Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)[CH3:2].C(N(CC)CC)C.[I:21]Cl>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[C:10]([I:21])[CH:11]=1)[CH3:2]
Reactant: ClI
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(N)c(I)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.4 %

Procedure:
To a cooled solution (5° C.) of (4-aminophenyl)acetic acid ethyl ester (25 g, 0.39 mol) in CH2Cl2 (150 mL) is added triethylamine (14.1 g, 0.139 mmol) followed by a solution of iodine monochloride (21.5 g, 0.132 mol) in CH2Cl2 (100 mL). Cooling is removed and the reaction mixture is stirred for 4 hours at room temperature. The solution is concentrated in vacuo and chromatographed with a gradient of hexane/ethyl acetate (5%-30%) within 1 hour to give the desired product (19.5 g, 46%). MS: 305.9 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][OH:14])=[N:8][CH:9]=2)[N:4]([CH3:15])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)O1>O1CCOCC1.O.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>[NH2:34][C:33]1[CH:35]=[CH:36][C:30]([C:2]2[C:10]3[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][OH:14])=[N:8][CH:9]=3)[N:4]([CH3:15])[N:3]=2)=[CH:31][CH:32]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Cn1nc(Cl)c2cnc(NCCO)nc21
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: C1COCCO1
Solvent: O
Product: Cn1nc(-c2ccc(N)cc2)c2cnc(NCCO)nc21
Temperature: 25 °C
Yield: 42.7 %

Procedure:
To a solution of 2-(3-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-ethanol (244 mg, 1.07 mmol) in dioxane (21 mL) and H2O (7 mL) was added anhydrous potassium carbonate (443 mg, 3.21 mmol, 3 eq), followed by 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (350 mg, 1.6 mmol, 1.5 eq). The reaction mixture was degassed and tetrakis(triphenylphosphine)palladium (61 mg, 0.053 mmol, 0.05 eq) was added. The system was then heated under reflux for 24 hours and cooled to room temperature. The layers were separated. The organic solution was treated with ethyl acetate (50 mL) and water (10 mL). The resulting organic layer was then separated, washed with brine, dried over MgSO4, filtered and evaporated. The product was purified by column chromatography (100% ethyl acetate) to give 130 mg (42% yield) of pure 2-[3-(4-amino-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)-ethanol; 1H-NMR (DMSO): δ 3.44 (m, 2H), 3.59 (m, 2H), 3.79 (s, 3H), 4.70 (br s, 1H), 5.32 (br s, 2H), 6.65 (d, 2H, J=8.5 Hz), 7.23 (br s, 1 H) 7.64 (d, 2H, J=8.5 Hz), 9.05 (br, 1H); LC/MS (m/e)=285.4 (MH+), Rt=1.54 min.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]([O:10]CC)(=[O:9])[CH3:8].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]2[CH2:24][NH:23]C(=O)C2)=[C:16]([CH:26]=C)[CH:15]=1.[BH4-].[Na+]>O.C(#N)C>[ClH:13].[NH2:23][CH2:24][C@@H:20]([C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][C:16]=1[CH2:26][OH:2])[CH2:8][C:7]([OH:10])=[O:9]
Reactant: CCOC(C)=O
Reactant: C=Cc1cc(Cl)ccc1[C@@H]1CNC(=O)C1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cl
Product: NC[C@H](CC(=O)O)c1ccc(Cl)cc1CO
Temperature: 90 °C
Reaction time: 0.03 h

