Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li:10]CCCC.ClB(Cl)C1CCCC1.O>CCOCC>[S:1]1[C:5]([Li:10])=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: c1ccc2sccc2c1
Reactant: [Li]CCCC
Agent: ClB(Cl)C1CCCC1
Solvent: O
Solvent: CCOCC
Product: [Li]c1cc2ccccc2s1
Temperature: -90 °C

Procedure:
A dry 100 mL round-bottomed flask equipped with a mechanical stirrer, a reflux condenser, a low temperature thermometer and a silicone rubber septum was flushed with argon. 2-benzo[B]thienyllithium was prepared in situ from 1.1 g of benzo[B]thiophene (8.21 mmol) and 3.3 mL of 2.5 m solution of n-BuLi (in hexanes) in 20 mL of ether. The mixture was cooled to -90° C. and the solution of dichlorocyclopentylborane obtained in step 1 was added over 10 min while stirring was maintained. The mixture was brought to 20° C. and stirred for 2 h at this temperature. Distilled water (20 mL) was added with vigorous stirring. The top layer formed was separated and discarded. The aqueous layer was poured into 30 mL of saturated solution of NME4CL and shaken. The precipitate formed was filtered, washed with 60 ml of distilled water, and recrystallized from acetone/methanol=3/2 yielding 1.2 g (79%) of white crystalline solid. m.p. 234-236° C. 1H NMR (D6 -DMSO, 200 MHz) δ 7.69 (d, J=7.6 Hz, 3H), 7.57 (d, J=7.6 Hz, 3H), 7.14 (t, J=7.4 Hz, 3H), 7.07 (s, 3H), 7.04 (t, J=7.4 Hz, 3H), 3.04 (s, 12H), 1.85 (m, 2H), 1.65 (m, 1H), 1.37 (br s, 6H). 13C NMR (D6 -DMSO, 50 MHz) δ 141.9, 124.1, 122.5, 121.4, 120.9, 54.51 (t, J=4 HZ), 31.38, 27.34. 11B NMR (DMSO, 128 MHz) δ -30.36. Anal. Calcd. for C33H36BNS3 : C, 71.59; H, 6.55; N, 2.53; S, 17.37. Found: C, 71.50; H, 6.63; N, 2.53; S, 17.30.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[C:16]([CH:19]1[CH2:23][CH2:22][CH2:21][C:20]1=O)(=O)[CH3:17].[O-]CC.[Na+]>C(O)C.O>[CH3:17][C:16]1[NH:2][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:20]2[CH2:21][CH2:22][CH2:23][C:19]=12
Reactant: CCOC(=O)CN
Reactant: CC(=O)C1CCCC1=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1[nH]c(C)c2c1CCC2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A procedure for the synthesis of pyrroles via N-(3-oxo-1-alkenyl)glycine ester was adapted from Hombrecher and Horter, Synthesis 389, 1990. Ethyl aminoacetate hydrochloride (28 g, 0.20 mol) and triethylamine (20.1 g, 0.20 mol) were added to a solution of 2-acetylcyclopentanone (25.0 g, 0.20mol) in ethanol (400 ml). The solution was stirred at room temperature for 15 hours and concentrated. The residue was combined with water (250 ml), and extracted with methylene chloride (4×100 ml). The combined extract was washed with water (100 ml), dried (sodium sulfate), and concentrated to leave a light brown oil. The oil was added with stirring at 50° C. to a solution of sodium ethoxide (14 g, 0.20 mol) in absolute ethanol (400 ml). The mixture was heated at 80° C. for 3 hours and poured into water (500 ml) to precipitate a light yellow solid. Recrystallization from ethanol gave ethyl 3-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrolecarboxylate 4j, 9.1 g (24%)as a pale yellow solid, mp 166°-167° C.; 1H NMR (CDCl3): δ 8.38 (s, 1H), 4.24 (q, 2H), 2.78 (t, 2H), 2.52 (t, 2H), 2.30 (m, 2H), 2.18 (s, 3H), 1.30 (t, 3H). Anal. calcd for C11H15NO2 : C, 68.39; H, 7.77; N, 7.25. Found, C, 68.40; H, 7.85; N, 7.15.
Reaction SMILES: I[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[C:10]([C:12]1[N:16]([CH3:17])[CH:15]=[N:14][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)#[CH:11].C(N(CC)CC)C>CN(C=O)C.[Cu]I>[CH3:17][N:16]1[C:12]([C:10]#[C:11][C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=2[NH2:9])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:14]=[CH:15]1
Reactant: Nc1ncnc(I)c1N
Reactant: C#Cc1c(-c2ccccc2)ncn1C
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cnc(-c2ccccc2)c1C#Cc1ncnc(N)c1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.4 %

