Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1(C[N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)CCCC1.C([Li])CCC.[C:17]([C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:29]=1[O:30]COCCOC)[C:24](N)=[O:25])([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[CH3:40][C:37]([C:28]1[CH:27]=[C:23]([C:24]([C:11]2[CH:10]=[CH:9][NH:8][N:7]=2)=[O:25])[CH:22]=[C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:29]=1[OH:30])([CH3:38])[CH3:39]
Reactant: COCCOCOc1c(C(C)(C)C)cc(C(N)=O)cc1C(C)(C)C
Reactant: c1cnn(CN2CCCC2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)c2cc[nH]n2)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
To a solution of 1-(1-pyrrolidinomethyl)-pyrazole (Katrikzky, A. R.; Rewcastle, G. W.; Fan, W-Q., J. Org. Chem., 1988, 53, 5688) (3.32 g, 0.022 mole) in THF (75 mL) at -70° C. is added 1.6M n-butyllithium (14 mL) over a 20-minute period. After stirring at that temperature 1.5 hours a solution of N-methoxy-N-methyl-[3,5-di-tert-butyl-4[(2-methoxyethoxy) methoxy] -benzamide (Example 6) (7.62 g, 0.02 mole) in THF (75 mL) is added over a 30-minute period. The reaction mixture is allowed in warm to room temperature, treated with ice-cold 2N HCl (200 mL) and concentrated to remove the THF. The concentrated mixture is extracted with CH2Cl2. The extracts are washed with saturated NaHCO3 and brine, dried with Na2SO4 and evaporated. The residue is purified by flash chromatography (0-30% EtOAc/CH2Cl2) on silica gel to give 6.25 g of an oil. This product is deprotected by allowing to stand in 5% (w/v) HCl/MeOH (150 mL) for 2 days. The acid solution is evaporated and the residue is taken up in Et2O. The resulting solution is washed with saturated NaHCO3 and brine, and dried with Na2SO4. The ethereal solution is concentrated causing the precipitation of 3.62 g (75% of a white solid, [3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1H-pyrazol-3-yl methanone, mp 216°-219° C. 1H NMR (DMSO-d6) δ 1.42 (s, 18H, tert-butyl), 6.84 (m, 1H, OH), 8.19 (s, 2H, phenyl aromatics); pyrazole aromatics and NH appear as several poorly defined signals because of tautomerization at 7.6-7.9, 13.4, 13.9; IR (KBr) 1430, 1592, 1643 cm-1 ; MS (DEI) m/e 301 (M+ +1), 300 (M+), 95.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:12][CH2:13][OH:14].[CH:15](O)=[O:16]>O>[CH:15]([O:14][CH2:13][CH2:12][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:16]
Reactant: O=CO
Reactant: Oc1ccc(Cl)cc1
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=COCCOc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
p-Chlorophenol (112 g) was added to a solution of sodium hydroxide (40 g) in water (100 ml). The mixture was heated to reflux, and 2-chloroethanol (80 g) was added dropwise with stirring. After cooling to room temperature, the mixture was extracted with ether. The organic phase was dried and evaporated to leave a residue which was refluxed with formic acid (150 ml) for 1 hour followed by distillation in vacuo. The product had boiling point 138°-40° C./1 mm Hg.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:9][CH2:8][C@H:7]2[CH2:10][C@@H:5]1[C:6]2([CH3:12])[CH3:11].C([Li])CCC.[CH:18](OCC)=[O:19]>C1COCC1>[CH3:1][O:2][N:3]=[C:4]1[C@@H:9]([CH:18]=[O:19])[CH2:8][C@H:7]2[CH2:10][C@@H:5]1[C:6]2([CH3:12])[CH3:11]
Reactant: CCOC=O
Reactant: CON=C1CC[C@H]2C[C@@H]1C2(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CON=C1[C@@H](C=O)C[C@H]2C[C@@H]1C2(C)C
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a cold (−78° C.) solution of (1R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-one O-methyl oxime, 77a, (1.27 g, 7.59 mmol) in THF (33 mL) was added dropwise a solution of n-butyllithium (3.34 mL of 2.5 M solution in hexanes, 8.35 mmol). After stirring the mixture 20 min at −78° C. ethyl formate (0.61 mL, 7.59 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 3 hours and then quenched by pouring into aqueous saturated NaHCO3 solution. The mixture was extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (0-20% EtOAc/Hexanes gradient) to afford 810 mg yellow oil: LCMS RT=3.54 (M+H) 196.28.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24](O)=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:60][CH2:61][CH2:62][CH2:63][NH:64][C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([NH:60][CH2:61][CH2:62][CH2:63][NH:64][C:65](=[O:71])[O:66][C:67]([CH3:69])([CH3:68])[CH3:70])=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NCCCNC(=O)OC(C)(C)C)c2n1
Reaction time: 3 h
Yield: 86.9 %

