Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[I:26]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1.C(OCC)(=O)C.O>[C:1]1([S:7]([N:10]2[C:14]3[C:13](=[C:18]([O:19][CH3:20])[CH:17]=[CH:16][N:15]=3)[CH:12]=[C:11]2[I:26])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccnc2c1ccn2S(=O)(=O)c1ccccc1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccnc2c1cc(I)n2S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 69.6 %

Procedure:
To a solution of 1-benzenesulfonyl-4-methoxy-1H-pyrrolo[2,3-b]pyridine (1.0 g, 3.47 mmol) in THF (50 mL) cooled in a dry ice-acetone bath was added n-BuLi (2.1M in hexanes, 2.0 mL). The mixture was stirred for 20 minutes, warmed to 0° C. and stirred for an additional 30 minutes, then cooled to −78° C. A solution of iodine (1.06 g, 4.16 mmol) in THF (10 mL) was added dropwise over 5 minutes and the mixture was warmed to 0° C. and stirred for one hour. Water (10 mL) was added followed by 10% aq. Na2S2O3 (10 mL) and stirred for 5 minutes. Ethyl acetate (50 mL) was added and the organic phase was washed with water, saturated aqueous sodium bicarbonate and brine, dried (MgSO4), filtered and concentrated to afford 1.0 g of 1-benzenesulfonyl-2-iodo-4-methoxy-7-azaindole as a yellow solid which was carried forward without further purification. MS m/z 415.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24]([OH:26])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:28]=[C:29]([C:31]1[CH:36]=[N:35][CH:34]=[CH:33][N:32]=1)[NH2:30]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:24]3[O:26][N:30]=[C:29]([C:31]4[CH:36]=[N:35][CH:34]=[CH:33][N:32]=4)[N:28]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: NC(=NO)c1cnccn1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4cnccn4)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1

Procedure:
80 mg (0.22 mmol) of 5-(4-ethylphenyl)-1-[(4-hydroxypiperidin-1-yl)carbonyl]piperidine-3-carboxylic acid (Example 59A) and 46 mg (0.33 mmol, 1.5 eq.) of N′-hydroxypyrazine-2-carboximidamide were reacted according to the General Method 2. Yield: 24 mg (23% of theory)
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:30])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:14][CH:13]=2)[CH:6]=1.[Li+].[OH-].C1(C)C=CC=CC=1.CO>O1CCCC1>[N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[CH2:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:31])=[O:2])[CH:10]=[CH:9][CH:8]=2)=[O:30])=[CH:13][CH:14]=1
Reactant: COC(=O)Cc1cccc(C(=O)c2ccc(OCc3ccc4ccccc4n3)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1cccc(C(=O)c2ccc(OCc3ccc4ccccc4n3)cc2)c1
Yield: 75.5 %

