Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@@H:10]([OH:29])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[C:18]=1[O:27][CH3:28])[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CN=C1.[C:42]([Si:46]([CH3:49])([CH3:48])Cl)([CH3:45])([CH3:44])[CH3:43]>CN(C=O)C>[C:1]([NH:8][C@@H:9]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@@H:10]([O:29][Si:46]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:49])[CH3:48])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[C:18]=1[O:27][CH3:28])[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(C[C@H](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)c(OC)c1OC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(C[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)c(OC)c1OC
Reaction time: 2.5 h

Procedure:
A solution of 1.308 g (2.597 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2,3,4-trimethoxyphenyl)methyl]hexanoic acid, 1.443 g (20.776 mmol) of imidazole and 1.816 g (11.686 mmol) of tert-butyldimethylchlorosilane in 13 ml of abs. DMF is stirred at RT for 17 h under argon. After that, the reaction mixture is poured onto ice-water and this mixture is extracted with ethyl acetate. The organic phase is washed with cold 10% citric acid solution and saline. The combined aqueous phases are reextracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and evaporated on a RE at approximately 30° C. The resulting product is dissolved in 34.51 ml of methanol and 11.82 ml of THF, and this solution is treated, at RT, with 2.08 g of potassium carbonate in 11.82 ml of water. After it has been stirred for 2.5 h, the reaction mixture is concentrated down, at approximately 30° C., to half its volume and treated with ethyl acetate and 10% citric acid solution (cold), and the phases are separated. The organic phase is washed a further two times with (cold) saline. The combined aqueous phases are reextracted with ethyl acetate. The combined organic phases are dried over Na2SO4 and concentrated. The residue is purified by chromatography on silica gel (hexane:ethyl acetate, 1:1 and then 1:1.5), and the title compound is obtained. TLC Rf (J)=0.02. FAB-MS (M+H)+ =618 IR(KBr) inter alia: 1712, 1495, 1366, 1101 and 836 cm-1. 1H-NMR(CD3OD) inter alia: 7.30-7.10 (m, 5H); 6.84 and 6.67 (each d, each 1H); 6.23 and 5.55 (each d, in all 1H from NH); 3.86, 3.81 and 3.80 (each s, each 3H); 1.31 and 1.20 (each s, in all 9H from Boc); 0.93 (s, 9H); 0.14 and 0.11 (each s, each 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:15])=[CH:6][CH:7]=1.[CH:16]1(C(O)=O)[CH2:19][CH2:18][CH2:17]1.OS(O)(=O)=O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].[OH-].[NH4+]>O.[N+]([O-])([O-])=O.[Ag+]>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:15])=[CH:6][C:7]=1[CH:16]1[CH2:19][CH2:18][CH2:17]1
Reactant: O=C(O)C1CCC1
Reactant: Cc1cccc(C)c1-c1ccc(Cl)nn1
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: O
Product: Cc1cccc(C)c1-c1cc(C2CCC2)c(Cl)nn1
Reaction time: 1 h

Procedure:
A mixture of 3-chloro-6-(2,6-dimethyl-phenyl)-pyridazine (210 mg, 0.78 mmol), cyclobutanecarboxylic acid (120 mg, 1.2 mmol), concentrated H2SO4 (300 mg) and water (3 mL) is degassed with N2 at 70° C. for 20 min. AgNO3 (34 mg, 0.2 mmol) is added followed by dropwise addition of a solution of ammonium persulfate (210 mg, 0.92 mmol) in water. The reaction mixture is stirred at the same temperature for one h. After cooled, the mixture is poured onto ice and water, neutralized with ammonium hydroxide to pH 8-9 and extracted with EtOAc. The extract is washed with water, dried and concentrated. The crude product is purified by flash silica gel column (Hexanes/EtOAc 4:1) to give 3-Chloro-4-cyclobutyl-6-(2,6-dimethyl-phenyl)-pyridazine as an oil. 1H NMR: (CDCl3) 7.26 (m, 2H), 7.14 (d, 2H), 3.78 (m, 1H), 2.48 (m, 2H), 2.00-2.20 (m, 9H), 1.90 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.N1CC[CH2:15][C@H:11]1[C:12](O)=O.CC(C)=O>CCO>[CH3:15][C:11]1[CH:12]=[CH:4][C:3]2[C:2](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Nc1ncccc1C=O
Solvent: CC(C)=O
Solvent: CCO
Product: Cc1ccc2cccnc2n1
Reaction time: 8 h
Yield: 887.8 %