Procedure:
6-Iodopyrimidine-4,5-diamine (Intermediate 89) (50 mg), CuI (2 mg), PdCl2dppf (16 mag), 5-ethynyl-1-methyl-4-phenyl-1H-imidazole (intermediate 26) (77 mg), and triethylamine (0.33 mL) in DMF (7 mL) were mixed together and then degassed. The reaction mixture was allowed to stir at ambient temperature under an inert atmosphere for 24 hours. The reaction mixture was filtered through diatomaceous earth, washing well with DCM and then MeCN. The organics were concentrated and the residue purified by chromatography on silica eluting with DCM:MeOH (9:1) to afford the title compound as a yellow solid (47 mg, 76%);
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[S:51][C:18]2[N:19]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[C:44]([C:49]#[N:50])=[CH:45][CH:46]=[CH:47][CH:48]=4)=[CH:39][CH:38]=3)[C:20](=[O:35])[N:21]([CH2:24][C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]>C(Cl)(Cl)Cl>[CH2:13]([C:15]1[S:51][C:18]2[N:19]([CH2:36][C:37]3[CH:38]=[CH:39][C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[C:49]4[NH:3][C:4](=[O:7])[O:5][N:50]=4)=[CH:41][CH:42]=3)[C:20](=[O:35])[N:21]([CH2:24][C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccccc3OC)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccccc3OC)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
A mixture of hydroxylammonium chloride (8.3 g), sodium hydrogencarbonate (13 g) and dimethyl sulfoxide (100 mL) was stirred at 40° C. for 30 min, 4′-{[6-ethyl-3-[2-(2-methoxyphenyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (4.12 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in methylene chloride (150 mL), N,N′-carbonyldiimidazole (1.25 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (1.06 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained solid was recrystallized from chloroform to give the title compound as colorless crystals (1.19 g, 26%).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.[NH2:17][C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([C:28]([NH2:30])=[O:29])[CH:27]=1)[N:24]=[CH:23][N:22]=[C:21]2[NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([C:40]([F:43])([F:42])[F:41])[CH:34]=1.C(N(CC)CC)C>C(Cl)Cl>[NH:7]([C:8]([NH:17][C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([C:28]([NH2:30])=[O:29])[CH:27]=1)[N:24]=[CH:23][N:22]=[C:21]2[NH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([C:40]([F:42])([F:43])[F:41])[CH:34]=1)=[O:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: NC(=O)c1cc(N)cc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)ncnc12
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1cc(NC(=O)Nc2ccccc2)cc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)ncnc12
Temperature: 40 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
Phenyl isocyanate (70 μL, 0.5 M in anhydrous DCM, 0.03 mmol, 1.1 equiv.) was added to a solution of TFA salt of 6-amino-4-{[4-chloro-3-(trifluoromethyl)benzyl]amino}quinazoline-8-carboxamide (16 mg, 0.03 mmol, 1.0 equiv.) and triethylamine (16 μL, 0.09 mmol, 3.0 equiv.) in anhydrous DCM (1 mL). The resulting mixture was stirred at 40° C. for 3 hrs. The title compound was obtained by pre-HPLC in 79% yield. Mass: M+H+: 515.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]1[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=1.C(N(CC)CC)C.CS([Cl:32])(=O)=O.O>ClCCl.CN(C)C1C=CN=CC=1>[Cl:32][CH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)=[C:2]([F:1])[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Nc1nc(CCc2ccc(CO)cc2F)cs1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(CCc2ccc(CCl)cc2F)cs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 28.7 %

