Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]C(OC)=O.[C:6]([O:10][C:11](=[O:20])[NH:12][CH:13]1[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1)(C)(C)C.N1C=CC=CC=1>C1COCC1>[ClH:1].[CH3:6][O:10][C:11](=[O:20])[NH:12][CH:13]1[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)NC1CCC(N)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 112.9 %

Procedure:
Methyl chloroformate (0.468 mL, 6.06 mmol) was added dropwise, over a period of 20 min, under argon atmosphere, at 0° C., to a mixture of (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (1.0 g, 4.67 mmol) and pyridine (0.479 mL, 6.06 mmol) in THF (6 mL) and the resulting mixture was stirred at RT for 24 h. The reaction mixture was then evaporated under reduced pressure and water (300 mL) was added to the solid residue. The resulting mixture was extracted 3 times with EtOAc (100 mL), the combined organics were washed 3 times with water (100 mL), twice with NaHSO4 (aq 1%, 150 mL) and twice with water (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The remaining white solid was mixed with HCl (2.0 M in MeOH, 200 mL) and the resulting mixture was stirred at RT for 5 h. The reaction mixture was then evaporated under reduced pressure to give 1.1 g of (4-amino-cyclohexyl)-carbamic acid methyl ester hydrochloride salt.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:23]([O-])=O)=[C:13]([S:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>O1CCCC1.CO.O.[Fe]>[NH2:23][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][C:13]=1[S:15][C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1Sc1ccc(O)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(OCc2ccccc2)cc1Sc1ccc(O)cc1
Temperature: 25 °C
Yield: 95.6 %

Procedure:
The product of Example 237B (0.390 g, 1.10 mmol), iron powder (0.248 g, 4.41 mmol, 4.0 eq) and ammonium chloride (0.071 g, 1.32 mmol, 1.2 eq) in tetrahydrofuran (6 mL), methanol (6 mL) and water (2 mL) was heated under reflux for 16 hours and then cooled to room temperature. The reaction mixture was filtered through Celite, rinsing with methanol, and the filtrate was evaporated under reduced pressure to provide the title compound (0.340 g, 95%) as a gray powder that was used in subsequent reactions without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:8].[Cl:16]N1C(=O)CCC1=O>ClCCl>[NH2:1][C:2]1[S:3][C:4]([Cl:16])=[CH:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:8]
Reactant: Nc1sccc1C(=O)c1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Nc1sc(Cl)cc1C(=O)c1ccc(F)cc1
Yield: 31.5 %

Procedure:
To a stirred solution of 0.26 g (1.18 mmol) (2-amino-thiophen-3-yl)-(4-fluoro-phenyl)-methanone (the preparation of which is described in example 22) in 10 ml dichloromethane at 0° C. was added 164 mg (1.18 mmol) N-chloro-succinimide (NCS). The mixture was then stirred from 0° C. to RT over night, and then poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentratedin vacuo. Flash chromatography (heptane/ethyl acetate 4:1) afforded 95 mg (32%) (2-amino-5-chloro-thiophen-3-yl)-(4-fluoro-phenyl)-methanone as a yellow solid. ES-MS m/e (%): 256 (M+H+, 100).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[CH:22][C:14]2[C:15]([CH3:21])([CH3:20])[O:16][C:17](=[O:19])[NH:18][C:13]=2[CH:12]=1)(=O)=O.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:23]=[CH:22][C:14]3[C:15]([CH3:20])([CH3:21])[O:16][C:17](=[O:19])[NH:18][C:13]=3[CH:12]=2)=[CH:27][CH:26]=1
Reactant: CC1(C)OC(=O)Nc2cc(OCCCCOS(C)(=O)=O)ccc21
Reactant: Sc1ccc(Cl)cc1
Product: CC1(C)OC(=O)Nc2cc(OCCCCSc3ccc(Cl)cc3)ccc21

