Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8](SC)=[C:7]([O:18][CH3:19])[CH:6]=2.Cl[C:31]1C=C(C=CC=1)C(OO)=O.C([O-])(O)=O.[Na+].[O-:46][S:47]([O-:50])(=S)=O.[Na+].[Na+]>ClCCl>[CH3:1][C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]([S:47]([CH3:31])(=[O:50])=[O:46])=[C:7]([O:18][CH3:19])[CH:6]=2
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC)c(SC)cc12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC)c(S(C)(=O)=O)cc12
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A solution of methyl 3-methyl-7-(methyloxy)-6-(methylthio)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (4.5 g, 8.54 mmol) and 3-chloroperoxybenzoic acid (3.85 g, 17.17 mmol) in dichloromethane (50 mL) was stirred overnight. Saturated aqueous NaHCO3 and Na2S2O3 were added slowly and the resulting mixture was stirred for 30 min. The mixture was extracted with methylene chloride (3 times). The combined organic extracts were washed with brine (2 times), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 0-15% ethyl acetate/methylene chloride) to give methyl 3-methyl-7-(methyloxy)-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.74 g, 71% yield). 1H NMR (400 MHz, DMSO-d6) δ8.25 (s, 1H), 7.99-8.06 (m, 2H), 7.92 (d, J=7.78 Hz, 1H), 7.82 (s, 1H), 7.76-7.82 (m, 1H), 4.11 (s, 3H), 4.09 (s, 3H), 3.41 (s, 3H), 2.38 (s, 3H); MS (m/z) 454.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:8]O)=[N:4][CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.N1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2([C:34]3[C:25](=[CH:26][C:27]4[O:32][CH2:31][CH2:30][O:29][C:28]=4[CH:33]=3)[O:24][CH2:23]2)[C:15]1=[O:35].[C:36](=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>ClCCl.CN(C)C=O>[Br:1][C:2]1[C:3]([CH2:8][CH:36]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]3([C:34]4[C:25](=[CH:26][C:27]5[O:32][CH2:31][CH2:30][O:29][C:28]=5[CH:33]=4)[O:24][CH2:23]3)[C:15]2=[O:35])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: OCc1ncccc1Br
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1C(Cc2ncccc2Br)c2ccccc2C12COc1cc3c(cc12)OCCO3
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.4 %

Procedure:
A mixture of (3-bromopyridin-2-yl)methanol (0.100 g, 0.530 mmol) and thionyl chloride (0.070 mL, 0.97 mmol) in dichloromethane (3 mL) and N,N-dimethylformamide (1 drop) was stirred at ambient temperature for 16 h. The reaction mixture was concentrated in vacuo and tetrahydrofuran (5 mL) and N,N-dimethylformamide (5 mL) were added, followed by 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.121 g, 0.41 mmol), cesium carbonate (0.374 g, 1.15 mmol), and potassium iodide (0.038 g, 0.23 mmol). The mixture was heated at 100° C. for 1 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was triturated sequentially with water and methanol and further purified by column chromatography and eluted with a 0% to 50% gradient of ethyl acetate in dichloromethane to afford 3′-[(3-bromopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one (0.113 g, 59%) as a colorless solid: mp 217-218° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.41 (d, 1H, J=4.0 Hz), 8.15 (d, J=8.1 Hz, 1H), 7.24 (m, 1H), 6.50 (s, 1H), 6.43 (s, 1H), 5.13 (ABq, 2H), 4.75 (ABq, 2H), 4.14-4.09 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 177.3, 155.0, 152.6, 148.3, 144.6, 143.3, 141.3, 138.2, 132.4, 129.1, 125.1, 123.9, 123.3, 122.1, 120.2, 112.3, 109.7, 99.0, 79.7, 64.7, 64.1, 57.7, 44.7; MS (ES+) m/z 464.6 (M+1), 466.6 (M+1).
Reaction SMILES: C(S(NC[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:31]([O:32][CH3:33])=[CH:30][N:29]=[CH:28][N:27]=2)[CH:22]([CH3:34])[CH2:21]1)(=O)=O)C.COC1[C:38](N2CCNCC2C)=[N:39]C=NC=1.[CH2:50]([S:52](Cl)(=[O:54])=[O:53])[CH3:51]>>[CH2:50]([S:52]([C:14]1[CH:15]=[CH:16][CH:8]=[C:9]2[C:10]=1[C:11]([CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]3[C:31]([O:32][CH3:33])=[CH:30][N:29]=[CH:28][N:27]=3)[CH:22]([CH3:34])[CH2:21]1)=[C:12]([NH2:13])[N:39]2[CH3:38])(=[O:54])=[O:53])[CH3:51]
Reactant: CCS(=O)(=O)Cl
Reactant: COc1cncnc1N1CCNCC1C
Reactant: CCS(=O)(=O)NCc1ccc2[nH]cc(CCCN3CCN(c4ncncc4OC)C(C)C3)c2c1
Product: CCS(=O)(=O)c1cccc2c1c(CCCN1CCN(c3ncncc3OC)C(C)C1)c(N)n2C