Procedure:
To a mixture of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation K, 200 mg, 0.560 mmol) and HATU (255 mg, 0.672 mmol) in DMF (2 mL) was added DIEA (292 μL, 1.68 mmol), followed by dropwise addition of tert-butyl 3-aminopropylcarbamate (117 mg, 0.672 mmol) at ambient temperature. After stirring for 3 hours, the reaction was directly purified by reverse-phase chromatography (5 to 70% acetonitrile/water) to yield the final product as white solid (250 mg, 87%). LCMS (apci) m/z=414.1 (M+H-Boc).
Reaction SMILES: O[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:17](=[O:20])([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][Br:32]>CC(C)=O>[Br:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:15]=[CH:16][C:2]([O:20][CH2:17][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][Br:32])=[CH:3][CH:4]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: BrCCCCCCCCBr
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1ccc(OCCCCCCCCBr)cc1)c1ccc(OCCCCCCCCBr)cc1
Reaction time: 12 h
Yield: 66 %

Procedure:
To a mixture of 4,4′-dihydroxybenzophenone (1.0 g, 4.7 mmol) and potassium carbonate (1.3 g, 9.3 mmol) in acetone (50 mL) was added 1,8-dibromooctane (3.8 g, 14.0 mmol). The mixture was refluxed under stirring for 12 h. After filtration and solvent evaporation, the crude product was purified by a silica gel column using chloroform as eluent. 4,4′-bis(8-bromooctyloxy)benzophenone was obtained as white powder in 66% yield (3.10 g). Rf=0.5 (chloroform). NMR (400 MHz, CDCl3), δ (ppm): 7.78 (d, 4H), 6.94 (d, 4H), 4.05 (t, 4H), 3.42 (t, 4H), 1.89□1.80 (m, 8H), 1.48-1.39 (m, 16H). 13C NMR (100 MHz, CDCl3), δ (ppm): 193.9, 161.8, 131.6, 129.9, 113.3, 67.5, 33.3, 32.1, 28.5, 28.4, 28.0, 27.4, 25.3.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.C([O-])(=O)C.[Ca+2:37].C([O-])(=O)C.CCCCCCC>C(O)C.O>[CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][C:10]([C:13]2[N:19]([CH3:20])[C:17](=[O:18])[C:16]([OH:21])=[C:15]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[O:23])[N:14]=2)([CH3:12])[CH3:11])=[O:8])=[N:4][N:3]=1.[Ca:37]
Reactant: [Ca+2]
Agent: CC(=O)[O-]
Agent: Cc1nnc(C(=O)NC(C)(C)c2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C)o1
Solvent: O
Solvent: CCCCCCC
Solvent: CCO
Product: [Ca]
Temperature: 67.5 °C
Reaction time: 6 h

Procedure:
Raltegravir (10 gm) was suspended in ethanol (60 ml) and then added a solution of calcium acetate (4 gm) in water (2 ml) at 25 to 30° C. The contents were heated to 65 to 70° C. and distilled off solvent completely under vacuum at 45° C. to obtain residue. To the residue was added n-heptane (50 ml) and again distilled to obtain residue. n-Heptane (100 ml) was added to the residue and stirred for 6 hours at room temperature. The solid obtained was collected by filtration and dried to obtain 9.9 gm of raltegravir calcium.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:17]1[N:18]=[CH:19][N:20]([C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([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]=1)CCC>>[C:35]1([C:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:20]2[CH:21]=[C:17]([C:2]3[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][N:3]=3)[N:18]=[CH:19]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: COC(=O)c1ccnc(Cl)c1
Product: COC(=O)c1ccnc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1

