Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])=[O:16])([CH3:13])([CH3:12])[CH3:11].C(Cl)CCl>C1COCC1.CN(C1C=CN=CC=1)C>[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]([O:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:22])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1cccc(C)c1O
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: C1CCOC1
Product: Cc1cccc(C)c1OC(=O)CCCNC(=O)OC(C)(C)C
Temperature: 1 °C
Reaction time: 17 h
Yield: 76.4 %

Procedure:
2,6-Dimethylphenol (0.257 g, 2.1 mmol) and 4-[(tert-butoxycarbonyl)amino]butanoic acid (0.427 g, 2.1 mmol) were dissolved in THF (10 ml, dry) and DMAP (0.005 g, 0.04 mmol) was added. After cooling down to 0-2° C., EDC (0.483 g, 2.52 mmol) was added portionwise under nitrogen atmosphere. The ice bath was removed and stirring was continued over night at rt. After 17 h, the mixture was diluted with DCM (50 ml) and extracted with water (20 ml), HCl (2N, 20 ml) and water (20 ml) again. The organic layer was dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel, using DCM/MeOH (95:5) as eluent, to give the title compound (0.493 g, 76%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 1.45 (s 9H), 1.94-2.01 (m, 2H), 2.14 (s, 6H), 2.66 (t, 2H), 3.24-3.29 (m, 2H), 4.66 (bs, 1H), 7.05 (s, 3H); Mass Spectrum: M-tert-Bu+H+ 252.1
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][N:10]3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Al](C)C.C1(C)C=CC=CC=1.C[O:29][C:30]([C:32]1[C:37]([CH3:38])=[CH:36][CH:35]=[C:34]([CH3:39])[N:33]=1)=O>O1CCOCC1>[CH3:38][C:37]1[C:32]([C:30]([NH:15][C:13]2[CH:12]=[CH:11][N:10]3[CH:16]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]3[N:14]=2)=[O:29])=[N:33][C:34]([CH3:39])=[CH:35][CH:36]=1
Reactant: COC(=O)c1nc(C)ccc1C
Reactant: Nc1ccn2cc(-c3ccccc3)nc2n1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)c(C(=O)Nc2ccn3cc(-c4ccccc4)nc3n2)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 43.7 %

Procedure:
To a white suspension of 2-phenyl-imidazo[1,2-a]pyrimidin-7-ylamine (example 1, step 1, 80 mg, 0.38 mmole) in dioxane (3 ml) is added at RT trimethyl aluminium sol. 2M in toluene (0.8 ml, 1.52 mmole, 4 eq.). The mixture is stirred for 45 min at RT. A solution of 3,6-dimethyl-pyridine-2-carboxylic acid methyl ester (63 mg, 0.38 mmole, 1 eq.) in dioxane (0.4 ml) is then added and the light brown solution is refluxed overnight. The brown solution is loaded on 2 g silica and purified by chromatography on a 12 g RediSep silica cartridge (eluent heptane/ethyl acetate 30-70% 15 min) affording 3,6-dimethyl-N-(2-phenylimidazo[1,2-a]pyrimidin-7-yl)picolinamide (57 mg, 43.6%) as a white solid. MS (m/e)=344.2 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5]Br)[CH3:2].[F:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC(C)=O>[F:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:7])=[CH:11][C:10]=1[CH3:16]
Reactant: Cc1cc(O)ccc1F
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(F)c(C)c1
Temperature: 63 °C
Reaction time: 3 h

Procedure:
To a solution of Bromo-acetic acid ethyl ester (1.3 g, 7.1 mmol) and 4-Fluoro-3-methyl-phenol (1.0 g, 7.1 mmol) in 10 mL acetone was added K2CO3 (979 mg, 7.1 mmol) and NaI (7.1 mg, 0.047 mmol) at 25° C. The reaction mixture was stirred for 3 h at 63° C. and the temperature was slowly reduced to room temperature over a period of 30 min. Evaporation of solvent left the crude from which the product was isolated by Flash column chromatography eluting with 0% to 10% ethyl acetate/hexane to give the title compound, 1.1 g, as a light yellow oil.
Reaction SMILES: N[C@@H](CCC(N[C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=O)[CH2:12]S)=O)C(O)=O.CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=[O:29])N2[C@H]1C(O)=O.N1CCC[C@H]1C(O)=O>>[NH:16]1[CH2:14][C@H:11]([OH:29])[CH2:12][C@H:17]1[C:18]([OH:20])=[O:19]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Product: O=C(O)[C@@H]1C[C@@H](O)CN1
Reaction time: 8 h

