Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]1>CCCCO>[Br:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24]2)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ccc(F)c(Cl)c1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4ccc(F)c(Cl)c4)c23)C1
Temperature: 155 °C
Reaction time: 16 h
Yield: 31.2 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-chloro-4-fluorobenzamide (240 mg, 0.621 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (373 mg, 1.86 mmol) in n-BuOH (3 mL) was stirred at 155° C. for 16 hours in a sealed tube. The reaction was then cooled to room temperature and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Gilson) to provide (R)-tert-butyl 1-(5-bromo-3-(3-chloro-4-fluorobenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (110 mg, 31% yield).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1.[CH2:24]([NH:27][CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26]>CN(C)C=O>[CH2:24]([N:27]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1)[CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26]
Reactant: CCCNCCC
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccccc2C1=O
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)no1
Yield: 92.5 %

Procedure:
3.3 g (10 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred with 5.06 g (50 mmol) of dipropylamine in 20 ml of N,N-dimethylformamide at room temperature for 4 hours. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. There were obtained 3.65 g (92%) of 3-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 130°-132°, which was converted into the hydrochloride of m.p. 213°-215°.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[C:8]=2[O:11][CH3:12])[C:3]1=[O:14].[Na].[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)([O-:18])=[O:17].O>CN(C)C=O>[CH3:12][O:11][C:8]1[C:7]([CH3:13])=[CH:6][CH:5]=[C:4]2[C:9]=1[CH2:10][CH:2]([O:25][C:22]1[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=1)[C:3]2=[O:14]
Reactant: COc1c(C)ccc2c1CC(Br)C2=O
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C)ccc2c1CC(Oc1ccc([N+](=O)[O-])cc1)C2=O
Temperature: 26.5 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
To a stirred solution of 2-Bromo-4-methoxy-5-methyl-indan-1-one (2.0 gm, 0.0078 mole) in Dimethylformamide (15 ml), added Sodium salt of 4-Nitrophenol (1.27 gm, 0.0078 mole) at 10-15° C. After 2 hours stirring at 25-28° C., reaction mixture was poured into water (50 ml). The separated solid was filtered, washed with hexane and dried under vacuum to give 1.8 gm of desired product as a solid
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=[O:13])[O:12][C@H:10]([CH3:11])[CH2:9]1.C([O-])([O-])=O.[K+].[K+]>>[C:2]1([NH:1][C@@H:10]([CH3:11])[CH2:9][C:8]([OH:13])=[O:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: C[C@@H]1CC(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C[C@@H](CC(=O)O)Nc1ccccc1
Temperature: 80.8499984741211 °C

Procedure:
A jacketed 30-L 3-neck bottom-valve cylindrical reactor equipped with overhead stirrer, reflux condenser, addition funnel, and N2 inlet was flushed with N2. Water (8.7 L) was charged followed by aniline (423 L, 4.9 mol). Stirring was initiated and the internal temperature set for 80° C. After the internal temperature reached 77° C., (R)-β-butyrolactone was charged over 1.5 h via addition funnel. The internal temperature was maintained between 80-81.7° C. during the course of addition. Once addition was completed, reaction was cooled to 20° C. over 1 h. K2CO3 (250 g, 1.8 mol, 0.75 equiv) was charged as a solid, and the aqueous pH was determined to be 10. The aqueous phase was extracted with MTBE (3×2 L), and the extracts were discarded. After adjusting the pH of the aqueous phase to 5 with 6 N HCl (225 mL), it was extracted with EtOAc (3×2 L). After each extraction, the pH was checked and was readjusted to 5 with 6 N HCl as necessary. The combined EtOAc extracts were washed with saturated brine (2 L), dried with MgSO4, and concentrated via rotary evaporation to produce a pink oil. Recovery: 300 g (72%). Enantiomeric excess was determined by chiral HPLC to be 94%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[CH:18])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2].I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[C:18][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCSc1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Reactant: Ic1ccccc1
Product: Cc1cc(SCC#Cc2ccccc2)ccc1OCC(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described in example 5B], (2-methyl-4-prop-2-ynylsulfanyl-phenoxy)-acetic acid tert-butyl ester (example 5A]) and iodo-benzene gave the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[NH:11][N:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25]Cl>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:28])([CH3:27])[CH3:20])[C:12]([C:14]([F:16])([F:17])[F:15])=[N:11][N:10]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1cc(C)cc(-c2n[nH]c(C(F)(F)F)n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(-c2nnc(C(F)(F)F)n2COCC[Si](C)(C)C)c1
Reaction time: 0.5 h

