Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([CH2:13][CH2:14][C:15]([OH:17])=O)=[O:12].[NH:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([CH2:13][CH2:14][C:15]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21])=[O:17])=[O:12]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(O)CCC(=O)c1ccc2ccccc2n1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)c1ccc2ccccc2n1

Procedure:
As for Example 6, 3-(2-quinolylcarbonyl)propionic acid (0.01 mole) is coupled to L-proline (0.011 mole) with 1,1'-carbonyldiimidazole (0.01 mole) in tetrahydrofuran to give 1-[3-(2-quinolylcarbonyl)propionyl]-L-proline. Bromination of the preceding compound and reaction of the resulting compound with sodium thioacetate gives the product of the Example.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:29])[C:4]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.I[CH2:31][CH3:32].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:31]([O:1][C:2]1[C:3](=[O:29])[C:4]([C:18]2[N:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:21]=[CH:20][CH:19]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:15])[F:17])[CH:9]=2)[CH:7]=1)[CH3:32]
Reactant: CCI
Reactant: O=c1c(O)cn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cn(-c2cccc(C(F)(F)F)c2)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.3 %

Procedure:
A suspension of 5-hydroxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (100 mg, 0.25 mmol), iodoethane (0.040 mL, 0.50 mmol), and K2CO3 (104 mg, 0.75 mmol) in DMF (1 mL) was stirred for 24 h at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane/AcOEt (1/1) to give the title compound (94.1 mg, 88% yield) as an off-white amorphous solid: 1H NMR (300 MHz, CDCl3): δ ppm 1.52 (3H, t, J=6.8 Hz), 4.21 (2H, q, J=6.8 Hz), 7.03 (1H, dd, J=1.9, 7.9 Hz), 7.18 (1H, s), 7.33-7.46 (7H, m), 7.55 (1H, d, J=7.9 Hz), 7.80 (1H, d, J=1.9 Hz), 7.94 (1H, s). LC-MS (ESI) m/z 427 [M+H]+. Anal. Calcd for C22H17F3N4O2: C, 61.97; H, 4.02; N, 13.14. Found: C, 61.82; H, 4.15; N, 13.17.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[S:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]2=[C:4]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:3]=1.[CH2:25]([CH2:27][NH2:28])[OH:26]>C(Cl)Cl>[C:11]1([C:10]2[C:5]3[C:6](=[N:7][C:2]([NH:28][CH2:27][CH2:25][OH:26])=[CH:3][C:4]=3[NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[S:8][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCCO
Reactant: Clc1cc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Solvent: ClCCl
Product: OCCNc1cc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Temperature: 200 °C

Procedure:
A mixture of (6-chloro-3-phenyl-thieno[2,3-b]pyridin-4-yl)-pyridin-2-ylmethyl-amine (20 mg, 0.57 mmol) and ethanolamine (1 ml) were heated to 200° C. in the microwave and maintained at this temperature for 90 min. On cooling, the reaction mixture was poured into DCM (50 ml) and washed with water (2×50 ml), dried (Na2SO4), and concentrated. The residue was purified on silica (ethyl acetate, 100%) to give 2-{3-phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-b]pyridin-6-ylamino}-ethanol as a white solid. Yield=18 mg (83.9%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:21])[NH:8][CH2:9][CH2:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[N:12]=2)=[C:5]([C:22](O)=[O:23])[N:4]=[C:3]1[CH3:25].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:16][N:15]1[C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[N:12]=[C:11]1[CH2:10][CH2:9][NH:8][C:7]([C:6]1[N:2]([CH3:1])[C:3]([CH3:25])=[N:4][C:5]=1[C:22]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:23])=[O:21]
Reactant: C1COCCN1
Reactant: Cc1nc(C(=O)O)c(C(=O)NCCc2nc3ccccc3n2C)n1C
Product: Cc1nc(C(=O)N2CCOCC2)c(C(=O)NCCc2nc3ccccc3n2C)n1C

Procedure:
The product was obtained starting from 1,2-dimethyl-5-(2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethylcarbamoyl)-1H-imidazole-4-carboxylic acid (51 mg, 149 μmol) and morpholine (39.0 μL, 448 μmol) according to the method described in example 8, step 3 as light brown waxy solid (17.3 mg, 42.1 μmol, 28.2%). MS: M=411.3 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:23](=O)([O-])[O-].[Na+].[Na+].CI>CN(C=O)C>[CH3:23][O:13][C:12](=[O:14])[C@@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.1 %

