Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][CH2:6][C:5]2=[O:16].CO[CH:19](OC)[N:20](C)[CH3:21].C(N(CC)CC)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][C:6](=[CH:19][NH:20][CH3:21])[C:5]2=[O:16]
Reactant: COC(OC)N(C)C
Reactant: CCC(=O)N1CCC(=O)c2cc(Cl)ccc21
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCC(=O)N1CC(=CNC)C(=O)c2cc(Cl)ccc21
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A solution of 6-chloro-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2 g), N,N-dimethylformamide dimethyl acetal (7.009 g), and triethylamine (0.87 g) in benzene (50 m) was refluxed with stirring for 1 hour and then about three-fourths of the solvent was distilled slowly at atmospheric pressure over a period ximately 1 hour. To the residue was added benzene (100 ml) and the solvent was distilled again. The resulting solid was collected by filtration, washed with diethyl ether, and dried to give 6-chloro-3-methylaminomethylene-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (2.02 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH2:12][CH3:13])[N:5]=[CH:4][N:3]=1.[CH3:14][Si:15]([CH3:24])([CH3:23])[C@@H:16]1[CH2:21][CH2:20][C@H:19]([NH2:22])[CH2:18][CH2:17]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:22][C@H:19]2[CH2:18][CH2:17][C@@H:16]([Si:15]([CH3:24])([CH3:23])[CH3:14])[CH2:21][CH2:20]2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9])[CH3:13]
Reactant: CCc1ncnc(Cl)c1C(=O)OC
Reactant: C[Si](C)(C)[C@H]1CC[C@@H](N)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCc1ncnc(N[C@H]2CC[C@@H]([Si](C)(C)C)CC2)c1C(=O)OC

Procedure:
12.4 g (62.0 mmol) of 4-chloro-6-ethyl-5-methoxycarbonylpyrimidine, 11.1 g (62.0 mmol) of cis-4-trimethylsilylcyclohexylamine and 12.55 g (124 mmol) of triethylamine were heated in 30 ml of toluene at 90° C. for 3 hours. After complete reaction, the mixture was partitioned between dichloromethane and water to give, after further extraction with dichloromethane and column chromatography on silica gel, 17.76 g (85.4% of theory) of the cyclohexylaminopyrimidine as a pale brown oil, nD21 =1.5230.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.Cl.O1CCOCC1>C(O)(=O)C.O1CCOCC1.[Zn]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Zn]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Nc1ccc(C=CC(=O)O)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 322.6 %