Procedure:
The title compound was prepared from methyl 2-chloropyridine-4-carboxylate and 4-(tributylstannyl)-1-tritylimidazole according to the procedure for Example 1. 1H NMR (400 MHz, DMSO-d6): δ 3.92 (3H, s), 7.16 (5H, m), 7.38-7.46 (11H, m), 7.60 (1H, d, J=1.3 Hz), 7.64 (1H, dd, J=1.6 Hz and 5.0 Hz), 8.32 (1H, s), 8.64 (1H, d, 5.0 Hz).
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([CH:8]=O)[CH:6]=[N:5][C:4]([S:10][CH2:11][CH2:12][CH2:13][CH3:14])=[N:3]1.[CH2:15]([O:17][CH2:18][C:19](OCC)=[O:20])[CH3:16].CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[CH2:11]([S:10][C:4]1[N:5]=[CH:6][CH:7]2[CH:8]=[C:18]([O:17][CH2:15][CH3:16])[C:19](=[O:20])[NH:1][CH:2]2[N:3]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCOCC(=O)OCC
Reactant: CCCCSC1=NC(N)C(C=O)C=N1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCSC1=NC2NC(=O)C(OCC)=CC2C=N1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-Amino-2-butylsulfanyl-4,5-dihydro-pyrimidine-5-carbaldehyde (3 g, 14.2 mmol, funished by scaleup) and ethyl ethoxyacetate (2.34 g, 2.4 ml, 17.75 mmol) were stirred in 80 ml toluene at 0°-5° C. under nitrogen. Potassium t-butoxide (1.75 g, 15.6 mmol) was added gradually. The mixture was stirred to ambient temperature, and then to 65° C. for 48 hours. An additional 20 ml of toluene and 2.4 ml ethyl ethoxyacetate were added and the reaction was maintained at 65° C. over the weekend. The reaction mixture was concentrated in vacuo and triturated with EtOAc to remove the remaining starting aldehyde. The remaining solid was further triturated with chloroform to remove additional impurities. 3.66 g of 2-Butylsulfanyl-6-ethoxy-8,8a-dihydro-4aHpyrido[2,3-d]pyrimidin-7-one (1A) of a purity greater than 80% as judged by MS/HPLC and NMR was collected.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][NH:11][CH2:10]3)=[CH:5][CH:4]=1.[Cl:17][CH2:18][CH2:19][CH2:20][N:21]1[CH:26]=[C:25]([CH:27]2[CH2:29][CH2:28]2)[C:24](=[O:30])[NH:23][C:22]1=[O:31].O>CN(C=O)C>[ClH:17].[CH:27]1([C:25]2[C:24](=[O:30])[NH:23][C:22](=[O:31])[N:21]([CH2:20][CH2:19][CH2:18][N:11]3[CH2:12][C@H:13]4[C@:9]([C:6]5[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=5)([CH2:14]4)[CH2:10]3)[CH:26]=2)[CH2:28][CH2:29]1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: O=c1[nH]c(=O)n(CCCCl)cc1C1CC1
Solvent: CN(C)C=O
Solvent: O
Product: Cl
Product: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1C1CC1
Temperature: 100 °C

Procedure:
A mixture of (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (Prep4, 35 mg, prepared following a similar procedure to that reported in WO 2005080382), 1-(3-chloropropyl)-5-cyclopropyl-2,4(1H,3H)-pyrimidinedione (Prep16, 46 mg) and TEA (0.042 mL) in DMF (0.5 mL) was heated at 100° C. for 24 hours. Water was then added and the solution was extracted with dichloromethane. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by preparative HPLC (column: XTerra Prep MS C18 30×150 mm, 10 uM; mobile phase A: H2O+0.1% formic acid, mobile phase B: acetonitrile+0.1% formic acid, gradient: from 1 to 25% (B) in 10 min, from 25 to 90% in 4.50 min, from 90 to 100% in 0.50 min; flow rate: 40 mL/min; UV wavelength range: 210-400 nm, ionization: ES+ and ES−; mass range: 150-900 amu (ES+)). The product thus obtained was loaded over a SCX cartridge and eluted with methanol to give 54 mg of the formiate of the title compound. To a solution of this material in dichloromethane (1 mL) HCl (1M in Et20, 1 eq) was added, the solvent was evaporated in vacuo and the material thus obtained triturated with Et2O to give 41 mg of the title compound as a white slightly hygroscopic solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH3:9])=[N:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])=[C:4]([CH2:20][CH3:21])[N:3]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:19][O:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[C:5]1[C:4]([CH2:20][CH3:21])=[N:3][C:2]([C:24]2[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=2[CH3:22])=[C:7]([CH2:8][CH3:9])[N:6]=1
Reactant: CCc1nc(-c2ccc(OC)cc2OC)c(CC)nc1Cl
Reactant: Cc1ccc(C)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCc1nc(-c2ccc(OC)cc2OC)c(CC)nc1-c1cc(C)ccc1C
Temperature: 80 °C

