Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23]Cl.CN(C)C=O>O>[Cl:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(O)cc2N1
Reactant: ClC/C=C\CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2ccc(OC/C=C\CCl)cc2N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.0 g of 7-hydroxy-3,4-dihydro-1H-quinolin-2-one, 1.7 g of potassium carbonate, 3.2 ml of cis-1,4-dichloro-2-butene and 50 ml of dimethylformamide was stirred at room temperature overnight. Water was added to the reaction solution, which was then extracted with ethyl acetate and, after washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), and 7-(4-chloro-(Z)-2-butenyloxy)-3,4-dihydro-1H-quinolin-2-one (1.3 g) was obtained in the form of a white powder.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C@:10]([OH:16])([CH3:15])[C:11]([F:14])([F:13])[F:12])=[C:4]([Cl:18])[C:3]=1[Cl:19].[SH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1.CCOC(C)=O.O>CN(C=O)C>[C:25]([C:24]1[CH:28]=[CH:29][C:21]([S:20][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])[C@:10]([OH:16])([CH3:15])[C:11]([F:14])([F:13])[F:12])=[C:4]([Cl:18])[C:3]=2[Cl:19])=[CH:22][CH:23]=1)([OH:27])=[O:26]
Reactant: C[C@@](O)(C(=O)Nc1ccc(I)c(Cl)c1Cl)C(F)(F)F
Reactant: O=C(O)c1ccc(S)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@](O)(C(=O)Nc1ccc(Sc2ccc(C(=O)O)cc2)c(Cl)c1Cl)C(F)(F)F
Temperature: 25 °C
Yield: 82.3 %

Procedure:
(R)-N-[4-Iodo-2,3-dichlorophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 4) (4.58 g, 10.7 mmol) was heated in DMF (30 ml) with stirring under argon for 4 hours with 4-mercaptobenzoic acid (2.31 g, 14.98 mmol) and cuprous oxide (765 mg) and allowed to cool to room temp. EtOAc and water were added, and the reaction mixture was filtered through a bed of diatomaceous earth, and washed with EtOAc/water. The organic layer was separated, washed with water, brine, dried and evaporated down to dryness. The resulting solid was purified using a Mega Bond Elut column, eluting with 5-50% EtOAc/isohexane to give the title compound (4.0 g) as a pale pink solid. NMR: 1.6 (s, 3H), 7.3 (d, 2H), 7.5 (d, 1H), 7.9 (m, 3H), 8.0 (d, 1H), 9.9 (s, 1H), 13.0 (s, 1H); m/z: 452.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[CH3:42][O:43][C:44]1[CH:56]=[CH:55][C:47](CN2C=CC(N)=N2)=[CH:46][CH:45]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:47]3[CH:55]=[CH:56][C:44]([O:43][CH3:42])=[CH:45][CH:46]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: COc1ccc(Cn2ccc(N)n2)cc1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COc1ccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.4 %

Procedure:
To a solution containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 100 mg, 0.30 mmol) in methylene chloride (20 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (181 μL, 0.36 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (70 μL, 0.61 mmol) was added to the solution at 0° C. After 1 h, the crude 1-(4-methoxy-benzyl)-1H-pyrazol-3-ylamine (0.42 mmol based on theory) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(4-methoxy-benzyl)-1H-pyrazol-3-yl]-propionamide (92 mg, 59%) as a white solid: ESI-LRMS m/e calcd for C26H30ClN3O4S [M+] 515.2, found 516.4 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.03-1.21 (m, 2H, CH2), 1.41-1.91 (m, 8H, 4×CH2), 2.10-2.26 (m, 1H, CH), 3.24 (s, 3H, SO2CH3), 3.54 (t, J=7.6 Hz, 1H, CH), 3.78 (s, 3H, OCH3), 5.05 (s, 2H, NCH2), 6.66 (d, J=2.3 Hz, 1H, Ar), 6.83 (d, Jo=8.5 Hz, 2H, Ar), 7.09 (d, Jo=8.5 Hz, 2H, Ar), 7.25 (d, J=2.3 Hz, 1H, Ar), 7.43 (dd, Jo=8.2, Jm=1.7 Hz, 1H, Ar), 7.57 (d, Jm=1.7 Hz, 1H, Ar), 8.05 (d, Jo=8.2 Hz, 1H, Ar), 8.30 (s, 1H, NH).