Procedure:
Prepared analogously to Example 210 from 7-(4-methanesulfonyloxy-butoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-chlorothiophenol.
Reaction SMILES: [OH:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]([I:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.ClC(Cl)C.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[I:12][C:8]1[CH:9]=[CH:10][N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:2](=[O:1])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1c(I)ccnc1O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: COC(=O)c1c(I)ccn(-c2ccccc2)c1=O
Temperature: 55 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
Methyl 2-hydroxy-4-iodonicotinate (123 mg, 441 μmol), phenylboronic acid (161 mg, 1322 μmol), copper acetate (160 mg, 882 μmol) were combined. Dichloroethane (6 mL) was added followed by molecular sieves 4 Å activated (490 mg) and pyridine (143 μl, 1763 μmol). The reaction mixture was stirred at 55° C. for 3 h. LCMS analysis of an aliquot showed the reaction was complete. The reaction mixture was diluted with dichloromethane and filtered through a pad of celite (rinsing with dichloromethane). The filtrate was concentrated in vacuo and purification by MPLC (ISCO, CH2Cl2/MeOH: 100/0 to 97.5/2.5) afforded methyl 4-iodo-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate (142 mg, 400 μmol, 91% yield). MS (ESI pos. ion) m/z: 356 (MH+). Calc'd exact mass for C13H10INO3: 355.
Reaction SMILES: [CH3:1][C:2]1([CH2:11][CH3:12])[C:7](=[O:8])[O:6][CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[OH:6][CH2:5][C:4]([NH:3][C:2]([CH3:1])([CH2:11][CH3:12])[CH2:7][OH:8])([CH3:10])[CH3:9]
Reactant: CCC1(C)NC(C)(C)COC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCC(C)(CO)NC(C)(C)CO
Yield: 80 %

Procedure:
In a manner analogous to that described in example 3A hereinabove, 3-methyl,3-ethyl-5,5-dimethyl-2-morpholone is reduced with LiAlH4 to provide a better than 80% yield of (1-hydroxy-2-methyl-2-propyl)(1-hydroxy-2-methyl-2-butyl)amine which has a b p of 136°-7° C./4 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH3:10])=[C:5]([NH2:11])[CH:4]=1.CO[C:14]([CH2:16][O:17][C:18]1[CH:31]=[CH:30][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[NH:25][C:24]2=[O:29])=[CH:20][CH:19]=1)=O.Cl.C(=O)([O-])O.[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[N:9]([CH3:10])[C:14]([CH2:16][O:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:22][CH:23]4[S:27][C:26](=[O:28])[NH:25][C:24]4=[O:29])=[CH:30][CH:31]=3)=[N:11][C:5]=2[CH:4]=1
Reactant: COC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CNc1ccc(OC)cc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc2c(c1)nc(COc1ccc(CC3SC(=O)NC3=O)cc1)n2C
Temperature: 0 °C
Yield: 9.8 %

Procedure:
A mixture of 1.17 g of 4-methoxy-N-methyl-1,2-phenylenediamine (prepared as described in Preparation 25), 3.0 g of 5-(4-methoxycarbonylmethoxybenzyl)thiazolidine-2,4-dione (prepared as described in Preparation 21), 20 ml of 1,4-dioxane and 60 ml of concentrated hydrochloric acid was heated under reflux for 2 days. At the end of this time, the reaction mixture was poured into ice-water and the resulting mixture was neutralized with sodium hydrogencarbonate, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, after which the residue was purified by column chromatography through silica gel, using a solution of methylene chloride containing 3% by volume ethanol as the eluent, to give 0.3 g of the title compound, melting at 209°-210° C. and having an Rf value=0.56 (on thin layer chromatography on silica gel; developing solvent: methylene chloride containing 5% by volume ethanol).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K]>CN(C)C=O>[OH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:19]1[C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]2[C:15]1=[O:25]
Reactant: OCCCCCCCCCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCCCCCCCCO
Temperature: 100 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of 45 g of 12-bromododecanol in 500 ml of dimethylformamide was added 75 g of potassium phthalimide and the mixture was stirred at 100° C. for 3 hours. After completion of the reaction, the solvent was distilled off and the residue was dispersed with water. The crude crystal thus separated out was recovered by filtration and recrystallized from methanol to afford 54 g of the title compound as a crystal.
Reaction SMILES: C1C2=C3C(=CC=C2)C(C(O)=O)=CC=C3C1.[CH2:16]1[C:26]2=[C:27]3[C:22](=[CH:23][CH:24]=[CH:25]2)[C:21]([C:28](Cl)=[O:29])=[CH:20][CH:19]=[C:18]3[CH2:17]1.[CH3:31][O:32][CH2:33][CH2:34][N:35]1[C:39]([CH3:40])=[C:38]([CH3:41])[S:37][C:36]1=N.CC[N:45](CC)CC>S(Cl)(Cl)=O.C1COCC1>[CH3:31][O:32][CH2:33][CH2:34][N:35]1[C:39]([CH3:40])=[C:38]([CH3:41])[S:37]/[C:36]/1=[C:19]1\[CH:18]2[C:27]3[C:22]([C:21]([C:28]([NH2:45])=[O:29])=[CH:20]\1)=[CH:23][CH:24]=[CH:25][C:26]=3[CH2:16][CH2:17]2
Reactant: O=C(Cl)c1ccc2c3c(cccc13)CC2
Reactant: COCCn1c(C)c(C)sc1=N
Reactant: CCN(CC)CC
Agent: O=C(O)c1ccc2c3c(cccc13)CC2
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COCCN1C(C)=C(C)S/C1=C1/C=C(C(N)=O)c2cccc3c2C1CC3
Yield: 22 %

