Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:9]2)[CH:7]=1.[C:28]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:28]([N:35]1[CH2:36][CH2:37][N:38]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:8]3[N:12]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=4[F:20])[N:11]=[C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:9]3)[CH:7]=2)[CH2:39][CH2:40]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cncc(Br)c2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2cncc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 52.2 %

Procedure:
5-(3-Bromo-pyridin-5-yl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (340.0 mg, 0.75 mmol) prepared in Step 4 of Preparation 10, 1-BOC-piperazine (208.0 mg, 1.12 mmol), Pd2(dba)3 (34.1 mg, cat.), BINAP (46.4 mg, cat.) and sodium t-butoxide (128.9 mg, 1.34 mmol) were added to toluene (10.0 mL). The reaction mixture was stirred at 100° C. for 12 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to give 220.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [F:1][C:2]([F:14])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13].[OH-:15].[Na+].OO.O>C(Cl)Cl>[F:1][C:2]([F:14])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:15]
Reactant: [OH-]
Reactant: C=CCCCCCCCCC=C(F)F
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: OCCCCCCCCCCC=C(F)F
Temperature: 20 °C
Reaction time: 60 h

Procedure:
With stirring, 14.5 grams (0.072 mole) of 1,1-difluorododec-1,11-diene was cooled to 0° C., and 25 ml (0.025 mole--1M in tetrahydrofuran) of borane·tetrahydrofuran complex was added dropwise. Upon completion of addition the reaction mixture was stirred for 30 minutes during which time the reaction mixture temperature was at 8°-12° C. After this time 25 ml of aqueous 3N sodium hydroxide was added dropwise. This was followed by 30 ml of aqueous 30% hydrogen peroxide. During the initial peroxide addition the exothermic reaction caused the reaction mixture temperature to rise to 30°-35° C. The reaction mixture was cooled to approximately 20° C., and the peroxide addition was continued. Upon completion of addition the reaction mixture was stirred at ambient temperature for 30 minutes, and then it was warmed to 45°-50° C. where it stirred for one hour. After this time it was allowed to cool to ambient temperature where it stood for 60 hours. The reaction mixture was shaken with 100 ml of water and 50 ml of methylene chloride. The methylene chloride layer was separated, and the water layer was extracted with two 50 ml portions of methylene chloride. The combined methylene chloride extracts were washed with 25 ml of water and 25 ml of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was distilled under reduced pressure yielding 7.6 grams of 12,12-difluoro-11-dodecenol; b.p. 80-85/0.2 mm. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: P(Br)(Br)[Br:2].O[CH:6]([C:8]1[O:9][C:10](=[O:25])[C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:7]>C(Cl)Cl>[Br:2][CH:6]([C:8]1[O:9][C:10](=[O:25])[C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([CH3:24])[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:7]
Reactant: BrP(Br)Br
Reactant: Cc1cc(-c2c(C(C)O)oc(=O)c3ccccc23)ccn1
Solvent: ClCCl
Product: Cc1cc(-c2c(C(C)Br)oc(=O)c3ccccc23)ccn1
Yield: 45 %

Procedure:
1 M PBr3 in DCM (846 μL, 0.846 mmol) was added to of 3-(1-hydroxyethyl)-4-(2-methylpyridin-4-yl)-1H-isochromen-1-one (intermediate B13, 140 mg, 0.498 mmol) in DCM at RT. Reaction mixture was concentrated under reduced pressure and straightforward purified via reverse phase chromatography with a Biotage C18 SNAP 60 g column (Phase A, water 95%, ACN 4.5%, formic acid 0.5%); Phase B ACN 99.5%, formic acid 0.5%) to give the title compound (80 mg, 45%).
Reaction SMILES: [C:1]1([C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].C(O)C>[C:1]1([C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCC=CCC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCCCCC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 6 h
Yield: 98.5 %