Reaction SMILES: [OH-].[Li+].C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:21](=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([S:30][CH3:31])[CH:25]=4)[N:23]=2)[N:20]=[CH:19][CH:18]=[CH:17]3)[CH2:10][CH2:9]1)=[O:7])C.CO>O.C1COCC1>[CH3:31][S:30][C:26]1[CH:25]=[C:24]([C:22]2[N:23]=[C:14]([CH:11]3[CH2:10][CH2:9][CH:8]([C:6]([OH:7])=[O:5])[CH2:13][CH2:12]3)[CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1CCC(c2cc3cccnc3c(-c3cccc(SC)c3)n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CSc1cccc(-c2nc(C3CCC(C(=O)O)CC3)cc3cccnc23)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Lithium hydroxide (168 mg, 1.76 mmol) in water (1.7 ml) is added to a solution of 4-[8-(3-methylsulfanyl-phenyl)-[1,7]naphthyridin-6-yl]-cyclohexanecarboxylic acid ethyl ester (650 mg, 1.6 mmol) in THF (3.2 ml) under argon. Methanol is added to maintain solution (4 ml) and the mixture is stirred at room temperature for 5 hours. The mixture is evaporated to dryness then partitioned between ethyl acetate and water. The aqueous layer is acidified to pH 2 then extracted into ethylacetate and dried over magnesium sulfate, Evaporation gives a green gum which is reevaporated from methanol then DCM/diethylether to give a yellow/green foam. The foam is triturated with 3:1 hexane:diethyl ether, 2:1 hexane:diethylether, ethylacetate/hexane/ether mixtures and finally 5:1 diethylether:ethanol to yield an off-white solid. This is then recrystallised from ethanol to yield the title compound. M.p 177.6-178.2° C., MS (AP+) 379.05
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]([N+:15]([O-])=O)=[C:11](/[CH:18]=[CH:19]/[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=2)[N:10]([CH3:31])[C:9]1=[O:32])(=[O:3])[CH3:2].[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)=O.CC(=O)OCC.O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[NH:15][C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=3)=[CH:18][C:11]=2[N:10]([CH3:31])[C:9]1=[O:32])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCn1c(=O)c([N+](=O)[O-])c(/C=C/c2cccc(OC(F)(F)F)c2)n(C)c1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=CO
Product: CC(=O)OCCCn1c(=O)c2[nH]c(-c3cccc(OC(F)(F)F)c3)cc2n(C)c1=O
Temperature: 140 °C
Yield: 43.1 %

Procedure:
To a solution of (E)-3-(3-methyl-5-nitro-2,6-dioxo-4-(3-(trifluoromethoxy)styryl)-2,3-dihydro pyrimidin-1(6H)-yl)propyl acetate (50 mg, 0.109 mmol) in HCOOH (3 mL) was added Na2S2O4 (114.0 mg, 0.655 mmol). The reaction was heated at 140° C. for 5 h, cooled to RT then diluted with EA (20 mL) and water (20 mL). The organic layer was dried over Na2SO4 and concentrated to give 3-(1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (20 mg, 43.1% yield) as an oil. LCMS: MH+ 426 and TR=1.597 min. Used without further purification.