Procedure:
In a similar manner to Example 32 1-[[5-[[(ethylsulfonyl)amino]methyl]-1H-indol-3-yl]propyl]-4-(5-methoxy-4-pyrimidinyl)-3-methylpiperazine was synthesized by utilizing 1-(5-methoxy-4-pyrimidinyl)-2-methylpiperazine in the coupling step and ethanesulfonyl chloride in the sulfonylation step: C24H34N6O3S/2.9 HCl, m.p. 202°-210° C. Elemental analysis calculated: C, 48.66; H, 6.28; N, 14.19; found: C, 48.41; H, 6.35; N, 13.93.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([NH2:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.Cl.C[CH:19]([NH2:34])[C:20]1C=[CH:24][C:23](CCC2C=CC=CC=2)=[CH:22][CH:21]=1>>[ClH:1].[C:7]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=[CH:9][C:4]([CH:3]([N:16]=[C:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:34]2)[CH3:2])=[CH:5][CH:6]=1
Reactant: CC(N)c1ccc(CCc2ccccc2)cc1
Reactant: CC(N)c1ccc(-c2ccccc2)cc1
Agent: Cl
Product: CC(N=C1CCCCCN1)c1ccc(-c2ccccc2)cc1

Procedure:
Following essentially the same procedure described in Example IV above and substituting α-methyl-ρ-phenylbenzylamine hydrochloride for the α-methyl-ρ-phenethylbenzylamine hydrochloride above, results in the formation of 2-[α-(4-biphenylyl)ethylimino]hexahydroazepine hydrochloride having a M.P. of 245°-7° C.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][N:10]=2)[CH2:5][CH2:4]1.[CH3:18][CH2:19][N:20]([CH:24]([CH3:26])[CH3:25])[CH:21](C)[CH3:22].[C:27](N1C=CN=C1)([N:29]1C=CN=C1)=[O:28].C(N1CCNCC1)(C)C>CN(C=O)C>[C:13]([C:12]1[CH:16]=[CH:17][C:9]([N:6]2[CH2:5][CH2:4][CH:3]([NH:2][C:27]([N:29]3[CH2:22][CH2:21][N:20]([CH:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]3)=[O:28])[CH2:8][CH2:7]2)=[N:10][CH:11]=1)(=[O:14])[NH2:15]
Reactant: NC(=O)c1ccc(N2CCC(N)CC2)nc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCN(C(C)C)C(C)C
Agent: CC(C)N1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)NC2CCN(c3ccc(C(N)=O)cn3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8 %

Procedure:
To a cooled solution (0-5° C.) of 6-(4-aminopiperidin-1-yl)nicotinamide hydrochloride (293 mg, 1 mmol) in 5 ml DMF was added DIPEA (645 mg, 2.2 mmol) and 1,1′-carbonyldiimidazole (170 mg, 1.05 mmol). After stirring for 1 h, 1-isopropylpiperazine (154 mg, 1.2 mmol) was added and the resulting mixture was warmed to room temperature for 16 h. The crude mixture was filtered through Celite and the filtrate was purified by preparative HPLC to give title compound (30 mg, 8%) as an off-white solid. [1HNMR (400 MHz, DMSO-d6) δ 8.60 (d, 1H), 7.94 (m, 1H), 7.73 (s, 1H), 7.10 (s, 1H), 6.86 (d, 1H), 6.21 (d, 1H), 4.37 (d, 2H), 3.65 (m, 1H), 3.23 (t, 4H), 2.94 (t, 2H) 2.62 (m, 1H), 2.34 (t, 4H), 1.78 (d, 2H), 1.36 (m, 2H), 0.96 (d, 6H); LCMS RtB=1.53 min, [M+H]+=375.2].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]2[C:24]([O:26]CC)=[O:25])=[CH:5][CH:4]=1.COC1C=CC(C2C3C(=CC=CC=3)C(C3C=CC=CC=3)=C2C(OCC)=O)=CC=1>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:10]2[C:24]([OH:26])=[O:25])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1C(c2ccccc2)c2ccccc2C1c1ccc(OC)cc1
Agent: [Pd]
Agent: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1c1ccc(OC)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(C2c3ccccc3C(c3ccccc3)C2C(=O)O)cc1
Reaction time: 24 h