Procedure:
To an ethanol solution (6.3 ml) of ethyl 8,8,8-triphenyloct-5-enoate (626 mg) was added 10% Pd-C (188 mg). The mixture was subjected to catalytic hydrogenation for six hours at ambient temperatures under atmospheric pressure. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The concentrate was purified by means of a silica gel column chromatography (hexane:ethyl acetate=10:1) to afford 620 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][S:8][C:9]([CH3:38])([CH3:37])[C:10]([NH:12][CH2:13][CH2:14][N:15]([CH2:34][CH2:35][NH2:36])[CH2:16][CH2:17][NH:18][C:19](=[O:33])[C:20]([CH3:32])([S:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH3:21])=[O:11])=[CH:5][CH:4]=1.[C:41](Cl)(Cl)=[S:42]>ClCCl>[CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][S:8][C:9]([CH3:38])([CH3:37])[C:10]([NH:12][CH2:13][CH2:14][N:15]([CH2:34][CH2:35][N:36]=[C:41]=[S:42])[CH2:16][CH2:17][NH:18][C:19](=[O:33])[C:20]([CH3:32])([S:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[CH3:21])=[O:11])=[CH:5][CH:4]=1
Reactant: S=C(Cl)Cl
Reactant: COc1ccc(CSC(C)(C)C(=O)NCCN(CCN)CCNC(=O)C(C)(C)SCc2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: COc1ccc(CSC(C)(C)C(=O)NCCN(CCN=C=S)CCNC(=O)C(C)(C)SCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
To a round bottom flask containing the aniline 24 (28.8 mg, 0.0487 mmol) and dichloromethane (10 mL) was added 0.2211 M solution of thiophosgene (0.22 mL, 0.0509 mmol) in dichloromethane. The heterogeneous reaction mixture was stirred at room temperature for 1 hour and the solvent was removed in vacuo. Flash chromatography of this crude product using 100% EtOAc gave the isothiocyanate 25 as a clear oil (18.9 mg, 61.3% yield). 1H NMR (in CDCl3): δ7.17 (d,j=8.5 Hz,4H,2H3 &H5 --Ar--OCH3), 7.07 (m,2H,2NH--CO), 6.82 (d,j=8.5 Hz,4H,2H2 &H6 --Ar--OCH3), 3.78 (s,6H, 2CH3O), 3.70 (s,4H,2S--CH2 --Ar), 3.49 (t,j=5.9 Hz,2H,N--CH2CH2 -NCS ), 3.21 (q,j=6.2 Hz,4H,2N--CH2CH2 --NHCO), 2.78 (t,j=5.9 Hz,2H,N--CH2CH2 --NCS), 2.58 (t,j=6.4 Hz,4H, 2N--CH2CH2 --NHCO), 1.54 (s,12H,4CH3 --C--S) ppm. MS (m/z,CI): 633(25, MH+). IR (CDCl3): 3370, 2950, 2920, 2850, 2100, 1720, 1655, 1610, 1510, 1245, 1170, 1030, 830 cm-1.
Reaction SMILES: Cl[C:2]1[C:3](=[O:19])[N:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2>C(O)(=O)C.[Zn]>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[NH:11][CH2:2][C:3]2=[O:19])=[CH:17][CH:16]=1
Reactant: O=c1c(Cl)nc2ccccc2n1-c1ccc(Cl)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1CNc2ccccc2N1c1ccc(Cl)cc1

Procedure:
To a stirred solution of 3-chloro-1-(4-chlorophenyl)-1,2-dihydroquinoxalin-2-one (20.0 g) in glacial acetic acid (250 ml) was added zinc powder (20.0 g) in small portions during 30 minutes. After a further 15 minutes the mixture was filtered, water was added and the product was extracted into dichloromethane. Evaporation of the solvent and recrystallisation of the residue from ethanol gave the sub-title compound mp 196°-199° C.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:20])([F:19])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13]C(=O)N(C)C)=[CH:9][CH:8]=1)[OH:6].CO>C1COCC1>[F:20][C:4]([F:3])([F:19])[CH:5]([C:7]1[CH:8]=[CH:9][C:10]([SH:13])=[CH:11][CH:12]=1)[OH:6]
Reactant: CN(C)C(=O)Sc1ccc(C(O)C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: OC(c1ccc(S)cc1)C(F)(F)F
Reaction time: 3 h
Yield: 87.1 %

