Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](/[CH:35]=[CH:36]/[C:37]([O:39][CH3:40])=[O:38])[C:5]2[N:6]([C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH:21]C(OC(C)(C)C)=O)[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1>[Pd].C(O)C.C1COCC1>[NH2:21][C:17]1([C:14]2[CH:15]=[CH:16][C:11]([C:9]3[N:10]=[C:5]4[C:4]([CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:3][CH:2]=[N:7][N:6]4[C:8]=3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:12][CH:13]=2)[CH2:18][CH2:19][CH2:20]1
Reactant: COC(=O)/C=C/c1cc(Br)nn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc12
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)CCc1ccnn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc12
Reaction time: 1 h
Yield: 1 %

Procedure:
To a mixture of methyl (2E)-3-[6-bromo-2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazin-8-yl]acrylate that was prepared in a manner analgous to that described for Example 72, Step 1 (0.50 g, 0.83 mmol) and 10% palladium on carbon (0.26 g) in a mixture of ethanol (14 mL) and THF (5 mL) was placed under a hydrogen atmosphere at room temperature for 1 h. The resulting mixture was treated with additional 10% palladium on carbon (0.26 g) and placed under a hydrogen atmosphere for 1 h. Solids were removed by filtration and washed with ethanol (20 mL). The combined organic solutions were treated with 10% palladium on carbon (0.26 g) and placed under a hydrogen atmosphere for 1 h. Solids were removed by filtration and washed with ethanol (20 mL). The combined organic solutions were concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; Snap 25 g cartridge, 100% hexane 2.0 min, gradient to 80% hexane/20% EtOAc 1.5 min, gradient to 74% hexane/26% EtOAc 2.5 min, gradient to 70% hexane/30% EtOAc 2.0 min, gradient to 50% hexane/50% EtOAc 3.0 min, 50% hexane/50% EtOAc 6.4 min, gradient to 25% hexane/75% EtOAc 3.5 min, 25% hexane/75% EtOAc 5.3 min gradient to 100% EtOAc 5.3 min, 100% EtOAc 21.2 min). The resulting material was further purified using preparative HPLC (Agilent Prep 1200 equipped with 2× Prep Pump, DLA, MWD, ELSD and Prep FC using an XBrigde C18 5 μm 100×30 mm column; gradient from 100% water with 0.1% HCO2H to 70% water with 0.1% HCO2H/30% MeOH over 1.0 min, gradient to 30% water with 0.1% HCO2H/70% MeOH over 7.0 min, gradient to 100% MeOH over 0.1 min, 100% MeOH 1.9 min) to give methyl 3-{2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazin-8-yl}propanoate (0.003 g, 1%):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].C(N(CC)CC)C.[NH2:18][CH2:19][C:20]1[CH:36]=[CH:35][C:23]([C:24]([N:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[CH3:27])=[O:25])=[CH:22][C:21]=1[CH3:37]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:18][CH2:19][C:20]1[CH:36]=[CH:35][C:23]([C:24]([N:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[CH3:27])=[O:25])=[CH:22][C:21]=1[CH3:37])=[O:6]
Reactant: Cc1cc(C(=O)N(C)c2ccc(Cl)cc2)ccc1CN
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)N(C)c2ccc(Cl)cc2)ccc1CNC(=O)c1cccc(Cl)c1
Reaction time: 1 h
Yield: 69 %