Procedure:
The acenaphthene-5-carboxylic acid (Aldrich, 0.29 g, 1.4 mmol) in 5 mL of thionyl chloride was converted to acenaphthene-5-carbonyl chloride using the method described in Example 134A. The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.3 mL, 2.2 mmol) and acenaphthene-5-carbonyl chloride in 30 mL THF were processed as in Example 134B to afford the title compound (87 mg, 0.24 mmol, 22% yield). 1H NMR (300 MHz, CD3OD) δ ppm 2.28 (d, J=0.7 Hz, 3H), 2.33 (d, J=0.7 Hz, 3H), 3.33 (s, 3H), 3.42 (s, 4H), 3.84 (t, J=5.3 Hz, 2H), 4.51 (t, J=5.3 Hz, 2H), 7.30-7.36 (m, 2H), 7.52 (dd, J=8.6, 7.0 Hz, 1H), 8.43 (d, J=7.5 Hz, 1H), 8.81 (d, J=8.8 Hz, 1H); MS (DCI/NH3) m/z 367 (M+H)+; Anal. calculated for C21H22N2O2S: C, 68.82; H, 6.05; N, 7.64. Found: C, 68.63; H, 5.72; N, 7.40.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][CH2:6][CH2:7][NH2:8])C.[CH:12]([C:14]([CH3:16])=O)=[CH2:13].Cl.Cl.[Br:19][C:20]1[CH:21]=[C:22]([N:26]([CH3:28])N)[CH:23]=[CH:24][CH:25]=1>CCOCC.CCO>[Br:19][C:20]1[CH:21]=[C:22]2[C:23]([C:12]3[CH2:13][N:8]4[CH:4]([CH2:5][CH2:6][CH2:7]4)[CH2:16][C:14]=3[N:26]2[CH3:28])=[CH:24][CH:25]=1
Reactant: C=CC(C)=O
Reactant: CN(N)c1cccc(Br)c1
Reactant: CCOC(CCCN)OCC
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: Cn1c2c(c3ccc(Br)cc31)CN1CCCC1C2
Temperature: 100 °C
Reaction time: 1 h
Yield: 18.5 %

