Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[NH:16][S:15]2(=[O:24])=[O:23])=[CH:10][CH:9]=1.[Br:25][CH2:26][CH2:27][CH2:28][CH2:29]Br>CN(C=O)C.C(OCC)C>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][N:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:14]([C:11]2[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=2)[S:15]1(=[O:23])=[O:24]
Reactant: BrCCCCBr
Reactant: O=S1(=O)Nc2ccccc2N1c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=S1(=O)N(CCCCBr)c2ccccc2N1c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 59 %

Procedure:
Cesium carbonate (0.29 g, 0.9 mmol) was added to a solution of 1-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (Made analogously as in general procedure I, 0.25 g, 0.9 mmol), and 1,4-dibromobutane (0.42 mL, 3.6 mmol) in dry DMF (5.0 mL) under nitrogen. After 3 h, the reaction mixture was diluted with diethyl ether and washed with water and brine. The ether layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give 0.41 g of crude product. The crude product was pre-adsorbed onto Celite and purified via Isco chromatography (Redisep, silica, gradient 5-30% ethyl acetate in hexane) to afford 0.22 g (59%) of 1-(4-bromobutyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide.
Reaction SMILES: [C:1]([C:3]1[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)=[CH:7][C:6]([NH:16][C@H:17]([CH2:21][O:22][CH3:23])[C:18]([NH2:20])=[O:19])=[C:5]([F:24])[CH:4]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:31]>CCO.CS(C)=O>[NH2:20][C:18](=[O:19])[C@H:17]([NH:16][C:6]1[C:5]([F:24])=[CH:4][C:3]([C:1]([NH2:2])=[O:31])=[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[CH:7]=1)[CH2:21][O:22][CH3:23]
Reactant: COC[C@@H](Nc1cc(Nc2cc(C)ns2)c(C#N)cc1F)C(N)=O
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: COC[C@@H](Nc1cc(Nc2cc(C)ns2)c(C(N)=O)cc1F)C(N)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of (R)-2-(4-cyano-2-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)-3-methoxypropanamide (10 mg, 0.028 mmol) in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.5 mL, 0.50 mmol) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 20 min. HOAc (0.5 mL) was added. The mixture was purified by HPLC to give the titled compound (9 mg). MS 368.2 (M+H); UV 219.3, 282.9, 302.6 nm.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]3[CH:13]=[CH:14][CH:15]=[C:8]23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[C:23]1(=[O:29])[O:28][C:26](=[O:27])[CH2:25][CH2:24]1.CC(=O)OCC.CO>CC#N.CC(=O)OCC>[O:29]=[C:23]([N:12]1[CH2:11][CH2:10][N:9]2[CH:13]=[CH:14][CH:15]=[C:8]2[CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:24][CH2:25][C:26]([OH:28])=[O:27]
Reactant: O=C1CCC(=O)O1
Reactant: c1ccc(C2NCCn3cccc32)cc1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)CCC(=O)N1CCn2cccc2C1c1ccccc1
Reaction time: 16 h
Yield: 43.7 %

