Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:47])/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([O:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[C:25](=[O:37])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[CH:20][CH:19]=1)(C)(C)C.Cl>CO>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:47])/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([O:38][CH2:39][CH2:40][N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[C:25](=[O:37])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccc(C(OCCN2CCOCC2)C(=O)Nc2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Solvent: CO
Product: Nc1ccccc1NC(=O)/C=C/c1ccc(C(OCCN2CCOCC2)C(=O)Nc2ccc(C(F)(F)F)cc2)cc1
Yield: 16.9 %

Procedure:
(E)-[2-(3-{4-[(2-Morpholin-4-yl-ethoxy)-(4-trifluoromethyl-phenylcarbamoyl)-methyl]-phenyl}-acryloylamino)-phenyl]-carbamic acid tert-butyl ester (118 mg, 0.177 mmol) was treated with 1.25M HCl in methanol (1 mL) at room temperature for 2 hours. The reaction was quenched slowly with solid sodium bicarbonate until the pH was 6-7. The mixture was diluted in acetonitrile with a small amount of dimethylsulfoxide, passed through a 40 μm pipette filter, and then purified by preparative HPLC to obtain 17 mg desired product (17%). MS: calc'd 569 (MH+) exp 569 (MH+). 1H NMR (d6-DMSO, 400 MHz) δ 10.6 (s, 1H, rotamer a), 10.4 (s, 1H, rotamer b), 9.43 (s, 1H), 7.91 (d, 2H, J=8.0 Hz), 7.70 (d, 2H, J=8.8 Hz), 7.65 (d, 2H, J=8.0 Hz), 7.58 (d, 2H, J=8.8 Hz), 7.55 (d, 1H, J=15.6 Hz), 7.34 (d, 1H, J=6.4 Hz), 6.92 (d, 1H, J=15.6 Hz), 6.91 (t, 1H, J=6.4 Hz), 6.75 (d, 1H, J=7.4 Hz), 6.57 (t, 1H, J=7.4 Hz), 5.11 (s, 1H), 4.96 (s, 2H), 3.70 (broad m, 4H), 3.55 (broad m, 2H), 2.70-2.35 (broad m, 6H).
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][CH2:4][C@H:3]([NH2:12])[CH2:2]1.CC1C=CC(S(O[CH2:24][C@H:25]([CH3:36])[CH2:26][S:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])(=O)=O)=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:35][O:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[S:27][CH2:26][C@@H:25]([CH3:36])[CH2:24][NH:12][C@H:3]1[CH2:4][S:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:1][CH2:2]1
Reactant: N[C@@H]1COc2ccccc2SC1
Reactant: COc1ccccc1SC[C@@H](C)COS(=O)(=O)c1ccc(C)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccccc1SC[C@@H](C)CN[C@@H]1COc2ccccc2SC1
Temperature: 105 °C
Reaction time: 24 h

Procedure:
6.5 g (35.9 mmol) of (R)-3,4-dihydro-2H-1,5-benzoxathiepin-3-amine and 11 g (30 mmol) of (S)-3-(2-methoxyphenyl-sulfanyl)-2-methylpropyl 4-methylbenzenesulfonate in 33 ml of toluene are introduced into a three-necked flask under an inert atmosphere. 6 g (60 mmol) of triethylamine are added and then the reaction mixture is heated with stirring at 105° C. for 24 hours. After returning to ambient temperature, 33 ml of toluene are added. The organic phase is washed twice with 66 ml of demineralised water and is then decolourised by stirring for one hour in the presence of 2 g of Black CXV. After concentrating under reduced pressure, driving-off with 33 ml of ethanol 100 is carried out. The title product is obtained in the form of a yellow oil (8.85 g; 79%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]([C:13]([OH:15])=O)[O:3]1.[N+]([O-])(O)=O.[N+:20]([O:23][CH2:24][CH2:25][NH2:26])([O-:22])=[O:21].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>>[N+:20]([O:23][CH2:24][CH2:25][NH:26][C:13]([CH:4]1[O:3][C:2](=[O:1])[NH:6][CH:5]1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:15])([O-:22])=[O:21]
