Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=O.Cl.[F:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]N)=[CH:12][CH:11]=1.C1(C)C=CC=CC=1.P(=O)(O)(O)O>O>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1[C:14]2[C:13](=[CH:12][CH:11]=[C:10]([F:9])[CH:15]=2)[NH:16][CH:6]=1
Reactant: NNc1ccc(F)cc1
Reactant: O=CCCCCCl
Agent: Cl
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc2[nH]cc(CCCCl)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The compound 5-chloropentan-1-ol (16.2 mL) was dissolved in cold 5 mM 2,2,6,6-tetramethylpiperidine-1-yloxy (tempo) in dichloromethane (240 mL) and cooled down to 0° C. with an ice bath. Potassium bromide (0.5 M in water, 24 mL) was added, and this was followed by the addition (in one portion at 5° C. under vigorous stirring) of a solution of sodium hydrogencarbonate (24 g) in aqueous sodium hypochlorite (0.3 M, 500 mL). The resulting mixture was stirred at 5° C. for 20 min, and the phases were separated. The water phase was extracted with dichloromethane (200 mL), and the combined organic phases were evaporated in vacuo giving 5-chloropentanal as a clear oil (16 g). Subsequently, 5-chloropentanal was suspended in water (100 mL) followed by addition of 4-fluorophenylhydrazine hydrochloride (19.5 g) and toluene (800 mL), and the mixture was stirred at room temperature for 15 min. Phosphoric acid (85%, 100 mL) was added and the mixture was boiled under reflux for 2 h. The mixture was cooled to room temperature and the phases were separated. The organic phase was washed with saturated aqueous sodium hydrogencarbonate, dried (MgSO4) and evaporated in vacuo to yield an orange oil. The crude product was purified by flash chromatography on silicagel (eluent: ethylacetate/heptane 1:4) to give the title compound as an orange oil (14 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:13]CC2SC(C3C=CC(C(F)(F)F)=CC=3)=NC=2C)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([OH:12])=[O:11].[C:31]1(C)C(O)=CC=C[CH:32]=1.S(Cl)(Cl)(=O)=O.[Sn]>>[SH:13][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([O:12][CH2:31][CH3:32])=[O:11])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1ccccc1O
Reactant: Cc1cc(SCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCC(=O)O
Agent: [Sn]
Solvent: O=S(=O)(Cl)Cl
Product: CCOC(=O)COc1ccc(S)cc1C

Procedure:
As an alternative synthesis method of GW501516, it is disclosed, as illustrated in the following scheme (2), that the compound (13) of GW501516 can be prepared by introducing ethyl acetate group to o-cresol (14), reacting the resulted compound (15) with sulfonyl chloride, reducing the resulted compound (16) with tin (Sn) under acidic condition to form ethyl (4-mercapto-2-methyl phenoxy)acetate (17), reacting it with 5-chloromethyl-4-methyl-2-(4-trifluoromethyl phenyl)thiazole (11) together with an excessive cesium carbonate to obtain the ethyl ester intermediate (18) of GW501516, and deprotecting the ester group of the intermediate compound with 1N lithium hydroxide.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:19]([F:22])([F:21])[F:20])[CH:10]([NH:14][C:15](=[O:18])[CH2:16]Cl)[CH:11]([CH3:13])[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Na+].[I-:24].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O.O>[Si:1]([O:8][CH:9]([C:19]([F:22])([F:21])[F:20])[CH:10]([NH:14][C:15](=[O:18])[CH2:16][I:24])[CH:11]([CH3:13])[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)C(NC(=O)CCl)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Reactant: [I-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)C(NC(=O)CI)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Reaction time: 8 h
Yield: 91.9 %