Procedure:
To a solution of N-(4-{2-[2-fluoro-4-(hydroxymethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (194.7 mg, 0.665 mmol) in anhydrous dichloromethane (2 ml) were added triethylamine (0.17 ml, 1.20 mmol) and 4-dimethylaminopyridine (8.1 mg, 0.066 mmol), and the mixture was cooled to 0° C. Methanesulfonyl chloride (77 μl, 1.0 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hr. The mixture was cooled to 0° C., triethylamine (93 μl, 0.67 mmol) and methanesulfonyl chloride (51 μl, 0.67 mmol) were added, and the mixture was stirred at room temperature for 5 min. Iced water (2 ml) was added to the reaction mixture, and the mixture was stood still and partitioned. The aqueous layer was extracted 3 times with dichloromethane, and the combined organic layer was washed with 1M hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (Merck 9385 16 g, ethyl acetate:hexane=2:3) to give N-(4-{2-[4-(chloromethyl)-2-fluorophenyl]ethyl}-1,3-thiazol-2-yl)acetamide (59.6 mg, 0.191 mmol, yield 28.7%) as a pale-yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[C:4]([F:13])[CH:3]=1.[BH4-].[Na+].O>CO.ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[OH:12])=[C:4]([F:13])[CH:3]=1
Reactant: O=C1CCCc2c(F)cc(Br)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: OC1CCCc2c(F)cc(Br)cc21
Reaction time: 2 h

Procedure:
To a solution of 7-bromo-5-fluoro-3,4-dihydro-2H-naphthalen-1-one (0.290 g, 1.145 mmol) in methanol (8 mL) and dichloromethane (2 mL) at 0° C. is added sodium borohydride (0.066 g, 1.718 mmol) in one portion. After 2 hours at 0° C., water (30 mL) is added and the volatile organics are removed in vacuo. The resulting mixture is extracted with dichloromethane, dried over magnesium sulfate, filtered, and concentrated to afford 7-bromo-5-fluoro-3,4-dihydro-2H-naphthalen-1-ol, which is used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[CH:22]1([CH2:25]Br)[CH2:24][CH2:23]1>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[O:8][CH2:25][CH:22]1[CH2:24][CH2:23]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)Cc1cc(Cl)c(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)Cc1cc(Cl)c(OCC2CC2)c(Br)c1
Temperature: 60 °C
Yield: 72 %

Procedure:
To a stirred solution of ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)acetate (4 g, 0.011 mol) and K2CO3 (2.8 g, 0.02 mol) in 100 ml of DMSO was slowly added cyclopropyl methylbromide (1.46 ml, 0.017 mol) at room temperature. Upon completion of the addition, the reaction mixture was heated at 60° C. for 4 h. Upon completion of the reaction, the mixture was poured onto water and extracted with EtOAc (×2). The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated in vacuo to give ethyl 2-(3-bromo-5-chloro-4-(cyclopropylmethoxy)phenyl)acetate in 72% yield. (93.4 g). 1HNMR (CDCl3): 7.38 (bs, 1H); 7.28 (s, 1H); 4.16 (q, 2H); 3.87 (d, 2H); 3.58 (s, 2H); 1.38 (m, 1H); 1.28 (t, 3H); 0.63 (m, 2H); 0.38 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12]C(=O)C)[CH2:4][CH2:3]1.Cl>O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH2:12])[CH2:4][CH2:3]1
Reactant: CC(=O)NC1CCC(=O)c2ccccc21
Agent: Cl
Solvent: O
Product: NC1CCC(=O)c2ccccc21