Reactant: O=C1NC(c2ccccc2)C(C(=O)O)O1
Reactant: NCCO[N+](=O)[O-]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O=[N+]([O-])O
Product: O=C1NC(c2ccccc2)C(C(=O)NCCO[N+](=O)[O-])O1
Yield: 7.5 %

Procedure:
Following a procedure similar to that described in Example 1, but using 112 mg of 2-oxo-4-phenyloxazolidine-5-carboxylic acid, 110 mg of N-(2-nitrooxyethyl)amine nitrate and 0.24 ml of diphenylphosphoryl azide, 12 mg of the title compound were obtained as colorless crystals, melting at 122°-124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Product: O=C(Nc1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1)c1ccccc1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridin-3-ylamine and benzoic acid as starting materials, MS (LC/MS): 379.2 (M+H).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24]O)[CH:16]=4)[CH:11]=[C:10]([C:26]([NH:28][CH2:29][C:30]4[C:31](=[O:38])[NH:32][C:33]([CH3:37])=[CH:34][C:35]=4[CH3:36])=[O:27])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:59].O>C(Cl)Cl>[Br:59][CH2:24][CH2:23][CH2:22][O:21][C:17]1[CH:16]=[C:15]([C:12]2[CH:11]=[C:10]([C:26]([NH:28][CH2:29][C:30]3[C:31](=[O:38])[NH:32][C:33]([CH3:37])=[CH:34][C:35]=3[CH3:36])=[O:27])[C:9]3[CH:8]=[N:7][N:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[C:14]=3[CH:13]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(OCCCO)c3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(OCCCBr)c3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.3 %

Procedure:
To a stirred solution of 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(3-(3-hydroxypropoxy)phenyl)-1H-indazole-4-carboxamide (0.35 g, 0.68 mmol) in DCM (5 mL), triphenyl phosphine (0.285 g, 1.08 mmol) was added and the reaction mixture stirred at room temperature for 10 min Finally CBr4 (0.36 g, 1.08 mmol) was added portion wise and resulting solution was stirred at room temperature for 4 h. On completion, water was added to the reaction mixture and extracted with 5% MeOH/DCM. The combined organic layer was dried over sodium sulfate and concentrated to give crude material which was purified by column chromatography over silica gel to afford 6-(3-(3-bromopropoxy) phenyl)-1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (0.28 g, 71%).
Reaction SMILES: C1CO[C:8]2[CH:7]=[CH:6][C:5]([NH:11][C:12]3[C:17]([F:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22](O)[CH:21]=4)[N:13]=3)=[CH:4][C:3]=2[O:2]1.[S:27]1[C:31]2C=CC=CC=2[C:29](CN)=[CH:28]1>>[S:27]1[C:28]2[CH:29]=[CH:21][CH:22]=[CH:23][C:24]=2[C:25]([CH2:20][NH:19][C:14]2[N:13]=[C:12]([NH:11][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=3)[C:17]([F:18])=[CH:16][N:15]=2)=[CH:31]1
Reactant: NCc1csc2ccccc12
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Product: Oc1cccc(Nc2nc(NCc3csc4ccccc34)ncc2F)c1
Yield: 53 %