Procedure:
A stirred solution of the product from step (ix) (17.46 g) in dry N,N-dimethylformamide (300 ml) was treated with 60% dispersion of sodium hydride (3.22 g) in portions at room temperature under nitrogen. After the initial effervescence had subsided the resultant orange oil was stirred for a further 30 min before being treated with 2-(trimethylsilyl)ethoxymethyl chloride (14.3 ml) dropwise giving a pale yellow suspension which was further stirred for 30 min. The mixture was carefully poured onto water (700 ml) and extracted with ethyl acetate (3×250 ml). The combined organic extracts were further washed with water (3×250 ml) and saturated brine (250 ml) before collecting, drying over magnesium sulphate and evapoaration of the solvent under reduced pressure to give the subtitle product as a yellow oil. Yield: 26.1 g. This was not purified but used directly in the next step.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1.[N:20]1([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[CH:30]([C:34](O)=[O:35])[CH2:29][CH2:28]3)[CH:24]=[N:23][N:22]=[N:21]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.ClC(Cl)C>[O:1]=[C:2]1[CH2:7][N:6]([C:34]([CH:30]2[C:31]3[C:27](=[CH:26][C:25]([N:20]4[CH:24]=[N:23][N:22]=[N:21]4)=[CH:33][CH:32]=3)[CH2:28][CH2:29]2)=[O:35])[CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1
Reactant: O=C(O)C1CCc2cc(-n3cnnn3)ccc21
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1=O)C2
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: N#Cc1ccc2c(c1)CCC(N1CCN(C(=O)C3CCc4cc(-n5cnnn5)ccc43)CC1=O)C2

Procedure:
A mixture of 6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (40 mg, 0.16 mmol) (20 mg, 0.078 mmol), 5-(1H-tetrazol-1-yl)-2,3-dihydro-1H-indene-1-carboxylic acid (18 mg, 0.078 mmol), DMAP (14 mg, 0.12 mmol), and EDC (23 mg, 0.12 mmol) was stirred in dichloroethane (2 mL) for 2 hours. The solvent was removed under vacuum, and the residue was redissolved in methanol, and purified by reverse phase HPLC to give the title product. LC-MS (IE, m/z): 468 [M+1]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.Cl[Si](C)(C)[CH3:14]>CO>[NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:14])=[O:8])=[CH:10][CH:11]=1
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 114.5 %

Procedure:
The mixture of 4-(aminomethyl)benzoic acid (1.0 g, 6.61 mmol) and chlorotrimethylsilane (3.35 mL, 26.44 mmol) was stirred for 30 minutes at room temperature, and anhydrous methanol (20 mL) was added thereto. The reaction mixture was stirred for 48 hours and then vacuum distilled to give methyl 4-(aminomethyl)benzoate (1.25 g, 94%). 1H NMR (500 MHz, D2O) δ 8.02 (d, 2H, J=6.4 Hz), 7.51 (d, 2H, J=8.2 Hz), 4.20 (s, 2H), 3.88 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=1.[NH2:18][C:19]1[N:20]=[CH:21][NH:22][C:23]=1[C:24]#[N:25]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[CH:21]=[N:22][C:23]([C:24]#[N:25])=[C:19]3[N:18]=2)=[CH:5][CH:4]=1
Reactant: N#Cc1[nH]cnc1N
Reactant: COc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Product: COc1ccc(-c2cc(C(F)(F)F)n3cnc(C#N)c3n2)cc1
Yield: 39.3 %

Procedure:
Reaction of 1-(4-methoxy-phenyl)-4,4,4-trifluoro-butane-1,3-dione (246 mg, 1.0 mmol), prepared from commercially available 4-methoxy-acetophenone according to general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (125 mg, 39%). MS (ISP) 319.1 [(M+H)+]; mp 192° C.
Reaction SMILES: [CH:1]1([NH:11][C:12](=[O:14])[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Br.[O:16]=O>C(O)(=O)C.C(C(C)=O)C(C)C>[O:16]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]([NH:11][C:12](=[O:14])[CH3:13])[CH2:2][CH2:3]1
Reactant: O=O
Reactant: CC(=O)NC1CCCc2ccccc21
Agent: Br
Solvent: CC(=O)CC(C)C
Solvent: CC(=O)O
Product: CC(=O)NC1CCC(=O)c2ccccc21
Temperature: 62 °C
Reaction time: 17 h