Procedure:
To a suspension of 2-aminonicotinaldehyde (732 mg, 6 mmol) and L-proline (69 mg, 0.6 mmol) in EtOH (15 mL) was added acetone (1.74 g, 30 mmol). Then the mixture was heated at reflux and stirred for 8 h. The resulting mixture was concentrated under reduced pressure to give a residue, which was washed with water (10 mL) and extracted with DCM (15 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford the crude product 2-methyl-1,8-naphthyridine as a yellow solid (768 mg). MS (ESI): m/z 145 [M+H]+. See e.g., Bioorg. Med. Chem. Lett., 2005, 15, 2679-84.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][OH:17])[CH:11]=[CH:12][CH:13]=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.Cl>C(Cl)(Cl)Cl.O>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][O:17][S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[CH:11]=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCc1cccc(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OCCCc2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
86 ml of pyridine are added dropwise to 90 g of 3-(3-chlorophenyl)propan-1-ol and 124 g of p-toluenesulfonic acid chloride in 300 ml of chloroform at 0° C. When the addition is complete, the mixture is stirred at room temperature for 3 hours, and the solution is poured into a mixture of 400 ml of water and 120 ml of concentrated hydrochloric acid. The organic phase is separated off, washed 3 times with water, dried over sodium sulfate and concentrated to a viscous oil in vacuo.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH2:22](Br)[CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:22]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Reactant: CCCCCBr
Product: CCCCCOc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
Alkylation reaction of phenol 58 with pentyl bromide gave 2-(3-(3-(pentyloxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.549 g, 46%): 1H NMR (400 MHz, CDCl3) δ 7.81-7.84 (m, 2H), 7.69-7.72 (m, 2H), 7.11-7.16 (m, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.73 (s, 1H), 6.66 (dd, J=7.8, 2.2 Hz, 1H), 3.91 (t, J=6.8 Hz, 2H), 3.74 (t, J=7.2 Hz, 2H), 2.65 (t, J=7.6 Hz, 2H), 2.01-2.07 (m, 2H), 1.73-1.78 (m, 2H), 1.34-1.48 (m, 4H), 0.92 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:28]([NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])[C:3]1=[O:20]
Reactant: O=C=Nc1ccccc1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)Nc2ccccc2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and phenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 260°-261° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH3:21])[CH:13]=1)([CH3:11])[C:9]#[N:10].C(OCC)(=O)C.[OH-].[Na+]>C1COCC1.CCOCC>[NH2:10][CH2:9][C:8]([CH3:11])([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH3:21])[CH:13]=1)[CH3:7]
Reactant: CCCOc1cccc(C(C)(C)C#N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCOc1cccc(C(C)(C)CN)c1
Reaction time: 0.33 h

Procedure:
To a suspension of LiAlH4 (1.0 g) in dry THF (25 ml) under dry N2 was added a solution of 2-methyl-2-(3-propyloxyphenyl)propionitrile (1.02 g) in dry THF (10 ml) over 10 minutes. After stirring at 25° for 20 minutes, the reaction mixture was heated under reflux for 5 hours, cooled to 0°, diluted with ether (50 ml) and cautiously decomposed with ethyl acetate (2 ml) followed by 5M NaOH (5 ml). The mixture was filtered and the residue triturated with ether (3×10 ml). The combined filtrates were extracted with 20% HCl (4×10 ml) and the combined extracts basified with 10M NaOH. The liberated oil was extracted into ether (3×15 ml) and the combined extracts dried over Na2SO4, filtered and evaporated to dryness to give a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[C:8]([CH:11]([CH3:13])[CH3:12])[CH:7]=[CH:6][C:5]=2[CH3:14].C([Li])CCC.[Cl-].[CH3:21][SiH:22]([CH3:36])[CH:23]1[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2.[Cl-].[NH4+]>CCOCC.CCCCCC>[CH3:21][Si:22]([CH3:36])([CH:3]1[C:4]2[C:9](=[C:8]([CH:11]([CH3:12])[CH3:13])[CH:7]=[CH:6][C:5]=2[CH3:14])[CH:10]=[C:2]1[CH3:1])[CH:23]1[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2
Reactant: CC1=Cc2c(C(C)C)ccc(C)c2C1
Reactant: C[SiH](C)C1c2ccccc2-c2ccccc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1=Cc2c(C(C)C)ccc(C)c2C1[Si](C)(C)C1c2ccccc2-c2ccccc21
Temperature: -78 °C
Yield: 45.5 %