Procedure:
Ethyl (1RS,2SR,3SR)-1-(4Methoxyphenyl)-3-phenylindane-2-carboxylate. To a solution of ethyl (RS)-I-(4methoxyphenyl)-3-phenylindene-2-carboxylate (5.75 g, 15 mmol) in EtOAc (150 ml) was added 5% palladium on activated carbon (600 mg). The resulting suspension was stirred under an atmosphere of H2 for 1 d, then was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford the title compound, which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:12]2[C:21]3[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:16]=3[N:15]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:14](=[O:33])[N:13]2[CH3:34])=[C:7]([CH:11]=1)[C:8](O)=[O:9])#[N:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+].C(O)(=O)C>C1COCC1.O>[OH:9][CH2:8][C:7]1[CH:11]=[C:3]([CH:4]=[CH:5][C:6]=1[CH:12]1[C:21]2[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:16]=2[N:15]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=2)[C:14](=[O:33])[N:13]1[CH3:34])[C:1]#[N:2]
Reactant: CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1CO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 5-cyano-2-[3-methyl-2,5-dioxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4,5,6,7,8-octahydro-quinazolin-4-yl]-benzoic acid (INTERMEDIATE 25, 710 mg, 1.51 mmol) in THF (11.2 mL) is added 1,1′-carbonyldiimidazole (270 mg, 1.66 mol) and the reaction mixture is stirred 90 min at room temp. The reaction mixture is cooled to 5° C. and a solution of sodium borohydride (85 mg, 2.27 mmol) in water (1.4 mL) is added dropwise. After stirring at room temp. for 3 h, the reaction mixture is acidified with dilute aqueous acetic acid, diluted with water and extracted with ethyl acetate. The organic phase is washed with water, dried over MgSO4 and concentrated under reduced pressure. The crude product is purified by reversed phase HPLC. Yield: 420 mg; ESI mass spectrum [M+H]+=456; Retention time HPLC: 0.62 min (X012_S02).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([C:7]1[CH:8]=[CH:9][C:10]([OH:18])=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[CH:12]=1)#[N:6].C(N(CC)CC)C.[CH2:26]([O:28]CC)[CH3:27]>>[C:1]([O:15][CH2:14][C:13]([C:11]1[CH:12]=[C:7]([C:5]#[N:6])[CH:8]=[CH:9][C:10]=1[O:18][C:26](=[O:28])[CH3:27])([CH3:16])[CH3:17])(=[O:3])[CH3:2]
Reactant: CC(C)(CO)c1cc(C#N)ccc1O
Reactant: CC(=O)Cl
Reactant: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)OCC(C)(C)c1cc(C#N)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Acetyl chloride (3.5 g) in diethyl ether (10 ml) was added portionwise with swirling and ice cooling (5°-10° C.) to 2-(5-cyano-2-hydroxyphenyl)-2-methyl-1-propanol (3.8 g) prepared as in Example 26 and triethylamine (4.6 g) in diethyl ether (40 ml). The mixture was allowed to warm to room temperature, and was left for three hours before washing with water twice, drying over magnesium sulphate, and running down. The crude product (4 g) was dissolved in toluene and filtered through a bed of aluminium oxide. Removal of the toluene left the title product (2.3 g) as a colourless oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[F:24][C:25]1[C:26]([O:34][CH3:35])=[N:27][CH:28]=[C:29](B(O)O)[CH:30]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:29]5[CH:28]=[N:27][C:26]([O:34][CH3:35])=[C:25]([F:24])[CH:30]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: COc1ncc(B(O)O)cc1F
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: COc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1F

