Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].[C:30]([C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[N:8]2[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C@@H:2]([NH:1][CH2:38][C:37]3[CH:40]=[CH:41][C:34]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:35][CH:36]=3)[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:10][CH2:9]2)=[CH:17][CH:16]=1
Reactant: CC(C)C[C@H](N)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NCc1ccc(C(C)(C)C)cc1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
(S)-2-Amino-1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-4-methyl-pentan-1-one (0.500 g, 1.25 mmol, Example 53) and 4-(tert-butyl)benzaldehyde (0.208 mL, 1.25 mmol, Aldrich, Milwaukee, Wis.) were mixed in CH2Cl2 (6 mL). After stirring at ambient temperature under nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (0.396 g, 1.87 mmol). The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. and 12 hours at ambient temperature. Twenty milliliters of saturated aqueous NaHCO3 solution was added to the reaction mixture and the resulting mixture was stirred for 15 minutes. The two layers were separated and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic solution was dried over Na2SO4. TLC (50% EtOAc in Hexanes as the eluant) showed two spots with Rf values 0.93 and 0.63. The solution was concentrated in vacuo affording a viscous oil. The lower spot on TLC (Rf=0.63) was isolated by flash chromatography (30% EtOAc in hexanes). 0.496 g (73%) of the pure titled compound was obtained as a white foam: mp 57-62° C. APCI-MS m/z 548.5 (MH+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[CH:12][CH:11]=1.[BH4-].[Na+]>CO>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=2)=[CH:2]1
Reactant: COc1ccc(CN)cc1
Reactant: O=Cc1ccoc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNCc2ccoc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-Furaldehyde (5 mmol, 437 μL) and (4-methoxyphenyl)methanamine in MeOH (20 mL) was stirred at ambient temperature overnight then sodium borohydride (300 mg, 7.89 mmol) was slowly added. The resulting mixture was stirred at room temperature for 15 minutes and quenched with NaOH (1 N, aq). Methanol was removed in vacuo and the resulting slurry was redissolved in ethyl acetate then, washed with water, brine, dried over sodium sulfate and concentrated. Purification by silica gel chromatography (Ethyl acetate:Hexanes 7:3) gave 1-(furan-3-yl)-N-(4-methoxybenzyl)methanamine as an oil. MS (M+H, 218.10); 1H NMR (400 MHz, CDCl3): δ, ppm: 3.64 (s, 2H), 3.74 (s, 2H), 3.80 (s, 3H), 6.39 (m, 1H), 6.86 (m, 1H), 6.88 (m, 1H), 7.23 (m, 1H), 7.25 (m, 1H), 7.35 (m, 1H), 7.38 (m, 1H).
Reaction SMILES: [H-].[Na+].O1CCCC1.[C:8]([CH2:10]P(=O)(OCC)OCC)#[N:9].[Br:19][C:20]1[C:28]2[O:29][CH2:30][CH2:31][C:27]=2[C:26]2[C:25](=O)[CH2:24][CH2:23][C:22]=2[CH:21]=1>O>[Br:19][C:20]1[C:28]2[O:29][CH2:30][CH2:31][C:27]=2[C:26]2/[C:25](=[CH:10]/[C:8]#[N:9])/[CH2:24][CH2:23][C:22]=2[CH:21]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1CCc2cc(Br)c3c(c21)CCO3
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#C/C=C1\CCc2cc(Br)c3c(c21)CCO3
Reaction time: 0.33 h
Yield: 43.1 %