Procedure:
3-Chlorobenzoyl chloride (61 mg, 0.35 mmol) and triethyl-amine (to pH9) were added to a solution of 4-aminomethyl-N-(4-chloro-phenyl)-3,N-dimethyl-benzamide from Example E115.2 (100 mg, 0.35 mmol) in dichloro-methane (5 ml) at room temperature. The mixture was stirred for 1 h then concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give a white solid identified as the title compound (101 mg, 69%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:9]([F:19])=[C:10]([OH:18])[C:11]([CH:14]3[CH2:17][CH2:16][CH2:15]3)=[CH:12][CH:13]=2)=[N:6][CH:7]=1.Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1.[OH-].[K+]>CS(C)=O>[CH:14]1([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=3)=[C:9]([F:19])[C:10]=2[O:18][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:15][CH2:16][CH2:17]1
Reactant: Fc1ccc(CBr)cc1
Reactant: Nc1cnc(-c2ccc(C3CCC3)c(O)c2F)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1cnc(-c2ccc(C3CCC3)c(OCc3ccc(F)cc3)c2F)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
To a solution of 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (50 mg, 0.19 mmol) and 1-(bromomethyl)-4-fluorobenzene (36 μL, 0.29 mmol) in DMSO (1 mL) was added 1 pellet (˜125 mg) of potassium hydroxide. The reaction was stirred for 16 hours at room temperature before filtering and purifying by HPLC to give 5-{4-cyclobutyl-2-fluoro-3-[(4-fluorobenzyl)oxy]phenyl}pyrazin-2-amine (37 mg, 39%). MS (ESI): mass calcd. for C21H19F2N3O, 367.15; m/z found, 368.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.30 (d, J=1.3, 1H), 8.22 (s, 1H), 7.58 (m, 1H), 7.50-7.43 (m, 2H), 7.20 (d, J=8.0, 1H), 7.15-7.07 (m, 2H), 5.01 (s, 2H), 3.83-3.68 (m, 1H), 2.31-2.21 (m, 2H), 2.18-1.93 (m, 3H), 1.87-1.78 (m, 1H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]([CH3:17])=[CH:7][C:8]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9]>C(Cl)Cl>[CH3:5][C:6]1([CH3:17])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10][C:8](=[O:9])[CH2:7]1
Reactant: CC(C)=CC(=O)Oc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CC(=O)Oc2ccccc21
Reaction time: 42 h

Procedure:
To a stirred, ice-cooled suspension of 10.4 g (78 mmol) of aluminum chloride in 160 ml of methylene chloride was added slowly under argon a solution of 7 g (39.8 mmol) of phenyl 3,3-dimethylacrylate (Compound 37) in 40 ml of methylene chloride. The cooling bath was removed and the mixture stirred for a further 42 h. The mixture was poured into a mixture of ice and brine and the organic layer separated. The aqueous layer was extracted with methylene chloride and the organic extracts were combined and washed with saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 10% ether in hexane) to give the title compound as a colorless oil. PMR (CDCl3 : & 1.30 (6 H, s), 2.56 (2 H, s), 7.06 (1 H, dd, J~8.0 Hz, 1.4 Hz), 7.16 (1 H, td, J~8.0 Hz, 1.4 Hz), 7.26 (1 H, td, J~8.0 Hz, 1.7 Hz), 7.33 (1 H, dd, J~8.0 Hz, 1.7 Hz). MS exact mass, m/e 176.0852 (calcd. for C11H12O2, 176.0837.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].[F:9][C:10]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:11]=1[CH2:12]Br>CN(C)C=O>[F:9][C:10]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:11]=1[CH2:12][O:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6]
Reactant: Fc1ccc(Br)cc1CBr
Reactant: OCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCCCOCc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
A solution of 1,4-dihydroxybutane (4.0 ml, 45.13 mmol) in N,N-dimethylformamide (62 ml) was treated with sodium hydride (1.98 g of a 60% solution, 49.63 mmol), and stirred for about 50 minutes at ambient temperature. The resulting mixture was cooled to 0° C. and treated with 2-fluoro-5-bromobenzyl bromide (3.0 g, 11.28 mmol). The reaction mixture was then stirred for four hours at ambient temperature. The reaction was quenched with water. The aqueous fraction was extracted with methylene chloride. The organic fractions were combined, and dried over sodium sulfate. The solvents were removed in vacuo. The desired title intermediate was further purified by high performance liquid chromatography.
Reaction SMILES: C1(=O)CCCCC1.[CH2:8]1[CH2:13][C:12]([CH:14]=[O:15])=[C:11]([Cl:16])[CH2:10][CH2:9]1.[BH4-].[Na+].[Cl-].[Ce+3].[Cl-].[Cl-]>>[Cl:16][C:11]1[CH2:10][CH2:9][CH2:8][CH2:13][C:12]=1[CH2:14][OH:15]
Reactant: O=CC1=C(Cl)CCCC1
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: O=C1CCCCC1
Product: OCC1=C(Cl)CCCC1
Yield: 46 %