Reaction SMILES: CO[CH:3](OC)[CH:4]([CH3:27])[N:5]1[C:9]2[CH:10]=[C:11]([O:14][C:15]3[CH:20]=[C:19]([F:21])[C:18]([C:22]([F:25])([F:24])[F:23])=[C:17]([Cl:26])[CH:16]=3)[CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1.OS(O)(=O)=O.Cl.[NH2:36][OH:37]>C(O)(=O)C.O.N1C=CC=CC=1.C(O)C>[Cl:26][C:17]1[CH:16]=[C:15]([O:14][C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[N:6][N:5]([CH:4]([CH3:27])[CH:3]=[N:36][OH:37])[C:9]=3[CH:10]=2)[CH:20]=[C:19]([F:21])[C:18]=1[C:22]([F:25])([F:24])[F:23]
Reactant: COC(OC)C(C)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Reactant: NO
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC(C=NO)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A solution of 6-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl)oxy]-α-methyl-1H-benzotriazole-1-acetaldehyde dimethyl acetal (23.0 g, 0.053 mole) in acetic acid is treated with 54 ml of 2.5N H2SO4 and stirred at 70° C. for 12 hours. A 15 ml portion of the reaction solution is diluted to a total volume of 100 ml with water, the resulting precipitate is separated, washed with water, treated with a solution of hydroxylamine hydrochloride (1.0 g, 0.014 mole) in pyridine and ethanol, heated at 85° C. for several hours, cooled and concentrated in vacuo to give a solid residue. Recrystallization from aqueous ethanol, ethanol and toluene gives the title compound mp 148°-151° C., identified by elemental and NMR analyses.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:16].O>ClCCl.C(OCC)(=O)C>[N:1]1([C:15]([O:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:16])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: C1CSCCN1
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCSCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7.7 g (74.4 mmol) of thiomorpholine were initially charged in 100 ml of dichloromethane and, while cooling with an ice bath, admixed with 20.7 ml (15.1 g, 148.8 mmol) of triethylamine. 10.0 g (49.6 mmol) of 4-nitrophenyl chloroformate were added in portions. The reaction mixture was stirred at RT for one hour, and admixed with water and ethyl acetate. The organic phase was removed, washed with 1 N hydrochloric acid and saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. Yield: 13.2 g (99% of theory)
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:17]([S:18][C:19]2[CH:24]=[C:23]3[O:25][CH2:26][O:27][C:22]3=[CH:21][C:20]=2I)=[N:16][C:10]2[C:11]([NH2:15])=[N:12][CH:13]=[N:14][C:9]1=2)[CH3:3].C([N:36]1[CH:40]=[CH:39][CH2:38][CH2:37]1)(OC(C)(C)C)=O.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.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>[NH:36]1[CH2:40][CH:39]=[CH:38][CH:37]1[C:20]1[C:19]([S:18][C:17]2[N:8]([CH2:7][CH2:6][CH2:5][NH:4][CH:2]([CH3:3])[CH3:1])[C:9]3[C:10]([N:16]=2)=[C:11]([NH2:15])[N:12]=[CH:13][N:14]=3)=[CH:24][C:23]2[O:25][CH2:26][O:27][C:22]=2[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1C=CCC1
Reactant: CC(C)NCCCn1c(Sc2cc3c(cc2I)OCO3)nc2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)NCCCn1c(Sc2cc3c(cc2C2C=CCN2)OCO3)nc2c(N)ncnc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 22.6 %

Procedure:
A solution of PU-H71 (30 mg, 0.0585 mmol) and N-Boc-2,3-dihydro-1H-pyrrole (19.8 mg, 20.2 μL, 0.117 mmol) in NMP (1.5 mL) was evacuated and back filled with nitrogen. This was repeated four times, then DIEA (15.1 mg, 21 μL, 0.117 mmol) and Pd(PPh3)4 (13.5 mg, 0.0117 mmol) were added and the reaction mixture was heated under nitrogen at 100° C. for 20 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH2Cl2:MeOH—NH3 (7N), 15:1) and the resulting residue was dissolved into 2 mL of CH2Cl2:TFA (4:1) and stirred for 1 h. Solvent was removed under reduced pressure and the resulting residue was purified by preparatory TLC (CH2Cl2:MeOH—NH3 (7N), 10:1) to give 6.0 mg (23%) of DZ3-141. 1H NMR (500 MHz, CDCl3/MeOH-d4) δ 8.19 (s, 1H), 6.98 (s, 2H), 6.04 (m, 1H), 6.01 (s, 2H), 5.74 (m, 1H), 5.62 (d, J=2.0 Hz, 1H), 4.31 (t, J=6.9 Hz, 2H), 3.81-3.88 (m, 1H), 3.89-3.95 (m, 1H), 2.87 (septet, J=6.3 Hz, 1H), 2.68 (t, J=6.7 Hz, 2H), 2.14 (m, 2H), 1.15 (d, J=6.3 Hz, 6H); HRMS (ESI) m/z [M+H]+ calcd. for C22H28N7O2S, 454.2025; found. 454.2046; HPLC: method A Rt=5.27, method B Rt=2.72.