Procedure:
A plasmid (pD4-α2, FIG. 68) encoding the gene for the carboxy terminal 219 amino acids of human Type I (α2) collagen with optimized E. coli codon usage as constructed in accordance with Example 14A fused to the 3′-end of the gene for glutathione S-transferase and under control of the tac promoter and containing the gene for ampicillin resistance was used to transform by electroporation proline auxotrophic E. coli strain JM109 (F-). Transformation cultures were plated on LB agar containing 100 μg/ml ampicillin. After overnight incubation at 37° C., a single colony from a fresh transformation plate was used to inoculate 100 ml of LB media containing 100 μg/ml ampicillin. This culture was grown to an OD600 nm of 0.5 and 100 μl aliquots transferred to 1.5 ml tubes. The tubes were stored at −80° C. For expression, a tube was thawed on ice and used to inoculate 25 ml of LB media containing 400 μg/ml ampicillin. After overnight growth at 37° C., a four ml aliquot was withdrawn, centrifuged, the cell pellet washed once with 1 ml of 2×YT media containing 400 μg/ml ampicillin, and the washed cells used to inoculate 1 L of 2×YT medium containing 400 μg/ml ampicillin. This culture was grown at 37° C. to an OD600 nm of 0.8. The culture was centrifuged and the cell pellet washed once with 100 ml of M9 medium (1×M9 salts, 0.5% glucose, 1 mM MgCl2, 0.01% thiamine, 200 μg/ml glycine, 200 μg/ml alanine, 100 μg/ml of the other amino acids except proline, and 400 μg/ml ampicillin). The cells were resuspended in 910 ml of M9 medium (1×M9 salts, 0.5% glucose, 1 mM MgCl2, 0.01% thiamine, 200 μg/ml glycine, 200 μg/ml alanine, 100 μg/ml of the other amino acids except proline, and 400 μg/ml ampicillin) and allowed to grow at 37° C. for 30 minutes. NaCl (80 ml of 5 M), hydroxyproline (7.5 ml of 2M), and IPTG (500 μl of 1 M) were added and growth continued for 3 hours. Cells were harvested by centrifugation and stored at −20° C.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)C=C1.IC>C1(C)C=CC=CC=1.C1COCC1>[CH3:4][CH:3]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:1]=[CH:2]1
Reactant: C1=Cc2ccccc2C1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CI
Product: CC1C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 63 %