Procedure:
60% Sodium hydride (0.17 g, 4.35 mmols) was added to a tetrahydrofuran (20 ml) solution of diethyl cyanomethylphosphonate (0.77 g, 4.35 mmols) while cooling with ice, and the mixture was stirred for 20 minutes. To this was added a tetrahydrofuran (10 ml) solution of 4-bromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (1.00 g, 3.95 mmols), and the mixture was stirred at room temperature further for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with a saturated saline solution, then dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified through silica-gel column chromatography (hexane/ethyl acetate=from 85/15 to 8/2) and then recrystallized from ethyl acetate/isopropyl ether to obtain 0.47 g (yield: 43%) of the target compound.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:5]2[CH2:14][S:15][C:16](=[C:17]([CH2:21][CH2:22][CH3:23])[C:18]([OH:20])=[O:19])[C@H:4]2[N:3]1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-].[Na+].[H][H]>O.[Pd]>[O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:5]2[CH2:14][S:15][CH:16]([CH:17]([CH2:21][CH2:22][CH3:23])[C:18]([OH:20])=[O:19])[C@H:4]2[N:3]1[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCCC(C(=O)O)=C1SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC(C(=O)O)C1SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Yield: 95.5 %

Procedure:
100 g of (3aS, 6aR)hexahydro2-oxo-1,3-dibenzylthieno[3,4-d]imidazol-4-ylidenepentanoic acid (formula I) are dissolved in 340 ml of water at 40° C., where the pH is set to 8.7 using aqueous sodium hydroxide solution. 25% by weight of 5% Pd/C are added to the solution. The mixture is subsequently hydrogenated at an H2 pressure of 3 bar and 100° C. until the takeup of hydrogen is complete. The catalyst is filtered off after cooling. The solution is set to pH=6.0 using hydrochloric acid and extracted with 300 ml of xylene. The aqueous phase is subsequently extracted again with 100 ml of xylene. The organic phases are combined, and the solvents are evaporated, leaving 96 g of (3aS, 6aR)-hexahydro-2-oxo-1,3-dibenzylthieno[3,4-d]imidazol-4-ylpentanoic acid (formula II) as a pale-yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.C([Li])CCC.[I:28]I>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[I:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: II
Reactant: CC(C)(C)OC(=O)Nc1ccncc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccncc1I
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 72.5 %

Procedure:
To a solution of pyridin-4-yl-carbamic acid tert-butyl ester (14.8 g, 76.3 mmol) (reference example 44b) in THF (300 mL) is added N,N,N′,N′-tetramethylethylene-diamine (34.5 mL, 230 mmol) and the solution cooled to −78° C. To this solution is added slowly (2.5M) n-butyllithium (91.5 mL, 230 mmol), the reaction temperature allowed to rise to −20° C. and the resulting mixture stirred for 1.5 hours. The mixture is cooled to −78° C. and a solution of iodine (29.04 g, 114 mmol) in THF (60 mL) is added then stirred for 10 min. The mixture is warmed to 20° C., stirred 30 min then diluted with ethyl acetate, washed with water, sat. sodium thiosulfate and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 20% ethyl acetate in hexanes) to give 17.7 g of title compound as a light yellow crystalline solid. 1H NMR (CDCl3) δ 1.54 (s, 9H), 7.03 (bs, 1H), 8.10 (d, J=6 Hz, 1H), 8.34 (d, J=6 Hz, 1H), 8.74 (s, 1H). MS (EI) m/z 320 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:10])([O-:3])=[O:2].[Cl:11][S:12](O)(=[O:14])=[O:13]>>[N+:1]([C:4]1[CH:9]=[C:8]([S:12]([Cl:11])(=[O:14])=[O:13])[CH:7]=[CH:6][C:5]=1[Cl:10])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: O=S(=O)(O)Cl
Product: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl

Procedure:
On the other hand, those compounds of formula (1) wherein X is hydroxy and A is a sulfonamido group can be prepared by treating, for example, ortho-nitro-chlorobenzene with chlorosulfonic acid to obtain 3-nitro-4-chlorobenzenesulfonylchloride, followed by treatment with a primary or secondary amine to yield the corresponding 3-nitro-4-chlorobenzene sulfonamido derivative. This product is then treated with caustic soda to yield the 3-nitro-4-hydroxybenzene sulfonamide and subsequently reduced to the desired 3-amino-4-hydroxybenzene sulfonamide.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]([CH3:12])=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13]([O:17][C:18]([NH:20][NH2:21])=[O:19])([CH3:16])([CH3:15])[CH3:14]>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:10](=[N:21][NH:20][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCOC(=O)C(=NOC)C(C)=O
Solvent: CCO
Product: CCOC(=O)C(=NOC)C(C)=NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 7.5 h