Procedure:
To a solution of the ester (5 g, 12.16 mmole) of Step G, in dry tetrahydrofuran (66 mL) is added 1N-LiOH (37 mL, 37 mmole) and the mixture is stirred under nitrogen at room temperature for 2.5 hours (TLC, toluene-MeOH 9:1 ). The tetrahydrofuran is evaporated and the residue is diluted with water, acidified (to pH 6.5) with 10% acetic acid and extracted with ethyl acetate (3x). The extracts are washed with brine, dried (MgSO4) and evaporated to dryness. The crude product (4.94 g, pale yellow solid) is recrystallized from ethyl acetate to provide 3.65 g (75%) of the pure title compound (white solid, m.p. 146°-147° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH2:17][OH:18])=[N:15][O:14][N:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].N1C(C)=CC=CC=1C.O([Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])S(C(F)(F)F)(=O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH2:17][O:18][Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])=[N:15][O:14][N:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CO
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)[Si](OCc1nonc1C(=O)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a stirred solution of N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-1,2,5-oxadiazole-3-carboxamide (3.2 g, 0.012 mol) in dichloromethane (DCM) (23 mL) at 0° C. was added 2,6-lutidine (3.4 mL, 0.029 mol) followed by triisopropylsilyl triflate (4.1 mL). The solution was stirred at 0° C. for 30 min and then the reaction was warmed to rt overnight. The reaction was concentrated and chromatographed on a silica column eluting with 15% ethyl acetate/hexane to yield a colorless oil (4.59 g, 91%). 1H NMR (400 MHz, DMSO-d6) δ: 11.03 (s, 1H), 8.01 (dd, J=6.7, 2.6 Hz, 1H), 7.67 (ddd, J=9.1, 4.3, 2.6 Hz, 1H), 7.44 (dd, J=9.1, 9.1 Hz, 1H), 5.2 (s, 2H), 1.09 (m, 3H), 0.99 (d, J=7.1 Hz, 18H); MF═C19H27ClFN3O3Si; LCMS calculated for C19H28ClFN3O3Si(M+H)+: m/z=428.157.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:25])[CH:5]=[CH:6][C:7]=1[CH:8]1[S:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]([CH3:24])[N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:9]1=2.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:33][C:34]1[C:39]([CH2:40]Cl)=[CH:38][CH:37]=[CH:36][N:35]=1>C(#N)C>[CH3:24][N:15]1[C:10]2[NH:11][CH2:12][CH2:13][S:14][CH:8]([C:7]3[CH:6]=[CH:5][C:4]([O:25][CH2:40][C:39]4[C:34]([CH3:33])=[N:35][CH:36]=[CH:37][CH:38]=4)=[CH:3][C:2]=3[CH3:1])[C:9]=2[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:16]1
Reactant: Cc1cc(O)ccc1C1SCCNc2c1c(-c1ccccn1)nn2C
Reactant: Cc1ncccc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(OCc2cccnc2C)ccc1C1SCCNc2c1c(-c1ccccn1)nn2C
Temperature: 60 °C
Yield: 55 %

Procedure:
A mixture of 3-methyl-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]phenol (0.078 g, 0.22 mmol, see Ex. #D.42), potassium carbonate (0.061 g, 0.44 mmol), and 2-methyl-3-chloromethylpyridine hydrochloride (0.0356 g, 0.2 mmol, US2005/124586) in acetonitrile (10 mL) was heated at about 60° C., for about 90 h. After cooling to rt the mixture was concentrated in vacuo. The residue was treated with DCM (50 mL) and water (20 mL). The layers were separated and the organic layer was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetate/methanol 9:1) followed by trituration with diethyl ether to give 1-methyl-4-[2-methyl-4-[(2-methyl-3-pyridyl)methoxy]phenyl]-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine (0.050 g. 0.11 mmol, 50%) as an off white solid: LC-MS (Table 1, Method e) Rt=5.00 min; m/z 458 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) 2.56 (3 H, s) 2.60 (3 H, s) 2.70 (1 H, ddd, J=14.9, 6.1, 2.2 Hz) 2.88 (1 H, ddd, J=14.9, 8.9, 2.6 Hz) 3.19-3.29 (1 H, m) 3.53-3.62 (1 H, m) 3.78 (1 H, br s) 3.84 (3 H, s) 4.97 (2 H, s) 6.63 (1 H, dd, J=8.4, 2.6 Hz) 6.64 (1 H, s) 6.82 (1 H, d, J=2.6 Hz) 7.07 (1 H, ddd, J=7.4, 4.9, 1.1 Hz) 7.11-7.16 (2 H, m) 7.58 (1 H, td, J=7.8, 1.9 Hz) 7.67 (1 H, dd, J=7.7, 1.1 Hz) 7.77 (1 H, dt, J=8.0, 1.0 Hz) 8.45 (1 H, dd, J=4.9, 1.6 Hz) 8.49 (1 H, d, J=4.9 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][NH2:12]>ClCCl.C(O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:12][CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CN
Solvent: ClCCl
Solvent: CCO
Product: CNC(=O)c1ccc(Cl)cc1
Reaction time: 16 h
Yield: 97 %