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3hydroxyphenyl)-4-pyrimidinediamine (50 mg, 0.21 mmol) and benzothiophen-3-ylmethylamine (100 mg, 0.61 mmol) gave N2-(benzothiophen-3-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine (40 mg, 53%). 1H NMR (CDCl3): δ 4.82 (d, J=6.0 Hz, 2H), 6.45 (dd, J=8.1 Hz, 1H), 6.70 (m, 1H), 6.80 (d, J=8.4 Hz, 1H), 7.03 (t, J=8.1 Hz, 1H), 7.22 (m, 1H), 7.34 (s, 1H), 7.39–7.46 (m, 2H), 7.82 (m, 1H), 7.89–7.92 (m, 2H); 19F NMR (282 MHz, CDCl3): δ −170.02; LCMS: ret. time: 21.29 min.; purity: 92.97%; MS (m/e): 367.03 (MH+).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[OH:14].[C:15](Cl)(=[O:17])[CH3:16]>CN(C=O)C.C(Cl)Cl>[C:15]([O:14][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH:1]=1)(=[O:17])[CH3:16]
Reactant: Oc1ccc2c(c1)[nH]c1ccccc12
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(c1)[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To 9H-carbazol-2-ol (915 mg, 5 mmol) in 10 mL DMF and 20 mL DCM was added TEA (1.0 g, 10 mmol), followed by acetyl chloride (589 mg, 7.5 mmol) at 0° C. The reaction mixture was then stirred at rt for 1 h and poured onto ice (50 g). The mixture was extracted with EtOAc (2×60 mL) and combined organic phase was dried over MgSO4 and concentrated. The crude product was purified by silica chromatography to afford 9H-carbazol-2-yl acetate (WZ02013) as an off-white solid (800 mg, 71%). MS (ESI) m/z 348 (M+H+).
Reaction SMILES: [CH2:1]([C:6]1[S:10][C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:22])[CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=2)=[O:13])=[N:8][C:7]=1[C:23](O)=[O:24])[CH2:2][CH:3]([CH3:5])[CH3:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][N:51]([CH2:53][CH2:54][CH2:55][NH2:56])[CH3:52]>CN(C=O)C.CN1CCOCC1>[CH3:50][N:51]([CH3:52])[CH2:53][CH2:54][CH2:55][NH:56][C:23]([C:7]1[N:8]=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:22])[CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=2)=[O:13])[S:10][C:6]=1[CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])=[O:24]
Reactant: CN(C)CCCN
Reactant: CC(C)CCc1sc(NC(=O)c2cc([N+](=O)[O-])cn2C)nc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)CCc1sc(NC(=O)c2cc([N+](=O)[O-])cn2C)nc1C(=O)NCCCN(C)C

Procedure:
5-Isopentyl-2-{[(1-methyl-4-nitro-1H-pyrrol-2-yl)carbonyl]amino}-1,3-thiazole-4-carboxylic acid (570 mg, 1.56 mmol; see step (iv) above) was dissolved in DMF (2.5 mL, dry) to which NMM (0.5 mL, dry), HBTU (1.18 g, 3.12 mmol) and dimethylaminopropylamine (318 mg, 3.12 mmol, Aldrich) were added at room temperature with stirring. After the standard work up and purification, the sub-title compound was obtained as a yellow solid (660 mg, 94%), m.p.>230° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([N+:27]([O-:29])=[O:28])=[C:24]([CH:26]=1)[NH2:25]>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([N+:27]([O-:29])=[O:28])=[C:24]([CH:26]=1)[NH:25][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: COc1ccc([N+](=O)[O-])c(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Product: COc1ccc([N+](=O)[O-])c(Nc2cc(C(F)(F)F)nc(-c3cnccn3)n2)c1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (40 mg, 0.153 mmol) and 5-methoxy-2-nitroaniline (39 mg, 0.230 mmol), similar to Example 180 and was isolated as an off white solid (35 mg, 58%). 1H NMR (CDCl3): 9.69 (d, J=1.5 Hz, 1H), 8.83 (dd, J=1.5, 2.4 Hz, 1H), 8.72 (d, J=2.4 Hz, 1H), 8.08 (d, J=9.6 Hz, 1H), 7.11 (s, 1H), 6.27 (dd, J=2.7, 9.6 Hz, 1H), 6.15 (d, J=2.7 Hz, 1H), 3.83 (s, 3H).