Reaction SMILES: [H-].[K+].[CH:3]1([CH2:6][N:7]2[CH2:16][CH2:15][C:14]34[C:17]5[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:18]=5[O:19][CH:13]3[CH:12]3[CH2:26][CH2:27][C:9]4([CH:10]([CH2:28][OH:29])[CH2:11]3)[C:8]2=[O:30])[CH2:5][CH2:4]1.C1(CN2[CH2:44][CH2:43][C:42]34C5C=CC=C(OC)C=5OC3[CH:40]3[CH2:54][CH2:55][C:37]4([CH:38](C(OC)=O)[CH2:39]3)C2=O)CC1.C(Br)C=CC1C=CC=CC=1>O1CCCC1.C(Cl)Cl.O.CCCCCC>[CH2:44]([O:29][CH2:28][CH:10]1[C:9]23[CH2:27][CH2:26][CH:12]([CH:13]4[O:19][C:18]5[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:17]=5[C:14]42[CH2:15][CH2:16][N:7]([CH2:6][CH:3]2[CH2:5][CH2:4]2)[C:8]3=[O:30])[CH2:11]1)[CH:43]=[CH:42][C:37]1[CH:55]=[CH:54][CH:40]=[CH:39][CH:38]=1
Reactant: COc1cccc2c1OC1C3CCC4(C(=O)N(CC5CC5)CCC214)C(CO)C3
Reactant: COC(=O)C1CC2CCC13C(=O)N(CC1CC1)CCC31c3cccc(OC)c3OC21
Agent: BrCC=Cc1ccccc1
Agent: [H-]
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2c1OC1C3CCC4(C(=O)N(CC5CC5)CCC214)C(COCC=Cc1ccccc1)C3

Procedure:
To a solution of 2.06 g of 35% potassium hydride in oil, prewashed with hexane, in 15 mL of tetrahydrofuran was added 0.70 g of 3-cyclopropylmethyl-5-hydroxymethyl-9-methoxy-1,2,5,6,7,7a-hexahydro-4a,7-ethanobenzofuro[3,2-e]isoquinolin-4(3H)-one (synthesized by following the procedures of Example 1, Method A, using 3-cyclopropylmethyl-9-methoxy-5-methoxycarbonyl-1,2,5,6,7,7a-hexahydro-4a,7-ethanobenzofuro[3,2-e]isoquinolin-4(3H)-one, U.S. Pat. No. 4,477,456, as the starting material) and the mixture was heated under reflux for 30 min. Cinnamyl bromide (2 mL) was added to the cooled mixture which was then heated under reflux for 20 minutes. Water and methylene chloride were added, and the aqueous layer was extracted with methylene chloride. Removal of the solvent from the dried organic phases gave 0.84 of 5-cinnamyloxymethyl-3-cyclopropylmethyl-9-methoxy-1,2,5,6,7,7a-hexahydro-4a,7-ethanobenzofuro[3,2-e]isoquinolin-4(3H)-one. NMR spectrum (δ in CDCl3): 7.1-7.4 (m, 5H); 6.8 (m, 2H); 6.7 (m, 1H); 6.6 (d, J=15 Hz, 1H); 6.3 (d/t, J=15/7 Hz, 1H), 4.4 (s, 1H); 5.8 (m, 2H); 3.9 (s, 3H); 0.5 (m, 2H); and 0.2 (m, 2H), among others.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1>C1(C)C=CC=CC=1>[C:1]1([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C1CCNC1
Reactant: O=C1CCCC1
Solvent: Cc1ccccc1
Product: C1=C(N2CCCC2)CCC1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of cyclopentanone (25.0 mL, 0.28 mol. 1.0 eq.) in toluene (100 mL), was added pyrrolidine (27.5 mL, 1.2 eq.). The reaction was equipped with a Dean-Stark and heated at reflux overnight. The reaction mixture was cooled to room temperature and concentrated to give the crude 1-cyclopent-1-enyl-pyrrolidine (45.8 g, >100%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:12]2[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=2[N:10]=1.[C:27]([C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1)#[CH:28].C(N(CC)CC)C>O1CCCC1.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)I>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:13]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:12]3[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:11]=3[N:10]=2)=[C:2]([C:28]#[C:27][C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[CH:7]=1
Reactant: C#Cc1ccc(C#N)cc1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3Br)n(CC3CCCCC3)c2cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1ccc(C#Cc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2CC2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 18 %

Procedure:
To a solution of 2-(2-bromo-4-chloro-phenyl)-1-cyclohexylmethyl-5,6-difluoro-1H-benzoimidazole (600 mg, 1.36 mmol) in tetrahydrofuran (20 ml) was added 4-ethynyl-benzonitrile (173.4 mg, 1.36 mmol; CAS Reg. No. 3032-92-6), bis(triphenylphosphine)palladium(ii) dichloride (57.2 mg, 0.08 mmol), copper iodide (7.7 mg, 0.04 mmol) and triethyl amine (20 ml) at 25° C. The resulting mixture was degassed and back-filled with nitrogen three times. It was then allowed to stir at 80° C. for 16 h. The reaction mixture was filtered through a bed of celite and solvents were removed under reduced pressure. The residue was purified by column chromatography over silica gel (10% ethyl acetate/n-hexane) to afford the desired compound as a yellow solid (18%). MS (Turbo Spray): m/z=485.6 (M+H).