Procedure:
1-Phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (A2) (396 mg, 2.0 mmol) and NEt3 (277 μl, 2.0 mmol) were added to a suspension of succinic anhydride (176 mg, 1.76 mmol) in MeCN (28 ml), and stirring was carried out for 16 h at RT. The mixture was then diluted with EA (30 ml) and washed with 2N hydrochloric acid (2×5 ml). The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was taken up in EA (50 ml) and again washed with 2N hydrochloric acid (20 ml) and then with a sat. aq. sodium carbonate solution (2×30 ml). The organic phase was again dried over MgSO4, filtered and concentrated in vacuo. CC (EA/MeOH 3:1) with the residue yielded 230 mg (0.77 mmol, 44%) of 4-oxo-4-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)butanoic acid (S3).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24](O)=[O:25])=[C:12]2[C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[BH4-].[Na+].Cl>O1CCCC1.CN(C)C=O.COCCOC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:13]([CH2:24][OH:25])=[C:12]2[C:27]1[S:28][CH:29]=[CH:30][CH:31]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Cn1c(C(=O)O)c(-c2cccs2)c2cc(OCc3ccccc3)ccc2c1=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CC(C)Cn1c(CO)c(-c2cccs2)c2cc(OCc3ccccc3)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of 6-(benzyloxy)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinecarboxylic acid (1.52 g, 3.5 mmol) in tetrahydrofuran (20 ml) were added oxalyl chloride (0.37 ml, 4.2 mmol) and N,N-dimethylformamide (2 drops). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 ml). The solution was added dropwise to a suspension of sodium tetrahydroborate (0.47 g, 12.3 mmol) in 1,2-dimethoxyethane (20 ml) at 0° C., and the mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 6-(benzyloxy)-3-(hydroxymethyl)-2-isobutyl-4-(2-thienyl)-1(2H)-isoquinolinone (1.36 g, 92.5%) as crystals.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:68])[C:49]4[CH:50]=[CH:51][N:52]5[C:65](=[O:66])[N:64]([CH3:67])[N:63]=[C:53]5[C:54]=4[O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:77]>CO.O>[ClH:77].[NH2:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:48](=[O:68])[C:49]4[CH:50]=[CH:51][N:52]5[C:65](=[O:66])[N:64]([CH3:67])[N:63]=[C:53]5[C:54]=4[O:55][C:56]=3[C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: Cn1nc2c3oc(-c4ccccc4)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(=O)c3ccn2c1=O
Agent: Cl
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cn1nc2c3oc(-c4ccccc4)c(-c4ccc(C5(N)CCC5)cc4)c(=O)c3ccn2c1=O
Yield: 77 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(2-methyl-3,6-dioxo-8-phenyl-2,6-dihydro-3H-9-oxa-1,2,3a-triaza-cyclopenta[a]naphthalen-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was treated with TFA. The resultant free base was dissolved in a mixture of MeOH (1.5 mL), water (3.5 mL) and 1 M HCl (0.1 mL) and chromatographed on a 5 g C18 cartridge {30 to 70% MeOH in water+1 M HCl (60 μL in each 10 mL of eluent)} to give the title compound as a white solid (13.5 mg, 77%). 1H NMR (400 MHz, DMSO-d6): δ 8.62 (br s, 3H), 7.86 (d, J=7.2 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.47-7.37 (m, 5H), 7.30 (d, J=8.3 Hz, 2H), 7.00 (d, J=7.2 Hz, 1H), 3.65 (s, 3H), 2.61-2.49 (m, 4H), 2.23-2.12 (m, 1H), 1.85-1.74 (m, 1H). LCMS (Method E): RT=2.95 min, [M+H]+=439.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([N:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]2=[O:13])=[CH:2]1.C(O[CH:19](N(C)C)[N:20]([CH3:22])[CH3:21])(C)(C)C>CN(C)C=O>[CH3:19][N:20]([CH3:22])[CH:21]=[CH:12][C:9]1[CH:10]=[CH:11][N:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)[C:7](=[O:13])[CH:8]=1
Reactant: Cc1ccn(-c2ccoc2)c(=O)c1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Cc1ccn(-c2ccoc2)c(=O)c1
Temperature: 150 °C