Procedure:
Cycloartenyl ester of p-nitro cinnamic acid (160.0 g, 0.266 mole) prepared according to the procedure of Example 101 was suspended in a mixture of acetic acid (1.5 l) and dioxane (1.5 l). To the suspension were added 6N-HCl-dioxane (95 ml) and zinc powder (80 g) and the mixture was stirred at 40° C. for 3 hours. After the reaction, zinc powder was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was extracted with chloroform. The extracts were washed successively with water and saturated aqueous NaHCO3, then dried, and concentrated under reduced pressure. The residual crystals were recrystallized from chloroform-ethanol (1:5, v/v), giving cycloartenyl ester of p-aminocinnamic acid (140.0 g), in a 92.0% yield. m.p. 185°-187° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Cl.Cl[CH2:21][C:22]1[C:23]([NH:35][CH3:36])=[N:24][C:25]2[CH:26]=[C:27]3[O:34][CH2:33][O:32][C:28]3=[CH:29][C:30]=2[CH:31]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[C:6]2[CH2:21][C:22]1[C:23]([NH:35][CH3:36])=[N:24][C:25]2[CH:26]=[C:27]3[O:34][CH2:33][O:32][C:28]3=[CH:29][C:30]=2[CH:31]=1
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Reactant: CNc1nc2cc3c(cc2cc1CCl)OCO3
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CNc1nc2cc3c(cc2cc1Cc1c(O)nc(C)c2cc(OC)c(OC)cc12)OCO3
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (147 mg, 670 μmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.70 mL, 1.40 mmol) at RT followed by 7-(chloromethyl)-N-methyl-[1,3]dioxolo[4,5-g]quinolin-6-amine hydrochloride CCH 34158B (200 mg, 697 μmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (80 mL) and the organic solution was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:7 N NH3 solution in MeOH=100:0 to 95:5) gave 6,7-dimethoxy-1-methyl-4-((6-(methylamino)-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)isoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.19 M HCl solution in MeOH (1 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-1-methyl-4-((6-(methylamino)-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)isoquinolin-3-ol dihydrochloride 60 as a brown solid (30 mg, 6% yield).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:15])=[C:9]([NH:11][C:12](=[O:14])C)[CH:10]=1)[CH3:2].[H-].[Na+].ClC1O[C:21]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([Cl:30])[CH:25]=2)=[CH:22][N:23]=1>CN(C=O)C>[Cl:30][C:26]1[CH:25]=[C:24]([C:21]2[O:14][C:12]([NH:11][C:9]3[CH:10]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[CH:6]=[CH:7][C:8]=3[CH3:15])=[N:23][CH:22]=2)[CH:29]=[CH:28][N:27]=1
Reactant: Clc1cc(-c2cnc(Cl)o2)ccn1
Reactant: CCOCc1ccc(C)c(NC(C)=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCc1ccc(C)c(Nc2ncc(-c3ccnc(Cl)c3)o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A solution of N-(5-(ethoxymethyl)-2-methylphenyl)ethanamide (344 mg, 1.66 mmol) in DMF (5 mL) was added to a suspension of NaH (133 mg, 3.32 mmol, 60% dispersion in mineral oil) in DMF (5 mL) at 0° C. under an atmosphere of argon. The mixture was stirred for 1 h at room temperature and cooled to 0° C. A solution of 2-chloro-5-(2-chloropyridin-4-yl)oxazole (357 mg, 1.66 mmol) in DMF (5 mL) was added dropwise to the mixture. After 1 h at 0° C., the reaction was poured into ice water (20 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and filtered. After removal of solvent the residue was silica gel column chromatographed (CH2Cl2/Ethanol:98/2) to give 474 mg of 5-(2-chloropyridin-4-yl)-N-(5-(ethoxymethyl)-2-methylphenyl) oxazol-2-amine (83%) as a beige solide.
Reaction SMILES: C(C(CC)CNCC1SC(C2C=C3C(=C(C(N)=O)C=2)NC=C3C2CCN(S(CC)(=O)=O)CC2)=CC=1)C.[CH:37]([C:39]1[S:43][C:42]([B:44]([OH:46])[OH:45])=[CH:41][CH:40]=1)=O.[CH2:47]([O:49][CH2:50][CH2:51][NH2:52])[CH3:48].[BH3-]C#N.[Na+]>>[CH2:47]([O:49][CH2:50][CH2:51][NH:52][CH2:37][C:39]1[S:43][C:42]([B:44]([OH:46])[OH:45])=[CH:41][CH:40]=1)[CH3:48]
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: CCOCCN
Agent: CCC(CC)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCOCCNCc1ccc(B(O)O)s1
Yield: 40.9 %