Procedure:
N-(2-tert-Butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)-2-chloroacetamide (15.56 g) was added to a solution of NaI (19.3 g) in acetone (130 mL). The mixture was stirred overnight and the yellow reaction mixture was diluted with water (180 mL). The resulting precipitate was filtered; washed with water and saturated aqueous sodium thiosulfate; and dried under vacuum at 40° C. overnight. After spectral data indicated the presence of starting material, the product was subjected to another iteration of the above reaction conditions. The subsequent work-up was identical except that no sodium thiosulfate wash was performed. Purification by chromatography, eluting with hexane:ethyl acetate (gradient, 80:20 and 50:50), and drying under vacuum afforded N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)-2-iodoacetamide (17.91 g); TLC: Rf =0.30, hexane:ethyl acetate (9:1); MS: m/z=454(M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([OH:8])[CH2:7][O:6][CH2:5]1.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16](=O)[O:17]C1C=CC=CN=1>C1COCC1.CCOC(C)=O>[C:16](=[O:17])([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=1)[O:8][C:4]1([CH3:3])[CH2:7][O:6][CH2:5]1
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Reactant: CC1(O)COC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(OC(=O)Oc2ccccn2)COC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
To a suspension of sodium hydride, 60% in mineral oil (0.817 g, 20.43 mmol) in THF (55 mL) was added 3-methyloxetan-3-ol (1.5 g, 17.03 mmol) at 0° C. After stirring 30 min, the solution was transferred to a solution of di(pyridin-2-yl)carbonate (3.68 g, 17.03 mmol) in THF (55 mL) through a cannula. The formed slurry was stirred at 0° C. for 30 min. The slurry was warmed to rt and stirred for 2 h. The reaction was diluted with EtOAc, washed with brine, dried over MgSO4, filtered, concentrated to give a residue that was purified by Biotage (5-40% EtOAc:Hex) to afford the desired product 3-methyloxetan-3-yl pyridin-2-yl carbonate (1.00 g, 28.1% yield) as an oil. 1H NMR (400 MHz, CHLOROFORM-d) d 8.52-8.35 (m, 1H), 7.84 (ddd, J=8.1, 7.3, 2.1 Hz, 1H), 7.31-7.27 (m, 1H), 7.15 (dt, J=8.1, 0.8 Hz, 1H), 4.97-4.85 (m, 2H), 4.54 (d, J=8.0 Hz, 2H), 1.86 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:22][C:21]3([CH3:24])[CH2:23][CH:17]2[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20]3)=[O:15])=[CH:10][C:9]=1[NH2:27])[CH3:2].C(=O)C.CN1C(=O)[CH2:36][CH2:35][CH2:34]1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][N:7]1[C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:22][C:21]4([CH3:24])[CH2:23][CH:17]3[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20]4)=[O:15])=[CH:10][C:9]=2[N:27]=[C:34]1[CH2:35][CH3:36])[CH3:2]
Reactant: CN1CCCC1=O
Reactant: CCOC(=O)CCNc1ccc(C(=O)N2CC3(C)CC2CC(C)(C)C3)cc1N
Agent: CC=O
Product: CCOC(=O)CCn1c(CC)nc2cc(C(=O)N3CC4(C)CC3CC(C)(C)C4)ccc21
Temperature: 50 °C
Reaction time: 16 h
Yield: 38 %

Procedure:
To a solution of 3-[2-amino-4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenylamino]-propionic acid ethyl ester (250 mg, 0.645 mmol) in dry NMP (10 mL) at room temperature under an inert atmosphere of nitrogen was added approx. 200 mg of molecular sieve 4 Å followed by acetaldehyde (93 uL, 1.29 mmol). The mixture was stirred for 16 hrs at 50° C. The reaction was quenched by the addition of water (100 mL) followed by extraction with diethyl ether (3×100 mL). The combined organic phases were washed with brine (4×200 mL), dried (MgSO4), filtered, and evaporated in vacuo. The resulting oil was purified by preparative HPLC, dried in vacuo at 50° C. affording 104 mg (38%) of the title compound as brown oil. MS-ESI m/z 426; 1H NMR (400 MHz, CDCl3) δ 0.88-1.06 (m, 6H), 1.11-1.23 (m, 7H), 1.24-1.28 (m) and 1.55-1.65 (m, 1H), 1.36-1.45 (m, 2H), 1.50 (t, 3H), 1.74-1.81 (m, 1H), 2.23-2.30 (m) and 3.12-3.20 (m, 1H), 2.81 (t, 2H), 2.96 (q, 2H), 3.22-3.35 (m, 1H), 3.32 (dd) and 3.62 (dd, 1H), 4.03-4.07 (m) and 4.63-4.67 (m, 1H), 4.13 (q, 2H), 4.45 (dt, 2H), 7.32-7.46 (m, 2H), 7.84 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[O:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14]C=O.C(=O)([O-])[O-].[K+].[K+].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Cu]>[Cl:21][C:19]1[CH:20]=[CH:2][C:3]2[O:4][CH2:5][O:6][C:7]3[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=3[NH:14][C:17]=2[CH:18]=1
Reactant: O=CNc1cc(Cl)ccc1OCOc1ccc(Cl)cc1Br
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: Clc1ccc2c(c1)Nc1cc(Cl)ccc1OCO2
Temperature: 20 °C
Reaction time: 10 h