Procedure:
A 100 ml four-necked flask equipped with a reflux tube, a thermometer and a dropping funnel was thoroughly purged with nitrogen and dried. To the flask, 2-methyl-4-i-propyl-7-methylindene (1.50 g, 8.06 mmol) and dehydrated ether (25 ml) were introduced. Under stirring at -78° C., a hexane solution of n-butyllithium (8.46 mmol) was dropwise added. After the dropwise addition, the temperature of the system was allowed to spontaneously and slowly rise to room temperature. The reaction mixture was stirred at room temperature over night, whereby a colourless solution came, through a white slurry and a light yellow slurry, to a yellow slurry. To the slurry, the dimethyl(9-fluorenyl)silane chloride (2.06 g, 8.06 mmol) synthesized above was added under stirring at 0° C., followed by stirring at room temperature for 1.5 hours. After ether (100 ml) and a saturated ammonium chloride aqueous solution (100 ml) were added, the resulting mixture was introduced into a separatory funnel to separate out an organic phase. The organic phase was washed with a saturated ammonium chloride aqueous solution, water and a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After the solvent was removed, the obtained product (a yellow oil) was purified by column chromatography (developer: hexane) to obtain 1.50 g of a yellow oil (yield: 46%).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[NH:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=O)[C:7]1=O>>[N:1]1[NH:2][C:3](=[S:4])[N:5]=[C:7]2[C:9]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=1[NH:6]2
Reactant: O=C1Nc2ccccc2C1=O
Reactant: NNC(N)=S
Product: S=c1nc2[nH]c3ccccc3c2n[nH]1

Procedure:
In the general synthetic scheme, thiosemicarbazide is reacted with isatin to form 5H-1,2,4-triazino[5,6-b]indole-3(2H)-thione. This product is alkylated with an appropriate halo-derivative to provide the sulfur-substituent desired in the final product.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[N:11]=[C:12]([C:24]([CH3:26])=[CH2:25])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([O:20][CH3:21])=[C:15]([O:22][CH3:23])[CH:14]=4)[CH:5]=2)[CH2:3][CH2:2]1>[Pd]>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[N:11]=[C:12]([CH:24]([CH3:26])[CH3:25])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([O:20][CH3:21])=[C:15]([O:22][CH3:23])[CH:14]=4)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C=C(C)c1nc(Nc2cc(C3CC3)[nH]n2)cc2cc(OC)c(OC)cc12
Agent: [Pd]
Product: COc1cc2cc(Nc3cc(C4CC4)[nH]n3)nc(C(C)C)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
The mixture of (5-Cyclopropyl-1H-pyrazol-3-yl)-(1-isopropenyl-6,7-dimethoxy-isoquinolin-3-yl)-amine (100 mg) and 10% Pd/C (15 mg) was sealed in high-pressure bottle under 40 psi H2 pressure and stirred at room temperature overnight. Then the mixture was filtered, and the filtrate was concentrated to give (5-Cyclopropyl-1H-pyrazol-3-yl)-(1-isopropyl-6,7-dimethoxy-isoquinolin-3-yl)-amine as oil (30 mg). LC-MS: m/e 353 (MH+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@:5]1([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=3)[CH2:22][CH2:21]2)=[O:19])[CH2:9][CH2:8][CH:7]([NH:10]C(=O)OC(C)(C)C)[CH2:6]1)[CH3:2].[ClH:36]>CCOCC>[ClH:36].[ClH:36].[CH2:1]([O:3][CH2:4][C@:5]1([C:18]([N:20]2[CH2:21][CH2:22][N:23]([C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=3)[CH2:24][CH2:25]2)=[O:19])[CH2:9][CH2:8][C@@H:7]([NH2:10])[CH2:6]1)[CH3:2]
Reactant: CCOC[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CCC(NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCOCC
Product: CCOC[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl [(3S)-3-(ethoxymethyl)-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentyl]carbamate (295 mg, 0.589 mol) was dissolved in a 2 M solution of hydrogen chloride in ether (10 mL). After being stirred at room temperature overnight, the reaction mixture was concentrated under vacuum to provide the desired product (330 mg) as a light yellow solid. MS calculated for C19H28F3N4O2: (M+H) 401.3; found 401.3.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:14]([NH:16][C@H:17]([C:21]([OH:23])=O)[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[NH:24]1[CH2:46][CH2:45][CH2:44][CH2:43][CH:25]1[C:26]([NH:28][CH:29]1[CH:33]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:32][C:31](=[O:42])[CH2:30]1)=[O:27].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C.ClCCl>[C:1]([NH:4][C@H:5]([C:14]([NH:16][C@H:17]([C:21]([N:24]1[CH2:46][CH2:45][CH2:44][CH2:43][CH:25]1[C:26]([NH:28][CH:29]1[CH:33]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[O:32][C:31](=[O:42])[CH2:30]1)=[O:27])=[O:23])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: O=C1CC(NC(=O)C2CCCCN2)C(OCc2ccccc2)O1
Reactant: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)O)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)N1CCCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1)C(C)C
Reaction time: 18 h
Yield: 45.7 %