Procedure:
To a cooled (0° C.) solution of sodium periodate (607 mg, 2.85 mmol) in water (3.8 mL) was added a catalytic amount of RuCl3(III) (27 mg, 0.13 mmol) followed by ethyl acetate (10 mL) and acetonitrile (10 mL). The reaction mixture was stirred for 5 min at 0° C. before (4R)-4-(4-chloro-2-vinylphenyl)pyrrolidin-2-one prepared as described above was added. After stirring for an additional two minutes, the reaction mixture was quenched with a Na2S2O3 aq. solution (2 M, 10 mL). The layers were separated and the aqueous phase was extracted with ethyl acetated (4×20 mL). The combined organic phases were dried over MgSO4 and concentrated in vacuo. The resulting crude (2-((3S)-5-oxopyrrolidin-3-yl)-5-chlorobenzaldehyde was dissolved in tetrahydrofuran/water (v/v 1:1, 4.5 mL) and sodium borohydride (70 mg, 1.85 mmol) was added. The mixture was stirred for 20 min at room temperature and then diluted with water (7 mL), extracted with dichloromethane (4×30 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The crude residue was then treated with a 6N HCl aqueous solution (1.5 mL) and heated overnight at 90° C. The final product was purified by HPLC to provide the title compound. 1H-NMR (400 MHz, CD3OD): δ 2.84-2.70 (m, 2H), 3.08-3.14 (m, 1H), 3.75-3.83 (m, 1H), 4.85 (s, 1H), 4.57-4.60 (d, J=12.0 Hz, 1H), 7.33-7.42 (m, 3H); MS (ESI) m/z 244.06 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:19])=O>>[C:1]1([CH2:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([Cl:19])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1Cc1ccccc1
Product: O=C(Cl)c1ccccc1Cc1ccccc1

Procedure:
A mixture of 5.0 g of 2-(phenylmethyl) benzoic acid in 5.0 ml of thionyl chloride is heated on a steam bath for 1 hour. The volatiles are evaporated in vacuo to give 5.74 g of the desired product as an oil. M+ =227 as methyl ester.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[N:18]([CH2:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:17]([CH2:26][CH3:27])=[N:16][C:10]=3[C:11]([NH2:15])=[N:12][C:13]=2[CH:14]=1.C(N(CC)CC)C.[CH:35]([N:38]=[C:39]=[O:40])([CH3:37])[CH3:36].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:15][C:11]1[C:10]2[N:16]=[C:17]([CH2:26][CH3:27])[N:18]([CH2:19][CH:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[C:9]=2[C:8]2[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][NH:1][C:39]([NH:38][CH:35]([CH3:37])[CH3:36])=[O:40])=[CH:14][C:13]=2[N:12]=1
Reactant: CCc1nc2c(N)nc3cc(CCCN)ccc3c2n1CC1CCOCC1
Reactant: CC(C)N=C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(N)nc3cc(CCCNC(=O)NC(C)C)ccc3c2n1CC1CCOCC1
Reaction time: 18 h
Yield: 22.4 %

Procedure:
7-(3-Aminopropyl)-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine (500 mg, 1.4 mmol), triethylamine (410 mg, 4.1 mmol), and isopropyl isocyanate (128 mg, 1.5 mmol) were combined in dichloromethane (50 mL) at 0° C. and the reaction was stirred for approximately 18 hours. Aqueous sodium carbonate (1%, 50 mL) was added and the reaction mixture was stirred for one additional hour. The fractions were separated and the aqueous fraction was extracted with chloroform (3×20 mL). The combined organic fractions were sequentially dried (MgSO4), filtered and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient, 0-20% CMA over 2000 mL). The desired product was further purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 10% methanol in dichloromethane over 1500 mL). A final purification by recrystallization from acetonitrile provided 142 mg of N-{3-[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]propyl}-N′-isopropylurea as a white solid, mp 213-216° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:3][CH:2]=1.O.O.O.[F:17][C:18]([F:26])([F:25])[C:19]([C:21]([F:24])([F:23])[F:22])=[O:20].C(#N)C>C1C=CC=CC=1>[F:17][C:18]([F:26])([F:25])[C:19]([C:11]1[S:10][C:9]([NH:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[N:13][CH:12]=1)([OH:20])[C:21]([F:24])([F:23])[F:22]
Reactant: c1cc(CNc2nccs2)ccn1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Solvent: c1ccccc1
Solvent: CC#N
Solvent: O
Product: OC(c1cnc(NCc2ccncc2)s1)(C(F)(F)F)C(F)(F)F
Temperature: 80 °C