Procedure:
A mixture of 41.4 g. of crude N-(1,2,3,4-tetrahydro-4-oxo-1-naphthyl)acetamide, 300 ml. of concentrated hydrochloric acid and 250 ml. of water is stirred and heated at reflux overnight. The mixture is decanted, filtered, and the cooled filtrate is extracted with 300 ml. of chloroform. The aqueous solution is evaporated to dryness in vacuo to afford 26.55 g. of the title product.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][N:5]=[C:6]=[O:7].[C:8]([C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].[Cl:19][C:20]1[CH:32]=[CH:31][C:23]([CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+]>CCOCC.C(O)C>[ClH:19].[ClH:19].[Cl:19][C:20]1[CH:32]=[CH:31][C:23]([CH2:24][N:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH:16][C:15]3[CH:14]=[CH:13][C:12]([C:8]([CH3:11])([CH3:9])[CH3:10])=[CH:18][CH:17]=3)=[O:7])[CH2:27][CH2:26]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Reactant: O=C=NCCCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CC(C)(C)c1ccc(NC(=O)NCCCN2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Product: Cl
Yield: 108.4 %

Procedure:
A solution of 3-iodopropyl isocyanate (4.22 g; 20 mmole) in ether (25 ml) was added to a solution of 4-t-butylaniline (2.98 g; 20 mmole) in ether (25 ml), and the resulting solution refluxed for 3 hours. After removal of the solvent, 4-chlorobenzylpiperazine (4.18 g; 20 mmole) in ethanol (50 ml) was added and the resulting solution refluxed for 24 hours. Aqueous sodium bicarbonate was added to the mixture and the product was extracted with methylene chloride, dried (sodium sulfate), and the salt precipitated with ethereal hydrochloric acid. Recrystallization several times with ethanol provided the title compound (3.73 g; 33% yield) as colorless crystals, m.p. 240°-241° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH:17]([CH3:20])[CH2:18]O)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.S([Cl:32])(C)(=O)=O>C(Cl)Cl>[Cl-:32].[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][N+:14]4([CH:17]([CH3:20])[CH2:18]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(CO)N1CCN(c2cccc3c2OCCO3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1C[N+]12CCN(c1cccc3c1OCCO3)CC2
Product: [Cl-]
Temperature: 10 °C
Reaction time: 8 h

Procedure:
Crude compound IV (29.4 g, 0.106 mol), and triethyl amine (16.2 mL, 0.116 mol) are dissolved in CH2Cl2 (150 mL) and to this solution is added a solution of mesyl chloride (8.6 mL, 0.111 mol) in CH2Cl2 (50 mL) under cooling at 5 to 15° C. over 0.5 h. Stirring is continued overnight at ambient temperature resulting in clear red solution. This solution is washed with water (1×100 mL) and 5% aq. NaHCO3 (1×100 mL). Combined aqueous layers were back-washed with CH2Cl2 (2×50 mL). Organic layers are dried with MgSO4 and concentrated to afford V as thick red oil, yield 31.6 g (101%). 1H NMR (CDCl3) δ 6.76 (t, J=7.5 Hz, 1H), 6.55 (m, 2H), 4.27 (m, 4H), 4.11 (m, 1H), 3.10 (m, 4H), 2.8–2.64 (m, 5H), 2.54 (dd, J=7.5, 15 Hz, 1H), 1.55 (d, 3H).
Reaction SMILES: [F:1][C:2]1([F:15])[C:6]([F:8])([F:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([CH2:13][Br:14])[C:4]=2[O:3]1.[C:16]1([P:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Br-:14].[F:1][C:2]1([F:15])[C:6]([F:8])([F:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([CH2:13][P+:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:4]=2[O:3]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: FC1(F)Oc2c(CBr)cccc2C1(F)F
Solvent: Cc1ccccc1
Product: FC1(F)Oc2c(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cccc2C1(F)F
Product: [Br-]