Procedure:
To a solution of 4-aminobutyraldehyde diethyl acetal (12.5 mL, 63.3 mmol) in Et2O (25 mL) was added methyl vinyl ketone (6.70 mL, 82.3 mmol). After 1 h, concentrated HCl (35 mL) was added, and the reaction mixture was heated at 100° C. for 3 h. After the mixture was concentrated, the residue was diluted with EtOH (25 mL), and 1-(3-bromophenyl)-1-methylhydrazine hydrochloride (3.90 g, 15.9 mmol) was added followed by concentrated HCl (25 mL). The reaction mixture was heated at reflux overnight. After the mixture was concentrated, the residue was purified by flash column chromatography (silica gel, 10% CH3OH in CH2Cl2) to give 8-bromo-10-methyl-2,3,5,10,11,11a-hexahydro-1H-indolizino[7,6-b]indole (0.90 g, 37%) as an orange solid. 8-Bromo-10-methyl-2,3,5,10,11,11a-hexahydro-1H-indolizino[7,6-b]indole (0.17 g, 0.56 mmol) was reacted according to the procedure of Example 2 (step b) to give a white solid in 22% (52 mg). The white solid was dissolved in CH3OH (1 mL) and was treated with 2 N HCl in Et2O (1 mL). The resulting solid was isolated by filtration and dried under vacuum to give the title compound (38 mg, 88%) as an off-white powder: mp 255-258° C.; 1H NMR (500 MHz, CD3OD) δ 7.65 (d, J=7.5 Hz, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.50-7.35 (m, 6H), 7.08 (dd, J=8.5, 2.0 Hz, 1H), 6.38 (dd, J=7.5, 2.5 Hz, 1H), 6.19 (d, J=2.5 Hz, 1H), 5.20 (s, 2H), 4.89 (d, J=14.0 Hz, 1H), 4.36 (d, J=14.0 Hz, 1H), 3.91-3.84 (m, 2H), 3.74 (s, 3H), 3.57 (dd, J=17.0, 4.0 Hz, 1H), 3.41-3.39 (m, 1H), 3.06 (dd, J=17.0, 11.0 Hz, 1H), 2.63-2.59 (m, 1H), 2.38-2.23 (m, 2H), 1.99-1.95 (m, 1H); ESI MS m/z 426 [M+H]+; HPLC (Method A) 98.0% (AUC), tR=13.0 min.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=1)=[O:12])[CH2:6]2.Cl.[CH3:27][N:28]([CH2:32][CH2:33]Cl)[CH2:29][CH2:30]Cl.C(=O)([O-])O.[Na+]>C(O)CCC>[CH3:27][N:28]1[CH2:32][CH2:33][N:1]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][CH:5]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=2)=[O:12])[CH2:6]3)[CH2:30][CH2:29]1
Reactant: Nc1cccc2c1CC(C(=O)Nc1ccc(N3CCOCC3)cc1)C2
Reactant: CN(CCCl)CCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: CN1CCN(c2cccc3c2CC(C(=O)Nc2ccc(N4CCOCC4)cc2)C3)CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 7.9 %

Procedure:
A mixture of 4-amino-N-(4-morpholinophenyl)indan-2-carboxamide (1.1 g, 3 mmol), N-methyl-bis-(2-chloroethyl)amine hydrochloride (2.0 g, 10 mmol) and sodium hydrogen carbonate (8.0 g, 95 mmol) in 1-butanol (100 mL) was stirred overnight at 120° C. The mixture was filtered and the solvent was evaporated in vacuo. The crude residue (oil) was purified on a silica gel column using methylene chloride as the eluent to afford 100 mg of the title compound: mp 248-249° C.; EIMS (70 eV) m/z (relative intensity) 420 (47, M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[F:9].[K].C[Si]([N-:15][Si](C)(C)C)(C)C.CCOCC.OS(O)(=O)=O.[C:30]1([CH3:36])[CH:35]=[CH:34]C=C[CH:31]=1>>[CH3:36][C:30]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[F:9])([CH2:35][CH3:34])[C:31]#[N:15].[CH3:36][C:30]([C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])([CH2:35][CH3:34])[C:31]#[N:15]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Fc1cccc(F)c1F
Reactant: Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [K]
Solvent: CCOCC
Product: CCC(C)(C#N)c1c(F)cccc1F
Product: CCC(C)(C#N)c1cccc(F)c1F
Temperature: 0 °C