Procedure:
To a suspension of (S)-3-[4-nitrophenyl]-2-tert-butoxycarbonylamino-propionic acid (70.2 g, 226.2 mmol) and sodium carbonate (95 g, 1.13 mole) in DMF (500 mL) was added methyl iodide (70.4 mL, 1.13 mole) at room temperature. The suspension was stirred for 15 h at room temperature at which time TLC analysis of the mixture indicated the absence of starting material and the excess methyl iodide and some DMF were removed under high vacuum. Then, it was poured into water (2 L) and stirred at room temperature as a precipitate formed slowly over 72 h. The precipitated solids were collected by filtration and washed with water (2 L). After air and vacuum drying, 72 g (98% yield) of (S)-3-[4-nitrophenyl]-2-tert-butoxycarbonylamino-propionic acid methyl ester was isolated as a light yellow solid (mp 95-96° C.). ES(+)-HRMS m/e calcd. for C15H20N2O6 (M+H)+ 325.1400, obsd. 325.1404.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][O:12][CH2:13][CH2:14]I.CC(C)=O.C([O-])([O-])=O.[K+].[K+].COCCI>C1(C)C=CC=CC=1.CC(C)=O>[CH3:11][O:12][CH2:13][CH2:14][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: COCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: COCCOc1ccc2[nH]ccc2c1
Yield: 86.2 %

Procedure:
To a solution of 5-hydroxy-indole (15.2 g, 114 mmol) in 250 ml of dry acetone 2-methoxyethyl iodide (15 ml, 141 mmol, 1.25 equiv) and anhydrous K2CO3 (46.7 g, 338 mmol, 3 equiv) are added and the mixture is refluxed. Additional amounts of 0.5 equiv of 2-methoxyethyl iodide and K2CO3 are added each day. After 6 days TLC (toluene-acetone, 9:1) indicates the absence of starting material. The solid is removed by filtration, and the solvent is evaporated. The residue is taken up in dichloromethane (800 ml) and the solution is washed with 2 M aqueous HCl, 10% aqueous NaHCO3, and water. The organic layer is dried and concentrated. Column chromatography (toluene-acetone, 9:1) provides 5-(2-methoxyethoxy)-1H-indole (18.8 g, 86%). M.p. 58-60° C. (from ethyl acetate-light petroleum).
Reaction SMILES: [CH3:1][CH:2]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)=[O:4].Cl.ClC1C=C(C(=O)C(NC(C)(C)C)C)C=CC=1.C(N(CC)CC)C.[C:41](Cl)(=[O:65])[O:42][CH2:43][O:44][C:45](=[O:64])[C:46]1[CH:51]=[C:50]([S:52]([NH2:55])(=[O:54])=[O:53])[C:49]([Cl:56])=[CH:48][C:47]=1[NH:57][CH2:58][C:59]1[O:60][CH:61]=[CH:62][CH:63]=1>C(#N)C>[NH2:55][S:52]([C:50]1[C:49]([Cl:56])=[CH:48][C:47]([NH:57][CH2:58][C:59]2[O:60][CH:61]=[CH:62][CH:63]=2)=[C:46]([CH:51]=1)[C:45]([O:44][CH2:43][O:42][C:41]([N:12]([C:13]([CH3:15])([CH3:14])[CH3:16])[CH:2]([CH3:1])[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)=[O:4])=[O:65])=[O:64])(=[O:53])=[O:54]
Reactant: CC(NC(C)(C)C)C(=O)c1cccc(Cl)c1
Reactant: NS(=O)(=O)c1cc(C(=O)OCOC(=O)Cl)c(NCc2ccco2)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C(=O)c1cccc(Cl)c1)N(C(=O)OCOC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1)C(C)(C)C