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[C:5]([CH2:11][CH3:12])[CH:4]=1.Br[C:16]1[CH:17]=[CH:18][C:19]2[N:25]([CH3:26])[CH2:24][CH2:23][C:22]([C:27]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([CH2:36][N:37]([CH3:44])[CH:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[CH:32][CH:31]=3)=[O:28])=[CH:21][C:20]=2[CH:45]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[CH2:11]([C:5]1[CH:4]=[C:3]([C:16]2[CH:17]=[CH:18][C:19]3[N:25]([CH3:26])[CH2:24][CH2:23][C:22]([C:27]([NH:29][C:30]4[CH:31]=[CH:32][C:33]([CH2:36][N:37]([CH3:44])[CH:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)=[CH:34][CH:35]=4)=[O:28])=[CH:21][C:20]=3[CH:45]=2)[CH:8]=[CH:7][C:6]=1[CH2:9][CH3:10])[CH3:12]
Reactant: CCc1ccc(OB([O-])[O-])cc1CC
Reactant: CN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
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: CCOC(C)=O
Solvent: CCO
Product: CCc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C)cc1CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
In a mixture of water:ethanol:toluene (1:1:10, v/v, 18.0 ml) were dissolved 3,4-diethylphenyl borate (264 mg) and 7-bromo-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (406 mg), and to the solution was added potassium carbonate (162 mg). The mixture was stirred under argon atmosphere at room temperature for 30 minutes, and to the mixture was added tetrakistriphenylphosphinepalladium (39 mg). The mixture was refluxed under argon atmosphere for 13 hours, diluted with ethyl acetate and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (45 g, ethyl acetate:ethanol=20:1) and recrystallized from ethanol to give 7-(3,4-diethylphenyl)-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (263 mg, 55%) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=3)[N:13]([CH2:21][CH2:22][CH3:23])[C:12]=2[CH3:24])=[CH:5][CH:4]=1.[CH2:25]([O:27][C:28](=[O:33])[C:29](Br)([CH3:31])[CH3:30])[CH3:26]>>[CH2:25]([O:27][C:28](=[O:33])[C:29]([O:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:21][CH2:22][CH3:23])[C:12]([CH3:24])=[C:11]2[CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)([CH3:31])[CH3:30])[CH3:26]
Reactant: CCCn1c(C)c(CCc2ccc(OC)cc2)c2cc(O)ccc21
Reactant: CCOC(=O)C(C)(C)Br
Product: CCCn1c(C)c(CCc2ccc(OC)cc2)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
In accordance with a procedure analogous to that of Example 10, the above compound was prepared from 3-[2-(4-methoxy-phenyl)-ethyl]-2-methyl-1-propyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester.
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:31])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[CH:17][C:16]=1[Cl:32].[CH3:41][C:42]1[S:43][C:44]([CH:48]=O)=[C:45]([CH3:47])[N:46]=1>O1CCCC1>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:31])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[CH:17][C:16]=1[Cl:32])=[CH:48]/[C:44]1[S:43][C:42]([CH3:41])=[N:46][C:45]=1[CH3:47]
Reactant: COC(=O)C(NC(=O)c1ccc(C(O)CCc2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Reactant: Cc1nc(C)c(C=O)s1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1sc(C)nc1C)NC(=O)c1ccc(C(O)CCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.2 %

Procedure:
1,1,3,3-Tetramethylguanidine (60 μL, 0.48 mmol) was added to a solution of rac.-N-[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propan-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 134; 120 mg, 0.24 mmol) in tetrahydrofuran (5 mL) at −20° C. After 10 min, 2,4-dimethylthiazole-5-carboxaldehyde (Example 43; 36 mg, 0.255 mmol) was added and the solution was stirred at room temperature for 16 h. After the volatiles were removed in vacuo, ethyl acetate (10 mL) was added. The resulting solution was washed with saturated sodium bicarbonate solution (5 μL) and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried (MgSO4), filtered, evaporated and chromatographed over silica gel (3:2 ethyl acetate/hexanes). The appropriate fractions were combined, evaporated and the residue triturated with diethyl ether to yield rac.-(Z)-2-[[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propan-1-yl]benzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid methyl ester (88 mg, 75% yield) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14](O)[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:4][CH:3]=1.[CH2:23]([O:25][C:26]([CH:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:27])[CH3:24].CP(C)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([C:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])([C:26]([O:25][CH2:23][CH3:24])=[O:27])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[C:19]([CH3:21])([CH3:22])[CH3:20])=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(O)CCC2
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)C1CCCc2nc(C(C)(C)C)n(Cc3ccc(Cl)cc3)c21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of Intermediate 54 (82 mg) and triethylmethanetricarboxylate (0.11 mL) in anhydrous toluene (3 mL) and anhydrous tetrahydrofuran (3.00 mL) under a nitrogen atmosphere was added trimethylphosphine, 1M in toluene (0.52 mL). The reaction was then cooled to −78° C. and diisopropyl azodicarboxylate (0.11 mL) added dropwise via syringe over 1 min. The reaction was stirred at −78° C. under an atmosphere of nitrogen for 60 mins before being allowed to warm to ambient temperature and stirred for a further 16 hr. The reaction was concentrated in vacuo. The residue was taken up in dichloromethane (40 mL) and washed with water (40 mL), dried (hydrophobic frit) and concentrated in vacuo. The sample was loaded in dichloromethane and purified on silica 0-100% ethyl acetate-cyclohexane gradient. The appropriate fractions were combined and evaporated in vacuo to give the required product (100 mg). LC/MS MH+533, Rt 2.18 mins (5 min run).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][C:31]=1[OH:32])[C:24]([O:26]CC)=[O:25].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[OH-].[K+].Cl>C1(=O)CCCCC1.[Al].O>[CH2:1]([O:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][C:31]=1[O:32][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:24]([OH:26])=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Reactant: CCCCCCCC/C=C\CCCCCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Al]
Solvent: O=C1CCCCC1
Solvent: O
Product: CCCCCCCCC=CCCCCCCCCOc1ccc(C(=O)O)cc1OCCCCCCCCC=CCCCCCCCC
Temperature: 100 °C
Reaction time: 18 h
Yield: 69.6 %

Procedure:
To a solution of oleyl bromide (1.8 g, 5.4 mmol) in cyclohexanone (20 ml) was added ethyl 3,4-dihydroxybenzoate 7b (0.45 g, 2.5 mmol), potassium carbonate (1.02 g, 7.4 mmol) and potassium iodide (0.05 g, 0.3 mmol). The suspension was stirred at 100° C. for 18 hours under nitrogen. Due to the light sensitivity of the oleyl bromide the flask was covered in aluminum foil. The hot reaction mixture was filtered to remove some of the particulates and the solvent was removed in vacuo. The residue containing ester 8b was dissolved in a solution of ethanol (20 mL) containing potassium hydroxide (0.8 g, 20 mmol) and refluxed for 4 h. The hot reaction mixture was added to water (30 mL) and acidifying with 1M HCl to pH 1 resulted in the precipitation of a white solid. The solid 8c was filtered off and washed several times with water. The crude acid was re-crystallized from ethanol (10 mL) to give the product 8c as a white solid (1.14 g, 70%); 1H NMR (500 MHz, CDCl3) d 7.73 (dd, 1H, phenyl), 7.58 (d, 1H, phenyl), 6.89 (d, 1H, phenyl), 5.35 (t, 4H, olefinic), 4.05 (2×t, 4H, 2×OCH2), 2.01 (m, 8H, CH2C═C), 1.85 (m, 4H, CH2CH2O), 1.48 (quin, 4H, 2×CH2), 1.41-1.19 (m, 40H, 20×CH2), 0.88 (t, 6H, CH3).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[S:5][CH:6]=1.Cl.[Br-:15].[K+].OO>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:15][C:7]([C:4]1[S:5][CH:6]=[C:2]([CH3:1])[N:3]=1)([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: [Br-]