Procedure:
In a 2-neck round bottom flask, NaOH (330 mg, 5.5 mmol) and dimethyl-thiocarbamic acid S-[4-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenyl]ester (4) (16 mg, 0.59 mmol) was dissolved in THF (5 mL) and MeOH (0.82 mL) under argon at 69° C. After 3 hours, the reaction mixture was quenched under argon with 1M HCl (3 mL) and was extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with H2O (3×30 mL), followed by brine (1×30 mL), and then dried over Na2SO4. The organic phase was collected by filtration and concentrated by rotary evaporation to yield intermediate compound (5) as a yellow oil (107 mg, 65%). 1H NMR (400 MHz, CHCl3): δ 7.53 (m, 2H), 7.43 (d, J=8.68, 2H), 5.01 (q, J=6.55, 1H); 19F NMR (376 MHz, CDCl3): −79 (d, J=6.7 Hz); 13C NMR (100 MHz, CDCl3): δ 133.2, 131.5, 129.3, 128.4, 124.4 (q, JCF=282.1 Hz), 72.5 (q, JCF=32 Hz).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[CH:6]1([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7]1.Cl>ClCCl>[CH:6]1([S:9][C:10]2[CH:15]=[CH:14][C:13]([C:1](=[O:3])[CH3:2])=[CH:12][CH:11]=2)[CH2:8][CH2:7]1
Reactant: c1ccc(SC2CC2)cc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(SC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70.8 %

Procedure:
To dichloromethane (6.7 mL), acetyl chloride (189 μL, 2.66 mmol) and alminium chloride (267 mg, 2.0 mmol) were added sequentially at 0° C., and the mixture was stirred at 0° C. for 10 minutes. Then, a solution of cyclopropyl(phenyl)sulfane (200 mg, 1.33 mmol) in dichloromethane (890 μL) was added, and stirred at 0° C. for 0.5 hours. The reaction solution was added 5% aqueous solution of hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and 1-(4-(cyclopropylthio)phenyl)ethanone (181 mg (yield 71%)) was obtained as a colorless oil.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[CH2:30]([NH:32][CH2:33][CH2:34][OH:35])[CH3:31]>CN(C)C(=O)C>[CH2:30]([N:32]([CH2:33][CH2:34][OH:35])[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1)[CH3:31]
Reactant: CCNCCO
Reactant: CN(C[C@H]1CC[C@H](COC/C=C/CBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)N(C)C
Product: CCN(C/C=C/COC[C@H]1CC[C@H](CN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1)CCO

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with ethyl-(2-hydroxy-ethyl)-amine in N,N-dimethylacetamide at room temperature to yield trans-N-(4-{4-[ethyl-(2-hydroxy-ethyl)-amino]-(E)-but-2-enyloxymethyl}-cyclohexylmethyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide as light yellow solid, MS: 507 (MH+).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]2[N:8]=[C:9]([C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:6]=2[S:5][C:4]=1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[OH:32][C:33]([CH3:38])([CH3:37])[C:34](O)=[O:35]>>[NH2:24][C:21]1[N:20]=[CH:19][C:18]([C:9]2[N:10]=[C:11]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[C:6]3[S:5][C:4]([CH2:25][N:26]4[CH2:31][CH2:30][N:29]([C:34](=[O:35])[C:33]([OH:32])([CH3:38])[CH3:37])[CH2:28][CH2:27]4)=[C:3]([CH3:2])[C:7]=3[N:8]=2)=[CH:23][N:22]=1
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Reactant: CC(C)(O)C(=O)O
Agent: Cl
Product: Cc1c(CN2CCN(C(=O)C(C)(C)O)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Yield: 65.6 %

Procedure:
Crude HCl salt of 5-(7-methyl-4-morpholino-6-(piperazin-1-ylmethyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine (74 mg) was reacted with 40 mg 2-hydroxy-2-methylpropanoic acid via General Procedure B to give 58.3 mg of 357 after reverse phase HPLC purification. MS (Q1) 513.3 (M)+.
Reaction SMILES: [NH2:1][C:2]1[C:44]([N+:45]([O-])=O)=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc([N+](=O)[O-])c1N
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Temperature: 100 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a solution of 4-(2-amino-3-nitrobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (3.88 g) in ethanol (40 ml) were added a solution of ammonium chloride (385 mg) in water (10 ml) and iron powder (2.01 g) and the mixture was stirred at 100° C. for 2 hours. The mixture was filtered through a bed of celite and the filtrate was concentrated in vacuo. The residue was diluted with ethyl acetate and the solution was washed with aqueous saturated sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate and the solution was concentrated in vacuo to give 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide as a yellow powder (3.42 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]=[CH:5][C:6]1[C:14]2[O:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[CH:11][C:10]=2[CH:9]=[C:8]([OH:22])[CH:7]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1[C:14]2[O:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[CH:11][C:10]=2[CH:9]=[C:8]([OH:22])[CH:7]=1
Reactant: COC(=O)C=Cc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Reaction time: 7 h
Yield: 15 %