Procedure:
A solution of bupropion[1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride (700), (U.S. Pat. Nos. 3,819,706 and 3,885,046) (0.025 mole), triethylamine (0.055 mole) and acetonitrile (30 mL) is stirred with cooling on an ice bath. A solution of 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxymethyl carbonochloridate (1010) (0.025 mole) in acetonitrile (30 mL) is added dropwise. After the addition is complete, the reaction is heated to reflux for 2 hours. The reaction is cooled, the volatiles removed by spin evaporation, and the residue partitioned between dichloromethane and 5% aqueous sodium bicarbonate. The organic layer is washed with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give a solid that may be recrystallized to give 2-[(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxymethoxycarbonyl)(1,1-dimethylethyl)amino]-1-(3-chlorophenyl)-1-propanone (1020). See eg., U.S. Pat. No. 5,104,870 and Sandler, et al., Organic Functional Group Preparations, p. 324 (1968).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]4[CH:26]=[CH:27][C:28]([C:30]5[CH:31]=[N:32][C:33]([O:36]C)=[CH:34][CH:35]=5)=[CH:29][C:24]4=[N:23][CH:22]=3)=[CH:17][CH:16]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>Br>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:25]4[CH:26]=[CH:27][C:28]([C:30]5[CH:35]=[CH:34][C:33](=[O:36])[NH:32][CH:31]=5)=[CH:29][C:24]4=[N:23][CH:22]=3)=[CH:19][CH:20]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(-c2ccn3c(-c4ccc(CNC(=O)Nc5cc(C(C)(C)C)on5)cc4)cnc3c2)cn1
Agent: Br
Product: CC(C)(C)c1cc(NC(=O)NCc2ccc(-c3cnc4cc(-c5ccc(=O)[nH]c5)ccn34)cc2)no1
Temperature: 80 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
Dissolve 1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(6-methoxy-pyridin-3-yl)-imidazo[1,2-a]pyridin-3-yl]-benzyl}-urea (0.408 g, 0.82 mmol, 1.0 eq.) in HBr (˜48%, 4 mL) and stir at 80° C. overnight under nitrogen. Evaporate the reaction mixture under vacuum and purify in four steps: 1) flash SCX, 2) reverse phase HPLC The mixture is purified via reversed phase C18 column HPLC employing a gradient of 5 to 65% acetonitrile vs 0.03% aqueous HCl, 3) flash SCX, and 4) silica gel chromatography using a 0-10% MeOH/DC gradient to give the title compound 0.156 g as a white solid: MS(ES), m/z 483 (M+1).
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:12](=[O:13])[C:11]([Cl:14])=[C:10]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=2)[C:9]([O:28][CH:29]([CH2:31][CH3:32])[CH3:30])=[N:8]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>COCCOC>[Cl:14][C:11]1[C:12](=[O:13])[NH:7][N:8]=[C:9]([O:28][CH:29]([CH2:31][CH3:32])[CH3:30])[C:10]=1[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH3:27])[CH:18]=1
Reactant: CCOc1cc(CNc2c(OC(C)CC)nn(COCC[Si](C)(C)C)c(=O)c2Cl)ccc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: COCCOC
Product: CCOc1cc(CNc2c(OC(C)CC)n[nH]c(=O)c2Cl)ccc1OC
Reaction time: 3 h

Procedure:
A mixture comprising 150 mg of 2-(2-trimethylsilylethoxymethyl)-4-chloro-5-(3-ethoxy-4-methoxybenzylamino)-6-sec-butoxy-3(2H)pyridazinone prepared in Reference Example 4, 1.46 ml of tetra-n-butylammonium fluoride (1M tetrahydrofuran solution) and 5 ml of 1,2-dimethoxyethane, was refluxed under stirring for 3 hours. The solvent was distilled off under reduced pressure, and the residue thereby obtained was extracted with chloroform. The extract was washed twice with 1N hydrochloric acid and once with water in this order and dried over sodium sulfate. Then, the solvent was distilled off to obtain a dark brown oily substance. The oily substance was purified by silica gel preparative thin layer chromatography by using ethyl acetate as the developer, to obtain a light yellow solid substance. The product was crystallized from chloroform-diethyl ether, to obtain 50 mg of the above identified compound having a melting point of from 130.5° to 132° C. as slightly yellow crystals.
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.[Cl:10][C:11]1[C:12]([F:19])=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=1[O:48][CH3:49]>C1COCC1.[Zn].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]>[Cl:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:13]([CH2:14][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=2[O:48][CH3:49])[C:12]=1[F:19]
Reactant: COc1ccc(Br)c(OC)c1
Reactant: Fc1c(Cl)cccc1CBr
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COc1ccc(Cc2cccc(Cl)c2F)c(OC)c1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
THF (5 volumes) and zinc dust (2.4 eq) were charged to a round bottom flask under nitrogen. The slurry was heated to 60° C. and held for 15 min. 1,2-Dibromoethane (0.2 eq) was added and the mixture agitated at 60° C. for 30 min. The mixture was cooled to ambient temperature before 0.4 eq. chlorotrimethylsilane was added. 3-Chloro-2-fluorobenzylbromide (2.0 eq) dissolved in THF was added over 2 h at 0° C. Agitation was stopped and the mixture allowed to settle overnight to give 7 as a solution in THF. Next, 0.16 eq Pd2dba3 and 0.35 eq. triphenylphosphine were charged to a separate flask under argon. THF (10 volumes) and 1-bromo-2,4-dimethoxybenzene were added followed by the solution of compound 7 prepared above. The mixture was heated to 65° C. and agitated overnight. The mixture was cooled to room temperature and quenched with aqueous NH4OH. The organic phase was purified by column chromatography to yield compound 5: 1H NMR (400 MHz, CDCl3): δ 7.33 (td, 1H, J=7, 2 Hz), 7.07-6.99 (m, 2H), 6.91 (d, 1H, J=8 Hz), 6.49 (d, 1H, J=8 Hz), 6.40 (dd, 1H, J=8, 2 Hz), 3.80 (s, 2H), 3.68 (s, 3H), 3.67 (s, 3H).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[C:11]([C:20]2[C:21]([CH3:35])=[CH:22][C:23]3[O:28][C:27]([CH3:30])([CH3:29])[C:26](=[O:31])[N:25]([CH2:32][CH3:33])[C:24]=3[CH:34]=2)[CH:10]=1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH2:32]([N:25]1[C:24]2[CH:34]=[C:20]([C:11]3[CH:10]=[C:9]([CH:8]=[CH:7][C:6]([OH:36])=[O:5])[CH:14]=[CH:13][C:12]=3[O:15][C:16]([F:19])([F:17])[F:18])[C:21]([CH3:35])=[CH:22][C:23]=2[O:28][C:27]([CH3:30])([CH3:29])[C:26]1=[O:31])[CH3:33]
Reactant: CCN1C(=O)C(C)(C)Oc2cc(C)c(-c3cc(C=CC(=O)OC(C)(C)C)ccc3OC(F)(F)F)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN1C(=O)C(C)(C)Oc2cc(C)c(-c3cc(C=CC(=O)O)ccc3OC(F)(F)F)cc21
Yield: 98.2 %