Procedure:
A mixture of N-(1,2,3,4-tetrahydro-1-naphthyl)-acetamide (30 g), cobaltous acetate tetrahydrate (13.12 g), 30% hydrobromic acid in acetic acid (4.28 g), methyl isobutyl ketone (400 ml) and acetic acid (100 ml) is stirred and oxygen is introduced via a capillary gas dispersion tube. The mixture is heated gradually to 62° C. and the reaction is run 17 hours at 62° C. The reaction mixture is then cooled, the oxygen flow terminated and water (500 ml) is added. The mixture is extracted with chloroform (500 ml and 2×300 ml), the chloroform extracts are combined, washed with saturated sodium chloride solution and evaporated to dryness in vacuo. Benzene (200 ml) is added to the residue, the solution is filtered and the filtrate evaporated to dryness in vacuo to afford 40.3 g (damp) of the title compound.
Reaction SMILES: [CH2:1]([NH:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10])[CH2:2][CH3:3].Cl.Cl[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.C1(O)C=CC=CC=1>ClCCl>[CH2:1]([N:4]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10])[CH2:2][CH3:3]
Reactant: CCCNN1CCCC1=O
Reactant: Clc1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: Oc1ccccc1
Product: CCCN(c1ccncc1)N1CCCC1=O
Temperature: 143 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
A slurry consisting of 1-(propylamino)-2-pyrrolidinone (7.96 g), 4-chloropyridine hydrochloride (6.31 g) and phenol (20.9 g) was heated in a 143° C. oil bath under nitrogen. After 30 min., the resulting solution was treated with additional 4-chloropyridine hydrochloride (6.30 g) and heated for an additional 30 minutes. The mixture was cooled to room temperature and diluted with dichloromethane. The organic layer was washed with dilute aqueous sodium bicarbonate and the combined aqueous layers back-extracted with dichloromethane and ether. The combined organic layers were washed with brine and dried (K2CO3). Filtration, concentration, and purification via flash column chromatography (silica gel, 10% MeOH/DCM) and preparative HPLC afforded 3.65 g (30%) of 1-(propyl-4-pyridinylamino)-2-pyrrolidinone as an oil. The oxalate was prepared with 1.0 eq. oxalic acid in absolute ethanol, m.p. 194°-195.5° C.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:8]([CH2:10][OH:11])[N:9]=1)(=O)C.[ClH:19]>C(O)C>[ClH:19].[ClH:19].[NH2:4][C:5]1[S:6][C:7]([S:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:8]([CH2:10][OH:11])[N:9]=1
Reactant: CC(=O)Nc1nc(CO)c(Sc2ccncc2)s1
Agent: Cl
Solvent: CCO
Product: Nc1nc(CO)c(Sc2ccncc2)s1
Yield: 75.3 %

Procedure:
A mixture of 2-acetylamino-4-hydroxymethyl-5-(4-pyridylthio)thiazole (3.0 g) in a mixture of concentrated hydrochloric acid (8 ml) and ethanol (100 ml) was refluxed for 2.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was triturated with acetone. The precipitates were collected by filtration, washed with isopropyl ether and were recrystallized from a mixture of ethanol and isopropyl ether to give 2-amino-4-hydroxymethy-5-(4-pyridylthio)thiazole dihydrochloride (2.5 g, yield: 75.3%).
Reaction SMILES: [P:1]([O:13][CH2:14][CH2:15][NH:16][CH2:17][CH3:18])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O=[CH:20][CH2:21][C@@H:22]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:34][C:33]=1[S:42]([C:45]([F:48])([F:47])[F:46])(=[O:44])=[O:43])[CH2:23][S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl.C(Cl)Cl>[P:1]([O:13][CH2:14][CH2:15][N:16]([CH2:17][CH3:18])[CH2:20][CH2:21][C@@H:22]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](=[O:39])(=[O:40])[NH2:41])=[CH:34][C:33]=1[S:42]([C:45]([F:48])([F:46])[F:47])(=[O:43])=[O:44])[CH2:23][S:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:2]
Reactant: CCNCCOP(=O)(OC(C)(C)C)OC(C)(C)C
Reactant: NS(=O)(=O)c1ccc(N[C@H](CC=O)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCN(CCOP(=O)(OC(C)(C)C)OC(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Reaction time: 4 h
Yield: 50.4 %

