Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:14]([CH3:15])[N:13]=[C:12]([C:16](=O)[CH3:17])[C:11]=3[OH:19])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH:20]([C:22]([C:24]1[S:28][C:27]([C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)=[O:30])=[CH:26][CH:25]=1)=[O:23])[NH2:21]>CS(C)=O>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:14]([CH3:15])[N:13]=[C:12]([C:16](=[N:21][NH:20][C:22]([C:24]4[S:28][C:27]([C:29]([NH:31][CH2:32][C:33]5[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=5)=[O:30])=[CH:26][CH:25]=4)=[O:23])[CH3:17])[C:11]=3[OH:19])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: NNC(=O)c1ccc(C(=O)NCc2ccncc2)s1
Reactant: CC(=O)c1nn(C)c(-c2ccc3c(c2)CCC3)c1O
Solvent: CS(C)=O
Product: CC(=NNC(=O)c1ccc(C(=O)NCc2ccncc2)s1)c1nn(C)c(-c2ccc3c(c2)CCC3)c1O
Yield: 73.1 %

Procedure:
1-[5-(2,3-Dihydro-1H-inden-5-yl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (30 mg, 0.117 mmol) and 5-(hydrazinecarbonyl)-N-(pyridine-4-ylmethyl)thiophene-2-carboxamide (32 mg, 0.117 mmol, synthesized in accordance with WO2007010954) in dimethyl sulfoxide (0.9 mL) was heated at 100° C. for 3 days with stirring. After the reaction, the reaction solution was concentrated under reduced pressure. After addition of chloroform and ethyl acetate, the resulting crystals were collected by filtration and dried under reduced pressure to obtain the desired product (44 mg, 73% yield).
Reaction SMILES: C([O:4][C:5](=[O:17])[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[CH:10]=1)CC.[OH-].[Na+]>O>[F:15][C:13]1[CH:14]=[C:9]([CH2:8][CH2:7][CH2:6][C:5]([OH:17])=[O:4])[CH:10]=[C:11]([F:16])[CH:12]=1
Reactant: CCCOC(=O)CCCc1cc(F)cc(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCc1cc(F)cc(F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 102.7 %

Procedure:
A mixture of crude 4-(3,5-difluoro-phenyl)-butyric acid propyl ester (3.3 kg), water (4.4 kg), and 50% sodium hydroxide (3.35 kg) were stirred at 50° C. for 1 hour. The hydrolysis was monitored by HPLC. The resulting solution was washed with hexane (4.2 kg) to remove organic impurities. The aqueous layer was acidified with conc. HCl (4.73 kg), and extracted with MTBE (4.23 kg). The solution was concentrated, and residual MTBE was removed by solvent exchange with n-heptane (4.0 liters) to give crude 4-(3,5-difluoro-phenyl)-butyric acid (2.8 kg) as an oil: H1 NMR (300 MHz): δ (CDCl3): 1.94 (2H, p, J=7.54 Hz), 2.38 (2H, t, J=7.54 Hz), 2.65 (2H, t, J=7.54 Hz), 6.63 (1H, tt, J=2.26, 9.04 Hz), 6.7 (2H, m, J=2.26, 6.4 Hz), 11.70 (1H, bs, COOH)
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.[CH2:21]([O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=2[CH2:4][N:5]2[C:13]3[C:8](=[CH:9][C:10]([C:14]([OH:16])=[O:15])=[CH:11][CH:12]=3)[CH:7]=[CH:6]2)=[CH:28][CH:27]=1)=[O:25])[CH3:22]
Reactant: O=C(O)c1ccc2c(ccn2Cc2ccccc2Br)c1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Product: CCOC(=O)c1ccc(-c2ccccc2Cn2ccc3cc(C(=O)O)ccc32)cc1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 38, using 1-(2-bromobenzyl)-1H-indole-5-carboxylic acid instead of the (S)-1-(4-bromobenzyl)-N-(1-(4-nitrophenyl)ethyl)-1H-indole-5-carboxamide and the (4-(ethoxycarbonyl)phenyl)boronic acid instead of the phenylboronic acid. ESI-MS (m/z): 400 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:5]([I:31])=[C:6]([C:21]([I:30])=[C:22]([N:25]([CH3:29])[C:26](=[O:28])[CH3:27])[C:23]=1[I:24])[NH:7][C:8](=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=[O:17])([OH:3])=[O:2].[OH-].[Na+].Cl>O>[C:1]([C:4]1[C:5]([I:31])=[C:6]([C:21]([I:30])=[C:22]([N:25]([CH3:29])[C:26](=[O:28])[CH3:27])[C:23]=1[I:24])[NH:7][C:8](=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])([OH:3])=[O:2]
Reactant: COC(=O)CCCCCCCC(=O)Nc1c(I)c(C(=O)O)c(I)c(N(C)C(C)=O)c1I
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N(C)c1c(I)c(NC(=O)CCCCCCCC(=O)O)c(I)c(C(=O)O)c1I