Procedure:
A solution of ethyl 2-methoxyiminoacetoacetate (a mixture of syn and anti isomers) (34.6 g.) and tert-butoxycarbonylhydrazine (26.4 g.) in ethanol (200 ml.) was stirred for 7.5 hours at ambient temperature and allowed to stand overnight to precipitate crystals. The crystals were collected by filtration, washed with ethanol and dried to give ethyl 2-methoxyimino-3-tert-butoxycarbonylhydrazonobutyrate (a mixture of syn and anti isomers) (41.7 g.), mp 144° to 145° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[N+:5]([O-:9])[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:12])=O>ClCCl>[Cl:12][CH2:2][C:3]1[CH:4]=[N+:5]([O-:9])[CH:6]=[CH:7][CH:8]=1
Reactant: [O-][n+]1cccc(CO)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: [O-][n+]1cccc(CCl)c1
Reaction time: 2 h
Yield: 52.2 %

Procedure:
To a solution of 3-hydroxymethyl-pyridine N-oxide (1.0 g, 8.0 mmol) in dichloromethane (40 mL) was added thionyl chloride (10 mL, 137 mmol). After stirring for 2 hours, the reaction mixture was concentrated in vacuo. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous layer was repeatedly extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 0.60 g of the title product as a white solid, m.p. 133–137° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][C:14]1[NH:18][N:17]=[C:16]([NH2:19])[CH:15]=1.CCN(CC)CC>CC#N>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C:16]2[CH:15]=[C:14]([CH3:13])[NH:18][N:17]=2)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Cl)ncc2C(F)(F)F)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.6 %

Procedure:
To a solution of 2,4-dichloro-5-trifluoromethylpyrimidine (1.27 g, 5.8 mmol) in MeCN (20 ml) was added 5-methyl-1H-pyrazol-3-ylamine (568 mg, 5.8 mmol) and Et3N (1.6 mL). The mixture was stirred at ambient temperature overnight. LC/MS showed the completion of the reaction. Evaporation of the solvent afforded yellow oil that was purified by Gilson (5-95% MeCN/H2O, 15 minutes) to give the titled compound as solid (300 mg). m/z 278.
Reaction SMILES: [C:1]([N:4]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:32]=[CH:31][C:20]([O:21][CH2:22][CH2:23][C:24]([CH3:30])([CH3:29])[C:25]([O:27]C)=[O:26])=[C:19]([F:33])[CH:18]=2)=[O:16])[C@@H:7]([CH3:34])[CH2:6]1)(=[O:3])[CH3:2].[Li+].[OH-]>CO.C1COCC1>[C:1]([N:4]([C:35]1[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:32]=[CH:31][C:20]([O:21][CH2:22][CH2:23][C:24]([CH3:30])([CH3:29])[C:25]([OH:27])=[O:26])=[C:19]([F:33])[CH:18]=2)=[O:16])[C@@H:7]([CH3:34])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(C)(C)CCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCC(C)(C)C(=O)O)c(F)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To the solution of methyl 4-(4-{[(2S,4R)-4-[acetyl(4-chlorophenyl)amino]-2-methyl-3,4-dihydroquinolin-1(2H)-yl]carbonyl}-2-fluorophenoxy)-2,2-dimethylbutanoate (176 mg, 0.30 mmol) in MeOH/THF (1 mL/1 mL) was added excessive LiOH (1N aqueous solution). The reaction mixture was stirred at r.t. overnight. The reaction was quenched by adding 6N HCl to PH 2. The mixture was concentrated under reduced pressure to remove MeOH and THF. DCM (30 mL) was added. The reaction mixture was washed with brine (30 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (hexanes-ethyl acetate system) to afford slightly yellow solid product (120 mg, 70%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][N:13]2C(=O)C3=CC=CC=C3C2=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].O.NN>C(O)C>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([CH2:10][CH2:11][CH2:12][NH2:13])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)N1CCN(CCCN)CC1
Reaction time: 3 h
Yield: 59.2 %