Procedure:
The product from step 3 (90 mg, 0.3 mmol), 2,5-dimethylphenylboronic acid (105 g, 1 mmol), tetrakis(triphenylphosphine)palladium(0) (50 mg), toluene (4 mL) and potassium carbonate (2M, 2 mL) were combined in a pressure tube and heated at 80° C. (oil bath temperature) for 16 hours. After cooling to room temperature, the upper layer is loaded onto a preparative thin layer chromatography plate and the desired product is obtained after elution with 20% ethyl acetate in hexanes. MS: 377. H-1 NMR (400 MHz, CDCl3): 1.13 (t, 3H), 1.14 (t, 3H), 2.06 (s, 3H), 2.34 (s, 3H), 2.65 (m, 4H), 3.78 (s, 3H), 3.86 (s, 3H), 6.56 (d, 1H), 6.62 (dd, 1H), 7.1-7.2 (m, 3H), 7.31 (d, 1H).
Reaction SMILES: [CH3:1][N:2]([CH:4]=[O:5])C.[F:6][C:7]1[C:12]([CH:13]([O:19][CH3:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:11][CH:10]=[CH:9][C:8]=1[C:21]1[N:22]=C(N)[S:24][CH:25]=1.[CH2:27]([O:29][C:30](=[O:43])[C:31]([CH3:42])=[CH:32][C:33]1[C:38]([F:39])=[CH:37][C:36](Br)=[CH:35][C:34]=1[F:41])[CH3:28].C(N(CC)CC)C>O>[F:39][C:38]1[CH:37]=[C:36]([C:4](=[O:5])[NH:2][C:1]2[S:24][CH:25]=[C:21]([C:8]3[CH:9]=[CH:10][CH:11]=[C:12]([CH:13]([O:19][CH3:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:7]=3[F:6])[N:22]=2)[CH:35]=[C:34]([F:41])[C:33]=1[CH:32]=[C:31]([CH3:42])[C:30]([O:29][CH2:27][CH3:28])=[O:43]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(C)=Cc1c(F)cc(Br)cc1F
Reactant: CCCCCC(OC)c1cccc(-c2csc(N)n2)c1F
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCC(OC)c1cccc(-c2csc(NC(=O)c3cc(F)c(C=C(C)C(=O)OCC)c(F)c3)n2)c1F
Temperature: 85 °C
Reaction time: 16 h