Procedure:
A mixture of 1-furan-3-yl-4-methyl-1H-pyridin-2-one (3.7 g, 21 mmol), tert-butoxybis(dimethylamino)methane (11 g, 63 mmol), and N,N-dimethylformamide (4 mL) is heated in a 150° C. oil bath for 2½ hours and then concentrated to dryness under reduced pressure. A quantitative yield of 4-(2-dimethylamino-vinyl)-1-furan-3-yl-1H-pyridin-2-one is assumed, and the material is carried on without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[O:21]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22]1>>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:26]([C:23]3[CH:24]=[CH:25][O:21][CH:22]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1ccoc1
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4ccoc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 53.8 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50 mg, 0.148 mmol) and 3-Furaldehyde (15.6 mg, 0.163 mmol) were reacted to produce 33 mg (54%) of the title compound. mp: 231-232° C., 1H NMR (300 MHz, DMSO-d6): 13.1 (s, 1H), 8.31 (s, 1H), 8.00 (s, 1H), 7.84 (s, 1H), 7.74 (br s, 1H), 7.21 (s, 1H), 7.10 (d, J=8 Hz, 1H), 7.01 (s, 1H), 6.40 (br s, 1H), 6.33 (br s, 1H), 5.15 (t, J=8 Hz, 1H), 2.87 (s, 1H), 2.74 (s, 1H), 2.60 (d, J=8 Hz, 1H), 2.23 (d, J=8 Hz, 1H), 1.37 (d, J=8 Hz, 1H). MS: 414-416 (M+H), HPLC: 2.27 min (G method)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20]OS(C)(=O)=O)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].[OH:33][CH2:34][C:35]1[O:39][C:38]([CH2:40][N:41]2[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[N:43]=[C:42]2[NH:50][CH:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)=[CH:37][CH:36]=1>>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:54]2[CH2:53][CH2:52][CH:51]([NH:50][C:42]3[N:41]([CH2:40][C:38]4[O:39][C:35]([CH2:34][OH:33])=[CH:36][CH:37]=4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:56][CH2:55]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Reactant: OCc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)o1
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4Cc4ccc(CO)o4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 1.6 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-methanesulfonyloxyethyl)-3-phenylpyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) and (1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine to give the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[C:3]([O:5][CH2:6][C:7](=[O:14])[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:4].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.CCC(COC(C(N(CC[NH+](C)C)C)=O)(C1C=CC=CC=1)C1C=CC=CC=1)CC.[Cl-].[OH-].[Na+]>C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1>[CH3:1][C:2]([CH3:16])([CH3:15])[C:3]([O:5][CH2:6][C@H:7]([OH:14])[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: CC(C)(C)C(=O)OCC(=O)c1cccnc1
Agent: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CC(C)(C)C(=O)OC[C@H](O)c1cccnc1
Reaction time: 2 h
Yield: 104.1 %

Procedure:
2-Oxo-2-pyridin-3-ylethyl 2,2-dimethylpropanoate (2 g), 2.8 g of glucose, 2.3 mg of NADP and 0.02 ml of Triton X-100 were added to 20 ml of the same culture fluid as used in Example 11, and the reaction was carried at 30° C. with stirring for 2 hours while adjusting the pH to 6.5 with a 5 N aqueous sodium hydroxide solution. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the extract was concentrated under reduced pressure to give 2.1 g of (R)-2-hydroxy-2-pyridin-3-ylethyl 2,2-dimethylpropanoate as a light-yellow oil. The optical purity was determined by the same method as used in Example 10 and was 100% ee.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:6]=[C:5](OC)[C:4]=1[C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[C:22]([O:24]C)=[O:23].B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:6]=[C:5]2[C:4]=1[C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[C:22](=[O:24])[O:23]2
Reactant: CCCCCc1cc(OC)c([C@@H]2CCCC[C@H]2C(=O)OC)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCc1cc(O)c2c(c1)OC(=O)[C@@H]1CCCC[C@@H]21
Reaction time: 0.33 h
Yield: 46.2 %