Procedure:
Commercially available cyclohexanone was converted to (2-chlorocyclohex-1-enyl)carboxaldehyde according to General Procedure E. Sodium borohydride/cerium chloride reduction of the above carboxaldehyde, in accordance with the method described in General Procedure C gave the intermediate (2-chlorocyclohex-1-enyl)-methanol in 46% yield, which was characterized: 1H NMR (CDCl3, 300 MHz) δ=1.61-1.75 (m, 4H), 2.15 (br s, 1H), 2.22-2.27 (m, 2H), 2.33-2.37 (m, 2H), 4.24 (br s, 2H). The title compound was obtained from (2-chloro-cyclohex-1-enyl)methanol according to General Procedure C. Spectroscopic data: 1H NMR (D6 DMSO, 300 MHz) δ=1.52-1.69 (m, 4H), 2.07-2.11 (m, 2H), 2.28-2.35 (m, 2H), 3.48 (br s, 4H), 4.22 (br s, 2H), 4.76 (s, 1H), 7.41 (s, 1H), 7.54 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14](Cl)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([Cl:37])[C:24]=1[N:25]1[CH2:30][CH2:29][CH:28]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH2:27][CH2:26]1)[NH2:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:21][C:20]3[CH:19]=[C:18]([Cl:17])[C:24]([N:25]4[CH2:26][CH2:27][CH:28]([N:31]5[CH2:32][CH2:33][O:34][CH2:35][CH2:36]5)[CH2:29][CH2:30]4)=[C:23]([Cl:37])[CH:22]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1cc(Cl)c(N2CCC(N3CCOCC3)CC2)c(Cl)c1
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(Cl)cc1
Product: Cc1c(C(=O)Nc2cc(Cl)c(N3CCC(N4CCOCC4)CC3)c(Cl)c2)cnn1-c1ccc(Cl)cc1
Yield: 60.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 150 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic chloride (0.77 g) and 3,5-dichloro-4-(4-morpholinopiperidin-1-yl)aniline (1.0 g), the title compound (1.0 g) was obtained, melting point: 246–248° C.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[OH:7][CH2:8][P:9]([O:14][CH2:15][CH3:16])(=[O:13])[O:10][CH2:11][CH3:12].C(N(CC)CC)C>C(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([O:7][CH2:8][P:9]([O:14][CH2:15][CH3:16])(=[O:13])[O:10][CH2:11][CH3:12])=[O:4]
Reactant: CC(Br)C(=O)Cl
Reactant: CCOP(=O)(CO)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(COC(=O)C(C)Br)OCC
Reaction time: 20 h
Yield: 32.3 %

Procedure:
A solution of 8.6 g (0.05 mol) of 2-bromo-propionyl chloride in 30 ml of methylene chloride was added dropwise to a mixture which had been cooled to 0°-10° C. and consisted of 8.4 g (0.05 mol) of diethyl hydroxymethanephosphonate, 6.1 g (0.06 mol) of triethylamine and 30 ml of methylene chloride. The reaction mixture was stirred for 20 hours at 10°-20° C. washed with aqueous sodium bicarbonate solution, dried, filtered, and evaporated down under reduced pressure. 4.9 g (32% of theory) of diethyl 2-bromopropionyloxymethanephosphonate were obtained as an oily residue. ##STR37##
Reaction SMILES: Br[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[C:11]1(=[O:24])[C:16]2[S:17][C:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[C:15]=2[CH2:14][CH2:13][NH:12]1.C([O-])([O-])=O.[K+].[K+].COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1>[Cu]I.O1CCOCC1>[Cl:10][C:6]1[CH:7]=[CH:8][N:9]=[C:2]([N:12]2[C:11](=[O:24])[C:16]3[S:17][C:18]4[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=4[C:15]=3[CH2:14][CH2:13]2)[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(Cl)ccnc1Br
Reactant: O=C1NCCc2c1sc1c2CCCC1
Agent: [Cu]I
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=Cc1c(Cl)ccnc1N1CCc2c(sc3c2CCCC3)C1=O
Temperature: 95 °C
Reaction time: 16 h
Yield: 17 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a reflux condenser was charged with 2-bromo-4-chloronicotinaldehyde 103a (1276 mg, 5.80 mmol), 8-thia-5-azatricyclo[7.4.0.02,7}]trideca-1(9),2(7)-dien-6-one 105e (600 mg, 2.90 mmol), CuI (551 mg, 2.90 mmol), K2CO3 (800 mg, 5.80 mmol), 4,7-dimethoxy-1,10-phenanthroline (696 mg, 2.90 mmol), and dioxane (20 mL). After bubbling nitrogen through the resulting solution for 10 min, the mixture was stirred at 95° C. for 16 h. It was then cooled to room temperature and filtered. To the residue was added water (20 mL). The aqueous layer was separated and extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with brine (50 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 10:1 petroleum ether/ethyl acetate to afford 169a (171 mg, 17%). LCMS-ESI: [M+H]+ 347
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:42][CH3:43])=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH3:29][O:28][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([O:42][CH3:43])=[C:35]3[C:39]=2[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: COc1ccc(N)c2c1CN(C)C2=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(OC)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-Amino-4-methoxy-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 205A). MS (ES+): m/z 610.25 (100) [MH+]; HPLC: tR=1.10 min (UPLC, purity).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([OH:14])[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1.N1C=CC=CC=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)(Cl)Cl.O>[CH3:31][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:1][CH2:2][CH2:3][C:4]2([OH:14])[CH2:13][CH2:12][C:7]3([O:11][CH2:10][CH2:9][O:8]3)[CH2:6][CH2:5]2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC1(O)CCC2(CC1)OCCO2
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCC2(O)CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To 30 mL of a chloroform solution containing 4.2 g of 8-(2-hydroxyethyl)-1,4-dioxaspiro(4.5)decan-8-ol, 2.18 mL of pyridine was added at room temperature, and 4.0 g of p-toluenesulfonyl chloride was dividedly added thereto under cooling with ice, the mixture was stirred at room temperature for 1 hour and 35 minutes, left to stand overnight, and then further stirred at 30 to 40° C. for 1 hour. The reaction mixture was added with water and chloroform under cooling with ice. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=50:1] to obtain 4.2 g of a yellow oily substance, 2-(8-hydroxy-1,4-dioxaspiro(4.5)decan-8-yl)ethyl 4-methylbenzenesulfonate.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[CH:20]=[C:19]([NH:21][C:22](=[O:27])[CH2:23][C:24]([OH:26])=O)[O:18][N:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[Br:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:46]([N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)=[O:47]>CN(C=O)C.O>[Br:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:46]([N:48]1[CH2:49][CH2:50][N:51]([C:24](=[O:26])[CH2:23][C:22]([NH:21][C:19]2[O:18][N:17]=[C:16]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:20]=2)=[O:27])[CH2:52][CH2:53]1)=[O:47]
Reactant: O=C(O)CC(=O)Nc1cc(-c2ccccc2)no1
Reactant: O=C(c1ccccc1Br)N1CCNCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1)Nc1cc(-c2ccccc2)no1
Reaction time: 0.03 h
Yield: 43.5 %