Procedure:
A solution of 5.0 g (37.85 mmol) of 1,2,3-trifluorobenzene, 3.30 g (39.74 mmol) of 2-methylbutylnitrile and 75.7 ml (0.5 M in toluene) of potassium-bis-trimethylsilylamide in 182 ml of toluene is heated for 3 hours at 60° C. It is mixed with ice water and ether. The organic phase is acidified with 10% H2SO4 and washed three times with water, dried (Na2SO4) and concentrated by evaporation in a vacuum. After chromatography on silica gel with 0–4% ether-hexane, 3.8 g of 2-methyl-2-(2,3-difluorophenyl)butyronitrile and 1.6 g of 2-methyl-2-(2,6-difluorophenyl)butyronitrile are obtained.
Reaction SMILES: B.C1COCC1.[CH2:7]([O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH2:25][C:26]([NH2:28])=O)[CH2:19][CH2:18]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][NH2:28])[CH2:19][CH2:18]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NC(=O)CCCC1CCN(CCOCc2ccccc2)CC1
Agent: B
Solvent: C1CCOC1
Product: NCCCCC1CCN(CCOCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a solution of BH3.THF (2.2 mL, 2.2 mmol) cooled to 0° C. was added compound 4a (100 mg, 0.3 mmol). The resulting mixture was stirred for 30 min, then warmed to room temperature and stirred overnight. The reaction was quenched with water, and extracted with Et2O. The organic solution was dried over Na2SO4 and concentrated under vacuum to provide 5a (85.2 mg, 89%) which was used directly without further purification. 1H NMR (500 MHz, CD3OD) δ 1.39 (m, 2H), 1.45 (m, 4H), 1.62 (m, 1H), 1.71 (m, 2H), 1.95 (m, 2H), 2.87 (m, 2H), 2.97 (m, 2H), 3.25 (m, 2H), 3.45 (d, 2H), 3.82 (m, 2H), 4.61 (s, 2H), 7.39 (m, 5H). m/z (ESI): 291 [C18H30N2O+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([CH3:17])=[C:11]([C:13]([O:15]C)=[O:14])[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[S:9][C:10]([CH3:17])=[C:11]([C:13]([OH:15])=[O:14])[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(-c2cccc(C)c2)sc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(-c2nc(C(=O)O)c(C)s2)c1
Yield: 106 %

Procedure:
0.2 g of methyl 2-(3-methylphenyl)-5-methyl-1,3-thiazole-4-carboxylate was dissolved in 10 ml methanol, 1 ml of 5N sodium hydroxide was added, and the mixture was heated under reflux for 1 hour. The reaction solution was ice-cooled and neutralized with 2N hydrochloric acid, followed by extracting with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated, to give 0.2 g of 2-(3-methylphenyl)-5-methyl-1,3-thiazole-4-carboxylic acid.
Reaction SMILES: Cl[P:2]([CH3:4])[CH3:3].[C:5]1([Li])[C:17]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1>CCCCC>[CH3:3][P:2]([CH3:4])[CH:16]1[C:17]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[C:10]2[C:15]1=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: CP(C)Cl
Reactant: [Li]c1cccc2c1Cc1ccccc1-2
Solvent: CCCCC
Product: CP(C)C1c2ccccc2-c2ccccc21
Temperature: -70 °C
Yield: 99.6 %

Procedure:
A solution of chlorodimethylphosphine, ClPMe2, (1.0 g, 10.39 mmol) in 20 ml of pentane was added at −70° C. over 10 min through a cannula to a suspension of fluorenyllithium, (C13H9)Li, (1.788 g, 10.39 mmol) in 30 ml of dry pentane. After brief stirring at −70° C., the cooling bath was removed and the mixture was stirred for 4 hours at room temperature under an Ar atmosphere (with occasional heating by means of a hairdryer). 20 ml of toluene were added to the suspension to assist the dissolution of the product. The pale yellow suspension was filtered and volatile components were removed from the filtrate under vacuum to leave 2.34 g (99.6%) of 9-dimethylphosphinofluorene in the form of a pale yellow oil, which is pure according to 1H and 31P NMR. The product, 9-dimethylphosphinofluorene, (2.34 g, 10.34 mmol) was diluted in 25 ml of pentane and cooled to −70° C. BuLi (4.20 ml of a 2.5 molar solution, 10.5 mmol) was added to the cooled solution and the mixture was stirred briefly at −70° C. and then at room temperature. The clear yellow solution slowly becomes turbid at room temperature and a yellow precipitate begins to form. After a reaction time of 5 hours at room temperature, the mixture was filtered through a cannula and the yellow solid was washed with dry pentane (3×5 ml) and dried under high vacuum to leave 1.91 g (80%) of a loose orange-yellow solid, which is the title compound, 9-dimethylphosphinofluorenyllithium, according to 1H and 31P NMR spectroscopy.
Reaction SMILES: C=O.N[C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[BH3-][C:20]#[N:21].[Na+].[CH3:23]C(O)=O>CC#N>[CH3:23][N:21]([CH3:20])[C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCc1cccc(N)c1
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)c1cccc(CNC(=O)OC(C)(C)C)c1
Reaction time: 1 h
Yield: 74 %