Procedure:
A suspension of 4.1 g. (0.01 moles) of (2-bromo-4-chlorophenoxy)-(2-formamido-4-chlorophenoxy)-methane (m.p.: 148° to 149° C.), 2.1 g. (0.015 moles) of potassium carbonate, 0.5 g. (0.008 gatom) of copper powder and 30 ml. of Dowtherm® A is heated up to 190° C. and is kept at this temperature for 10 hours, while stirred vigorously. Thereafter the reaction mixture is filtered and from the filtrate the solvent is distilled off in vacuo. The remaining tar is boiled in a mixture of 45 ml. of ethanol and 4.5 ml. of a 20% aqueous sodium hydroxide solution for one hour, then cooled to 20° C. It is then neutralized with a 37% aqueous hydrochloric acid solution and the solvent is eliminated. The residue is extracted three times with 80 ml. portions each of hot cyclohexane, the combined extracts are decoloured while hot and the solvent is eliminated. Recrystallization of the crude product from carbon tetrachloride affords a white product weighing 0.6 g. (21.4%) and melting at 194° to 196° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH2:18][CH:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][N:15]=3)=[CH:10][CH:9]=2)=[CH:4][CH2:3]1.CC1(C)[O:31][C@H:30]([C:32](Cl)=O)[CH2:29][O:28]1>>[OH:31][C@H:30]([CH2:29][OH:28])[CH2:32][N:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH2:18][CH:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][N:15]=3)=[CH:10][CH:9]=2)=[CH:4][CH2:3]1
Reactant: C1=C(c2ccc(C3=NOC(COc4ccon4)C3)cc2)CCNC1
Reactant: CC1(C)OC[C@@H](C(=O)Cl)O1
Agent: Cl
Product: OC[C@@H](O)CN1CC=C(c2ccc(C3=NOC(COc4ccon4)C3)cc2)CC1

Procedure:
(5RS)-3-(4-(1,2,5,6-Tetrahydropyrid-4-yl)phenyl)-5-isoxazol-3-yloxymethyl-4,5-dihydro-isoxazole hydrochloride (300 mg, 0.83 mM) was treated with (4S)-2,2-dimethyl-1,3-dioxolan-4-ylcarbonyl chloride under essentially the conditions of Example 2. Crude product was chromatographed on a 20 g silica Mega Bond Elut® column, eluting with 5% methanol in dichloromethane. Relevant fractions were combined to give the desired product (43 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([NH2:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:24]([O:26][CH:27]([O:30][CH2:31][CH3:32])[CH2:28]Br)[CH3:25]>O>[CH2:24]([O:26][CH:27]([O:30][CH2:31][CH3:32])[CH2:28][NH:12][CH:10]([CH3:11])[CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:25]
Reactant: CCOC(CBr)OCC
Reactant: COc1cccc(CC(C)N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(CNC(C)Cc1cccc(OC)c1)OCC
Temperature: 130 °C
Yield: 68 %

Procedure:
(+)-2-(3-methoxyphenyl)-1-methylethylamine (472.8 g, 2.86 mol), potassium carbonate (sesquihydrate) (1133.8 g, 6.88 mol) and dimethylformamide (2400 ml) were mixed and heated to 130° C. in a reaction flask fitted with an efficient stirrer and a reflux condenser. Bromoacetaldehyde diethylacetal (630 g, 3.20 mol) was added dropwise over a 45 min period while maintaining the temperature at 130° C. The reaction was mildly exothermic. The temperature was maintained at 130° C. for 1 hr. The reaction mixture was cooled to 45° C., and 325 ml of water was added. After stirring at least 1 hr and after the temperature of the mixture reached 30°, it was filtered from the salts and the solvent evaporated under vacuum on a rotatory evaporator. The residual oil was filtered from some inorganic salts and distilled under vacuum; collected fractions boiling at 115°-130° C. at 0.05 mmHg, yield 68% of (+)-N-(2,2-diethoxyethyl)-2-(3-methoxyphenyl)-1-methylethylamine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8](Br)[C:7]([F:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20].[Si:22]([C:26]#[CH:27])([CH3:25])([CH3:24])[CH3:23].N(C(C)C)C(C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:27]#[C:26][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:7]([F:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)c1cc(C#C[Si](C)(C)C)c(F)c(F)c1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.7 %