Procedure:
To a solution of N-[3-(4-isopropyl-1-piperazinyl)propyl]phthalimide (43.1 g) in ethanol (350 ml) was added 100% hydrazine hydrate (11.2 g). The resulting mixture was refluxed with stirring for 3 hours. The reaction mixture was cooled and then filtered. The filter cake was washed with ethanol. The filtrate and washing were combined and concentrated under reduced pressure. The residual oil was subjected to column chromatography (aluminum oxide), eluting with a mixture of chloroform and methanol (20:1). The fractions containing the object compound were collected and then evaporated under reduced pressure. The residual oil was distilled under reduced pressure to give 3-(4-isopropyl-1-piperazinyl)propylamine (15.0 g), (bp 45 mmHg/150° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([CH2:12][N+:13]([O-:15])=[O:14])=O.C([O-])(=O)C.[NH4+:20]>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9]/[C:10](/[NH2:20])=[CH:12]/[N+:13]([O-:15])=[O:14]
Reactant: O=C(Cc1ccc(F)cc1F)C[N+](=O)[O-]
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: N/C(=C\[N+](=O)[O-])Cc1ccc(F)cc1F

Procedure:
The mixture of 1-(2,4-difluorophenyl)-3-nitroacetone (9.4 g, 43.7 mmol) and ammonium acetate (16.8 g, 219 mmol) in 250 ml benzene was refluxed with Dean-Stark setup for 5 hours. The reaction mixture was then partitioned between ether and water. The organic portion was washed with brine and dried over sodium sulfate. Removing the solvent afforded 8.5 g light brown solid. 1H-NMR (400 MHz, CD3OD) δ 7.20 (m, 1H), 6.84 (m, 3H), 3.65 (s, 2H) ppm. ESI-MS m/z 215 (M+H)+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([N:16]1[CH2:21][CH2:20][C:19]([CH3:27])([C:22]([O:24]CC)=O)[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[Cl:28][CH2:29]I.C(O)(=O)C>C1COCC1>[Cl:28][CH2:29][C:22]([C:19]1([CH3:27])[CH2:18][CH2:17][N:16]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:21][CH2:20]1)=[O:24]
Reactant: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Reactant: ClCI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)CCl)CC1
Reaction time: 0.17 h
Yield: 44.9 %

Procedure:
Lithium diisopropylamide (30.9 mL, 46.4 mmol) was added dropwise to a solution containing ethyl N-Boc-4-methylpiperidine-4-carboxylate (2.52 g, 9.28 mmol), and chloroiodomethane (6.55 g, 37.1 mmol) in THF (100 mL) at −78° C. over 30 minutes. After addition, the reaction was stirred for 10 minutes, and then a solution of acetic acid (5 mL) in THF (45 mL) was added while keeping reaction mixture below −65° C. The reaction was stirred for an additional 10 minutes and partitioned between ethyl acetate and brine, washed with saturated bicarbonate, concentrated and purified by silica gel (10%-20% ethyl acetate in hexanes) to afford tert-butyl 4-(2-chloroacetyl)-4-methylpiperidine-1-carboxylate (1.15 g, 44.92% yield).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH:9]=[C:8]([O:10][Si](C)(C)C)[CH:7]=[CH:6][N:5]=1.[CH3:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>C(Cl)Cl>[OH:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([O:3][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([CH3:17])=[CH:19][CH:20]=2)[CH:9]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: C[Si](C)(C)Oc1ccnc(O[Si](C)(C)C)c1
Solvent: ClCCl
Product: Cc1ccc(C(=O)Oc2cc(O)ccn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
To 3.5 g of 2,4-bis(trimethylsilyloxy)-pyridine in 50 ml of methylene chloride was added 2.34 g of p-methylbenzoyl chloride and the mixture was stirred at room temperature for one hour. Following thereafter the general procedure of Example 27, 1.86 g of the title compound was produced in a yield of 59.2%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@H:9]3[CH2:14][C@H:10]3[C:11]=2[NH:12][N:13]=1)=[O:5])[CH3:2].Br[CH:16]([CH3:18])[CH3:17]>CN(C=O)C.CCOC(C)=O>[CH:16]([N:12]1[C:11]2[C@@H:10]3[CH2:14][C@@H:9]3[CH2:8][C:7]=2[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[N:13]1)([CH3:18])[CH3:17]
Reactant: CC(C)Br
Reactant: CCOC(=O)c1n[nH]c2c1C[C@H]1C[C@@H]21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(C(C)C)c2c1C[C@H]1C[C@@H]21
Temperature: 25 °C
Yield: 59.9 %