Reactant: CCOC(=O)C(C)c1nc(C)cs1
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Br)c1nc(C)cs1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
To a solution of ethyl 2-(4-methyl-1,3-thiazol-2-yl)propanoate (3.91 g, 19.62 mmol) in toluene (95 mL) was added hydrochloric acid (1.77 mL, 21.58 mmol). The mixture was stirred at room temperature for 10 minutes. The mixture was cooled to 0° C. and then potassium bromide (MERCK, 2.57 g, 21.58 mmol) and hydrogen peroxide (2.37 mL, 25.5 mmol) were added. Reaction mixture was stirred at 0° C. for 5 hours, at which point TLC (1:1 EtOAc-Hex) showed reaction had gone to completion. Reaction mixture was quenched with 1N Na2S2O3 (60 mL) and saturated NaHCO3 (60 mL). Organic phase was separated and the aqueous phase was extracted with ethyl acetate (2×60 mL). Combined organics were washed with brine, dried over sodium sulfate and concentrated to give the title compound (5.02 g, 18.05 mmol, 92% yield) as a red oil. 1H-NMR (300 MHz, DMSO-d6) δ ppm: 7.41 (s, 1H), 4.23 (q, 3H), 2.33 (s, 3H), 2.28 (s, 3H), 1.20 (t, 3H). [ES+MS] m/z 278 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:39])[CH:5]=[C:6]([Cl:38])[C:7]=1[CH2:8][C@H:9]([O:20][C:21]([C:23]1[S:24][C:25]([CH2:28][CH2:29][O:30][Si](C(C)(C)C)(C)C)=[CH:26][CH:27]=1)=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1>N1C=CC=CC=1>[Cl:38][C:6]1[CH:5]=[N+:4]([O-:39])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@H:9]([O:20][C:21]([C:23]1[S:24][C:25]([CH2:28][CH2:29][OH:30])=[CH:26][CH:27]=1)=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(CCO[Si](C)(C)C(C)(C)C)s2)cc1OC
Solvent: c1ccncc1
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(CCO)s2)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a solution of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]5-[2-[tert-butyl(dimethyl)silyl]oxyethyl]thiophene-2-carboxylate (400 mg, 0.65 mmol) in pyridine (6 mL) was added HF.pyridine (0.88 ml) dropwise and the mixture was allowed to stir at room temperature for 3 h. The mixture was cooled to 0° C. and quenched with saturated aqueous sodium bicarbonate solution (10 mL). The mixture was extracted with ethyl acetate (3×30 mL) and the combined organic fractions were passed through a hydrophobic fit and the solvent was removed by evaporation under reduced pressure. The crude material was purified by silica gel column chromatography, eluting with 0-100% ethyl acetate/10% methanol in ethyl acetate, to afford the title compound (323 mg, quantitative yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]/OCC)=[C:4]([CH3:16])[CH:3]=1.S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([CH3:16])[CH:3]=1)[NH:8][C:9](=[O:15])[CH:10]=[CH:11]2
Reactant: CCO/C=C/C(=O)Nc1ccc(Br)cc1C
Agent: O=S(=O)(O)O
Product: Cc1cc(Br)cc2ccc(=O)[nH]c12

Procedure:
Trans-N-(4-bromo-2-methylphenyl)-3-ethoxypropenamide (2.0 g) was added portionwise with stirring to 98% sulphuric acid (15 cm3) at room temperature. After 16 hours the solution was poured onto ice (100 cm3) and the resulting precipitate was filtered off and dried (1.5 g). Recrystallisation from ethyl acetate-methanol afforded 6-bromo-8-methyl-2-(1H)-quinolone, m.p. 272°-274°.