Procedure:
A solution of Compound 1E (1.71 g, 3.4 mmol) in 15 mL of dichloromethane and 5 mL of trifluoroacetic acid was stirred at room temperature overnight. The reaction mixture was then concentrated on the rotary evaporator and redissolved in 20 mL of diethyl ether. To this solution, hexanes were added to give a cloudy solution from which 1.5 g (100%) of product precipitated out as a white solid (Compound 1). MS (electrospray): mass calculated for C23H22F3NO5, 449.15; m/z found 462.3, [M+H]+.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:13]2[S:14][C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:16]([CH3:18])[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11].[F:24][B-](F)(F)F.O=[N+]=O>C(Cl)Cl>[F:24][C:2]1[CH:3]=[C:4]([C:13]2[S:14][C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:16]([CH3:18])[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: CCOC(=O)c1sc(-c2ccc(OCC(C)C)c(N)c2)nc1C
Reactant: F[B-](F)(F)F
Agent: O=[N+]=O
Solvent: ClCCl
Product: CCOC(=O)c1sc(-c2ccc(OCC(C)C)c(F)c2)nc1C
Reaction time: 4 h
Yield: 53 %

Procedure:
330 mg of Ethyl 2-(3-amino-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylate was dissolved in 15 ml of methylene chloride, 130 mg of nitronium tetrafluoroborate was added thereto with ice cooling, followed by stirring for 4 hours. The reaction mixture was concentrated, irradiated with a UV lamp at 300 nm for 20 hours and purified by silica gel chromatography to give 175 mg of ethyl 2-(3-fluoro-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylate. This product was hydrolyzed by a conventional process and recrystallized from acetone-water to give 108 mg of 2-(3-fluoro-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid (yield: 35%).
Reaction SMILES: [Br:1][CH:2]([CH:5]=O)[CH:3]=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].Cl>C(O)C>[Br:1][C:2]1[CH:3]=[N:12][C:11]2[C:13]([CH:5]=1)=[CH:14][CH:15]=[C:9]([O:8][CH3:7])[CH:10]=2
Reactant: COc1cccc(N)c1
Reactant: O=CC(Br)C=O
Agent: Cl
Solvent: CCO
Product: COc1ccc2cc(Br)cnc2c1
Temperature: 30 °C
Reaction time: 24 h
Yield: 3.5 %

Procedure:
To a solution of bromo-malonaldehyde (10 g, 66.2 mmol) in absolute ethanol (100 mL) was added 3-methoxyaniline (7.3 g, 59.6 mmol). The mixture was heated to 30° C. and stirred at that temperature for 24 h. Conc. HCl (100 mL) was added, and the reaction mixture was heated at 100° C. for two days. After the mixture was concentrated and the residue was partitioned between ethyl acetate (150 mL) and saturated sodium carbonate (50 mL). The organic phase was washed with brine, dried with anhydrous Na2SO4 and concentrated to give a black oil, which was purified by column chromatography (PE/EA=3/1) to give Intermediate 13 as a brown oil (500 mg, 3.8%). MS (ESI): m/z 237.9 [M+1]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1Br.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.C(O)C>C(OCC)C.O.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>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: Brc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(=O)c1cccc(-c2ccccc2Br)c1
Temperature: 90 °C
Yield: 63.2 %