Procedure:
(1aR,5aR)-1a,2,5,5a-Tetrahydro-1H-2,3-diazacyclopropa[a]pentalene-4-carboxylic acid ethyl ester (0.100 g, 0.520 mmol) (from Example 1.4, Step A) was dissolved in anhydrous DMF (5.20 mL). CsCO3 (0.678 g, 2.081 mmol) was added to give a suspension which was stirred at 25° C. for several minutes. 2-Bromopropane (0.098 mL, 1.041 mmol) was added dropwise at 25° C. After stirring for 4 h, the reaction was diluted with EtOAc (50 mL), washed with water (2×10 mL), brine, and dried over MgSO4. The solvent was evaporated under reduced pressure. The oil residue was purified by silica gel column chromatography to give the title compound as an oil (0.073 g). LCMS m/z=235.3 [M+H]+; 1H NMR (400 MHz, CDCl3) ppm 0.29-0.35 (m, 1H), 1.12 (td, J=8.02, 4.93 Hz, 1H), 1.34 (t, J=7.20 Hz, 3H), 1.46 (dd, J=15.16, 6.57 Hz, 6H), 2.04-2.12 (m, 1H), 2.16-2.24 (m, 1H), 2.74-2.82 (m, 1H), 2.90-2.99 (m, 1H), 4.27 (q, J=7.07 Hz, 2H), 5.31-5.43 (m, 1H).
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[C:32]([OH:39])[CH:31]=1)(=[O:29])=[O:28]>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][S:27]([C:30]2[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[C:32]([OH:39])[CH:31]=2)(=[O:29])=[O:28])=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(CCc2c(Cc3ccccc3)sc3ccccc23)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: O=C(O)c1ccc(S(=O)(=O)Oc2ccc(CCc3c(Cc4ccccc4)sc4ccccc34)cc2)cc1O

Procedure:
The title compound was prepared according to the procedure in Example 4 using 4-[2-(2-benzyl-benzo[b]thiophen-3-yl)-ethyl]-phenol (0.400 g, 1.16 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.550 g, 2.32 mmol). Purification on 2% H3PO4/MeOH treated silica gel, eluting with 20% EtOAc/hexane gave the title compound as an off white solid, mp 57-59° C. 1H NMR (DMSO-d6) δ 2.74 (t, 2H), 3.09 (t, 2H), 4.00 (s, 2H), 6.97 (d, 2H), 7.19-7.23 (m, 5H), 7.27-7.38 (m, 6H), 7.76 (d, 1H), 7.83 (dd, 1H), 7.98 (d, 1H). IR (KBr) 3400, 2950, 1675, 1390 and 1190 cm−1. mass spectrum (−ESI) m/z 543 (M−H).
Reaction SMILES: [C:1]([O:20][CH2:21][CH:22]([CH2:30][O:31][C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[O:23][C:24](=[O:29])[NH:25][CH2:26][CH2:27]Br)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:51][NH:52][CH2:53][CH2:54][OH:55].C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[CH3:51][N:52]([CH2:27][CH2:26][NH:25][C:24]([O:23][CH:22]([CH2:30][O:31][C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:21][O:20][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:29])[CH2:53][CH2:54][OH:55]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)OC(=O)NCCBr
Reactant: CNCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)OC(=O)NCCN(C)CCO
Temperature: 80 °C
Yield: 74.7 %