Procedure:
To a 0° C. solution of the 4-chlorobenzoyl chloride (4.50 g) in dichloromethane (10 mL) was added an 8M solution of methylamine in ethanol dropwise. The solution was stirred for 16 h and then evaporated to dryness. The residue was diluted with saturated sodium bicarbonate solution (10 mL) and extracted three times with ethyl acetate (3×20 mL), the organics washed with brine (10 mL), dried (MgSO4) and concentrated in vacuo to afford the sub-title compound as a white solid (4.33 g; 97%): 1H NMR (400 MHz, CDCl3) δ 3.00 (3H, s), 7.40 (1H, brs) 7.40 (1H, d), 7.70 (1H, d)
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14]2O[C:16]([CH3:29])=[C:17]([CH2:27][CH3:28])[C:18]3[C:19]=2[CH:20]=[C:21]([O:25][CH3:26])[C:22](=[O:24])[CH:23]=3)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].C1C2C=CC=CC=2CC=[N:32][N:31]=1>C(O)(=O)C.[OH-].[Na+]>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:14]2[C:19]3[CH:20]=[C:21]([O:25][CH3:26])[C:22]([OH:24])=[CH:23][C:18]=3[CH:17]([CH2:27][CH3:28])[C:16]([CH3:29])=[N:32][N:31]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: C1=NN=Cc2ccccc2C1
Reactant: CCc1c2cc(=O)c(OC)cc-2c(-c2ccc(OC)c(OC)c2)oc1C
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCC1C(C)=NN=C(c2ccc(OC)c(OC)c2)c2cc(OC)c(O)cc21
Reaction time: 1 h
Yield: 94 %

Procedure:
34.5 ml of 98% hydrazine hydrate are added dropwise, within 5 minutes, to a stirred solution of 115 g (0.325 mole) of 1-(3,4-dimethoxyphenyl)-3-methyl-4-ethyl-7-methoxy-6H-2-benzopyran-6-one in 115 ml of glacial acetic acid. During this operation the solution is maintained at 80° to 100° C. The solution is immersed into a water bath (95° to 100° C.) for one hour, then it is diluted with 140 ml of 2% aqueous sodium hydroxide solution and cooled. The 5H-2,3-benzodiazepine derivative separates as a beige crystalline substance. The solids are filtered off, washed four times with 50 ml of water each and dried. 111.7 g of the crude product are obtained; m.p.: 210°-212° C. To purify the crude product it is dissolved in 223 ml of dimethyl formamide at 100° to 130° C., and the solution is decolorized with 2 g of activated carbon. The carbon is filtered off and washed thrice with 50 ml of dimethyl formamide each. The solution is filtered with 1300 ml of distilled water, whereupon the pure product separates in crystalline form. 110.35 g (94%) of the title compound are obtained; m.p.: 210°-212° C. According to gas chromatographical examination the purity grade of the product is above 99%. C21H24N2O4 =368.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[CH:10]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1)([CH3:12])[CH3:11].O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:17][C:16]2[CH:19]=[CH:20][C:13]([CH:10]([CH3:12])[CH3:11])=[CH:14][CH:15]=2)[CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: Cc1cccc(Cl)c1O
Reactant: CC(C)c1ccc(CCl)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(Cc2ccc(C(C)C)cc2)cc(Cl)c1O
Temperature: 60 °C
Reaction time: 5.5 h

Procedure:
85.8 g (0.6 mol) 2-chloro-6-methylphenol and 33.8 g (0.2 mol) 4-isopropylbenzyl chloride, dissolved in 160 ml chloroform, are reacted with 18 g water-free zinc chloride. At a bath temperature of 60° C. the reaction mixture is stirred 5-6 h, and then washed three times each with 150 ml water for the purpose of removing excess zinc chloride, dried across sodium sulfate and subjected to a driving-off of the solvent chloroform in a vacuum.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:46])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33](=[O:46])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:41]=[CH:42][N:43]=[CH:44][CH:45]=2)[CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccncc2)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) according to the general procedure M. Obtained as a light yellow solid (299 mg).
Reaction SMILES: [CH3:1][C@H:2]([CH2:9][CH:10]=[O:11])[CH2:3][CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7].C(N([CH2:17][CH3:18])CC)C.C([O:22][CH2:23][CH3:24])(=O)C>C(O)C.[Br-].C([N+]1C(C)=C(CCO)SC=1)C>[OH:11][CH:10]([CH2:9][C@@H:2]([CH3:1])[CH2:3][CH2:4][CH:5]=[C:6]([CH3:7])[CH3:8])[C:23](=[O:22])[CH2:24][C@@H:17]([CH3:18])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:9])[CH3:1]
Reactant: CCOC(C)=O
Reactant: CC(C)=CCC[C@H](C)CC=O
Reactant: CCN(CC)CC
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CCO
Product: CC(C)=CCC[C@H](C)CC(=O)C(O)C[C@@H](C)CCC=C(C)C
Yield: 75 %