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and 3-fluoro-2-methoxypyridine-5-boronic acid (Apollo Scientific, Cheshire, United Kingdom, 21 mg, 0.123 mmol) to give the title compound as a pink solid. (HPLC: tR 2.70 min (Method A); M+H=419 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.18-8.05 (m, 3H), 7.96-7.89 (m, 1H), 7.81-7.74 (m, 1H), 7.49 (s, 1H), 3.99 (s, 3H), 3.92 (s, 3H), 3.59 (s, 3H), 1.98 (s, 3H))
Reaction SMILES: CC1(C)[O:9][CH2:8][CH2:7][C@H:6]2[N:3]1[C:4](=[O:15])[C@@H:5]2[C:10]([O:13][CH3:14])([CH3:12])[CH3:11]>C(O)(=O)C.O>[OH:9][CH2:8][CH2:7][C@H:6]1[NH:3][C:4](=[O:15])[C@@H:5]1[C:10]([O:13][CH3:14])([CH3:12])[CH3:11]
Reactant: COC(C)(C)[C@H]1C(=O)N2[C@@H]1CCOC2(C)C
Solvent: O
Solvent: CC(=O)O
Product: COC(C)(C)[C@H]1C(=O)N[C@@H]1CCO
Temperature: 65 °C
Yield: 95 %

Procedure:
A solution of (6R, 7S)-2,2-dimethyl-7-(1-methoxy-1-methylethyl)-1-aza-3-oxabicyclo[4.2.0]octan-8-one (142.3 mg) in a mixture of acetic acid (2.28 ml) and water (0.57 ml) was heated at 65° C. for 1.5 hours. The mixture was cooled to ambient temperature and then evaporated in vacuo. Xylene was added to the residue and the resultant suspension was evaporated in vacuo. The residue was dissolved in a mixture of methanol and xylene, and the resultant solution was evaporated in vacuo. This operation was repeated once and the residue was chromatographed on silica gel (1.5 g) eluting with a mixture of methylene chloride and acetone (10:1 to 1:1) to give (3S, 4R)-4-(2-hydroxyethyl)-3-(1-methoxy-1-methylethyl)azetidin-2-one (111.3 mg).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.[S:24]1[CH2:29][CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH2:26][CH2:25]1>>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C@H:12]([O:11][C:10]1[C:5]2[O:4][CH:3]=[C:2]([C:27]3[CH2:28][CH2:29][S:24][CH2:25][CH:26]=3)[C:6]=2[CH:7]=[N:8][C:9]=1[NH2:23])[CH3:13]
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: CC1(C)OB(C2=CCSCC2)OC1(C)C
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCSCC3)coc12)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared according to General procedure A with starting materials 3-Bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-furo[3,2-c]pyridin-6-ylamine and 2-(3,6-Dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane. 1H-NMR (CDCl3, 400 MHz): 6=1.79 (d, J=6.8 Hz, 3H), 2.47-2.68 (m, 2H), 2.82 (t, J=5.8 Hz, 2H), 3.20-3.46 (m, 2H), 4.68 (br. s., 2H), 6.31-6.38 (m, 1H), 6.44 (q, J=6.7 Hz, 1H), 6.97 (t, J=8.5 Hz, 1H), 7.30 (s, 1H), 8.14 (s, 1H). MS (ES+): m/z (MH+, 35Cl, 37Cl), 440.94 (MH+, 37Cl, 37Cl). HPLC: tR=3.69 min (polar—5 min, ZQ3).
Reaction SMILES: N1C=CC(/C=C/C(O)=O)=C1.[C:11]([O:15][C:16](=[O:24])/[CH:17]=[CH:18]/[C:19]1[CH:23]=[CH:22][NH:21][CH:20]=1)([CH3:14])([CH3:13])[CH3:12].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[S:35][C:34]([S:36](Cl)(=[O:38])=[O:37])=[CH:33][CH:32]=1>>[C:11]([O:15][C:16](=[O:24])/[CH:17]=[CH:18]/[C:19]1[CH:23]=[CH:22][N:21]([S:36]([C:34]2[S:35][C:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=3)=[CH:32][CH:33]=2)(=[O:37])=[O:38])[CH:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Agent: O=C(O)/C=C/c1cc[nH]c1
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(-c3ccccn3)s2)c1