Procedure:
This compound is prepared in a manner analogous to that of Step A of Example 2, using 14.0 grams (0.049 mole) of 2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-7-ylmethyl bromide and 13.0 grams (0.050 mole) of triphenylphosphine in about 100 mL of toluene, yielding (2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-7-ylmethyl)triphenylphosphonium bromide.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([OH:5])=[O:4].C.[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].S([O-])(O)(=O)=O.[Na+]>O.C1(C)C=CC=CC=1>[OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([O:5][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:4]
Reactant: CSCCC(O)C(=O)O
Reactant: CCCCCCCCO
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCOC(=O)C(O)CCSC
Temperature: 25 °C

Procedure:
To a multi-neck 5 L round bottom flask fitted with a mechanical stirrer, reflux condenser, and dean stark trap was added 2-hydroxy-4-(methylthio)butanoic acid (650 g, 4.33 mol, obtained for example by stirring Alimet over activated charcoal, filtering and concentrating in a rotovap), 1-octanol (845.4 g, 6.49 mol), sodium hydrogen sulfate (10.4 g, 86 mmol), and toluene (2.7 L).The resulting solution was heated to reflux with removal of water (˜146 mL) during the course of about 5.5 hours and the reaction was monitored by GC analysis. The reaction was cooled to room temperature overnight and then washed with saturated NaHCO3 (1×1.5 L), DI water (1×1.5 L) and brine (1×1.5 L), dried over sodium sulfate, filtered and evaporated to give a dark oil (1,525 g). The oil was purified by kugelrohr distillation at 130-150° C. and 0.1 mm Hg vacuum to give a pale yellow oil (507.6 g, 45%). m/z 285 (MNa+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[CH2:10]2)=[CH:5][CH:4]=1.N1C[CH2:17][CH2:16][CH2:15]1.O.C(Br)C=C>C1C=CC=CC=1>[CH2:17]([CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:13])[CH:16]=[CH2:15]
Reactant: COc1ccc2c(c1)CC(=O)CC2
Reactant: C1CCNC1
Solvent: O
Solvent: C=CCBr
Solvent: c1ccccc1
Product: C=CCC1C(=O)CCc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 104.1 g (0.59 mole) 3,4-dihydro-7-methoxy-2(1H)naphthalenone in 100 ml dry benzene was added dropwise under nitrogen with stirring at room temperature 62.5 g (0.88 mole) pyrrolidine. After the addition (10-15 min), the reaction mixture was refluxed for 2.5 hr with azeotropic removal of water and then cooled to room temperature. The enamine solution was added dropwise to 143.8 g (1.19 mole) allyl bromide with stirring at a rate sufficient to maintain normal refluxing to provide a heavy precipitate. Benzene (50 ml) was added to facilitate stirring and reflux continued for 4 hr; then, 700 ml of water was added and refluxing resumed. After 2 hr, the reaction mixture was cooled to room temperature and diluted with 100 ml benzene. The benzene layer was separated and the aqueous phase extracted with benzene (2×100 ml). The combined extracts were washed with water (2×100 ml) and dried (Na2SO4). After evaporation of the solvent, the residue was distilled to give 113.5 g (89%) of VIIIa, b.p. 114°-118°/0.1-0.05 mm Hg. NMR: δ 2.40-3.10 (m, 6, allylic and alicyclic), 3.45 (t, 1, C1 --H, J=6.5), 3.75 (s, 3, OCH3), 4.8-6.1 (m, 3, olefinic), 6.7-7.2 (m, 3, ArH). IR: (neat) 1715 cm-1.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[O:41][CH3:42])[CH2:31][CH2:30]1>C(#N)C.O>[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:1][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][N:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])[CH2:31][CH2:30]2)[CH2:22][CH2:21]1
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Reactant: Fc1ccc2[nH]cc(CC3CCNCC3)c2c1
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCCN2CCC(Cc3c[nH]c4ccc(F)cc34)CC2)CC1
Yield: 73 %