Procedure:
To a 250 mL of two-necked round-bottom (RB) flask containing (−) citronellal (25.0 g, 163 mmol) in 50 mL of ethanol under argon was added the catalyst of 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (4.1 g, 16.3 mmol) and triethylamine (17.0 mL, 120 mmol). The mixture was then heated to reflux over night. After removal of the solvent under reduced pressure, the resulted mixture was poured into 100 mL of water and extracted by ethyl ether (3×60 mL). The combined organic layer was dried over anhydrous MgSO4 and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (hexane:ethyl acetate=20:1, v/v) to afford 18.5 g of product as a colorless oil (yield: 75%). 1H NMR (400 MHz, CDCl3) δ 5.08 (m, 2H), 4.15 (m, 1H), 3.47 (dd, 1H, J=5.04 Hz), 2.40 (m, 1H), 2.2 (m, 1H), 1.9-2.1 (m, 6H), 1.60 (d, 12H), 1.1-1.3 (m, 4H), 0.8-1.0 (m, 6H). 13C NMR (400 MHz, CDCl3) δ 212.63, 131.63, 131.30, 124.52, 124.40, 124.00, 75.59, 74.70, 45.16, 45.15, 41.15, 41.00, 37.95, 36.85, 36.83, 35.56, 29.36, 29.04, 28.92, 28.81, 25.65, 25.42, 25.39, 25.36, 25.22, 20.29, 19.82, 19.65, 18.46, 17.60.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([CH2:17][OH:18])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH:8]=[CH:7][CH2:6]1.CC(C)=[O:21].OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:17]([OH:21])=[O:18])[CH:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:9][CH:8]=[CH:7][CH2:6]1
Reactant: CC(C)=O
Reactant: OCC1(CCCCl)CC=CCC1c1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: O=C(O)C1(CCCCl)CC=CCC1c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
Ethyl 1-(3-chloropropyl)-6-phenyl-3-cyclohexene-1-carboxylate (8.65 g, 29.4 mmol) dissolved in toluene (200 ml) was added dropwise to a 1.0M stock solution of diisobutylaluminum hydride (DIBAL, 2.2 equiv., 64.6 ml). The contents were stirred for 16 hrs. under N2 at ambient temperature. The reaction was then chilled to 0° C. and water (100 ml) added. The resulting precipitate was filtered off and the filtrate was dried over MgSO4, filtered, and concentrated in vacuo to afford 7.21 g (92% yield) of 1-(3-chloropropyl)-6-phenyl-3-cyclohexene-1-methanol as a clear mobile oil. Infrared spectroscopy indicated the disappearance of an ester carbonyl band and the appearance of hydroxyl stretching between 3200-3400 cm-1. To this alcohol (27 mmol) dissolved in acetone (100 ml) and cooled to 0° C. was added Jones reagent (2.67M, 2.0 equiv., 20.3 ml). The contents were stirred for 2 hr. at which time isopropyl alcohol (20 ml) was added to quench unreacted Jones reagent. The solution was concentrated in vacuo. The residue was washed with water and extracted three times with 100 ml of ethyl ether. The combined organic extracts were dried over MgSO4, filtered through celite and concentrated in vacuo to afford 1-(3-chloropropyl)-6-phenyl-3-cyclohexene-1-carboxylic acid (4.95 g, 87% yield) as a clear viscous oil. Infrared spectroscopy indicated the appearance of the carboxyl stretch at 1700 cm-1.
Reaction SMILES: FC1C=CC(C(C2C=CC(F)=CC=2)=C(C2N(C)N=NN=2)C=[O:11])=CC=1.[C:25]1([P:31](=CC=O)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1C=CC=CC=1>[C:25]1([P:31](=[O:11])([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cn1nnnc1C(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To a mixture of 3,3-bis(4-fluorophenyl)-2-(1-methyl-1H-tetrazol-5-yl)-2-propenal (71.6 g, 0.22 mole) and triphenylphosphoranylidene acetaldehyde (66.8 g, 0.22 mole) was added 1.1 liters of dry benzene and the suspension was heated to reflux temperature over a period of 30 minutes. The reaction was allowed to proceed at reflux temperature for 2 hours. Analytical TLC eluted five times with 30% (v/v) ethyl acetate in hexanes showed only one major spot at Rf =0.37 for the desired product. The crude hot reaction mixture was diluted with an equal volume of hexane and the warm mixture was quickly filtered through a bed of activated charcoal. The filtrate was allowed to stand at room temperature from which 58.12 g (75.2%) of the desired product was collected. A second crystallization from the filtrate yielded mostly triphenylphosphine oxide. Concentration of the filtrate yielded an additional amount of the desired product to give a total of 71 g (91.8%) of the title compound. The combined material was recrystallized from ethyl acetate-hexane to give pure title compound; m.p.=164°-165° C. A 1H NMR of the recrystallized material showed no detectable double homologated product.
Reaction SMILES: OCCCN[C:6](=O)[C@H:7]([C:9]([CH2:12][OH:13])(C)C)[OH:8].CN(C1C=CC=CN=1)C.C([O:27][C:28](=[O:30])[CH3:29])(=O)C>>[CH3:6][C:7]([CH2:9][C:12]([CH2:29][C:28]([OH:27])=[O:30])=[O:13])=[O:8]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(CO)[C@H](O)C(=O)NCCCO
Agent: CN(C)c1ccccn1
Product: CC(=O)CC(=O)CC(=O)O
Temperature: 80 °C
Reaction time: 9 h