Procedure:
To a solution of 3-[5-hydroxy-2-(4-hydroxy-phenyl)benzofuran-7-yl]-acrylic acid methyl ester 59 (0.1 g, 0.32 mmol) in methanol (5 mL) and purged with nitrogen was added catalytic 10% palladium on carbon. The reaction vessel was evacuated and a balloon of hydrogen was added. After 7 hours, the reaction was filtered and the solvent removed in vacuo. The product was purified via flash chromatography on silica gel, eluting with 7% methanol in dichloromethane to give 0.015 g of 3-[5-hydroxy-2-(4-hydroxy-phenyl)-benzofuran-7-yl]-propionic acid methyl ester 60: Mp=167-170° C.; 1H NMR (DMSO-d6) δ 9.83 (s, 1 H), 9.08 (s, 1 H), 7.70 (d, 2 H, J=8.6 Hz), 7.00 (s, 1 H), 6.87 (d, 2 H, J=8.6 Hz), 6.73 (d, 1 H, J=2.3 Hz), 6.53 (d, 1 H, J=2.2 Hz), 3.59 (s, 3 H), 3.07 (t, 2 H, J=7.5 Hz), 2.77 (t, 2 H, J=7.6 Hz); MS 313 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH2:8][O:7][C:6]2[N:11]=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4([NH:31]C(=O)OC(C)(C)C)[CH2:30][CH2:29][CH2:28]4)=[CH:23][CH:22]=3)[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:14][C:5]1=2)([CH3:3])[CH3:2]>C(O)(C(F)(F)F)=O>[NH2:31][C:27]1([C:24]2[CH:23]=[CH:22][C:21]([C:12]3[C:13]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:14][C:5]4[N:4]([CH:1]([CH3:3])[CH3:2])[C:9](=[O:10])[CH2:8][O:7][C:6]=4[N:11]=3)=[CH:26][CH:25]=2)[CH2:28][CH2:29][CH2:30]1
Reactant: CC(C)N1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Reaction time: 0.01 h
Yield: 120.9 %

Procedure:
tert-Butyl 1-(4-(1-isopropyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (7 mg, 0.014 mmol) was dissolved in TFA (2 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (2 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed by freeze drying overnight to give the desired compound as an off-white solid (7 mg, 97% yield). 1H-NMR (500 MHz, MeOD) δ 7.64 (1H, s), 7.41 (2H, d), 7.36 (2H, d), 7.26-7.32 (3H, m), 7.19-7.26 (2H, m), 4.80 (2H, s), 4.75 (1H, sep), 2.68-2.80 (2H, m), 2.50-2.62 (2H, m), 2.13-2.29 (1H, m), 1.89-2.00 (1H, m), 1.48 (6H, d). LCMS (Method A) RT=4.20 min, M+2H+=415.19.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[C:12]2[CH:11]=[CH:10][S:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+]>ClCCl>[Br:1][C:11]1[C:12]2[C:4]([F:3])=[CH:5][CH:6]=[CH:7][C:8]=2[S:9][CH:10]=1
Reactant: Fc1cccc2sccc12
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Fc1cccc2scc(Br)c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of bromine (9.2 ml) in dichloromethane (200 ml) was added dropwise under nitrogen at −5° C. over 30 minutes to a stirred mixture of 4-fluorobenzo[b]thiophene (24.7 g), sodium acetate (20 g) and dichloromethane (200 ml). The mixture was stirred at ambient temperature for 24 hours, then it was filtered and the solvent was removed in vacuo. The residue was dissolved in dichloromethane (50 ml), water (200 ml) and zinc dust (34.3 g) were added, then the mixture was stirred and heated under reflux for 10 hours, cooled to ambient temperature and filtered through Celite. The Celite was washed with ethyl acetate (200 ml) then the combined organic solutions were washed with saturated aqueous sodium chloride solution (100 ml), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by distillation in vacuo to give 3-bromo-4-fluorobenzo[b]thiophene (12.5 g) as a pale yellow oil, b.p. 70-85° C. @ 0.53 mbar.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([NH:16][C:17]([C:19]3[N:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])=[CH:14][C:13]([C:25]3[CH:26]=[N:27][C:28]([N:31]4[CH2:36][CH2:35][C:34]([CH3:42])([C:37]([O:39]CC)=[O:38])[CH2:33][CH2:32]4)=[N:29][CH:30]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].CC(C)([O-])C.[K+]>CS(C)=O>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([NH:16][C:17]([C:19]3[N:20]=[CH:21][CH:22]=[CH:23][N:24]=3)=[O:18])=[CH:14][C:13]([C:25]3[CH:26]=[N:27][C:28]([N:31]4[CH2:32][CH2:33][C:34]([CH3:42])([C:37]([OH:39])=[O:38])[CH2:35][CH2:36]4)=[N:29][CH:30]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(NC(=O)c3ncccn3)c2s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cc(NC(=O)c3ncccn3)c2s1
Yield: 5.2 %