Procedure:
A mixture of 136.5 g. of methyl 3'-carboxy-2',4',6'-triiodo-5'-(N-methylacetamido)azelanilate and 180 ml. of water was treated with 10% aqueous sodium hydroxide (about 140 ml.), added dropwise until solution was complete. The mixture was heated on a steam bath for ten minutes, 18 ml. more of 10% sodium hydroxide was added, and the mixture heated one hour longer. The reaction mixture was cooled, acidified with 3% hydrochloric acid, and the solid product collected, washed with water, dried and recrystallized from acetic acid to give 3'-carboxy-2',4',6'-triiodo-5'-(N-methylacetamido)azelanilic acid as a colorless solid, m.p. 205°-208° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@@H:10]([O:13][Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Rh]>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:24][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1)[C@@H:10]([O:13][Si:14]([CH:15]([CH3:16])[CH3:17])([CH:18]([CH3:19])[CH3:20])[CH:21]([CH3:22])[CH3:23])[CH2:11][OH:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)[Si](O[C@@H](CO)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Agent: [Rh]
Solvent: CO
Product: CC(C)[Si](O[C@@H](CO)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)(C(C)C)C(C)C
Yield: 66.9 %

Procedure:
The alcohol of Step 2 (12.8 g, 29.3 mmol) was dissolved in MeOH (135 mL) and hydrogenated with 5% Rh/C at 60 psi and 60° C. for 30 hours. The filtrate was concentrated and purified by medium pressure column chromatography (silica gel, 15% ethyl acetate in hexane) to give the title compound as a white solid (8.70 g, 67% yield, mp 61°-63° C.).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:22]3[CH2:25][CH:24]([C:26]([O:28]C)=[O:27])[CH2:23]3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[Li+].[OH-]>CO>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:22]3[CH2:23][CH:24]([C:26]([OH:28])=[O:27])[CH2:25]3)=[O:21])[N:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:8]=1
Reactant: COC(=O)C1CN(C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CN(C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.9 %

Procedure:
(Z)-methyl 1-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)azetidine-3-carboxylate (0.1 g, 1.0 eq.) was dissolved in methanol:water (10 mL, 1:1). LiOH (0.010 g, 1.0 eq.) was added. The reaction mixture was stirred at room temperature for 1-2 h. The reaction mixture was quenched with 10 mL water and acidified with dilute HCl until pH=2-3. The aqueous layer was extracted with ethyl acetate (10 mL×3). The organic layer was washed with brine, dried over sodium sulphate and concentrated under reduced pressure to afford 0.060 g of (Z)-1-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)azetidine-3-carboxylic acid (62.5% yield). 1H NMR (400 MHz, DMSO) δ=9.38 (s, 1H), 8.54 (s, 2H), 8.29 (s, 1H), 7.40-7.42 (d, J=10.4 Hz, 1H), 5.93-5.96 (d, J=10.4 Hz, 1H), 4.23-4.27 (m, 2H), 4.12-4.16 (m, 3H). LCMS calcd. for C17H13F6N4O3 [M+H]+: 435.29. Found: 435.14, at 2.55 min retention time.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)=[O:7].O1CCCC1>O>[O:14]=[C:11]1[N:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:13]=[CH:12]1
Reactant: COC(=O)c1ccc(=O)n(-c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(=O)n(-c2ccccc2)c1
Reaction time: 1 h
Yield: 78.7 %