Procedure:
260 mg (0.75 mmol) of methyl trans-2-(2,6-dimethoxy-4-pentylphenyl)cyclo-hexanecarboxylate were initially introduced in 10 ml of dichloromethane, and 191 μl (2 mmol) of boron tribromide were added at −70° C. After 20 min, the cooling was removed, and the batch was hydrolysed at 0° C. using sat. sodium hydrogencarbonate soln. The mixture was extracted with dichloromethane, dried over sodium sulfate and evaporated. Chromatography with heptane/ethyl acetate (7:1) gave 100 mg (45%) of (6aR*,10aR*)-1-hydroxy-3-pentyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-6-one as a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:20]([OH:23])(=[O:22])=[O:21])[CH:5]=[C:6]2[C:11]=1[C:10]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9][C:8]([S:16]([OH:19])(=[O:18])=[O:17])=[CH:7]2.C1C(N=NC2C(=O)N(C3C=CC(S([O-])(=O)=O)=CC=3)N=C2C([O-])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[N+:64]([C:67]1[CH:72]=[C:71]([CH3:73])[C:70]([S:74](Cl)(=[O:76])=[O:75])=[CH:69][CH:68]=1)([O-:66])=[O:65]>O>[N+:64]([C:67]1[CH:72]=[C:71]([CH3:73])[C:70]([S:74]([NH:1][C:2]2[CH:3]=[C:4]([S:20]([OH:23])(=[O:22])=[O:21])[CH:5]=[C:6]3[C:11]=2[C:10]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9][C:8]([S:16]([OH:19])(=[O:17])=[O:18])=[CH:7]3)(=[O:76])=[O:75])=[CH:69][CH:68]=1)([O-:66])=[O:65]
Reactant: Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c12
Reactant: Cc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Agent: O=C([O-])C1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1N=Nc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1S(=O)(=O)Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 841.4 %

Procedure:
A mixture of 17.0 g of 8-amino-1,3,6-naphthalenetrisulfonic acid, trisodium salt, 17.5 g of the preceding compound and 7.8 g of anhydrous sodium carbonate in 210 ml of water is stirred at room temperature for 18 hours, then an additional 0.5 g of sodium carbonate and 1.0 g of 5-nitro-o-toluenesulfonyl chloride is added and stirring is continued for 18 hours longer. The reaction mixture is evaporated and 100 ml of water is added with stirring. The mixture is filtered and 900 ml of absolute ethanol is added to the filtrate with stirring. The mixture is stirred for 2 hours, then the precipitate is collected and is washed with ethanol and ether and is dried to yield 20.8 g of 8-(5-nitro-o-toluenesulfonamido)-1,3,6-naphthalenetrisulfonic acid, trisodium salt.
Reaction SMILES: [CH2:1]([O:3][P:4](=[S:9])([SH:8])[O:5][CH2:6][CH3:7])[CH3:2].Br[CH2:11][CH:12]=[CH:13][CH2:14]Br>C(O)C.O>[CH2:1]([O:3][P:4](=[S:8])([O:5][CH2:6][CH3:7])[S:9][CH2:11][CH:12]=[CH:13][CH2:14][S:9][P:4]([O:5][CH2:6][CH3:7])([O:3][CH2:1][CH3:2])=[S:8])[CH3:2]
Reactant: BrCC=CCBr
Reactant: CCOP(=S)(S)OCC
Solvent: O
Solvent: CCO
Product: CCOP(=S)(OCC)SCC=CCSP(=S)(OCC)OCC
Yield: 100.9 %

Procedure:
To a stirred solution of the ammonium salt of dithiophosphoric acid O,O-diethyl ester (15.8 g, 78 mmol) in ethanol (130 mL) at 80° C. is added 1,4-dibromo-2-butene (7.55 g, 35 mmol) in portions. The resulting mixture is cooled, diluted with water (150 mL) and extracted with methylene chloride (3×100 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to yield 15 g (99%) of S-[4-(diethoxy-thiophosphorylsulfanyl)-but-2-enyl]dithiophosphoric acid O,O′-diethyl ester, having the structure:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[O:12][C:11](=[O:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:23]([C:26]1[CH:37]=[CH:36][C:29]([O:30][CH2:31][CH:32]([OH:35])[CH2:33]Cl)=[C:28]([CH2:38][CH2:39][CH3:40])[C:27]=1[OH:41])(=[O:25])[CH3:24]>CN(C=O)C>[C:23]([C:26]1[CH:37]=[CH:36][C:29]([O:30][CH2:31][CH:32]([OH:35])[CH2:33][O:19][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11](=[O:20])[O:12]3)=[CH:17][CH:16]=2)=[C:28]([CH2:38][CH2:39][CH3:40])[C:27]=1[OH:41])(=[O:25])[CH3:24]
Reactant: CCCc1c(OCC(O)CCl)ccc(C(C)=O)c1O
Reactant: O=c1cc(OCc2ccccc2)c2ccc(O)cc2o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCC(O)COc2ccc3c(OCc4ccccc4)cc(=O)oc3c2)ccc(C(C)=O)c1O
Reaction time: 1 h