Procedure:
Molecular sieves powder (4A) (1 g) was added to a mixture of crude intermediate N-(pyridin-4ylmethyl)-1,3-thiazol-2-amine prepared above (2.5 g 13 mmol) and hexafluoroacetone trihydrate (4 g, 18.1 mmol) in benzene (3 ml). The mixture was heated at 80° C. for 24 h. Acetonitrile was added and mixture was filtered. Solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with a 95:5 mixture of CHCl3 and CH3OH, to afford the title compound as an orange solid (1.1 g). 1H NMR (DMSO-d6) δ 4.3 (d, 2H), 7.10 (s, 1H), 7.42 (d, 2H); 7.78 (d, 2H), 8.45 (brs, 1H), 8.82 (brs, 1H); ESIMS: m/z 356 (M−H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[OH:12].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[CH:17]=O.[C:26](#[N:30])[CH2:27][C:28]#[N:29].C1N2CCN(CC2)C1>C(O)C.O>[NH2:30][C:26]1[O:12][C:7]2[C:6]([CH:17]([C:16]3[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:14]([Br:13])[CH:15]=3)[C:27]=1[C:28]#[N:29])=[CH:5][CH:4]=[C:3]1[C:2]([NH2:1])=[CH:11][CH:10]=[CH:9][C:8]=21
Reactant: COc1cc(C=O)cc(Br)c1OC
Reactant: N#CCC#N
Reactant: Nc1cccc2c(O)cccc12
Agent: C1CN2CCN1CC2
Solvent: CCO
Solvent: O
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2c(N)cccc32)cc(Br)c1OC
Temperature: 80 °C
Reaction time: 18 h

Procedure:
5-Amino-naphthol (700 mg, 4.4 mmol), 3-bromo-4,5-dimethoxy-benzaldehyde (1077 mg, 4.4 mmol) and malononitrile (295 mg, 4.4 mmol) were taken in 40 ml ethanol at room temperature, charged with DABCO (48.4 μl, 1.46 mmol) and then stirred at 80° C. under LC-MS control for 18 h. The reaction mixture was then cooled down to room temperature. The mixture was diluted with water to about 100 ml, stirred at room temperature for 1 h and the precipitates were separated by filtration. It was washed well with 50% aqueous ethanol and dried under vacuum (1.58 g, 3.5 mmol, 79.5%).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].C(OC(=O)C)(=O)C.[N+:13]([CH2:16][CH2:17]O)([O-:15])=[O:14]>C(OCC)(=O)C.[Cl-].[Na+].O>[N+:13]([CH2:16][CH2:17][O:3][C:1](=[O:4])[CH3:2])([O-:15])=[O:14]
Reactant: O=[N+]([O-])CCO
Reactant: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)OCC[N+](=O)[O-]
Temperature: 2.5 °C
Reaction time: 1.17 h
Yield: 366 %

Procedure:
Ex-2a) A mixture of sodium acetate (6.4 g, 78 mmol) and acetic anhydride (30 mL, 330 mmol) was stirred at 0-5° C. To this slurry was added 2-nitroethanol (30 g, 280 mmol) dropwise over a period of approximately 1 hour. After the 2-nitroethanol addition, the orange reaction mixture was stirred at 0-5° C. for an additional hour and then at ambient temperature for approximately 70 min, the exotherm of the reaction increased the temperature to 30° C. and the mixture was cooled with an ice bath to 20° C. The reaction was then stirred at ambient temperature under N2 overnight. The reaction mixture was diluted with ethyl acetate (EtOAc, 40 mL) and saturated brine (80 mL). The layers were separated and the bottom aqueous layer was extracted again with ethyl acetate (25 mL). The combined ethyl acetate layers were washed once with saturated brine (50 mL), dried (MgSO4), filtered and concentrated to afford 38 g of 2-nitroethylacetate as a reddish orange oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:20][C@H:21]([CH3:30])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[OH-:31].[Na+].Cl.[CH3:34]O>>[CH3:34][O:31][C:2]1[N:3]=[C:4]([NH:20][C@H:21]([CH3:30])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11]
Reactant: C[C@H](COc1ccccc1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: [OH-]
Reactant: CO
Agent: Cl
Agent: [Na+]
Product: COc1nc(N[C@H](C)COc2ccccc2)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1