Procedure:
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [2-(ethyloxy)ethyl]amine (30 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[2-(ethyloxy)ethyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[2-(ethyloxy)ethyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). The crude product was purified once on an Agilent MDAP using the procedure shown for preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide to give 6 mg of the title compound (7%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16](=O)[NH2:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][CH2:15][C:16]#[N:17])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(OCC(N)=O)CC1
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OCC#N)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-carbamoylmethoxypiperidine-1-carboxylic acid tert-butyl ester (Preparation 13, 235 mg, 0.91 mmol) and triethylamine (140 μl, 1 mmol) in anhydrous CH2Cl2 (5 ml) was cooled to 0° C. and a solution of trichloroacetyl chloride (174 mg, 0.96 mmol) in anhydrous CH2Cl2 added dropwise. The reaction mixture was stirred at rt for 1 h, the solvent was removed and the residue purified by flash chromatography (IH-EtOAc, 1:1) to afford the title compound: δH (CDCl3) 1.50 (9H, s), 1.58-1.65 (2H, m), 1.89-1.95 (2H, m), 3.20 (2H, m), 3.74-3.79 (3H, m), 4.33 (2H, s).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:5][O:6][CH2:7][CH3:8])[CH2:3][OH:4].[CH3:10][Si:11](Cl)([CH3:13])[CH3:12]>>[CH3:1][C:2]([CH3:9])([CH2:3][O:4][Si:11]([CH3:13])([CH3:12])[CH3:10])[CH2:5][O:6][CH2:7][CH3:8]
Reactant: C[Si](C)(C)Cl
Reactant: CCOCC(C)(C)CO
Product: CCOCC(C)(C)CO[Si](C)(C)C

Procedure:
According to the procedure as described in Example 1,2,2-dimethyl-1-ethoxy-3-[(trimethylsilyl)oxy]propane was prepared from intermediate 2,2-dimethyl-3-ethoxy-1-propanol and reagent trimethylsilyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)[C:7]([C:16]([F:19])([F:18])[F:17])=[CH:6][C:5]=1[N+:20]([O-])=O>C(O)C.[Ni]>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)[C:7]([C:16]([F:17])([F:18])[F:19])=[CH:6][C:5]=1[NH2:20]
Reactant: COC(=O)c1cc(N2CCSCC2)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: COC(=O)c1cc(N2CCSCC2)c(C(F)(F)F)cc1N
Yield: 84.9 %

Procedure:
300 mg of 2-nitro-5-thiomorpholin-4-yl-4-trifluoromethyl-benzoic acid methyl ester in 10 ml of dry ethanol are hydrogenated in presence of 60 mg of Raney nickel, After filtration of the catalyst the solution is evaporated to dryness yielding 233 mg of 2-amino-5-thiomorpholin-4-yl-4-trifluoromethyl-benzoic acid methyl ester as yellow powder, m.p. 85-117° C. (decomp.).
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[CH3:29][O:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=1[S:38](Cl)(=[O:40])=[O:39]>N.CO>[CH3:29][O:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:32]=1[S:38]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:39])=[O:40]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: COc1cc(C)ccc1S(=O)(=O)Cl
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(C)ccc1S(=O)(=O)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 41.9 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 2-Methoxy-4-methylbenzenesulfonyl chloride (22 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (7.8 mg). MS m/z 373 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH:6]([C:8](=O)[CH2:9][CH3:10])[CH3:7]>C(O)C>[NH2:1][C:2]1[S:3][C:6]([CH3:7])=[C:8]([CH2:9][CH3:10])[N:4]=1
Reactant: NC(N)=S
Reactant: CCC(=O)C(C)Br
Solvent: CCO
Product: CCc1nc(N)sc1C
Reaction time: 2 h
Yield: 42.5 %