Procedure:
N-Acetyl-tyrosinyl-valine (464 mg, 1.44 mmol) and N-Pipecolyl-4-amino-5-benzyloxy-2-oxotetrahydrofuran (412 mg, 1.3 mmol) were dissolved in 5 ml each of dimethylformamide and dichloromethane and cooled to 0° C. To the cooled solution was added 1-hydroxybenzotriazole (HOBT; 210 mg, 1.56 mmol) followed by the addition of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDC; 326 mg, 1.7 mmol). After stirring for 18 hours, the mixture was diluted with ethyl acetate and washed with water, 10 sodium hydrogen sulfate, 10% sodium bicarbonate, and water. The organic layer was concentrated to give a crude solid that was purified by flash chromatography (SiO2) eluting with 94:6:1 (dichloromethane:isopropanol:pyridine) to give 370 mg of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([S:12]([N:15]2[CH2:21][CH:20]3[CH2:22][CH2:23][CH:17]([CH2:18][CH2:19]3)[CH2:16]2)(=[O:14])=[O:13])[CH:3]=1.Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Cl)[CH:26]=1.[H-].[Na+]>CN(C=O)C>[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([S:12]([N:15]3[CH2:21][CH:20]4[CH2:22][CH2:23][CH:17]([CH2:18][CH2:19]4)[CH2:16]3)(=[O:14])=[O:13])[CH:3]=2)[CH:26]=1
Reactant: O=S(=O)(c1cc(O)c2ccccc2c1)N1CC2CCC(CC2)C1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1cc(OCc2cccnc2)c2ccccc2c1)N1CC2CCC(CC2)C1
Temperature: 90 °C
Reaction time: 15 h
Yield: 66 %

Procedure:
The product from Example 52 (147 mg, 0.44 mmol), 3-picolylchloride hydrochloride (73 mg, 0.44 mmol and a crystal of KI were combined in DMF (30 ml). Sodium hydride (44 mg, 1.1 mmol, a 60% dispersion in oil) was added and the mixture was stirred at 90° C. for 15 hr. At this time the solvent was evaporated under reduced pressure and the residue was partitioned between 1N aq KOH and CHCl3. The CHCl3 phase was dried (Na2SO4) and concentrated and the residue was purified by flash chromatography using 5% acetone in CHCl3. The pure product was obtained as a tan foam (124 mg, 66% yield): 1H NMR (CDCl3) δ 1.53-1.76 (8H, m, 4×CH2), 2.06 (2H, s, 2×CH), 3.21 (4H, d, J=4.19 Hz, 2×CH2), 5.34 (2H, s, CH2Ar), 7.12 (1H, s, ArH), 7.37 (1H, m, ArH), 7.64 (2H, m, ArH), 7.82-7.98 (3H, m, ArH), 8.35 (1H, m, ArH), 8.62 (1H, m, ArH), 8.80 (1H, m, ArH).
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]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].C(N(CC)CC)C.[I-].[Na+].I.[CH2:43]([O:45][CH2:46][CH2:47][N:48]1[C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=2[N:50]=[C:49]1[N:57]1[CH2:63][CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1)[CH3:44]>C(#N)C.CO.ClCCl.ClCCl>[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]([CH2:13][CH2:14][N:60]2[CH2:61][CH2:62][CH2:63][N:57]([C:49]3[N:48]([CH2:47][CH2:46][O:45][CH2:43][CH3:44])[C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=4[N:50]=3)[CH2:58][CH2:59]2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Agent: I
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 40 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) (1.43 g, 3.1 mmol), triethylamine (2.05 mL, 14.75 mmol), sodium iodide (0.46 g, 3.1 mmol), and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (1.6 g, 2.95 mmol) in acetonitrile (40 ml). Heat to reflux. After 40 hours, evaporate in vacuo to give a residue. Partition the residue between dichloromethane and water. Separate the layers and extract the organic layer with a saturated aqueous sodium bicarbonate solution, water, and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with dichloromethane, 5% methanol/dichloromethane, and then 10% methanol/dichloromethane to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C([Sn](CCCC)(CCCC)C1C=CC(F)=CC=1[N+]([O-])=O)CCC.FC(F)(F)S(O[C:41]1[CH2:50][CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[C:46]([O:51][CH3:52])[CH:47]=2)[CH:42]=1)(=O)=O>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:41]2[CH2:50][CH2:49][C:48]3[C:43]([CH:42]=2)=[CH:44][CH:45]=[C:46]([O:51][CH3:52])[CH:47]=3)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1Br
Reactant: COc1ccc2c(c1)CCC(OS(=O)(=O)C(F)(F)F)=C2
Agent: CCCC[Sn](CCCC)(CCCC)c1ccc(F)cc1[N+](=O)[O-]
Product: COc1ccc2c(c1)CCC(c1ccc(F)cc1[N+](=O)[O-])=C2