Procedure:
A mixture of 5-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (8.02 g, 21.3 mmol, prepared as described in Example 1), TMS-acetylene (3.80 mL, 26.4 mmol), Pd(PPh3)2Cl2 (1.52 g, 2.12 mmol), CuI (405 mg, 2.12 mmol), and i-Pr2NH (6.00 mL, 42.6 mmol) in THF (120 mL) was stirred for 3 days at room temperature. The reaction mixture was concentrated in vacuo, diluted with EtOAc, and washed with saturated aqueous NH4Cl and brine. The organic layer was dried over MgSO4, and filtered. The organic layer was concentrated to give the crude material which was purified by silica gel flash column chromatography (100% Hexane to 1% to 2% EtOAc in Hexane) to afford the desired product (7.11 g, 85%).
Reaction SMILES: Cl[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.C([O-])([O-])=O.[Cs+].[Cs+].[SH:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]>CN(C=O)C>[Cl:10][C:6]1[CH:7]=[N:8][CH:9]=[C:2]2[S:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:4][C:3]=12
Reactant: COC(=O)CS
Reactant: O=Cc1c(Cl)cncc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(Cl)cncc2s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3,5-Dichloroisonicotinaldehyde (20.39 g, 115.8 mmol) obtained from Aldrich was dissolved in 250 mL DMF. To this solution was added Cs2CO3 (12.9 g, 121.59 mmol) and then methyl 2-mercaptoacetate (56.6 g, 173.7 mmol). The mixture was stirred at room temperature for 3 hours. After removing 200 mL DMF under a reduced pressure, the remaining residue was mixed with 100 mL water. After filtration, the filter cake was washed thoroughly with water and air dried. An off-white solid was obtained as the pure product (23.15 g, y=88%). LCMS (API-ES) m/z (%): 228.2 (100%, M++H); 1H NMR (300 MHz, DMSO-d6) δ ppm 3.96 (s, 3H) 8.12 (s, 1H) 8.64 (s, 1H) 9.36 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])[N:14]=2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[N:16]=[C:15]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])[N:14]=2)[CH2:9]1
Reactant: Cc1ccc2c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3ccccc3O)nc2c1
Reaction time: 0.83 h

Procedure:
To 850 mg (2.02 mmol) of (R)-{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester was added at room temperature 4 mL of 1:1 TFA:CH2Cl2. The reaction mixture was stirred for 50 min and diluted with 20 mL of CH2Cl2 and extracted with 15 mL of satd. NaHCO3 solution. The organic layer was separated and dried over Na2SO4, and the solvent was removed under reduced pressure to give (R)-2-[4-(3-amino-pyrrolidin-1-yl)-7-methyl-quinazolin-2-yl]-phenol as an oil which was used without further purification.
Reaction SMILES: [NH2:1][CH:2]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])[CH:20]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[OH:4].[F:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([C:43](O)=[O:44])=[CH:35][CH:34]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([C:43]([NH:1][CH:2]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:30])([F:31])[CH:27]([F:28])[F:29])[CH:20]=2)[CH:3]([OH:4])[C:5]2[CH:6]=[CH:7][C:8]([O:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:9][CH:10]=2)=[O:44])=[CH:35][CH:34]=1
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccccc2)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-phenoxyphenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol (300 mg, 0.69 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (131 mg, 0.69 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (198 mg, 1.03 mmol) and 1-hydroxybenzotriazole hydrate (105 mg, 0.69 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted-with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-ethyl acetate). Recrystallization from ethyl-acetate-hexane gave the objective substance (286 mg, 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH2:12][O:13][CH3:14])[C:6]([CH3:15])=[C:5](Br)[C:4]=1[O:17][CH2:18][O:19][CH3:20].C([Li])CCC.CN(C)[CH:28]=[O:29]>CCOCC.CCCCCC>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH2:12][O:13][CH3:14])[C:6]([CH3:15])=[C:5]([CH:28]=[O:29])[C:4]=1[O:17][CH2:18][O:19][CH3:20]
Reactant: CN(C)C=O
Reactant: COCOc1c(C)c(Br)c(OCOC)c(OC)c1OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COCOc1c(C)c(C=O)c(OCOC)c(OC)c1OC
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a cold solution of 2,3-dimethoxy-5-methyl-1,4-bismethoxymethyloxy-6-bromobenzene [oily substance, δ 2.34 (3H), 3.57 (3H), 3.64 (3H), 3.84 (6H), 5.01 (2H), 5.09 (2H)] (9.00 g, 25.6 mmol) in absolute ether (90 ml) was added a solution of 15% n-butyllithium in hexane (17.6 ml). The mixture was stirred for 30 minutes. Dimethylformamide (9.36 g, 128 mmol) was added and the reaction was continued under the same conditions for 30 minutes. Working up in a conventional manner gave 2,3-dimethoxy-5-methyl-1,4-bismethoxymethyloxy-6-formylbenzene [oily substance, δ 2.48 (3H), 3.55 (3H), 3.58 (3H), 3.85 (3H), 3.95 (3H), 4.99 (2H), 5.13 (2H)]. Yield 80%.
Reaction SMILES: CC[C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH3:20])[C:10]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=O.[OH-].[K+]>C(O)C.O>[CH3:3][NH:5][C:6]1[S:7][CH:8]=[C:9]([CH3:20])[C:10]=1[C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: CCC(=O)Nc1scc(C)c1C(=O)c1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CNc1scc(C)c1C(=O)c1ccccc1Cl
Temperature: 95 °C