Procedure:
140 ml (0.35 mol) of a 2.5 M solution of n-butyllithium in toluene were added dropwise to a solution of 45.0 g of indene (0.35 mol) in 200 ml of THF at 0° C. in the course of 30 min in a 500 ml four-necked flask having a dropping funnel. After warming up to room temperature, the solution was stirred for a further hour. Thereafter, it was again cooled to 0° C., and 99.4 g (0.70 mol) of iodomethane were added dropwise in the course of 2 h. After warming up to room temperature, stirring was effected for a further 24 h. The solvents were distilled off on a rotary evaporator at a bath temperature of 40° C. and 100 mbar. The black residue was extracted by shaking three times with 200 ml of pentane each time. After concentration of the combined pentane fractions on a rotary evaporator, the crude product was fractionated over a 25 cm Vigreux column. 28.6 g (0.22 mol; 63% yield) of colorless methylindene were obtained under a vacuum from a diaphragm pump at 19 mbar and a top temperature of 71-73° C. The 1H-NMR spectrum shows an isomer mixture of 1- and 3-methylindene in the ratio of 1:1.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:29])[C:18]([NH:21]C(OC(C)(C)C)=O)([CH3:20])[CH3:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCCC1>[NH2:21][C:18]([CH3:20])([CH3:19])[C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13]1)=[O:29]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(N)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-methylpropionic acid (10 g) in tetrahydrofuran (20 mL) were added 1-(benzyloxycarbonyl)piperazine (16.3 g), 1-hydroxybenzotriazole (8.02 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (11.4 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was dissolved in a mixed solvent of n-hexane and ethyl acetate (1/1) (40 mL) at 60° C. with heating, and the solution was stirred at room temperature overnight. To the mixture was added the same solvent (30 mL), and the mixture was further stirred overnight. The precipitated crystals were collected by filtration, and washed with the same solvent and dried under reduced pressure to give 4-benzyloxycarbonyl-1-[2-(tert-butoxycarbonylamino)-2-methylpropionyl]piperazine (13.5 g). To a solution of the obtained 4-benzyloxycarbonyl-1-[2-(tert-butoxycarbonylamino)-2-methylpropionyl]piperazine (5 g) in tetrahydrofuran (30 mL) was added hydrochloric acid (4 mol/L 1,4-dioxane solution, 40 mL), and the mixture was stirred at room temperature overnight. The precipitated crystals were collected by filtration. The obtained crystals were dissolved in ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (3.65 g).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1.CO.[OH-].[Na+].Cl>C1COCC1>[OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:19]([OH:21])=[O:20])=[CH:14][CH:15]=3)[N:10]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cnc(N[C@H]3CC[C@H](O)CC3)nc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 2-[(trans-4-hydroxycyclohexyl)amino]quinazoline-7-carboxylate (3090 mg, 10.3 mmol) in THF (100 mL) was added MeOH (20 mL) followed by 2 M NaOH (20 mL, 40 mmol) and the mix stirred at R.T. for 3 hours. The solvents were stripped and the mix acidified with a stoichiometric amount of 1 M HCl giving a yellow precipitate that was filtered off and washed with water and air dried to yield the title compound as a bright yellow solid, 2.7 g, 92%. 1H NMR (400 MHz, DMSO-D6) δ ppm 13.30 (1H, s) 9.17 (1H, s) 7.96 (1H, s) 7.85 (1H, d, J=8.34 Hz) 7.64 (1H, d, J=8.34 Hz) 7.48 (1H, s) 4.57 (1H, s) 3.79 (1H, s) 1.79-2.04 (4H, m) 1.17-1.43 (4H, m); MS (API−) for C15H17N3O3 m/z 286.1 (M−H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]1[CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[H-].[Na+].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].[Cl-].[NH4+]>CN(C=O)C>[C:27]([O:26][C:24]([CH2:23][N:7]1[C:6](=[O:8])[CH:5]=[CH:4][N:3]([CH2:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[C:2]1=[O:1])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(Cn1ccc(=O)[nH]c1=O)OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1c(=O)ccn(CC(=O)OCc2ccccc2)c1=O
Reaction time: 0.25 h
Yield: 83.4 %

Procedure:
To a solution of phenylmethyl 2-(2,4-dioxo-1,3-dihydropyrimidinyl)acetate (1.0 g) in anhydrous DMF (10 ml) at 0° C. was added portionwise sodium hydride (0.18 g). After the reaction mixture was stirred for 15 minutes with cooling in an ice bath, tert-butyl bromoacetate (0.9 g) was added. After stirring the mixture at room temperature for 1 hour, to the reaction mixture was added saturated aqueous ammonium chloride solution, and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with brine and dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, n-hexane:ethyl acetate 2:1) to give phenylmethyl 2-(3-{[(tert-butyl)oxycarbonyl]methyl}-2,4-dioxo-1,3-dihydropyrimidinyl)acetate (1.2 g) as a colorless oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH:14]=O)=[C:8]([CH:13]=1)[C:9]([O:11]C)=O.[N+:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])#[C-].C(O)(=O)C>CN(C=O)C>[Cl:3][C:4]1[CH:13]=[C:8]2[C:7]([CH:14]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:16][C:9]2=[O:11])=[CH:6][CH:5]=1
Reactant: COC(=O)c1cc(Cl)ccc1C=O
Reactant: [C-]#[N+]CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(Cl)cc2c(=O)[nH]1
Temperature: 20 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
To a stirred mixture of NaH (1.81 g, 30.3 mmol) in DMF (20 mL) was added a solution of methyl 5-chloro-2-formylbenzoate (5.0 g, 25 mmol) and ethyl 2-isocyanoacetate (2.85 g, 25 mmol) in DMF (60 mL) at 40° C. over a 20 minute period. The reaction mixture was stirred at 20° C. for 2 hours. Its pH was adjusted to 7.0 with acetic acid (10%) and the mixture was extracted with DCM (3×200 mL). The organic layers were combined, washed with brine (200 mL), dried over Na2SO4, and concentrated. The crude product was purified by silica gel column chromatography eluting with petroleum ether and ethyl acetate (PE/EtOAc=15:1-5:1 gradient) to give the title compound (2.0 g, 31%). ESI-MS m/z [M+H]+252.1.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:31])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]>CC(C)=O>[OH:1][C:2]1[C:3]([CH3:31])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[N:24]([CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][CH2:5]2
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=O)N(CC(=O)OC(C)(C)C)C3=O)cc1)O2