Procedure:
Thiourea (20.9 g., 0.275 mole) was dissolved in 250 ml. of refluxing ethanol. 2-Bromo-3-pentanone (41.3 g., 0.25 mole), dissolved in 50 ml. of ethanol, was added dropwise over 25 minutes to the refluxing thiourea solution. Following an additional 2 hours of reflux, the reaction was boiled down to approximately 100 ml., cooled and the crude product recovered as the hydrobromide salt by filtration. Purified 2-amino-4-ethyl-5-methylthiazole (15.1 g.; m.p. 45°-50° C.; m/e calcd: 142; found: 142) was obtained by dissolution in water and reprecipitation with aqueous 3 N potassium hydroxide.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.CC(O)C>O>[Cl:22][C:16]1[N:15]=[C:14]2[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)=[N:13]2)=[CH:18][CH:17]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(O)c1ccc(F)cc1
Solvent: CC(C)O
Solvent: O
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1ccc(F)cc1
Temperature: 4 °C
Yield: 68.9 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-fluorobenzoic acid (11.2 g), N,N'-carbonyldiimidazole (12.9 g) and 2-amino-7-chloro-1,8-naphthyridine (8.9 g). The product produced by precipitation in water (14.3 g; m.p. 230° C.) is dissolved in boiling 2-propanol (800 cc). After 4 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with 2-propanol (3×10 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-chloro-1,8-naphthyridin-2-yl)-4-fluorobenzamide (10.3 g) is produced, m.p. 236° C. EXAMPLE 16
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:14][O:13][C:12]3[C:15]4[C:20]([C:21]([OH:24])=[C:22]([CH3:23])[C:11]2=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:25][C:26]([F:32])([F:31])[S:27]([O-])(=[O:29])=[O:28].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[F:25][C:26]([F:32])([F:31])[S:27]([O:24][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:12]2[O:13][CH2:14][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)[C:11]=2[C:22]=1[CH3:23])(=[O:29])=[O:28]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: Cc1c2c(c3ccccc3c1O)OCC2c1ccc(C(C)C)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1c2c(c3ccccc3c1OS(=O)(=O)C(F)(F)F)OCC2c1ccc(C(C)C)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 3-(4-isopropylphenyl)-4-methyl-2,3-dihydronaphtho[1,2-b]furan-5-ol obtained in Reference Example 252 (2.60 g, 8.17 mmol) and 4-dimethylaminopyridine (2.0 g, 16.3 mmol) in pyridine (30 mL) was added anhydrous trifluoromethanesulfonate (1.51 mL, 9.00 mmol) at room temperature at 0° C., and the mixture was stirred at 50° C. for 8 hours. Water was added to the reaction solution to separate the organic layer, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with 1 N hydrochloric acid and a saturated sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain 2.8 g (yield 76%) of the title compound. Oily matter.
Reaction SMILES: [CH3:1]OC(=O)CCC(C1C=CC(O)=CC=1)=O.[C:16]([C:19]1[CH:43]=[CH:42][C:22]([O:23][C@H:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([O:30][C:31]3[CH:36]=[CH:35][C:34]([CH2:37][C:38]([OH:40])=[O:39])=[CH:33][C:32]=3Br)[CH2:25]2)=[C:21]([CH2:44][CH2:45][CH3:46])[C:20]=1[OH:47])(=[O:18])[CH3:17].C(C1C=CC(O[C@@H]2CCC[C@H](OS(C)(=O)=O)C2)=C(CCC)C=1O)(=O)C>>[C:16]([C:19]1[CH:43]=[CH:42][C:22]([O:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([O:30][C:31]3[CH:36]=[CH:35][C:34]([CH2:37][C:38]([O:40][CH3:1])=[O:39])=[CH:33][CH:32]=3)[CH2:25]2)=[C:21]([CH2:44][CH2:45][CH3:46])[C:20]=1[OH:47])(=[O:18])[CH3:17]
Reactant: CCCc1c(O[C@H]2CCC[C@H](Oc3ccc(CC(=O)O)cc3Br)C2)ccc(C(C)=O)c1O
Reactant: COC(=O)CCC(=O)c1ccc(O)cc1
Agent: CCCc1c(O[C@@H]2CCC[C@H](OS(C)(=O)=O)C2)ccc(C(C)=O)c1O
Product: CCCc1c(O[C@@H]2CCC[C@H](Oc3ccc(CC(=O)OC)cc3)C2)ccc(C(C)=O)c1O