Procedure:
CH2O (aq. 37%, 1.57 mL, 21.1 mmol, 10 eq) was added to a stirred solution of tert-butyl 3-aminobenzylcarbamate (0.47 g, 2.1 mmol, 1 eq) in 10 mL CH3CN. The resulting solution was treated with NaBH3CN (0.42 g, 6.3 mmol, 3 eq) followed by the dropwise addition of HOAc to pH=7. The solution was stirred for 1 h adding HOAc occasionally to keep the pH close to 7. The reaction was concentrated in vacuo and the resulting residue was diluted with sat. NaHCO3 and extracted into EtOAc (×1). The organic layer was washed with water (×3), brine (×1), and dried over Na2SO4. The inorganics were filtered off, and the solvent removed in vacuo. Purification via flash chromatography on silica gel yielded 0.39 g (1.6 mmol, 74% yield) of tert-butyl 3-(dimethylamino)benzylcarbamate.
Reaction SMILES: [C:1]([O:4][CH:5]=[CH2:6])(=[O:3])[CH3:2].[C:7](O)(=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CC.C([O-])(=O)C.[Na+]>S(=O)(=O)(O)O>[C:1]([O:4][CH:5]=[CH2:6])(=[O:3])[CH2:2][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=COC(C)=O
Reactant: CCCCCCCCCCCC(=O)O
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: C=COC(=O)CCCCCCCCCCC
Temperature: 25 °C

Procedure:
51.5 g of vinyl acetate and 20 g (0.1 mole) of lauric acid were introduced into a 100-ml two-necked round-bottomed flask. The acid was dissolved by warming and 0.4 g of mercuric acetate was added under a stream of nitrogen. The mixture was thus maintained for 30 minutes at ambient temperature, with magnetic stirring, under nitrogen. Two drops of sulfuric acid (95%) were then added and the reaction mixture was heated under reflux for 3 hours. It was then permitted to cool to ambient temperature and 0.21 g of sodium acetate was then added.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:16][O:15][C:11](=[O:14])[CH:12]=[CH:13][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: COC(=O)C=Cc1ccc2cc[nH]c2c1
Temperature: 100 °C
Reaction time: 20 h
Yield: 72.6 %

Procedure:
To a resealable reaction tube was added 6-bromoindole (5 g, 26 mmol), methyl acrylate (2.9 ml, 32 mmol), TEA (4.4 ml, 32 mmol), (o-Tol)3P (0.78 g, 2.6 mmol) and Pd(OAc)2 (0.29 g, 1.3 mmol). The reaction tube was sealed and the resulting mixture was stirred at 100° C. for 20 hours, then cooled to room temperature, diluted with DCM, and filtered through celite. The filter cake was washed with DCM. The filtrate was concentrated and purified via flash chromatography (hexane/EtOAc) to provide 3-(1H-indol-6-yl)-acrylic acid methyl ester XXX (3.8 g, 73% yield) as a bright yellow solid.
Reaction SMILES: [CH3:1]CN(CC)CC.[OH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18]C)=O)[CH2:12][CH2:11]1.[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[CH3:27][C:26]1[CH:28]=[CH:29][C:23]([S:20]([O:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([C:16](=[O:18])[CH3:1])[CH2:14][CH2:15]2)(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: COC(=O)N1CCC(CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(COS(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Et3N (0.16 g, 1.60 mmol) and DMAP (0.39 g, 0.32 mmol) were added to a solution of methyl 4-(hydroxymethyl)piperidine-1-carboxylate (1.0 g, 3.20 mmol) in DCM (20 mL). The reaction mixture was cooled to 0° C. and TsCl (0.73 g, 3.80 mmol) was added. The reaction mixture was stirred for 1 h at room temperature, diluted with EtOAc, washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (50% EtOAc:hexane) gave (1-acetylpiperidin-4-yl)methyl 4-methylbenzenesulfonate as a pale yellow semi-solid. Yield (1.2 g, 63%); 1H NMR (400 MHz, CDCl3); δ 7.77 (d, J=8.4 Hz, 2H), 7.63 (d, J=7.6 Hz, 2H), 4.64 (d, J=14.4 Hz, 2H), 3.92 (dd, J=6.0, 2.4 Hz, 2H), 3.84 (t, J=3.2 Hz, 4H), 3.02 (d, J=13.6 Hz, 2H), 2.54-2.49 (m, 2H), 2.45 (s, 3H), 1.72-1.62 (m, 1H), 1.16 (dt, J=12.4, 3.6 Hz, 1H); MS: m/z 312.05 [M+H]+.