Procedure:
2-Methoxy- N-[(R)-1-phenoxy-2-propyl]adenosine was prepared by reacting 2-chloro- N-((R)1-phenoxy-2-propyl)adenosine (Example 2)(0.30 g, 0.69 mmol) with a mixture of sodium hydroxide (0.32 g, 8.0 mmol) and methanol (15 ml) in a sealed vessel at 80°-90° C. for 4 h. The cooled reaction mixture was neutralised with concentrated hydrochloric acid and evaporated to dryness. Water (30 ml) was added and the mixture was extracted with dichloromethane (2×30 ml). The combined extracts were dried (MgSO4) and coevaporated with dichloromethane (30 ml), giving the title compound as a foam (0.19 g, 60%), 1H NMR (DMSO-d6)δ 1.32 (3H, d, --CHC H3), 3.55 (1H, m, H-5'a), 3.65 (1H, m, H5'b), 3.72 (3H, s, --CH3), 3.91-3.99 and 4.10-4.20 (4H, 2 m, H-3', H-4' and --CH2 --), 4.51 (1H, dd, H-2'), 4.67 (1H, m, --C HCH3), 5.84 (1H, d, H-1'), 6.89-6.98 (3H, m, Ar--H), 7.26 (2H, dd, Ar--H) 8.12 (1H, br, --NH), 8.46 (1H, s, H-8).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CI.[C:14](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:14])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(C(C)(C)C)cc1
Yield: 94.5 %

Procedure:
To 15.0 g of 4-tert-butylphenol dissolved in 100 ml of acetone were added 37.5 ml of methyl iodide and 83.0 g of potassium carbonate and heated at reflux for 20 hours. The reaction mixture was filtered and the filtrate was concentrated at reduced pressure. Diethyl ether was added to the residue to remove the insoluble matters by the filtration and the filtrate was concentrated at reduced pressure. The residue was purified by vacuum distillation to give 15.5 g of the title compound having the following physical properties.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:30])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][N:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:29])[CH:14]=2)[CH:9]=1>C1COCC1.O>[F:29][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:30])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][N:20]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(C)(=O)=O)cn2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(C)(=O)=O)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67 %

Procedure:
Lithium hydroxide monohydrate (0.0045 g, 0.107 mmol) was added to a mixture of [6-fluoro-4-(5-methanesulfonyl-pyridin-2-yl)-3-methyl-naphthalen-2-yl]acetic acid methyl ester (0.014 g, 0.036 mmol) in a 1:1 mixture of THF—H2O mixture (2 mL). The reaction mixture was stirred for 5 hours at room temperature. The reaction mixture was concentrated to remove the THF, and the aqueous residue was combined with a 1.0 N aqueous solution of hydrochloric acid. The resulting mixture was extracted with ethyl acetate. The collected organic layers were dried over anhydrous MgSO4, filtered, and concentrated to provide [6-fluoro-4-(5-methanesulfonyl-pyridin-2-yl)-3-methyl-naphthalen-2-yl]acetic acid (0.009 g) as a white solid. The final product contained a significant amount of water as an impurity. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.35 (br. s, 1 H), 9.26 (dd, J=2.42, 0.60 Hz, 1 H), 8.49 (dd, J=8.00, 2.26 Hz, 1 H), 8.03 (dd, J=8.80, 6.80 Hz, 1 H), 7.95 (s, 1 H), 7.73 (d, J=8.15 Hz, 1 H), 7.40 (td, J=8.80, 2.40 Hz, 1 H), 6.75 (dd, J=11.00, 2.40 Hz, 1 H), 3.87 (s, 2 H), 3.45 (s, 3 H), 2.07 (s, 3 H). MS calcd. for C19H17FNO4S [(M+H)+] 374, obsd. 374.0.
Reaction SMILES: CCN(CC)CC.[CH3:8][O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([CH3:17])[CH:11]=1.Cl[CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23].CC([O-])(C)C.[K+]>C1COCC1.O>[CH3:8][O:9][C:10]1[CH:16]=[CH:15][C:13]([N:14]2[CH2:19][CH2:20][CH2:21][C:22]2=[O:23])=[C:12]([CH3:17])[CH:11]=1
Reactant: COc1ccc(N)c(C)c1
Reactant: O=C(Cl)CCCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCCC2=O)c(C)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
To a solution of Et3N (156 mL, 1 eq) and 4-methoxy-2-methylaniline (150 g, 1.09 mole) in anh. THF (2.4 L), in a 10 L reaction vessel, at 0° C., under N2, was added dropwise a solution of 4-chlorobutyryl chloride (126 mL, 1 eq) in anh. THF (480 mL). The internal temperature was maintained at circa 10° C. and the reaction mixture was stirred for 1.5 hr. It was cooled down to 0° C. and KOt-Bu 1M/THF (2.64 L, 2.4 eq) was added dropwise over a period of 1.5 hr, keeping the internal temperature <10° C. The reaction mixture was stirred at that temperature for 30 min. Water (1.5 L) was then added slowly (20 min) and the phases were separated. The organic layer was treated with conc. HCl (250 mL) and water (1.26 L) and the phases were separated. The combined aqueous layers were extracted with EtOAc (2.6 L) and the combined organic layers were washed with brine (2 L). The solvent was evaporated and the residue purified by flash chromatography (Biotage 150, EtOAc/cHex 8:2) to give the title compound as a pale brown solid (206 g, 92%).
Reaction SMILES: [Br:1]Br.[NH:3]1[C:13]2[CH2:12][CH2:11][CH2:10][C:9](=[O:14])[C:8]=2[CH2:7][CH2:6][C:4]1=[O:5]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:6]1[CH2:7][C:8]2[C:9](=[O:14])[CH2:10][CH2:11][CH2:12][C:13]=2[NH:3][C:4]1=[O:5]
Reactant: BrBr
Reactant: O=C1CCC2=C(CCCC2=O)N1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1CCCC2=C1CC(Br)C(=O)N2
Reaction time: 0.02 h