Procedure:
Lithium hydroxide monohydrate (0.366 g, 8.73 mmol) was added to a mixture of methyl-6-oxo-1-phenyl-1,6-dihydropyridine-3-carboxylate (1.0 g, 4.37 mmol), tetrahydrofuran (9 mL) and water (6 mL) at 0° C. The mixture was stirred for 1 hour, diluted with water and washed with ethyl acetate. The pH of the aqueous layer was adjusted to 2 using 2 N hydrochloric acid and the precipitate was filtered to give the title compound as a brown solid (0.740 g, 79%). m.p. 256-263° C.; 1H NMR (400 MHz, DMSO-d6) δ 6.53 (d, J=9.4 Hz, 1H), 7.40-7.49 (m, 5H), 7.87 (dd, J=2.5, 9.8 Hz, 1H), 8.23 (d, J=2.5 Hz, 1H); IR (KBr) u 3446, 1708, 1645, 1577, 1263, 1228 cm−1; MS 214 (M−1).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[I:34][C:35]1[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:38]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[NH:37][N:36]=1.O[CH2:51][CH:52]([NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58])[CH3:53]>C1COCC1.C(OCC)(=O)C>[C:57]([O:56][C:55]([NH:54][CH:52]([CH3:53])[CH2:51][N:37]1[C:38]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([I:34])=[N:36]1)=[O:61])([CH3:60])([CH3:59])[CH3:58]
Reactant: CC(CO)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1[nH]nc(I)c1C(=O)OCC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(I)nn(CC(C)NC(=O)OC(C)(C)C)c1C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
To a stirred suspension of PPh3 (12.41 g, 47.3 mmol) in THF (100 mL) was added DIAD (9.20 mL, 47.3 mmol) at 10° C. and allowed to stir at 0° C. for 0.5 h. Intermediate 104C (8.0 g, 23.66 mmol) was added as a solution in THF (10 mL) at 0° C. and stirred at RT for 45 min. The reaction mixture was cooled again to 0° C. and tert-butyl (1-hydroxypropan-2-yl)carbamate (5.39 g, 30.8 mmol) was added as a solution in THF (10 mL) and the mixture was stirred at RT for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water and brine. The organic layer was dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (40 g REDISEP® column, eluting with 15% EtOAc in hexane). Fractions containing the product were combined and evaporated to afford the Intermediate 340A as a brown liquid (7.0 g) contaminated with impurities arising from the coupling reagents. MS(ES): m/z=496 [M+H]+. The crude intermediate was taken to the next step without further purification.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[S:20](Cl)(=[O:22])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>ClCCl>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[S:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)(=[O:22])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CNCCN1
Reactant: O=S(=O)(Cl)c1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Solvent: ClCCl
Product: O=S(=O)(c1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1)N1CCNCC1
Reaction time: 2 h

Procedure:
The requisite 1-(1-benzenesulphonyl-5-chloroindol-2-ylsulphonyl)piperazine starting material was prepared as follows. A solution of 1-benzenesulphonyl-5-chloroindol-2-ylsulphonyl chloride (10.0 g, 25.6 mmol) in dichloromethane (100 ml) was added dropwise to a stirred solution of piperazine (13.23 g, 6 eq.) in dichloromethane (200 ml), and the mixture stirred for a further 2 hrs. The reaction mixture was then washed with water (3×200 ml), dried (Phase-Separating paper) and evaporated to give a red oil which was purified by flash chromatography using Merck silica (Art. 9385), eluting with dichloromethane containing methanol (0-6%), to give 1-(1-benzene sulphonyl-5-chloroindol-2-ylsulphonyl)piperazine as a colourless solid, 1H NMR (CDCl3) 2.95 ppm (m, 4H), 3.4 ppm (m, 4H), 7.4 ppm (m, 4H), 7.55 ppm (m, 2H), 8.0 ppm (d, 2H), 8.0 ppm (d, 1H); MS (M+H)+ 440/442.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH:8](C(OC)=O)[C:7](=[O:16])[C:6]=2[CH:5]=[N:4][CH:3]=1.Cl>>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[O:16])[C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: COC(=O)C1CCc2c(Br)cncc2C1=O
Agent: Cl
Product: O=C1CCCc2c(Br)cncc21