Procedure:
Following the procedure described in Example 44, 1 g of 5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione [prepared as described in Example 27(b)], 0.47 g of anhydrous potassium carbonate, 0.93 g of t-butyl bromoacetate and 8 ml of acetone gave the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20]O)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: OCCCCc1ccc(F)cc1
Product: O=Cc1ccc(OCCCCc2ccc(F)cc2)cc1
Yield: 43 %

Procedure:
Following the process described in example 18 (point A), starting from 4-hydroxybenzaldehyde and 4-(4-fluorophenyl)-1-butanol, the title compound was prepared (43% yield).
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-])=O)(=[O:7])=[O:6])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[S:5]([NH:4][CH:1]([CH3:3])[CH3:2])(=[O:7])=[O:6]
Reactant: [H][H]
Reactant: CC(C)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CC(C)NS(=O)(=O)c1ccccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-isopropyl-2-nitrobenzenesulfonamide (774 mg) in methanol (50 mL) was added Pd/C (10% Pd in carbon, 150 mg, 19 wt %) under argon protection. A hydrogen balloon was used as the hydrogen source. The reaction was stirred at room temperature overnight. The mixture was filtered through celite and the celite pad was washed several times. The solvent was removed and the crude was purified by silica gel chromatography to obtain the desired product 2-amino-N-isopropylbenzenesulfonamide (quantitative yield).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:28]([O:32][C:33](=[O:42])[N:34]([CH3:41])[CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([CH3:31])([CH3:30])[CH3:29]>C(Cl)Cl>[C:28]([O:32][C:33](=[O:42])[N:34]([CH:35]1[CH2:36][CH2:37][N:38]([S:17]([C:13]2[S:14][C:15]([Br:16])=[C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])[CH:12]=2)(=[O:19])=[O:18])[CH2:39][CH2:40]1)[CH3:41])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CCC(N(C)C(=O)OC(C)(C)C)CC3)sc2Br)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (300 mg; 0.72 mmol; 1 eq), is dissolved in anhydrous DCM (20 ml). The reaction mixture is put under nitrogen. Triethylamine (0.5 ml; 3.61 mmol; 5 eq) and methyl-piperidine-4-yl-carbamic acid tert-butyl ester (773.2 mg; 3.61 mmol; 5 eq) are added successively and the reaction mixture is stirred for 30 minutes at room temperature. It is then washed with water, NaHCO3 sat., brine and dried over MgSO4, affording the title compound (470 mg; quantitative).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([F:12])[CH:6]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])=[C:7]([F:12])[CH:6]=1
Reactant: COC(=O)Cc1ccc(O)c(F)c1
Reactant: CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)OC)cc1F
Yield: 97.5 %

Procedure:
A mixture of 23.0 g of product from Example 60, 34.6 g of 1-bromotetradecane, 54.6 g of potassium carbonate and 250 ml of acetone is heated at reflux temperature for 48 hours. The cooled reaction is filtered and concentrated in vacuo. The residue is purified by column chromatography (silica gel:0-4.5% ethyl acetate/hexane) to give 46.3 g of the desired product as colorless prisms.
Reaction SMILES: [CH3:1][C:2]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:13])O[C:4](=[O:5])[CH:3]=1.Cl.[NH2:15][NH2:16]>C(O)C>[CH3:12][O:11][C:9]([C:8]1[C:2]([CH3:1])=[CH:3][C:4](=[O:5])[N:15]([NH2:16])[C:7]=1[CH3:13])=[O:10]
Reactant: COC(=O)c1c(C)cc(=O)oc1C
Reactant: NN
Agent: Cl
Solvent: CCO
Product: COC(=O)c1c(C)cc(=O)n(N)c1C
Temperature: 160 °C