Procedure:
By following Step A of Example 10, but substituting para-hydroxybenzeneacetic acid methyl ester for 4-(4-hydroxyphenyl)-4-oxobutyric acid methyl ester and substituting the title compound of Step D of Example 8 for the title compound of Step C of Example 8, the title compound of this step was obtained as an oil.
Reaction SMILES: CS(Cl)(=O)=O.[N:6]1([CH2:19][C@H:20](O)[CH3:21])[CH:10]=[CH:9][C:8]2[CH2:11][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:7]1=2.C(N(CC)CC)C.[N-:30]=[N+:31]=[N-:32].[Na+]>ClCCl.C(OCC)C.CN(C)C=O.O>[N:30]([C@@H:20]([CH3:21])[CH2:19][N:6]1[CH:10]=[CH:9][C:8]2[CH2:11][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:7]1=2)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H](O)Cn1ccc2c1-c1ccccc1OC2
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@H](Cn1ccc2c1-c1ccccc1OC2)N=[N+]=[N-]
Yield: 80.1 %

Procedure:
1.27 ml of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 1.88 g of (R)-1-(1,4-dihydro-[1]benzopyrano[4,3-b]pyrrol-1-yl)-propan-2-ol and 4.57 ml of triethylamine in 50 ml of anhydrous dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 280 ml of diethyl ether, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of diethyl ether. The combined organic phases were washed with 140 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown solid obtained was dissolved in 50 ml of anhydrous dimethylformamide, treated with 1.0 g of sodium azide and the reaction mixture was heated to 60° for 18 hours while stirring. After cooling the solution was poured into 140 ml of water and extracted twice with 140 ml of diethyl ether each time. The combined organic phases were washed once with 100 ml of water and once with 100 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 1.67 g (80%) of (S)-1-(2-azido-propyl)-1,4-dihydro-[1]benzopyrano[4,3-b]-pyrrole were obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=2[F:29])=[N:12]1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].N[C@@H](C(C)(C)C)[C:34](NCCO)=[O:35]>>[OH:35][CH2:34][CH2:7][NH:6][C:4](=[O:5])[C@@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=2[F:29])=[N:12]1)=[O:10])[C:2]([CH3:31])([CH3:30])[CH3:1]
Reactant: CC(C)(C)[C@H](N)C(=O)NCCO
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C
Product: CN1CCc2c(c(-c3cc(F)c(F)cc3F)nn2C(=O)N[C@H](C(=O)NCCO)C(C)(C)C)C1

Procedure:
Compound 40 was prepared according to the procedure described for the synthesis of compound 37 by replacing tert-leucine methyl amide with intermediate 23. 1H NMR (CDCl3) δ 7.87 (d, J=9.2 Hz, 1H), 7.47-7.53 (m, 1H), 6.98-7.05 (m, 1H), 6.81 (br, 1H), 4.21 (d, J=9.2 Hz, 1H), 3.69 (br, 2H), 3.39-3.43 (m, 4H), 3.17 (br, 2H), 2.74 (t, J=5.9 Hz, 2H), 2.46 (s, 3H), 1.08 (s, 9H). LCMS (+ESI) m/z=468 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])=[O:5].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26].[Na].[OH-].[Na+:32].C(=O)=O>C(O)(C)C.CC(OC)(C)C.O>[OH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O-:27])=[O:26])=[O:5].[Na+:32]
Reactant: CCOC(=O)CCCCCCCBr
Reactant: O=C(c1ccccc1O)c1ccccc1O
Agent: O=C=O
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC(C)O
Solvent: COC(C)(C)C
Product: O=C([O-])CCCCCCCOc1ccccc1C(=O)c1ccccc1O