Procedure:
The crude methyl 4-bromo-8-oxo-5,6,7,8-tetrahydroisoquinoline-7-carboxylate (7.79 g, 27.4 mmol) was dissolved (small amount of not dissolved material) in aq. 6M HCl (84.1 mL, 505 mmol) and heated at reflux for 2.5 h (dark brown solution, no more SM visible on TLC). The acidic solution was concentrated in vacuo, suspended in water (ca. 25 mL), cooled in ice, and basified with 6.0 M KOH. The aqueous solution was washed with Et2O (2×) and CH2Cl2 (3×), the combined organic layers were dried over Na2SO4, filtered and concentrated to afford after high vacuum drying the title compound (4.30 g, 69%) as brown solid. MS: 226.0 (M+H+, 1Br).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH:26][C@@H:27]([CH2:40][NH2:41])[CH2:28][O:29][C:30]1[C:38]2[NH:37][C:36](=[O:39])[NH:35][C:34]=2[CH:33]=[CH:32][CH:31]=1>>[OH:26][C@H:27]([CH2:28][O:29][C:30]1[C:38]2[NH:37][C:36](=[O:39])[NH:35][C:34]=2[CH:33]=[CH:32][CH:31]=1)[CH2:40][NH:41][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: CCCCCCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Product: CCCCCCCCS(=O)(=O)Nc1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1

Procedure:
The title compound was prepared from octane-1-sulfonic acid [4-(4-oxo-piperidine-1-yl)-phenyl]-amide (which was obtained in Example 230) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 5,786,356/1998) according to the procedure of Example 255 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.85 (t, J=7.0 Hz, 3H), 1.10-1.40 (m, 10H), 1.50-1.70 (m, 4H), 1.95-2.16 (m, 2H), 2.67 (brt, J=11.1 Hz, 2H), 2.93 (brt, J=7.9 Hz, 2H), 2.95-3.20 (m, 3H), 3.62-3.75 (m, 2H), 4.00-4.12 (m, 2H), 4.12-4.30 (m, 1H), 6.59 (d, J=7.8 Hz, 1H), 6.63 (d, J=8.3 Hz, 1H), 6.80-7.00 (m, 3H), 7.07 (d, J=9.0 Hz, 2H), 9.33 (brs, 1H), 10.60 (brs, 1H), 10.75 (brs, 1H); MS (ES) m/z: 574.1 (MH+); HRMS Calcd. for C29H44N5O5S(MH+): 574.3063. Found: 574.3084.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[O:12][C:13]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[N:14][N:15]=2)=[O:10])=[CH:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.O>[C:2]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[O:12][C:13]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[N:14][N:15]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(Nc1ccc(I)cc1)c1nnc(Nc2ccccc2F)o1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: O=C(Nc1ccc(-c2ccccc2)cc1)c1nnc(Nc2ccccc2F)o1
Yield: 19 %