Procedure:
A solution of 4-benzyloxy-7-hydroxycoumarin (5.36g; 6.02 mole) in dry DMF (30 ml) was treated with 100% sodium hydride (0.48g; 0.02 mole) and stirred at 100° for about 1 hr. To this was added a solution of 1-(4Acetyl-3-hydroxy-2-n-propylphenoxy)-3-chloro-2-propanol (7g) in DMF (2ml) and the mixture stirred at 100° for an additional 4hrs. After removal of the solvent in vacuo, water was added and the product extracted into chloroform. Chromatography of the extract on 300g of silica gel eluting with chloroform afforded the title compound as a white crystalline solid of Rf 0.38. mp (EtOH) 172°-173°. Yield 4.38g (42%). νmax (mull) 1715; 1630; 1620 cm-1. (DMSO) 9.19 (3H, t, J 7.0Hz); 8.58 (2H, sextuplet, J. 7.0Hz); 7.48 (3H, S + 2H m); 6.71 (1H sharp exchangeable); 5.80 (5H, S); 4.68 (2H, S), 4.50 (1H, broad exchangeable); 4.13 (1H, S); 3.32 (1H, d, J 9Hz); 3.12-2.15 (12H, m); 1 low field sharp exchangeable. (Found; C, 69.30; H, 5.80; C30H30O8 requires; C 69.49; H, 5.83%).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3](=[O:22])[CH2:4][N:5]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:24](OC(C)(C)C)(=[O:32])[C:25](OC(C)(C)C)=[O:26].CC(C)([O-])C.[K+].C(O)(=O)C>C(O)(C)(C)C.C1COCC1>[CH3:23][N:2]([CH3:1])[C:3]([C:4]1[N:5]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[C:25]([OH:26])[C:24]=1[OH:32])=[O:22]
Reactant: CC(C)(C)OC(=O)C(=O)OC(C)(C)C
Reactant: COc1ccc(N(CC(=O)OC(C)(C)C)CC(=O)N(C)C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(-n2c(C(=O)OC(C)(C)C)c(O)c(O)c2C(=O)N(C)C)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 38.5 %

Procedure:
To a solution of tert-butyl 2-((2-(dimethylamino)-2-oxoethyl)(4-methoxyphenyl)amino)acetate (16) (1.98 g, 6.14 mmol) and di-tert-butyl oxalate (1.37 g, 6.76 mmol) in anhydrous tert-butanol (6 mL) was added potassium tert-butoxide (20 wt. % in THF) (10.77 ml, 15.35 mmol) and the reaction was stirred at 100° C. for 1.5 h, di-tert-butyl oxalate (300 mg, 1.5 mmol), potassium tert-butoxide (20 wt. % in THF) (4 mL, 5.71 mmol), THF (10 mL), and tert-butanol (4 mL) were added and the mixture stirred for a further 1 h. The mixture was allowed to cool to RT and acetic acid (4 ml, 69.9 mmol) added, the mixture was poured on to ice-cold water (50 mL) and the resulting precipitate was collected by vacuum filtration and recrystallised from hot ethanol to afford tert-butyl 5-(dimethylcarbamoyl)-3,4-dihydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate (UL1-036) (890 mg, 37%) as a white powder: m/z 377 (M+H)+ (ES+); 375 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 8.62 (s, 1H), 8.45 (s, 1H), 7.12-6.99 (m, 2H), 6.94-6.81 (m, 2H), 3.76 (s, 3H), 2.83 (br s, 6H), 1.17 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2)nc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2ccc(C(=O)O)cn2)cc1
Yield: 70.7 %