Procedure:
Starting from 2,2′-dihydroxybenzophenone and ethyl 8-bromooctanoate, the title compound was prepared and then converted into the sodium salt as follows: the free acid (3.56 g, 9.99 mmol) was dissolved in 40 mL of isopropanol, and treated with sodium hydroxide solution (1.7 mL) prepared from of sodium hydroxide (0.90 g, 22.5 mmol) and water (3.7 mL). Isopropanol and MTBE were added causing a solid to precipitate. Heating this mixture caused most of the solid to dissolve. The remaining solids were removed by filtration. The off-white solid that formed upon cooling with dry ice was isolated by filtration and dried under reduced pressure. Combustion analysis: Found: C, 65.02%; H, 6.22%; C21H23O5Na requires C, 66.00; H, 6.65%; 1H NMR (d6-DMSO): δ 12.6, bs, 1H (OH); δ 7.41, t, 1H, (aryl H); δ 7.31, t, 1H (aryl H); δ 7.27, dd, 1H (aryl H); δ 7.15, dd, 1H (aryl H); δ 7.03, d, 1H (aryl H); δ 6.97, t, 1H (aryl H); δ 6.91, d, 1H (aryl H); δ 6.65, t, 1H (aryl H); δ 3.83, t, 2H, (CH2 α to O); δ 1.82, t, 2H (CH2 α to COONa); δ 1.3, m, 4H (other two CH2's); δ1.0, m, 6H (CH2's in middle of chain). 13C NMR (d6-DMSO): 198.59, 177.35, 161.35, 156.10, 134.56, 131.98, 131.78, 129.55, 128.57, 123.57, 120.18, 118.00, 117.09, 112.51, 67.74, 37.87, 28.83, 28.35, 28.27, 25.84, 24.87.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:21])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[H][H]>[Pd].CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([OH:21])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: [H][H]
Reactant: COc1ccc(CC(=O)c2cc(OC)cc(OC)c2)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(CC(O)c2cc(OC)cc(OC)c2)cc1
Yield: 88.4 %

Procedure:
160 ml of methanol, 32.6 g of recrystallized 1-(3,5-dimethoxyphenyl)-2-(4-methoxyphenyl)ethanone prepared according to Example 4 (114 mmol) and 3.25 g of 5% Pd/C of JM type 87 L are introduced into a hydrogenation reactor and hydrogen is introduced under a pressure of 5 to 6 bar at ambient temperature for 10 h. The catalyst is filtered off at 40° C. and the temperature is brought back to ambient temperature in order to recover 29 g of 1-(3,5-dimethoxyphenyl)-2-(4-methoxyphenyl)ethanol, i.e. a yield of 88.4% with respect to the starting ketone, which exhibits a melting point of 101-102° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[S:9]1[CH:13]=[CH:12][N:11]=[C:10]1[C:14]1[N:19]=[C:18]([C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[F:8][C:6]1[CH:7]=[C:2]([C:13]2[S:9][C:10]([C:14]3[N:19]=[C:18]([C:20]4[N:21]=[CH:22][CH:23]=[CH:24][N:25]=4)[CH:17]=[CH:16][CH:15]=3)=[N:11][CH:12]=2)[CH:3]=[N:4][CH:5]=1
Reactant: c1cnc(-c2cccc(-c3nccs3)n2)nc1
Reactant: Fc1cncc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1cncc(-c2cnc(-c3cccc(-c4ncccn4)n3)s2)c1

Procedure:
Under argon, 88 mg (0.50 mmol) of 3-bromo-5-fluoropyridine, 120 mg (0.50 mmol) of 2-[6-(1,3-thiazol-2-yl)pyridin-2-yl]pyrimidine (cf. Example K, step 1), 326 mg (1.0 mmol) of cesium carbonate and 8 mg (0.01 mmol) of [(t-Bu)2P(OH)]2PdCl2 (“POPd”) in 10 ml of N,N-dimethylformamide were stirred at 120° C. for 16 hours. For work-up, the solvent was removed under reduced pressure, the residue was partitioned between ethyl acetate and water and the organic phase was dried, concentrated under reduced pressure and purified by column chromatography on silica gel RP-18 (mobile phase: water/acetonitrile/formic acid). This gave 11 mg (7% of theory) of 2-{6-[5-(5-fluoropyridin-3-yl)-1,3-thiazol-2-yl]pyridin-2-yl}pyrimidine.