Procedure:
DIPEA (69.2 mg, 0.55 mmol) was added to a stirred solution of N-(3-phenyl-isoxazol-5-yl)-malonamic acid (45 mg, 0.18 mmol) in DMF (2 mL) followed by HOBt (29 mg, 0.22 mmol). After 2 minutes of stirring, (2-bromo-phenyl)-piperazin-1-yl-methanone hydrochloride (67 mg, 0.22 mmol) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to afford 38.9 mg (43.22% Yield) of 3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-N-(3-phenyl-isoxazol-5-yl)-propionamide. LC/MS [M+1]+: 497.07, 97.0%. 1H NMR: (300 MHz, DMSO-d6): δ 11.8 (bs, 1H), 7.92-7.8 (m, 2H), 7.5 (d, 1H), 7.6-7.3 (m, 6H), 6.8-6.7 (d, 1H), 3.8-3.4 (m, 8H), 3.24-3.04 (m, 2H).
Reaction SMILES: [OH:1][C:2]([P:18](=[O:21])([OH:20])[OH:19])([P:14](=[O:17])([OH:16])[OH:15])[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[S:10]C(=O)C>Cl.O>[OH:1][C:2]([P:14](=[O:15])([OH:16])[OH:17])([P:18](=[O:19])([OH:20])[OH:21])[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[SH:10]
Reactant: CC(=O)SC1CCCCC1CC(O)(P(=O)(O)O)P(=O)(O)O
Agent: Cl
Solvent: O
Product: O=P(O)(O)C(O)(CC1CCCCC1S)P(=O)(O)O

Procedure:
[1-Hydroxy-2-(2-(acetylthio)cyclohexyl)ethylidene]bis[phosphonic acid] is heated at reflux in concentrated hydrochloric acid for 7 hours. The reaction is concentrated under reduced pressure and the solid residue is triturated in ethanol. The product is obtained by recrystallization the crude solid in ethanol and water.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[C:13](NC1C=CC(C(O)=O)=CC=1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]>>[C:13]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)cc1
Reactant: COc1cc(C(=O)O)ccc1N
Product: COc1cc(C(=O)O)ccc1NC(=O)OC(C)(C)C