Procedure:
To a DMF (6 mL) solution of 4-[2-fluoro-3-(1-methyloxyhexyl)phenyl]thiazol-2-ylamine (318 mg), 3-(4-bromo-2,6-difluoropheny)-2-methylacrylic acid ethyl ester (300 mg), and dichlorobistriphenylphosphinepalladium (36 mg) was added triethylamine (0.43 mL). The reaction mixture was stirred under carbon monoxide atomosphere at 85° C. for 16 h. Water was poured into the reaction mixture, and the reaction mixture extracted with ethyl acetate, and the organic layer was washed with water, and brine, dried over magnesium sulfate, and evaporated. The obtained residue was purified by Colum chromatography (hexane:ethyl acetate=4:1) to obtain the compound (20) 500 mg.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:14])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:15]O>>[CH3:15][O:13][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CO
Reactant: O=C(O)c1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Concentrated sulfuric acid (3.4 mL) was added drop-wise to an ice cold mixture of 3-methanesulfanyl benzoic acid (5.0 g, 30 mmol) and methanol (30 mL). After the addition was complete, the reaction mixture was warmed to room temperature, then stirred overnight. The reaction mixture was concentrated in vacuo. The resulting oil was diluted with ethyl acetate, and then washed with water followed by saturated sodium bicarbonate. The organic phase was dried over MgSO4, filtered, and concentrated to give 5.4 g of 3-methanesulfanyl benzoic acid methyl ester as a clear oil. This crude product was used in subsequent steps without further purification.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][CH:22]=1)[O:8][C:9]1[C:14]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:12]=[CH:11][N:10]=1.[CH:23]([O:25][CH3:26])=O.Cl>CN(C=O)C.O>[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:20]=[CH:21][CH:22]=1)[O:8][C:9]1[C:14](/[C:15](=[CH:23]\[O:25][CH3:26])/[C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: COC=O
Reactant: COC(=O)Cc1cccnc1Oc1cccc(CO)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CO/C=C(/C(=O)OC)c1cccnc1Oc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 15 %

Procedure:
To a stirred suspension of sodium hydride (1.056 g, 50% dispersion in oil, pre-washed with petroleum ether) in dry DMF (15 ml) at 0°-5° C. was added dropwise over 5 minutes a solution containing methyl 2-(3-hydroxymethylphenoxy)pyridin-3-ylacetate (2.0 g) and methyl formate (9 ml) in DMF (effervescence). After the addition was complete, the reaction mixture was allowed to warm to room temperature. After stirring for a further 3 hours, the reaction mixture was carefully poured into water, neutralised with 2N hydrochloric acid and then extracted thoroughly with ether (×6). The combined ether layers were dried, filtered and evaporated to afford a crude residue which was used without further purification. The residue was dissolved in DMF (10 ml) and then treated with potassium carbonate (0.60 g) and dimethyl sulphate (0.64 g). Standard work-up and chromatography on silica gel (eluent petroleum ether-ether, 1:1) afforded (E)-methyl 2-[2-(3-hydroxymethylphenoxy)pyridin-3-yl]-3-methoxypropenoate (0.35 g, 15%); mass spectrum m/e 315 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:9][S:10]([CH2:12][CH2:13][NH2:14])=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:15][S:16][C:17](S(C)=O)=[CH:18][N+:19]([O-:21])=[O:20]>>[CH3:15][S:16][C:17]([NH:14][CH2:13][CH2:12][S:10]([CH2:9][C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:11])=[CH:18][N+:19]([O-:21])=[O:20]
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Reactant: COc1cccnc1CS(=O)CCN
Product: COc1cccnc1CS(=O)CCNC(=C[N+](=O)[O-])SC

Procedure:
Reaction of 3-methoxy-2-(2-aminoethylsulphinylmethyl)-pyridine with 1-methylthio-1-methylsulphinyl-2-nitroethylene yields 1-methylthio-2-nitro-1-[2-((3-methoxy-2-pyridyl)methylsulphinyl)ethylamino]ethylene which, when reacted with 4-(4-aminobutyl)imidazole yields 1-nitro-2-[2-((3-methoxy-2-pyridyl)methylsulphinyl)ethylamino]-2-[4-(4-imidazolyl)butylamino]ethylene.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[Br:9]Br.O>N1C=CC=CC=1>[Br:9][C:7]1[C:2]([OH:1])=[CH:3][CH:4]=[C:5]([CH3:8])[N:6]=1
Reactant: Cc1ccc(O)cn1
Reactant: BrBr
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(O)c(Br)n1
Reaction time: 1.5 h