Procedure:
D-panthenol (88 grams, 0.424 moles) and polymer bound dimethylaminopyridine (2 grams) were added to a flask. Acetic anhydride (144.4 grams, 3.3 moles) was slowly added to the stirring mixture, and the resultant exotherm was controlled when the temperature reached 80° C. The mixture was heated at 80° C. and stirred for 9 hours. The flask was then fitted for vacuum distillation, and the acetic acid was removed under reduced pressure to a concentration of about 4% w/w. The catalyst (P-DMAP) was filtered out from the reaction mixture. The solution was treated with a 50% w/w solution of sodium hydroxide in a volume sufficient to neutralize the residual acetic acid, and the resultant solids of sodium acetate were removed by filtration. The residual water was then removed under vacuum to afford about 80% of the desired product, D-panthenyl triacetate.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].CC(C)([O-])C.[K+].Cl[C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1>C1COCC1>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1
Reactant: Clc1cnccn1
Reactant: CN1CCC[C@H]1CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCC[C@H]1COc1cnccn1
Reaction time: 0.17 h

Procedure:
A solution of (S)-1-methyl-2-pyrrolidinemethanol (1.15 g) in THF (45 mL) was treated with potassium tert-butoxide (1.2 g). After 10 min, chloropyrazine was added and the reaction stirred for 1.5 h. The reaction was quenched with 5N HCl (4 mL) and the solvent evaporated. The residue was suspended in water and extracted with ether. The aqueous fraction was made basic and extracted with CHCl3. The extracts were dried, the solvent evaporated, and the residue purified by radial chromatography eluting with 20%-EtOH-2%-NH4OH--CHCl3 to give (S)-2-(1-methyl-2-pyrrolidinylmethoxy)pyrazine (1.1). The HCl salt crystallized from EtOAc as a white solid, m.p. 121°-122° C. (Compound 28)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH:10]2[CH2:23]OS(C)(=O)=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C>[N:29]([CH2:23][CH:10]1[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)=[N+:30]=[N-:31]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(COS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CN=[N+]=[N-])C1
Temperature: 70 °C
Reaction time: 18 h
Yield: 98.6 %