Procedure:
A mixture of methyl isodehydroacetate (24.0 g, 132 mmol) and hydrazine monohydrochloride (9.6 g, 140 mmol) in ethanol (30 mL) was heated under microwave irradiation at 160° C. for 2 hours. It was filtered and the obtained solution was evaporated. The oil was partitioned between sat. aq. Na2CO3 and ethyl acetate (3×250 mL). The combined organic solution was washed with brine, dried (Na2SO4) and evaporated. The title product was purified by flash chromatography (yield 2.8 g, 10%). LC-MS (m/z) 197.0 (MH+); tR=0.57 (method C). 1H NMR (600 MHz, CDCl3): 2.20 (s, 3H, Me), 2.52 (s, 3H, Me), 3.88 (s, 3H, OMe), 5.16 (s, 2H, NH2), 6.35 (s, 1H, C5-H).
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][O:51]CC1C=CC=CC=1)[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:38]=2[F:44])=[CH:33][CH:32]=1)=[O:17])C1C=CC=CC=1>[Pd].O1CCCC1>[OH:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:38]=2[F:44])=[CH:33][CH:32]=1)=[O:17]
Reactant: O=C(OCCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1)C(CCCCCCOCc1ccccc1)CCCCCCOCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(OCCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1)C(CCCCCCO)CCCCCCO
Temperature: 25 °C
Reaction time: 48 h
Yield: 97.5 %

Procedure:
First, 4.9 g of 11-[2,3-difluorobiphenyl-4'-yl]oxyundecyl 2,2-bis(6-benzyloxyhexyl)acetate, 1.5 g of 10% Pd-C, and 100 ml of tetrahydrofuran were placed in a 300 ml autoclave. The mixture was stirred at room temperature for 2 days under a hydrogen pressure of 10 kg/cm2. The catalyst was filtered away and a filtrate was concentrated. Thereafter, the residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=7/3) to obtain 3.7 g of 11-[2,3-difluorobiphenyl-4'-yl]oxyundecyl 2,2-bis(6-hydroxyhexyl)acetate (Y: 97.5%). The compound thus obtained had a purity of 98% by HPLC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([NH:13][CH:14]=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.[OH-].[NH4+].CO.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([NH:13][CH3:14])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=CNc1cnn(-c2ccc(F)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CNc1cnn(-c2ccc(F)cc2)c1
Temperature: 45 °C
Yield: 90.4 %

Procedure:
A mixture of N-[1-(4-fluorophenyl)pyrazol-4-yl]formamide (0.275 g, 1.33 mmol) and LiAlH4 (1.33 mL, 2.66 mmol, 2 M in THF) in THF (5 mL) was heated at 45° C. for 1 h. The reaction mixture was cooled to room temperature and diluted with 5 mL of concentrated ammonium hydroxide and 80 mL of 20% MeOH/CH2Cl2. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (SiO2, 0-100% EtOAc/CH2Cl2 gradient elution) to give 1-(4-fluorophenyl)-N-methylpyrazol-4-amine as an oil (0.23 g, 90%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[S:13])[NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:15][CH:16]=O.C(=O)([O-])O.[Na+]>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2[S:13][CH:15]=[CH:16][N:12]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NC(=S)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cc2nccs2)cc1

Procedure:
A mixture of 2-(4-nitrophenyl)ethanethioamide (0.80 g), chloroacetaldehyde (40% aqueous solution, 2.88 g) and ethanol (20 mL) was heated under reflux for 15 hrs. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and 2-(4-nitrobenzyl)-1,3-thiazole was obtained as an orange oil (0.35 g, yield 39%) from a fraction eluted with hexane-ethyl acetate (9:1-2:1, v/v).