Procedure:
To a solution of 5-hydroxy-2-methylpyridine (Commercial, Aldrich, 44.5 g) in pyridine (400 ml) is added dropwise over 30 min at room temperature a solution of bromine (71.64 g) in pyridine (550 ml). The reaction mixture was stirred for an additional 1.5 h. The reaction mixture was poured into water (4 liters), stirred for a few minutes and extracted with diethyl ether (4×300 ml). The combined organics were dried over sodium sulphate and concentrated in vacuo to give a brown solid that was purified through silica using a 0-30% ethyl acetate in hexane system, to give the title compound as a beige solid, 37 g.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C@H:10]2[CH2:25][N:13]3[CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][C@@H:12]3[CH2:11]2)=[N:7][CH:8]=1.C(N(CC)CC)C.[F:35][C:36]([F:48])([F:47])[C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>ClCCl.FC(F)(F)C(O)=O>[F:48][C:36]([F:35])([F:47])[C:37]1[CH:38]=[CH:39][C:40]([S:43]([N:16]2[CH2:15][CH2:14][N:13]3[CH2:25][C@H:10]([O:9][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:27])[F:26])=[CH:8][N:7]=4)[CH2:11][C@H:12]3[CH2:17]2)(=[O:45])=[O:44])=[CH:41][CH:42]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@H](Oc3ccc(C(F)(F)F)cn3)C[C@H]2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCN2C[C@H](Oc3ccc(C(F)(F)F)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.8 %

Procedure:
A solution of the product from Example 226A (0.14 g, 0.361 mmol) in dichloromethane (2.5 mL) and trifluoroacetic acid (2.5 mL) was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in a mixture of dichloromethane (3 mL) and triethylamine (0.30 mL, 2.17 mmol), and 4-(trifluoromethyl)benzene-1-sulfonyl chloride (0.097 g, 0.398 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours, and then it was partitioned between water and dichloromethane. The organic extract was dried over Na2SO4. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-3% ethyl acetate in heptane to give the title compound as a colorless solid (0.132 g, 74%). 1H NMR (300 MHz, CDCl3) δ ppm 1.72-1.90 (m, 1H) 1.91-2.06 (m, 1H) 2.06-2.20 (m, 1H) 2.33 (dd, J=9.49, 4.75 Hz, 1H) 2.37-2.70 (m, 3H) 3.00 (d, J=7.80 Hz, 1H) 3.58-3.73 (m, 1H) 3.77 (d, J=8.82 Hz, 1H) 3.92 (d, J=10.17 Hz, 1H) 5.41 (q, J=6.22 Hz, 1H) 6.79 (d, J=8.82 Hz, 1H) 7.76 (dd, J=8.65, 2.54 Hz, 1H) 7.79-7.94 (m, 4H) 8.39 (d, J=2.37 Hz, 1H); MS (ESI) m/z 496 (M+H)+.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])(OCC)=O)C.[CH2:20]([C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[C:24]([O:36]COC)=[C:25]([O:34][CH3:35])[CH:26]=[C:27]2[CH:32]=O)[CH3:21].O>CN(C)C=O>[CH2:20]([C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[C:24]([OH:36])=[C:25]([O:34][CH3:35])[CH:26]=[C:27]2/[CH:32]=[CH:11]/[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:13])[CH3:21]
Reactant: CCOP(=O)(CC(=O)N1CCCCC1)OCC
Reactant: CCc1cccc2c(C=O)cc(OC)c(OCOC)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cccc2c(/C=C/C(=O)N3CCCCC3)cc(OC)c(O)c12
Reaction time: 0.17 h
Yield: 111.1 %

Procedure:
0.15 g of 60% sodium hydride was suspended in 20 ml of N,N-dimethylformamide, to which 1.15 g of N-(diethoxyphosphoryl)acetylpiperidine was gradually added at room temperature. After stirring for 10 minutes, a solution of 800 mg of 5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthalenecarbaldehyde in N,N-dimethylformamide (10 ml) was gradually added. After stirring for 20 minutes, water was added, followed by extraction with ethyl acetate. The combined extracts were washed with water and dried over anhydrous magnesium sulfate. After removal of the solvent, the resultant residue was purified by silica gel column chromatography (30% ethyl acetate/hexane) to obtain 1.1 g of the titled compound as pale yellow crystals.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>>[OH:4][CH2:3][CH2:2][N:1]([CH2:14][C:13]1[CH:16]=[CH:17][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1)[CH2:5][CH2:6][OH:7]
Reactant: OCCNCCO
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(CN(CCO)CCO)cc1

Procedure:
2-[(2-Hydroxy-ethyl)-(4-methoxy-benzyl)-amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (12.0 g, 114 mmol) and 4-methoxybenzyl chloride (14.2 g, 100 mmol). Yield 17.5 g, (77%); yellow oil; MS: 226 (M+H).