Procedure:
Starting from (E)-3-(1H-pyrrol-3-yl)-acrylic acid tent-butyl ester (compound D1) and art-known 5-pyridin-2-yl-thiophene-2-sulfonylchloride the title compound can be obtained analogously or similarly as described for compound C1.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([OH:20])=O.CCN(CC)CC.[Cl-].CC(C)(C#C)C.[NH2:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1.Cl>N1C=CC=CC=1.CC#N>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:22])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:21])=[CH:17]/[C:18]([NH:37][C:38]1[CH:39]=[CH:40][C:41]([OH:44])=[CH:42][CH:43]=1)=[O:20]
Reactant: Nc1ccc(O)cc1
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1
Agent: C#CC(C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)Nc2ccc(O)cc2)C(C)(C)CCC1
Reaction time: 3.5 h
Yield: 96.5 %

Procedure:
To a 250 milliliter round bottom flask was charged 2.00 grams (6.67 mmol) of retinoic acid and 20 milliliters of CH3CN. The slurry was cooled to an external temperature of 0-10° C. while 1.0 milliliters of Et3N (7.3 mmol) was charged via syringe. To the slurry was added 0.96 milliliters (7.0 mmol) of 2,2-dimethylbutyrichloride via syringe over about 10 minutes. A thick, unstirrable slurry formed. Ten milliliters of additional CH3CN was added to improve the stirring. After about 3.5 hours, the activation was judged to be complete by HPLC analysis. To the slurry was added 2.0 milliliters of pyridine via syringe. 4-aminophenol (1.53 grams, 14.0 mmol) was then added as a solid in 2 portions over about 15 minutes. After stirring for 2 hours, the reaction was held overnight in the refrigerator (about 0-10° C.). The following morning the reaction was judged to be complete by HPLC analysis. At an external temperature of 0-10° C., 20 milliliters of 3M HCl was added dropwise over about 15 min. After stirring for about 15 minutes, about 20 milliliters of solvent was removed via rotary evaporation (45° C. bath temperature). The slurry was filtered, washed twice with 10 milliliters of water and once with 15 milliliters of heptane. The dark brown solid was dried at about 40° C. overnight on a high vacuum pump to give 2.52 grams of fenretinide (97% yield, 97% pure by area, 1.4% retinoic acid).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.C(OCC)(OCC)OCC.[N-:28]=[N+:29]=[N-:30].[Na+].[C:32](O)(=O)C>O>[CH3:10][C:8]1([CH3:11])[CH2:7][C:6]2[CH:12]=[C:2]([N:1]3[CH:32]=[N:30][N:29]=[N:28]3)[CH:3]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]=2[O:9]1
Reactant: CCOC(=O)c1cc(N)cc2c1OC(C)(C)C2
Reactant: CC(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(OCC)OCC
Solvent: O
Product: CCOC(=O)c1cc(-n2cnnn2)cc2c1OC(C)(C)C2
Temperature: 25 °C
Yield: 50 %

Procedure:
A solution of ethyl 5-amino-2,2-dimethyl-2,3-dihydrobenzofuran-7-carboxylate (675) (300 mg, 1.28 mmol), triethyl orthoformate (0.42 mL, 2.55 mmol), sodium azide (124.8 mg, 1.92 mmol), and acetic acid (12 mL) was heated at 100° C. for 2 hours. The reaction was cooled to room temperature and water was added. The aqueous phase was extracted with ethyl acetate and the combined organic layers dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (50%) to afford ethyl 2,2-dimethyl-5-(1H-tetrazol-1-yl)-2,3-dihydrobenzofuran-7-carboxylate (676) (184 mg, 50%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:15]#[CH:16])[C:12]=1[O:13][CH3:14])[C:6]([O:8]C)=[O:7])#[N:2].O.[OH-].[Li+]>O1CCCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:15]#[CH:16])[C:12]=1[O:13][CH3:14])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: C#Cc1cc(C(=O)OC)cc(C#N)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cc(C(=O)O)cc(C#N)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 102 %