Procedure:
In a similar manner to that described in Example 2, a reaction was carried out using methyl 6-(4-methoxyphenyl)nicotinate (3.95 g) and aqueous sodium hydroxide solution (1N, 32.5 ml) and the reaction mixture was treated to afford the title compound (2.63 g) as colorless crystals.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[C:10]=1[C:16]([F:19])([F:18])[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C:21]1=[O:26]>>[CH2:1]([S:8][C:9]1[C:10]([C:16]([F:19])([F:18])[F:17])=[C:11]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]2=[O:26])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCN1
Reactant: FC(F)(F)c1c(Br)cccc1SCc1ccccc1
Product: O=C1CCCCN1c1cccc(SCc2ccccc2)c1C(F)(F)F

Procedure:
Intermediate 24 (10.5 g, 30.24 mmol) was coupled with piperidin-2-one (3.597 g, 36.29 mmol) in close analogy to the procedure described in step 1.6). After workup the crude oil is purified by chromatography on silica gel (n-heptane-ethyl acetate 4:1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[Li]CCCC.[O:17]1[C@H:19]([CH2:20][CH3:21])[CH2:18]1>C1COCC1>[F:9][C:8]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:18][C@H:19]([OH:17])[CH2:20][CH3:21]
Reactant: FC(F)(F)c1ccccc1I
Reactant: CC[C@@H]1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC[C@@H](O)Cc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Iodobenzotrifluoride (3 g) was dissolved in THF (18 ml) and was cooled to −78° C. n-BuLi (2.5 M in hexanes, 13.23 ml) was added dropwise to the reaction mixture. After 1 h, (R)-(+)-1,2-epoxybutane (1.4 ml) in THF (18 ml) was added. The reaction temperature was slowly increased to rt. The mixture was poured into ice-water (100 ml), and the product was extracted with heptane. The organic phase was washed with brine and water, dried (Na2SO4) ja evaporated under vacuum. The title compound was obtained by separation method E. (Yield 1.05 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([CH:18]([O:20][CH2:21][C:22]3([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH3:19])[N:9]=2)=[CH:4][CH:3]=1.C=O.[C:36](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:11]=[C:10]([CH:18]([O:20][CH2:21][C:22]3([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:27][CH2:26][N:25]([CH3:36])[CH2:24][CH2:23]3)[CH3:19])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(OCC1(c2ccccc2)CCNCC1)c1cc(C(F)(F)F)cc(-c2ccc(F)cc2)n1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(OCC1(c2ccccc2)CCN(C)CC1)c1cc(C(F)(F)F)cc(-c2ccc(F)cc2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-(4-fluorophenyl)-6-(1-((4-phenylpiperidin-4-yl)methoxy)ethyl)-4-(trifluoromethyl)pyridine (40 mg, 0.08 mmol), and formaldehyde (37 wt. % solution in water, 0.2 mL, 7.5 mmol) were combined in dichloromethane (2.0 mL) and cooled to 0° C. The reaction was treated with sodium triacetoxyborohydride (74 mg, 0.3 mmol) and a drop of acetic acid. The reaction was stirred at 0° C. for 30 min and at room temperature for 1 h. The solvent was removed in vacuo and the resulting crude mixture was concentrated and purified by preparative HPLC which afforded 10.0 mg (27%) 1H-NMR (CD3OD, 400 MHz) δ 8.09 (m, 1H), 7.93 (m, 1H), 7.14-7.58 (m, 9H), 4.51 (q, 1H), 3.36-3.52 (m, 2H), 2.80-2.93 (m, 2H), 2.59-2.79 (m, 5H), 2.04-2.24 (m, 2H), 1.42 (d, 3H), LC: Tr=1.952 min HPLC Method 1. Mass spec.: 473.36 (MH)+.