Procedure:
4-Amino-3-methoxybenzoic acid (1 g, 5.98 mmol) was reacted according to the same procedure as that used in the process for preparing N-BOC-4-aminobenzoic acid. The resulting solid was recrystallized from ethyl acetate and hexanes to provide the desired product (1.5 g) as tan crystals: m.p. 176-178° C.; 1H NMR (CD3OD) d 1.52 (9H, s), 3.92 (3H, s), 7.56 (1H, s), 7.62 (1H, d, J=8.4 Hz), 7.96 (1H, s), 8.03 (1H, d, J=8.4 Hz); 13C NMR (CD3OD) d 28.53, 56.35, 81.78, 112.01, 118.58, 124.20, 125.76, 133.84, 149.04, 154.20, 169.60; HRMS Calc. for C13H17NO5, 267.1107; Found, 267.1103.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][S:13][C:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[CH:20][CH:21]=2)[N:16]([C:31]2[N:36]=[CH:35][C:34]([C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)=[CH:33][N:32]=2)[CH:15]=1>ClCCl>[CH3:12][S:13]([C:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[CH:20][CH:21]=2)[N:16]([C:31]2[N:32]=[CH:33][C:34]([C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)=[CH:35][N:36]=2)[CH:15]=1)=[O:6]
Reactant: CSc1cn(-c2ncc(-c3cccnc3)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1cn(-c2ncc(-c3cccnc3)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
m-Chloroperoxybenzoic acid (48 mg, 0.21 mmol) was added at 0° C. to a solution of 49a) (0.18 g, 0.25 mmol) in dichloromethane (20 mL) and the resulting mixture was stirred at room temperature for 4 h. The reaction was quenched with saturated sodium sulfite solution (20 mL) and stirred for further 5 min. The organic layer was separated, washed with saturated sodium hydrogen carbonate solution (2×20 mL) and brine (1×20 mL), dried over sodium sulphate and concentrated. The residue was purified by flash column chromatography [methanol/dichloromethane=1:25]. White solid. Yield: 0.06 g (53% of theory)
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:10]=2)O1.Br[C:30]1[CH:31]=[C:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[S:33][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[S:18]([N:11]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:17]2[C:9]([C:30]2[CH:31]=[C:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[S:33][CH:34]=2)=[CH:10]1)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cccnc32)cc1
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)cs1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3csc(NC(=O)OC(C)(C)C)c3)c3cccnc32)cc1
Reaction time: 0.17 h
Yield: 38 %

Procedure:
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (398 mg, 1 mmol), tert-butyl 4-bromothiophen-2-ylcarbamate (190 mg, 0.68 mmol), potassium carbonate (310 mg, 2.25 mmol), and tetrakis(triphenylphosphine) palladium (0) (20 mg) were combined in 4 mL DME, 1 mL water, and heated to 160° C. in the microwave for 10 minutes, followed by 170° C. for 10 minutes. The reaction mixture was diluted with EtOAc and washed with saturated sodium bicarbonate. The organic layer was filtered through celite and concentrated to an oil which was purified by column chromatography on silica (15 to 60% EtOAc/hexanes) to give the product as a brown foam, 0.12 g, 0.26 mmol, 38% yield. MH+ 470.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:5][CH2:6]O.S(Cl)([Cl:15])=O>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:5][CH2:6][Cl:15]
Reactant: COc1ccc(CCO)cc1O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CCCl)cc1O
Yield: 33 %

Procedure:
A mixture of 3-hydroxy-4-methoxyphenethyl alcohol (2.25 g) and thionyl chloride (5 ml) in methylene chloride (120 ml) was heated under reflux for 16 hours and evaporated. The residue was azeotroped twice with hexane and purified by chromatography on silica (30 g) using methylene chloride plus 0-6% methanol as the eluant. Appropriate fractions were combined and evaporated to give the title compound as a colourless solid (0.82 g, 33%), m.p. 53°-54°, which was characterised by its 1H-n.m.r. spectrum.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH:7][C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=1>[OH-].[Na+]>[F:15][C:14]([F:16])([F:17])[C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[O:7][CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C(O)CCCl
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCOc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 16.9 %

Procedure:
3-Chloropropionic acid (25 g) was added dropwise to a 2 N aqueous sodium hydroxide solution (120 mL) of 3-hydroxybenzotrifluoride (25 g). The reaction mixture was refluxed for one hour while the pH was maintained at 10 or more with a 5 N aqueous sodium hydroxide solution. The reaction mixture was cooled to room temperature and was then washed with diethyl ether. Subsequently, 1 N hydrochloric acid was added thereto so that the solution became acidic. The reaction mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and a saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and n-hexane was then added to the residue to perform crystallization. The title compound (6.1 g) was obtained as colorless crystals.