Procedure:
A mixture of 3-acetylphenylboronic acid (1.64 g, 10 mmol), 1,2-dibromobenzene (4.72 g, 20 mmol), potassium carbonate (6.9 g, 50 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.58 g, 0.5 mmol) in 1:1 toluene/ethanol (40 ml) was stirred and heated at 90° C. under nitrogen for 16 hours. After cooling the mixture was diluted with diethyl ether and water and the organic phase dried (MgSO4) and evaporated to dryness. The residue was purified by chromatography using Biotage with iso-hexane containing a gradient of dichloromethane (20-50%) to yield the title compound as a white solid (1.74 g 63%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:11]=O)[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.O1CCC[CH2:14]1>>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2([CH:11]=[CH2:14])[CH2:10][CH2:9]2)[CH:3]=1
Reactant: O=CC1(c2cncc(Br)c2)CC1
Reactant: C1CCOC1
Product: C=CC1(c2cncc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyltriphenylphosphonium bromide-sodium amide complex (510 mg, 01.22 mmol) in tetrahydrofuran (2.0 mL) was added a solution of the title compound from Example 73 Step B (97 mg, 0.43 mmol) in tetrahydrofuran (1.0 mL) The reaction stirred at room temperature for 16 hours. It was then quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic extracts were combined, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel (0-100% ethyl acetate in hexanes) provided the title compound: LCMS m/z 225.77 [M+H]+; 1H NMR (500 MHz, CD3OD) δ 8.54 (s, 1H), 8.47 (s, 1H), 7.50 (s, 1H), 5.68 (dd, J=10.4, 17.1, 1 H), 4.98 (d, J=10.4, 1 H), 4.62 (d, J=17.1, 1 H), 1.12-1.05 (m, 4H).
Reaction SMILES: [S:1]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(O)(=[O:3])=[O:2].O=P(Cl)(Cl)[Cl:13]>>[Cl:13][S:1]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)CS(=O)(=O)O
Product: CCOC(=O)CS(=O)(=O)Cl

Procedure:
1H NMR (CDCl3):δ1.35 (t, 3H), 4.1 (s, 2H), 4.25 (q, 2H). Amixture of ethyl sulfoacetate (16.82 g, 100 mM) and POCl3 (30.67 g, 200 mM) was heated at 125° C. for 5 hours. The mixture was cooled and filtered, and excess POCl3 was removed to give ethyl chlorosulfonylacetate. The ethyl chlorosulfonylacetate (8.18 g, 43.83 mM) was added dropwise with stirring to a solution of 2,6-diisopropylaniline (15.54 g, 87.66 mM) in 50 mL CH2Cl2 maintained at 0° C. The mixture was stirred at room temperature for an additional 18 hours. The solvent was removed and the residue was redissolved in 100 mL ethyl acetate and washed with 1N HCl and brine. The ethyl acetate was evaporatedand the pure compound was isolated by chromatography over silica gel (EtOAc/hexane, 1:4 as eluant) as a white powder identified as ethyl (2,6-diisopropylphenylsulfamoyl)acetate, 7.0 g (≈50%), mp 74°-77° C.
Reaction SMILES: [OH:1][P:2]([CH:16]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH2:4][CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6](O)=[O:7])=[O:3].[NH2:35][C@H:36]([C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[OH:3][P:2]([CH2:4][CH:5]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:6]([NH:35][C@H:36]([C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:7])([CH:16]([NH:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:1]
Reactant: O=C(NC(Cc1ccccc1)P(=O)(O)CC(Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC(Cc1ccccc1)P(=O)(O)CC(Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Yield: 70.3 %

Procedure:
To 200 mg (0.42 mmol) of 3-[hydroxy[2-phenyl-1-[[(phenylmethoxy)carbonyl]amino]ethyl]phosphinyl]-2-(phenylmethyl)propanoic acid, 178 mg (0.42 mmol) of phenylmethyl L-phenylalaninate in the form of the p-toluenesulphonic acid salt and 384 mg (0.87 mmol) of BOP in 0.8 ml of dimethylformamide is added, with stirring at a temperature in the region of 20° C., 0.7 ml of diisopropylethylamine. After reaction for 30 minutes at this temperature, the dimethylformamide is evaporated off under reduced pressure and 12 ml of 1N hydrochloric acid are added to the oily residue obtained. The precipitate is filtered off, washed with water and dried. 210 mg of product are recovered (yield=70.3%).