Reaction SMILES: ClN1C(=O)CCC1=O.[C:9]([O:13][C:14](=[O:24])[NH:15][CH:16]([CH:21]=[N:22][OH:23])[CH2:17][CH:18]([CH3:20])[CH3:19])([CH3:12])([CH3:11])[CH3:10].[CH2:25]([Br:28])[C:26]#[CH:27].C(N(CC)CC)C>C(Cl)(Cl)Cl.O.N1C=CC=CC=1>[C:9]([O:13][C:14](=[O:24])[NH:15][CH:16]([C:21]1[CH:27]=[C:26]([CH2:25][Br:28])[O:23][N:22]=1)[CH2:17][CH:18]([CH3:20])[CH3:19])([CH3:11])([CH3:10])[CH3:12]
Reactant: CC(C)CC(C=NO)NC(=O)OC(C)(C)C
Reactant: C#CCBr
Agent: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)CC(NC(=O)OC(C)(C)C)c1cc(CBr)on1
Temperature: 45 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
N-Chlorosuccinimide (5.80 g, 43.4 mmol, 1.00 equivalents), [1-(hydroxyimino-methyl)-3-methyl-butyl]-carbamic acid tert-butyl ester (10.00 g, 43.4 mmol, 1.00 equivalents) and pyridine (0.70 mL) were stirred in chloroform (70 mL) at room temperature for 1 hour. Propargyl bromide (4.83 mL, 54.3 mmol, 1.25 equivalents) was added and the reaction was heated to 45° C. Triethylamine (6.35 mL, 45.6 mmol, 1.05 equivalents) was added dropwise over 20 minutes at 45° C. The reaction was stirred for an additional 1 hour, then it was diluted with water (200 mL) and extracted with dichloromethane (2×200 mL). The combined organic extracts were washed with saturated sodium bicarbonate (2×200 mL) and brine (200 mL). The organic portion was dried over sodium sulfate. Evaporation of the solvent gave a brown residue that was chromatographed by flash chromatography on silica gel to give the title compound as a white solid (6.48 g, 43%). MS (CI) m/z 247.0 (M−99)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B(O)O)[CH:6]=[CH:5][N:4]=1.Cl[C:13]1[N:22]=[CH:21][C:20]2[NH:19][CH2:18][CH:17]3[CH2:23][O:24][CH2:25][CH2:26][N:16]3[C:15]=2[N:14]=1>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:13]2[N:22]=[CH:21][C:20]3[NH:19][CH2:18][CH:17]4[CH2:23][O:24][CH2:25][CH2:26][N:16]4[C:15]=3[N:14]=2)[CH:6]=[CH:5][N:4]=1
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Reactant: COc1cc(B(O)O)ccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: COc1cc(-c2ncc3c(n2)N2CCOCC2CN3)ccn1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 1 using 2-methoxypyridin-4-ylboronic acid (270 mg, 1.765 mmol), 2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 200 mg, 0.882 mmol), and PdCl2(dppf) (51.7 mg, 0.071 mmol) in dioxane (5 mL) and aqueous saturated NaHCO3 (1 mL). 1H NMR (400 MHz, DMSO-d6) δ 3.01-3.23 (m, 7H), 3.89 (m, 3H), 3.92-3.97 (m, 1H), 3.99-4.06 (m, 1H), 4.53-4.62 (m, 1H), 7.47 (d, J=0.76 Hz, 1H), 7.62 (s, 1H), 7.68 (dd, J=5.31, 1.52 Hz, 1H), 8.24 (d, J=5.56 Hz, 1H). ESI-MS m/z [M+H]+ calc'd for C15H17N5O2, 299.14. found 300.2.