Procedure:
A solution of di-tert-butyl 2-(ethylamino)ethyl phosphate (INTERMEDIATE 49, 455 mg, 1.62 mmol) in 1,2-dichloroethane (0.5 ml) at r.t was added to a solution (R)-4-(4-oxo-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 45, 0.78 g, 1.62 mmol) and 1,2-dichloroethane (10.0 ml). The resulting reaction mixture was stirred for 15 minutes at r.t and solid sodium triacetoxyborohydride (0.514 g, 2.42 mmol) was added. The resulting mixture was stirred at r.t for 4 hours. A solution of NaOH (aq., 0.5 N, 40 ml) and DCM (20 ml) were added to the reaction mixture. After stirring for 15 min at r.t, the layers were separated. After separation, the organic layer was washed with saturated NaHCO3, brine, dried (Na2SO4), and concentrated in vacuo. The concentrate was purified by column chromatography (ISCO, silica gel, eluting with 0→100% EtOAc/hexanes) to give the title compound (610 mg, yield: 50%).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:23]1[CH:32]=[N:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>C(#N)C>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:31]=[CH:32][C:23]=1[O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:14][CH:15]=1
Reactant: CCOC(=O)C(C)Oc1ccc(O)cc1
Reactant: Clc1cnc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)Oc1ccc(Oc2cnc3ccccc3n2)cc1
Yield: 103.6 %

Procedure:
In 50 ml of acetonitrile, 2.1 g of ethyl 2-(4-hydroxyphenoxy)propionate and 1.66 g of potassium carbonate were added and the mixture was refluxed for 1 hour and then, 1.65 g of 2-chloroquinoxaline was added and the mixture was further refluxed for 30 hours. After cooling, the precipitated inorganic salt was separated by a filtration. Acetone was distilled off from the filtrate under a reduced pressure to obtain 3.5 g of the oily residue. The residue was purified by a silica gel column chromatography (developer solvent: chloroform) to obtain 2.6 g (yield 77%) of the object compound.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]2[C@H:13]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[C@@H:14]([O:17][C@@H:18]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=3)[CH3:19])[O:15][CH2:16][C@@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[F:33][C:30]([F:31])([F:32])[C:22]1[CH:21]=[C:20]([C@H:18]([O:17][C@H:14]2[O:15][CH2:16][C@@H:10]3[CH2:9][NH:8][CH2:12][C@H:11]3[C@@H:13]2[C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)[CH3:19])[CH:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:23]=1
Reactant: C[C@@H](O[C@H]1OC[C@@H]2CN(Cc3ccccc3)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H](O[C@H]1OC[C@@H]2CNC[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
(3aS,6R,7R,7aR)-2-Benzyl-6-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluorophenyl)octahydropyrano[3,4-c]pyrrole (example 1: 1.60 g, 2.82 mmol) was combined 0.75 g 20% Pd(OH)2 and suspended in 30 mL ethanol in a Parr apparatus. The reaction vessel was shaken vigorously under 45 psi hydrogen for 4 hr. The reaction mixture was filtered through a pad of celite and rinsed copiously with methanol. The volatiles were removed in vacuo and the crude residue was purified on silica gel and eluted with a combination of methanol/DCM (1-10% methanol/DCM linear gradient) which furnished the title compound. 1H-NMR (CD3OD): δ 1.38 (d, 3H, J=7.0 Hz), 1.90-2.10 (m, 2H), 2.47 (dd, 1H, J=10.5, 10.5 Hz), 2.56 (dd, 1H, J=10.5, 10.5 Hz), 2.65 (dd, 1H, J=8.0, 11.0 Hz), 2.75 (dd, 1H, J=6.5, 10.5 Hz), 3.11 (dd, 1H, J=6.5, 10.0 Hz), 3.56 (dd, 1H, J=10.5, 10.5 Hz), 4.24 (dd, 1H, J=4.0, 11.0 Hz), 4.37 (d, 1H, J=8.0 Hz), 5.07 (q, 1H, J=6.5 Hz), 6.96 (dd, 2H, J=9.0, 9.0 Hz), 7.16 (dd, 2H, J=5.5, 9.0 Hz), 7.20-7.30 (m, 5H), 7.38 (s, 2H), 7.75 (s, 1H) ppm. MS: (MH)+478.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12][CH2:13][CH2:14][OH:15])[N:11]=[C:4]2[N:3]=1.[CH3:16][N:17]([CH3:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23](O)=[CH:22][CH:21]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12][CH2:13][CH2:14][O:15][C:23]3[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:17]([CH3:16])[CH3:27])=[CH:21][CH:22]=3)[N:11]=[C:4]2[N:3]=1
Reactant: Cc1cc(C)n2nc(SCCO)nc2n1
Reactant: CN(C)CCc1ccc(O)cc1
Product: Cc1cc(C)n2nc(SCCOc3ccc(CCN(C)C)cc3)nc2n1
Yield: 48 %