Procedure:
N-(4-Iodophenyl)-5-[(2-fluorophenyl)amino]-1,3,4-oxadiazole-2-carboxamide (Intermediate 35), 150 mg, 0.36 mmol), phenyl boronic acid (35 mg, 0.29 mmol), potassium phosphate (230 mg, 1.44 mmol), and tetrakis(triphenyl phosphine)palladium(0) (22 mg, 0.02 mmol) were stirred in DME (1.2 mL) and water (0.6 mL), in a microwave tube, and heated at 110° C. for 3 h. The reaction mixture was partitioned between ethyl acetate (10 mL) and water (10 mL), and extracted with ethyl acetate (2×10 mL). The organics were combined, and dried by passing through a Varian Chem elut column. The filtrate was concentrated in vacuo and purified by preparative HPLC to afford the title compound as a cream solid (25 mg, 19%):
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH:2]=[CH2:3].F[C:12]1[CH:25]=[CH:24][C:15]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:21]1[CH:22]=[CH:23][C:18]([C:16]([C:15]2[CH:24]=[CH:25][CH:12]=[CH:13][CH:14]=2)=[O:17])=[CH:19][CH:20]=1)=[CH:2][CH3:3]
Reactant: C=CCc1ccccc1O
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: CC=Cc1ccccc1Oc1ccc(C(=O)c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
o-Allylphenol (33.5 g), 4-fluorobenzophenone (50.05 g), potassium carbonate (24.20 g), dry N-methylpyrrolidone (160 ml) and toluene (60 ml) are placed in a 3-necked 500 ml flask fitted with a stirrer, reflex condensor and thermometer and the mixture is heated under nitrogen to a temperature between 155°-160° C. and stirred for 3 hours. Water and toluene are separated via a Dean Stark trap and finally after 3 hours the reaction mixture reaches a temperature of 160° C. The mixture is cooled to 100° C. and a 1:1 mixture of toluene/water (400 ml) is added while stirring. After phase separation the aqueous layer is washed with toluene (50 ml) and the combined toluene layers are washed 4 times with water (150 ml). The toluene phase is dried over sodium sulphate and toluene distilled off by use of a rotary evaporator finally in vacuum leaving 4-[o-(1-propenyl)phenoxy]-benzophenone as a light yellow melt. The yield is 73 g.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][C@@H:11]([CH3:24])[CH:12]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13][CH:14]=[CH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B1C2CCCC1CCC2.[OH-:35].[Na+].OO>O1CCCC1.O>[CH2:1]([O:8][C:9](=[O:25])[NH:10][C@@H:11]([CH3:24])[CH:12]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])[CH2:13][CH2:14][CH2:15][OH:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: C=CCC(O[Si](C)(C)C(C)(C)C)[C@H](C)NC(=O)OCc1ccccc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](NC(=O)OCc1ccccc1)C(CCCO)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution (10 mL) of benzyl((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylpent-4-en-1-yl)carbamate (600 mg) in tetrahydrofuran was added 0.5 mol/L solution (13.2 mL) of 9-BBN in tetrahydrofuran under ice-cooling, and the mixture was stirred at room temperature for 18 hr. To the reaction mixture were added 1 mol/L aqueous sodium hydroxide solution (12 mL) and 30% aqueous hydrogen peroxide (5 mL), and the mixture was stirred at room temperature for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: hexane:ethyl acetate=9:1→1:1) to give the title compound as a colorless oil (yield: 436 mg).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:17])=[C:3](\[C:9](=[S:16])[NH:10][C:11](OCC)=[O:12])/[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O)(=O)C>C(N(CC)CC)C>[OH:12][C:11]1[N:10]=[C:9]([SH:16])[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([CH3:17])[N:1]=1
Reactant: CCOC(=O)NC(=S)/C(C(=O)OCC)=C(/C)N
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nc(O)nc1S
Temperature: 70 °C
Reaction time: 2 h

Procedure:
(Z)-ethyl 3-amino-2-(ethoxycarbonylcarbamothioyl)but-2-enoate was dissolved in 30% aqueous triethyl amine and the reaction mixture stirred at 70° C. After 2 hours, the reaction mixture was cooled and neutralized with glacial acetic acid and the aqueous mixture extracted with EtOAc. The organic layer was washed with water, dried over Na2SO4 and concentrated under vacuum to give the desired product. 1H NMR (400 MHz, DMSO-d6): δ 12.54 (s, 1H), 11.85 (s, 1H), 4.21 (q, J=7.6 Hz, 2H), 2.03 (s, 3H), 1.24 (t. J=7.6 Hz, 3H); MS m/z 213.1 (M−1).
Reaction SMILES: O[C:2]1([OH:14])[C:9]([CH2:10][CH2:11][CH3:12])=[C:8]([OH:13])[CH:7]=[CH:6][CH:3]1[CH:4]=[O:5].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.[I-].[K+]>[CH2:15]([O:13][C:8]1[C:9]([CH2:10][CH2:11][CH3:12])=[C:2]([OH:14])[C:3](=[CH:6][CH:7]=1)[CH:4]=[O:5])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: CCCC1=C(O)C=CC(C=O)C1(O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCc2ccccc2)ccc(C=O)c1O
Yield: 71 %