Procedure:
Synthesized from 1-bromo-4-fluoro-2-nitrobenzene according to an analogous synthetic method to Preparation Example 76, tributyl(4-fluoro-2-nitrophenyl)tin (7.1 g) and 6-methoxy-3,4-dihydronaphthalen-2-yl trifluoromethanesulfonate (2.2 g) were used according to an analogous synthetic method to Preparation Example 77 to provide 3-(4-fluoro-2-nitrophenyl)-7-methoxy-1,2-dihydronaphthalene (1.4 g). The total amount of this compound was used according to an analogous synthetic method to Example 30 to provide the title compound (1.1 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:11][CH2:12]Cl)[CH2:8][CH2:9]Cl)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[CH2:23][C:24]#[N:25].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:7]1[CH2:11][CH2:12][C:23]([C:24]#[N:25])([C:17]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=2[F:15])[CH2:9][CH2:8]1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: N#CCc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.8 %

Procedure:
To bis(2-chloroethyl)-carbamic acid tert-butyl ester (1.0 g, 3.8 mmol) and 2,4-difluorophenyl acetonitrile (0.581 g, 3.8 mmol) in DMF (35 ml), NaH (95%) (0.258 g, 9.68 mmol) was added in one batch at 0° C. The solution was stirred for 10 minutes at room temperature. When foaming subsided, the solution was heated at 60° C. for 24 hours. It was then quenched with water at 0° C. and concentrated. The residue was extracted with ethyl acetate (25 mL) and washed three times with water (15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (hexane:ethyl acetate 4:1) yielded 0.720 g (62%) of the product as a syrup.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[Na+]>>[O:1]=[C:2]([CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)CC(=O)CC1CCOCC1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CC(=O)CC1CCOCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension of ethyl 3-oxo-4-(tetrahydro-2H-pyran-4-yl)butanoate (960 mg, 4.48 mmol) and 1N aqueous sodium hydroxide (9.00 mL, 9.00 mmol) was stirred at room temperature for 48 h. The reaction mixture was washed with diethyl ether and then acidified to pH 3 with 0.5N sulfuric acid. The mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate, filtrated and concentrated in vacuo to give 3-oxo-4-(tetrahydro-2H-pyran-4-yl)butanoic acid. MS (ESI): m/z 185 (M−H).
Reaction SMILES: [C:1](=[O:8])(OC)[O:2][CH2:3][CH2:4][Cl:5].C(Cl)(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[Br-].C([P+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:2][CH2:3][CH2:4][Cl:5])(=[O:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)OCCCl
Reactant: O=C(Cl)c1ccccc1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: O=C(OCCCl)c1ccccc1
Temperature: 150 °C
Reaction time: 3 h
Yield: 58.9 %

Procedure:
A mixture of 6.93 g (0.05 mole) of 2-chloroethyl methyl carbonate, 7.03 g (0.05 mole) of benzoyl chloride and 0.85 g (0.0025 mole) of tetra-n-butylphosphonium bromide was heated to 150° C. After 3 hours, gas evolution had ceased and distillation gave 5.44 g (59 percent yield) of 2-chloroethyl benzoate at b.p. 81° C.-82° C./0.4 mm Hg.