaction mixture was then stirred at room temperature (about 25° C.) for 4 hr. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure to obtain 2.9 g of crude product. The crude product so obtained was then purified by column chromatography over silica gel (100-200 mesh) using 1.5% methanol in DCM as an eluent to obtain the title compound (2.2 g, 73.82%).
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:19][C:20]1[S:21][C:22]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:23]=2[N:24]=1.[Br:30]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:30][CH2:19][C:20]1[S:21][C:22]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:23]=2[N:24]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2cc(F)ccc2s1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc2sc(CBr)nc2c1
Yield: 6.6 %

Procedure:
127 mg of dibenzoyl peroxide were added to a solution of 8.79 g of 2-methyl-5-fluorobenzothiazole and 20.6 g of N-bromosuccinimide in 88 ml of carbon tetrachloride at room temperature and the resulting mixture was stirred under reflux for 6 hours. At the end of this time, the reaction mixture was filtered and the resulting filtrate was concentrated by evaporation under reduced pressure to give a crude crystalline solid which was purified by column chromatography through silica gel using a 10:1 by volume mixture of hexane and ethyl acetate to give 850 mg (yield 7%) of the title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:17][CH:18]=[CH:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17]/[CH:18]=[CH:19]/[C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: BrCC=Cc1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OC/C=C/c2ccc3ccccc3c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 48.9 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.01 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.262 g), stirred for 15 minutes and treated with 2-(3-bromo-1-propenyl)naphthalene (1.7 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material from dichloromethane extraction was purified by HPLC (dichloromethane-hexane; 4:1) and crystallized from dichloromethane-diethyl ether to provide 0.95 g of (E)-4-[[3-(2-naphthalenyl)-2-propenyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 100°-102° C.