Procedure:
The title compound was prepared according to the experimentals described for Example 31 above from of 2-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl sulfanyl)ethan-1-ol and N,N-dimethyltyramine in 48% yield; EM (calc.): 371.2; MS (ESI) m/e: 372.2 (M+H)+.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.S(C1C=CC(C)=CC=1)(O)(=O)=O.C1(=O)[N:27]([C:28]([N:45]2C(=O)C3=CC=CC=C3C2=O)([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[O:29][O:30][O:31][O:32][OH:33])C(=O)C2=CC=CC=C12.O.NN>C(O)C>[NH2:45][C:28]([NH2:27])([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[O:29][O:30][O:31][O:32][OH:33]
Reactant: CCCCCCCCCCCC(OOOOO)(N1C(=O)c2ccccc2C1=O)N1C(=O)c2ccccc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCC(N)(N)OOOOO
Temperature: 25 °C
Reaction time: 3 h
Yield: 173.6 %

Procedure:
A solution of diphthalimide (Step 4:60 g), hydrazine hydrate (15 g) and ethanol (500 mL) is heated at 100° C. with stirring for 3 hrs. The reaction mixture is cooled to room temperature and filtered. The solid is washed with cold ethanol. The combined filtrate is concentrated under vacuum in a rotary evaporator to afford 33 g of yellow oil.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])O)[OH:4].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[CH2:11]1[O:12][CH:5]([CH:3]([OH:4])[CH2:2][OH:1])[C@@H:7]([OH:8])[CH:9]1[OH:10]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: OCC(O)C1OCC(O)[C@@H]1O

Procedure:
364 g sorbitol (2 moles), 600 ml toluene and 1 g concentrated sulfuric acid were placed into the equipment described above. The reaction mixture was heated to reflux temperature and 40 ml water (2.2 moles) was collected by azeotropic distillation within 6 hours. The toluene phase was decanted and the sorbitan formed was dissolved in 300 ml DMSO and placed into the reactor together with 3 ml 50% sodium hydroxide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([S:14][CH2:15][CH3:16])[N:11]=[C:10]([NH2:17])[CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:19][CH:20](OC)OC>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([S:14][CH2:15][CH3:16])[N:11]3[CH:19]=[CH:20][N:17]=[C:10]3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCSc1nc(N)cc(-c2ccc(Br)cc2)n1
Reactant: COC(CBr)OC
Solvent: C1CCOC1
Solvent: O
Product: CCSc1nc(-c2ccc(Br)cc2)cc2nccn12
Reaction time: 24 h
Yield: 77.3 %

Procedure:
To a slurry of 6-(4-bromophenyl)-2-(ethylthio)pyrimidin-4-amine (35.00 g, 112.8 mmol) in 20 mL of THF and 200 mL of water was added 2-bromo-1,1-dimethoxyethane (38.14 g, 225.7 mmol) at ambient temperature. The reaction flask was fitted with a condenser and the mixture was allowed to proceed with stirring at reflux overnight. After 24 hours, the reaction mixture was cooled and poured into 400 mL of water. The solid was collected by vacuum filtration. The wet solid was suspended in 500 mL of aqueous saturated sodium bicarbonate and gas evolution was observed. The mixture was stirred at ambient temperature for 10 minutes before it was extracted with DCM (8×500 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was then dried under high vacuum overnight to afford 7-(4-bromophenyl)-5-(ethylthio)imidazo[1,2-c]pyrimidine (31 g, 87.18 mmol, 77.27% yield). MS (apci) m/z=334.0 (M+H).