Procedure:
In 10 ml of chloroform was dissolved 173 mg (0.224 mmol) of 1,3-O-dioleoyl-2-O-(2-bromoethyl)carbamoylglycerol followed by addition of 543 mg (7.228 mmol) of 2-(methylamino)ethanol and 27 mg (0.209 mmol of diisopropylethylamine and the mixture was refluxed at 80° C. overnight. The reaction mixture was then washed with 5% sodium dihydrogen phosphate-H2O, dried, and concentrated. The residue was subjected to column chromatography (silica gel/methylene chloride-methanol) to provide 128 mg (74.3%) of the title compound of the invention.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:11])[CH2:9]O)=[C:4]([F:12])[CH:3]=1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:11])[CH2:9][N:17]2[C:13](=[O:23])[C:14]3[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16]2=[O:18])=[C:4]([F:12])[CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[C@@H](CO)c1ccc(Br)cc1F
Product: C[C@@H](CN1C(=O)c2ccccc2C1=O)c1ccc(Br)cc1F
Yield: 69 %

Procedure:
Following the procedure described for Example 633, (R)-2-(4-bromo-2-fluorophenyl)propan-1-ol (1.5 mg, 6.4 mmol) was reacted with phthalimide (1.0 mg, 7.008 mmol) to obtain the desired product (1.6 g, 69%) as a white solid: ESI MS m/z 363 [C17H13BrFNO2+H]+
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])(=O)[CH3:2].Br[CH:14](C(OCC)=O)[C:15]([O:17]CC)=[O:16].[OH-].[K+]>C(O)C>[CH3:2][C:1]1[C:4]2[C:5](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=[O:7])[O:8][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: CC(=O)c1ccccc1C(=O)O
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(=O)O)oc(=O)c2ccccc12
Reaction time: 2 h

Procedure:
A mixture of 2-acetylbenzoic acid (6.21g), diethyl bromomalonate (9.0g.) and potassium hydroxide (2.12g.) in ethanol (50ml.) was heated under reflux for 6 hours. The cooled mixture was evaporated to dryness, water (100ml.) added and extracted with ether. The combined ethereal extracts were washed with water, dried and evaporated to dryness. The residue was heated under reflux with a mixture of concentrated hydrochloric acid (160ml.) -- acetic acid (100ml.) for two hours, cooled and poured into iced water (1 litre). Filtration gave the product as a white solid, mp. 250°-2°, (lit mp. 248°-9°) (Found: C, 64.59; H, 4.01. C11H8O4 requires C, 64.70; H, 3.95).
Reaction SMILES: [Na].[CH2:2]([OH:8])[CH:3]1[O:7][CH2:6][CH2:5][CH2:4]1.Cl[CH2:10][Si:11]([CH3:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>[I-].[K+].C1(C)C=CC=CC=1>[CH2:2]([O:8][CH2:10][Si:11]([CH3:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[CH:3]1[O:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCO[Si](C)(CCl)OCC
Reactant: OCC1CCCO1
Agent: [I-]
Agent: [K+]
Agent: [Na]
Solvent: Cc1ccccc1
Product: CCO[Si](C)(COCC1CCCO1)OCC

Procedure:
Under conditions similar to Example 3, the reaction product of sodium metal and tetrahydrofurfuryl alcohol was reacted with chloromethylmethyldiethoxysilane in the presence of potassium iodide catalyst in toluene. The reaction proceeded to the desired product only to the extent of 20% with the formation of significant amounts of byproducts.