Procedure:
Ethyl 1-[5-[2-(ethylcarbamoylamino)-7-(pyrimidine-2-carbonylamino)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (100 mg, 0.17 mmol) was dissolved in DMSO (0.5 mL) with stirring and potassium-t-butoxide (40 mg, 0.35 mmol) added. The reaction was allowed to stir at rt for 2 h. The reaction mixture was filtered and purified by preparative HPLC to afford Compound 146 as a solid (5 mg). 1H NMR (DMSO-d6): δ 11.01 (1H, s), 9.12 (2H, d, J=4.86 Hz), 8.77 (2H, s), 7.83 (1H, d, J=4.75 Hz), 7.82 (1H, t, J=1.44 Hz), 7.67 (1H, d, J=1.66 Hz), 7.01 (1H, s), 4.32 (2H, d, J=13.32 Hz), 3.22 (2H, p, J=7.59 Hz), 2.05 (2H, dd, J=13.04, 4.48 Hz), 1.42 (2H, t, J=11.27 Hz), 1.22 (3H, s), 1.13 (3H, dd, J=7.16, 7.16 Hz). MS: 562 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:4]=1[CH:5]=CC=O.[O-:17][Mn](=O)(=O)=O.[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:4]=1[CH:5]=[O:17]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1cc(OC)c(OC)cc1C=CC=O
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OC)c(OC)cc1C=O
Reaction time: 24 h
Yield: 45.3 %

Procedure:
A solution of the 2,4,5-Trimethoxycinnamaldehyde (0.5 g) was treated with KMnO4 (0.5 g) in dry acetone (20 ml). The reaction mixture was left at room temperature for 24 hr, manganese dioxide was filtered off and the solvent was removed. The residue was dissolved in ethyl acetate and washed carefully with 10% NaHCO3, brine, and dried over anhydrous Na2SO4. Evaporation of the solvent afforded a crude solid, which was further recrystallised from water to afford 0.2 g 2,4,5-trimethoxybenzaldehyde as a colorless solid, mp 114° C. (lit. mp 114° C.); IR (film) νmax 1662 (carbonyl group), 1620, 1518, 1481, 1419, 1361, 1300, 1278, 1222, 1199, 1138, 1025, 865 cm−1; 1H NMR δ 10.32 (1H, s, CHO), 7.33 (1H, s, 6H), 6.50 (1H, s, 3H), 3.98 (3H, s, 2-OCH3), 3.93 ((3H, s, 4-OCH3), 3.88 (3H, s, 5-OCH3); 13C NMR δ 187.96 (CHO), 158.60 (C-2), 155.76 (C-4), 143.56 (C-5), 117.35 (C-1), 109.03 (C-6), 56.19 (2-OCH3, 4-OCH3 and 5-OCH3); EIMS m/z 196 [M]+ (100), 181 (49), 150 (32), 125 (33), 110 (23), 69 (37).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:9]([C:10](OCC)=[O:11])=[CH:8][N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[N:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:9]([CH2:10][OH:11])=[CH:8][N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[N:6]=1
Reactant: CCOC(=O)c1cn(-c2ccccc2C)nc1OCOC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COCOc1nn(-c2ccccc2C)cc1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a solution of ethyl 3-(methoxymethoxy)-1-(2-methylphenyl)-1H-pyrazole-4-carboxylate (2.39 g) in tetrahydrofuran (60 mL) was added lithium aluminum hydride (0.323 g) at 0° C. and the mixture was stirred at room temperature for 16 hrs. Sodium sulfate decahydrate (2.78 g) was added to the reaction mixture and the mixture was stirred at room temperature for 1 hr. After removing the precipitate by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1-4:1, v/v) to give [3-(methoxymethoxy)-1-(2-methylphenyl)-1H-pyrazol-4-yl]methanol as a pale-yellow oil (1.84 g, yield 90%).