Procedure:
A solution of 3.6 g of bromine in 50 ml of carbon tetrachloride was added, while stirring under ice-cooling, to a solution of 4.0 g of 3,4,5,6,7,8-hexahydrocarbostyril-5-one in 50 ml of carbon tetrachloride. After allowing the mixture to stand for one minute, the precipitate formed was removed by decantation. The carbon tetrachloride layer was distilled at room temperature to remove the solvent (CCl4), and the resulting crystals were combined with the above precipitate followed by being washed with acetone to give quantitatively 8-(or 6-) bromo-3,4,5,6,7,8-hexahydrocarbostyril-5-one having a melting point of 126°-127° C. as yellow crystals. The thus obtained crystals were dissolved in 80 ml of carbon tetrachloride, and 3.0 g of 3-chloro-1,2-propanediol and 1.5 g of 2,4,6-tribromophenol were added to the solution. The mixture was heated at reflux for 2 hours and thereafter worked up in the same manner as described in Example 6 to give 2.1 g of 5-(2-hydroxy- 3-chloro)propoxy-3,4-dihydrocarbostyril having a melting point of 157°-158° C. as colorless amorphous crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[CH2:8]([O:10][CH:11](OCC)[CH:12](N)[CH2:13][CH3:14])[CH3:9].C([N:21](CC)CC)C>C(Cl)Cl>[CH:3]([S:4]([N:21]1[CH2:14][CH2:13][CH2:12][CH:11]1[O:10][CH2:8][CH3:9])(=[O:6])=[O:5])=[CH2:2]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CCN(CC)CC
Reactant: CCOC(OCC)C(N)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)N1CCCC1OCC
Reaction time: 2 h
Yield: 79.2 %