Procedure:
To a solution of 29.6 g of 2-(N-methylacetylamino)-3-(o-chlorobenzoyl)-4-methylthiophene in 592 ml of ethanol, is added 6.97 g of potassium hydroxide in 190 ml of water. The mixture is heated at 95°C for 1 hour, evaporated under reduced pressure to a residue. Water is added to the residue and extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate, then evaporated under reduced pressure to give an oil. The residual oil is chromatographed on silica gel, using chloroform as an eluent to give 2-methylamino-3-(o-chlorobenzoyl)-4-methylthiophene as crystals having a melting point of 132° - 134°C (after recrystallization from ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:11][CH:10]2[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:15]([NH:22][CH2:23][CH2:24][OH:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1>[CH2:15]([N:22]([CH2:23][CH2:24][OH:25])[C:12]([CH:10]1[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:11]1)=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)C1OC1c1ccc(Cl)c(Cl)c1
Reactant: OCCNCc1ccccc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(C1OC1c1ccc(Cl)c(Cl)c1)N(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
To a mixed solution of (2RS,3SR)-3-(3,4-dichlorophenyl)oxirane-2-carboxylic acid (50.0 g) and 2-(benzylamino)ethanol (38.9 g) in THF (700 mL)-methanol (100 mL) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (71.2 g), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, the residue was diluted with ethyl acetate, and the mixture was washed with saturated aqueous sodium hydrogen carbonate, water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (42.2 g).
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[C:35]([CH:40]([F:42])[F:41])[CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[F:42][CH:40]([F:41])[C:35]1[CH:34]=[C:33]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH3:32])[CH:38]=[CH:37][C:36]=1[F:39]
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CN(C[C@@H](N)c1ccc(F)c(C(F)F)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(F)c(C(F)F)c1

Procedure:
Compound 51 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(3-difluoromethyl-4-fluoro-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [391 (M+H)].
Reaction SMILES: [S:1]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH:20]=O)=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:22]([C:25]1([NH2:38])[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)[CH:23]=[CH2:24].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:22]([C:25]1([NH:38][CH2:20][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]([S:1]([C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=3)(=[O:3])=[O:2])[CH:12]=2)[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)[CH:23]=[CH2:24]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)c3ccccc32)cc1
Reactant: C=CCC1(N)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C=CCC1(NCc2cn(S(=O)(=O)c3ccc(C)cc3)c3ccccc23)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Yield: 60.1 %

Procedure:
To a solution of 1-tosyl-1H-indole-3-carbaldehyde [50562-79-3] (1.90 g, 6.35 mmol) in 1,2-dichloroethane (30 mL) were added tert-butyl 4-allyl-4-aminopiperidine-1-carboxylate [741687-08-1] (1.52 g, 6.35 mmol) and acetic acid (381 mg, 6.35 mmol). The resulting solution was heated at 60° C. for 3 h. Then NaBH(OAc)3 was added and the reaction mixture was heated at 60° C. for 38 h. The mixture was cooled to rt, saturated NaHCO3 solution (30 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water and brine, then dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude mixture was purified by flash-column chromatography over silicagel (eluent: 20% ethyl acetate/hexane) to yield the title compound (2.0 g, 60%). [LCMS RtE=0.34 min, [M+H]+=524.0]