Procedure:
Methyl 3-cyano-5-ethynyl-4-methoxybenzoate (640 mg) was dissolved in tetrahydrofuran (6 mL) and water (3 mL), and lithium hydroxide monohydrate (495 mg) was added to the solution, and then the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure and 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (610 mg) as a brown crystal.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.[CH2:11]([C:15]([CH3:17])=O)[CH:12]([CH3:14])[CH3:13]>S(=O)(=O)(O)O>[CH3:17][C:15](=[N:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1)[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(=O)CC(C)C
Reactant: Nc1cc(O)c(Cl)cc1F
Agent: O=S(=O)(O)O
Product: CC(CC(C)C)=Nc1cc(O)c(Cl)cc1F
Temperature: 100 °C
Yield: 98.2 %

Procedure:
A 50-ml four-neck flask equipped with a Vigreux column (2 cmφ×25 cm) and a dehydrating column attached thereon was charged with 5-amino-2-chloro-4-fluorophenol (1.62 g), methyl isobutyl ketone (32.4 g) and concentrated sulfuric acid (50 mg). The mixture was dehydrated under reflux at 100° C. under reduced pressure (constant at 500 mmHg) for 7 hours. The concentration under reduced pressure gave 2.4 g of 5-(1,3-dimethylbutylidenamino)-2-chloro-4-fluorophenol (yield, 98%). It was found that the mass spectrum and NMR spectrum of the compound thus obtained correspond to those of the compound obtained in Example 1.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:2]=1.[CH2:13]=[O:14].[C:15](=[O:18])([O-])[O-].[K+].[K+]>>[C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:11][C:10]([CH2:15][OH:18])=[C:9]([CH2:13][OH:14])[N:8]=2)[CH:2]=1
Reactant: Cc1cccc(-c2ncc[nH]2)c1
Reactant: O=C([O-])[O-]
Reactant: C=O
Agent: [K+]
Product: Cc1cccc(-c2nc(CO)c(CO)[nH]2)c1
Temperature: 90 °C
Yield: 9 %

Procedure:
A reaction vessel equipped with a stirrer and a reflux condenser was charged with 15.8 g (0.1 mole) of 2-m-tolylimidazole, 24 ml (0.3 mole) of 37% formalin and 2 g (0.015 mole) of potassium carbonate. They were heated at about 90° C. for 1 hour with stirring. The contents were cooled, and the crystals were collected by filtration. The crystals collected were boiled together with 50 ml of water, cooled, and again collected by filtration. The crystals so collected were then boiled together with 20 ml of toluene, cooled, and collected by filtration. The crystals were recrystallized from methanol to afford 2-m-tolyl-4,5-dihydroxymethyl imidazole as a final product in an amount of 2 g (yield 9%). The thin-layer chromatography (Alumina G, ethanol) of these crystals gave only one spot at Rf = 0.7.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH3:17])[CH2:12][CH2:11]2)=O)=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1.CSC>C1COCC1>[CH2:16]([N:13]1[CH2:14][CH2:15][N:10]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=2[C:18]([F:21])([F:19])[F:20])[CH2:11][CH2:12]1)[CH3:17]
Reactant: CCN1CCN(C(=O)c2ccc(N)cc2C(F)(F)F)CC1
Solvent: CSC
Solvent: C1CCOC1
Product: CCN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 69.3 %

Procedure:
To a mixture of (4-amino-2-trifluoromethyl-phenyl)-(4-ethyl-piperazin-1-yl)-methanone (20 g, 66.4 mmol) in THF (500 mL) was added BH3.DMS (19.91 mL, 199 mmol) dropwise. Then the mixture was stirred at 80° C. for 4 h. The mixture was quenched by adding MeOH and then concentrated. The residue was purified by silica column chromatography on silica gel (PE:EA=2:1, Rf=0.35) to give a white solid of 4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (14 g, 46.0 mmol, 69.4% yield): 1H NMR (400 MHz, CDCl3) δ: 7.48 (d, J=8.4 Hz, 1H), 6.91 (d, J=2.8 Hz, 1H), 6.79 (dd, J=2.4, 8.4 Hz, 1H), 3.76 (s, 2H), 3.53 (s, 2H), 2.45-2.39 (m, 8H), 1.08 (t, J=7.2 Hz, 3H); ES-LCMS m/z 288 (M+H).