Procedure:
To a vigorously stirred mixture of 25.7 g (0.158 mol) of 2-chloroethanesulfonyl chloride in 100 mL of CH2Cl2 was slowly added a mixture of 25.4 g (0.158 mol) of aminobutyraldehyde diethyl acetal, 35 g (0.34 mol) of triethylamine and 50 mL of CH2Cl2. The temperature was maintained below 10° C. Stirring was continued for 2 h. The solution was filtered to remove solid Et3NHCl and extracted with 10 mL of 10% HCl (pH 3.0), then 10 mL of 4% NaHCO3. The organic layer was dried with MgSO4 and concentrated on a rotary evaporator to yield 25.7 g of brown liquid containing one major and one significant minor component by gc (~78% at 10.83 min, 8% at 9.12 min). Distillation of an aliquot on a kugelrohr apparatus (130° C., 0.5 torr) increased the ratio of the short retention time peak.
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([CH:46]=[CH:47][CH:48]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([O:22][CH:23]([CH3:25])[CH3:24])[CH:19]=[CH:18][C:17]=2[NH:26][C:27]([C:29]2[CH:30]=[C:31]([CH:43]=[CH:44][CH:45]=2)[CH2:32][S:33][CH2:34][CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])=[O:28])[CH:11]=1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([CH:46]=[CH:47][CH:48]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([O:22][CH:23]([CH3:24])[CH3:25])[CH:19]=[CH:18][C:17]=2[NH:26][C:27]([C:29]2[CH:30]=[C:31]([CH:43]=[CH:44][CH:45]=2)[CH2:32][S:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:28])[CH:11]=1)=[O:9]
Reactant: CC(C)Oc1ccc(NC(=O)c2cccc(CSCCC(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Oc1ccc(NC(=O)c2cccc(CSCCC(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-isopropoxyphenyl)carbamoyl)-benzylthio)propanoate (230 mg, 0.28 mmol, 1.00 equiv, 85%) in dichloromethane (5 mL), and trifluoroacetic acid (1 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (180 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 139.8 mg (76%) of a white solid. 1H-NMR (400 MHz, DMSO-d6, ppm): δ 12.52 (s, 1H), 12.23 (s, 1H), 9.57 (t, J=8 Hz, 1H), 8.96 (d, J=4 Hz, 1H), 8.41-8.36 (m, 2H), 7.88-7.84 (m, 2H), 7.79-7.63 (m, 2H), 7.60-7.52 (m, 2H), 7.50-7.48 (m, 4H), 7.16-7.13 (d, J=12 Hz, 1H), 4.76-4.70 (m, 1H), 4.62 (d, J=6 Hz, 2H), 3.88 (s, 2H), 2.63-2.53 (m, 4H), 1.30 (s, 6H). MS (ES, m/z): 652 [M+H]+.
Reaction SMILES: [C:1]1([CH:13]([CH3:16])[CH2:14][OH:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[H][H]>[Ni].C(O)C>[CH:1]1([CH:13]([CH3:16])[CH2:14][OH:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(CO)C1=CCCCCCCCCCC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CC(CO)C1CCCCCCCCCCC1

Procedure:
45 g of the mixture of isomers of 2-cyclododecenylpropan-l-ol from Example 1 were heated for 7 hours at 200° with 2 g of Raney nickel and 10 ml of ethanol in a shaken autoclave with 200 bar of hydrogen After removal of catalyst and solvent, the reaction mixture was distilled. At 105-110° C. and 0.7 mbar, 35 g of 2-cyclododecylpropan-l-ol were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[Cl:17][CH:18]([Cl:22])[C:19](Cl)=[O:20]>C1C=CC=CC=1>[ClH:17].[Cl:17][CH:18]([Cl:22])[C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1)=[O:20]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: Nc1ccc(-c2nc3ccccc3s2)cc1
Solvent: c1ccccc1
Product: Cl
Product: O=C(Nc1ccc(-c2nc3ccccc3s2)cc1)C(Cl)Cl
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of 2(4'-aminophenyl)benzothiazole (0.4 g, 1.77 mmol) in benzene (20 ml) was added dropwise dichloroacetyl chloride (0.34 ml) at 80° C. The yellow precipitate was formed and the mixture was stirred at 80° C. for 30 minutes. The precipitate was filtered off, washed with benzene and diethyl ether to give (2-(4'-dichloroacetamidophenyl) benzothiazole hydrochloride as a yellow powder (0.56 g, 84,8%). A fine powder of the above salt (0.25 g) was treated with 10% aqueous Na2CO3 (15 ml) for 50° C. for 1 hour, the product was collected by filtration, washed with water and dried to afford a white powder (0.2 g, 88.6%), m.p. 223.0-225.2° C.