Procedure:
A mixture of 2,4-dihydroxy-3-propylsalicylaldehyde (15.5 g), benzyl chloride (12.0 g), potassium carbonate (13 g) and potassium iodide (0.5 g) in dry acetone (350 ml) was heated under reflux for 24 hours. The solid was removed by filtration and the solution evaporated to dryness. The oil obtained was distilled and the fraction bp0.5 mm 220-224° was collected to yield 15.0 g of 4-benzyloxy-3-propylsalicylaldehyde.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[O:14][CH3:15])([CH3:3])[CH3:2].S(Cl)([Cl:18])=O>ClCCl>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:18])=[O:10])=[CH:7][C:6]=1[O:14][CH3:15])([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)O)ccc1OC(C)C
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C(=O)Cl)ccc1OC(C)C
Temperature: 30 °C
Reaction time: 8 h
Yield: 101.8 %

Procedure:
To a stirring solution of 4-isopropoxy-3-methoxy-benzoic acid (40.0 g, 190.3 mmol) in anhydrous dichloromethane (400 mL) at room temperature was slowly added thionyl chloride (27.8 mL, 381 mmol). The reaction was then transferred from a room temperature water bath to an oil bath that was then warmed to 30° C. The solution was allowed to stir overnight at 30° C. The reaction mixture was allowed to cool to room temperature prior to the addition of additional thionyl chloride (10.0 mL, 137 mmol). The reaction was allowed to stir at 40° C. for 3 hours. After completion, the reaction mixture was concentrated under reduced pressure, azeotrophing with toluene to provide 4-isopropoxy-3-methoxy-benzoyl chloride (44.3 g) as a yellow oil. The product was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[CH:13]=[C:12]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]=2[O:22][CH2:23][O:24][CH3:25])=[CH:6][C:3]=1[CH:4]=O.Cl[CH2:27][C:28](=[O:30])[CH3:29].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:28]([C:27]1[O:1][C:2]2[CH:9]=[CH:8][C:7]([C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[CH:13]=[C:12]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]=3[O:22][CH2:23][O:24][CH3:25])=[CH:6][C:3]=2[CH:4]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)CCl
Reactant: CCc1cc(-c2ccc(O)c(C=O)c2)c(OCOC)c(C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(-c2ccc3oc(C(C)=O)cc3c2)c(OCOC)c(C(C)(C)C)c1
Temperature: 60 °C
Yield: 54 %

Procedure:
A mixture of 333 mg (0.969 mmol) of 2-hydroxy-5-(5-ethyl-3-tert-butyl-2-methoxymethoxyphenyl)-benzaldehyde, 116 mg (1.26 mmol, 0.1 mL) of chloroacetone and 473 mg (1.45 mmol, 1.5 equivalents) of Cs2CO3 in 5 mL of dry DMF was heated to 60° C. overnight. After cooling, water was added (15 mL) and the solution was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over MgSO4. Evaporation of the solvents followed by purification over a short silica plug afforded 2-acetyl-5-(5-ethyl-3-tert-butyl-2-methoxymethoxyphenyl)-benzo[b]furan as a clear yellow oil (200 mg, 0526 mmol, yield: 54%). 1H NMR(CDCl3), δ:7.85 (d, J=1.4 Hz, 1H), 7.68 (dd, J=8.7, 1.7 Hz, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.19 (d, J=2.1 Hz, 1H), 7.02 (d, J=2.3 Hz, 1H), 4.44 (s, 2H), 3.21 (s, 3H), 2.65 (m, 2H), 2.63 (s, 3H), 1.48 (s, 9H), 1.27 (t, J=7.7 Hz, 3H).