Procedure:
To a solution of tert-butyl (6RS,7RS)-7-(3,4-dichlorophenyl)-6-{[(methylsulfonyl)oxy]methyl}-1,4-oxazepane-4-carboxylate (830 mg) in DMF (10 mL) was added sodium azide (178 mg), and the mixture was stirred at 70° C. for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (723 mg).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[C:8]2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:32]([O-:35])([O-:34])=[O:33].[Na+:36].[Na+]>C(O)C.O>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[C:8]2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][S:32]([O-:35])(=[O:34])=[O:33])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+:36]
Reactant: O=S([O-])[O-]
Reactant: BrCCCCCCOc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])CCCCCCOc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Yield: 15.2 %

Procedure:
1,4,5-Triphenyl-2-(6-bromohexyloxy)imidazole (0.95 g) was dissolved in hot ethanol (5 ml) and a solution of sodium sulphite (0.25 g) in hot water (3 ml) was added. The white suspension was heated at reflux for 24 hours then evaporated to dryness. The residue was recrystallised from ethanol then methanol/ethanol to give sodium 6-(1,4,5-triphenylimidazol-2-yloxy)hexane-sulphonate (0.15 g, 15%) as a colourless solid, m.p. 265° C.
Reaction SMILES: [I-].[NH:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([CH2:15][N+:16]([CH3:19])([CH3:18])C)=[N:3]1.[C:20]1([CH:26]2[CH2:31]CNC[CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.O>CN(C=O)C>[C:20]1([CH:26]2[CH2:31][CH2:18][N:16]([CH2:15][C:4]3[C:5]4[CH2:6][CH2:7][C:8]5[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=5[C:10]=4[NH:2][N:3]=3)[CH2:19][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[N+](C)(C)Cc1n[nH]c2c1CCc1ccccc1-2
Reactant: c1ccc(C2CCNCC2)cc1
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: c1ccc(C2CCN(Cc3n[nH]c4c3CCc3ccccc3-4)CC2)cc1

Procedure:
A solution of (4,5-dihydro-1H-benzo[g]indazol-3-ylmethyl)-trimethylammonium iodide (0.30 g), 4-phenylpiperidine (0.15 g) and diisopropylethylamine (0.30 cm3) in DMF (10 cm3) was heated under argon at 80° C. for 24 hours. The mixture was cooled, poured into water (25 cm3) and extracted with 50% ethyl acetate-diethyl ether (2×25 cm3). The extracts were dried (MgSO4), filtered and concentrated to give the title compound as a brown oil. This was crystallised as the half-oxalate salt from DMF-ethanol-ethyl acetate (0.045 g; 12%), m.p. 128°-230° C. (from DMF-EtOH-EtOAc); Found: C, 73.85; H, 6.8; N, 10.8. C23H25N3.0.5(CO2H)2.0.1(H2O) requires C, 73.9; H, 6.8; N, 10.8%. δH (360 MHz; d6 -DMSO; 353K) 1.70-1.92 (4H, m, 2 x NCH2CH2), 2.40-2.56 (2H, m, 2 x NCHAHBCH2 ; partially obscured by DMSO peak), 2.58-2.64 (1H, m, NCH2CH2CH), 2.78 (2H, t, J 7.5, --CH2 --), 2.90 (2H, t, J 7.5, --CH2 --), 3.16 (2H, broad d, J 11, 2 x NCHA HBCH2), 3.82 (2H, s, --CH2N), 7.15-7.30 (8H, m, 8 of ArH) and 7.66 (1H, d, J 7.7, 1 of ArH); m/z (CI+ ; NH3) 344 (MH+ ; 5%), 235 (5), 185 (18) and 162 (100).