Procedure:
Pulverized potassium carbonate (0.33 g, 2.4 mmole) and potassium iodide (0.40 g, 2.4 mmole) was added to a mixture of 4-(5-fluoro-1H-indol-3-yl)methylpiperidine (0.5 g, 2.3 mmole) and 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine (0.58 g, 2.3 mmole) in 20 ml of acetonitrile. The resulting mixture was heated to reflux under nitrogen for 3 hours. After cooling, it was diluted with water (150 ml) and the product extracted into ethyl acetate (50 ml). The organic layer was washed with water (50 ml), brine (50 ml), and after drying over sodium sulfate, filtration and concentration in vacuo afforded the required product as a white solid (0.78 g, 76%). Treatment with an excess of 0.25M ethanolic fumaric acid solution gave the acid addition salt, which was recrystallized from ethanol/diethyl ether to afford the title product as white needles.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12][Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)Cc1cccc(F)c1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 104.1 %

Procedure:
To a solution of 3-fluorophenylacetic acid (5.0 g, 32 mmol) in MeOH (25 mL) and CH2Cl2 (25 mL) at 0° C. was added trimethylsilyldiazomethane (2 M in hexane, 30 mL, 60 mmol). After stirring at room temperature for 15 min, the reaction mixture was concentrated to dryness, and the residue was azeotroped with toluene to give the crude methyl 3-fluorophenylacetate (5.6 g), which was used without further purification. Thus, the crude methyl 3-fluorophenylacetate obtained above (2.5 g, 15 mmol) was converted to the title compound (purified on silica gel) by reacting with 4-chlorobenzyl bromide (4.6 g, 22 mmol) and sodium hexamethyldisilazide (1 M in THF, 15 mL, 15 mmol) following the procedure described in Reference Example 10, Step A. 1H NMR (400 MHz, CD3OD): δ 7.35-6.88 (m, 8H), 3.92 (t, 1H), 3.60 (s, 3H), 3.34 (dd, 1H), 3.00 (dd, 1H). LC-MS: m/e 305 (M+Na)+ (3.9 min).
Reaction SMILES: [CH2:1]([N:5]([CH2:31][CH2:32][CH2:33][CH3:34])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:18][CH:17]=2)=[CH:13][CH:14]=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:35][C:36]([CH3:39])([O-])[CH3:37].[K+]>CN(C=O)C>[CH2:1]([N:5]([CH2:31][CH2:32][CH2:33][CH3:34])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:18][CH:17]=2)=[CH:13][CH:14]=[CH:35][C:36]2[CH:39]=[CH:39][C:36]([CH:35]=[CH:14][CH:13]=[C:12]([C:16]3[CH:17]=[CH:18][C:19]([N:22]([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:21]=3)[C:9]3[CH:10]=[CH:11][C:6]([N:5]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][CH:8]=3)=[CH:37][CH:37]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)c1ccc(C(=CC=O)c2ccc(N(CCCC)CCCC)cc2)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCN(CCCC)c1ccc(C(=CC=Cc2ccc(C=CC=C(c3ccc(N(CCCC)CCCC)cc3)c3ccc(N(CCCC)CCCC)cc3)cc2)c2ccc(N(CCCC)CCCC)cc2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 59.7 %

Procedure:
In 100 ml of DMF were dissolved 2.21 g of 3,3-bis(p-dibutylaminophenyl)acrolein and 1.0 g of p-xylene-α,α' -diylbis(diethyl phosphonate), and then 0.59 g of potassium tert-butoxide was added to the solution at room temperature. Thereafter, the reaction was carried out for 4 hours at room temperature with stirring and the reaction mixture was poured into 100 ml of ice-water. Then, precipitates thus deposited were collected by filtration, dissolved in benzene, and separated and purified by silica gel column chromatography (eluent: benzene). After distilling off benzene from the effluent, the residue was recrystallized from ethyl acetate to provide 1.42 g (yield 58.8%) of red crystals having a melting point of from 107.0° C. to 111.5° C.