Reaction SMILES: SC1SCCN=1.O[C:8]1[CH:28]=[CH:27][C:11]([C:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][C:17](O)=[CH:18][C:19]=3O)[O:14][C:13]=2CBr)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[C:12]([C:11]2[CH:27]=[CH:28][CH:8]=[CH:9][CH:10]=2)=[CH:13]1
Reactant: O=c1c(-c2ccc(O)cc2)c(CBr)oc2cc(O)cc(O)c12
Agent: O=C([O-])[O-]
Agent: SC1=NCCS1
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c(-c2ccccc2)coc2ccccc12
Temperature: 25 °C
Reaction time: 10 h

Procedure:
2-Mercaptothiazoline (35 mg) was added to a mixture of 4',5,7-trihydroxy-2-bromomethylisoflavone (50 mg), anhydrous potassium carbonate (21 mg) and N,N-dimethylformamide (1 ml), and the resulting mixture was stirred at room temperature for 10 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform), giving 32 mg of 4',5,7-trihydroxy-2-[2-thiazolin-2-ylthio)-methyl]isoflavone as amorphous powder.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1Br)(=[O:3])[CH3:2].[CH3:25][S:26](=[S:29])([O-:28])=[O:27].[Na+].CN(C=O)C.[O-]S([O-])(=O)=O.[Na+].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:25][S:26](=[S:29])([O:28][C@@H:6]1[O:7][C@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:5]1[O:4][C:1](=[O:3])[CH3:2])=[O:27]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CS(=O)([O-])=S
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](OS(C)(=O)=S)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 75 %

Procedure:
2,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl bromide (1 g, 2.44 mmol) and sodium methanethiosulfonate (0.4 g, 3.05 mmol) were placed under nitrogen. 30 ml of anhydrous toluene was added followed by tetrabutylammonium bromide (69 mg, 0.21 mmol) and the mixture heated under reflux for 75 minutes. Part way through 6 ml of DMF were added as it seemed that 2,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl bromide was insoluble in toluene. Reaction continued to reflux despite the fact that solution not formed. Thin Layer Chromatography (“TLC”) at end of reaction showed reaction to have gone to completion. Solution reduced on high pressure rotary evaporator to remove DMF. Product purified on flash silica gel column, reaction mixture added directly onto column (adding a small amount of Celite to reaction mixture sufficient to avoid salt cake forming on top of column.) Petroleum Ether: Ethyl Acetate 60:40 was used as the eluting solvent. Yield=75%.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:12][CH2:13][CH2:14][CH3:15])[O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.[CH3:16][C:17]([CH3:19])=O>C(O)C.[Pd]>[CH2:12]([CH:6]1[C:5]2[C:10](=[CH:11][C:2]([NH:1][CH:17]([CH3:19])[CH3:16])=[CH:3][CH:4]=2)[C:8](=[O:9])[O:7]1)[CH2:13][CH2:14][CH3:15]
Reactant: CC(C)=O
Reactant: CCCCC1OC(=O)c2cc(N)ccc21
Agent: [Pd]
Solvent: CCO
Product: CCCCC1OC(=O)c2cc(NC(C)C)ccc21

Procedure:
To a solution of 4.1 g (20.0 mmol) of compound obtained in Example 4 in 4 ml of acetone and 96 ml of anhydrous ethanol there is added 10% Pd—C catalyst. The mixture is hydrogenated under a hydrogen pressure of 3-3.5 kg/cm2. After the absorption of hydrogen is complete, the catalyst is filtered off and the filtrate is concentrated in vacuo to dryness. The residue is crystallised from dilute ethanol to give the title compound.