Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([C:7]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([CH2:17][CH3:18])[C:8]=1[NH2:9])[CH3:6]>C1(C)C=CC=CC=1>[CH2:17]([C:10]1[CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=[C:7]([CH2:5][CH3:6])[C:8]=1[N:9]=[C:1]=[O:2])[CH3:18]
Reactant: O=C(Cl)Cl
Reactant: CCc1cc([N+](=O)[O-])cc(CC)c1N
Solvent: Cc1ccccc1
Product: CCc1cc([N+](=O)[O-])cc(CC)c1N=C=O

Procedure:
Excess phosgene is bubbled into a warm solution of 21.5 g (0.11 moles) of 2,6-diethyl-4-nitroaniline in toluene (250 ml). After the addition, the mixture is heated to reflux and approximately 200 ml of toluene are distilled. The remainder of the toluene is removed under vacuum and the remaining brown semi-solid is distilled under vacuum to give 2,6-diethyl-4-nitrophenylisocyanate, b.p. 135°-144° C./1 mm, as a yellow liquid which crystallized on standing.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH3:17][C:18]1[CH:22]=[C:21]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[O:24])[NH:20][C:19]=1[CH:32]=O>>[CH3:17][C:18]1[CH:22]=[C:21]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)=[O:24])[NH:20][C:19]=1[CH:32]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[CH:4]2[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]2)[NH:11][C:10]1=[O:16]
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: Cc1cc(C(=O)N2CCN(C)CC2)[nH]c1C=O
Product: Cc1cc(C(=O)N2CCN(C)CC2)[nH]c1C=C1C(=O)Nc2cccc(C3CCNCC3)c21

Procedure:
4-Piperidin-4-yl-1,3-dihydro-indol-2-one (45 mg, 0.2 mmol) was condensed with 3-methyl-5-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (52 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:49])[CH:5]=[C:6]([Cl:48])[C:7]=1[CH2:8][C@H:9]([O:20][C:21]([C:23]1[S:24][C:25]([CH2:28][NH:29][CH:30]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:31](=[O:41])[O:32][C@@H:33]2[CH:38]3[CH2:39][CH2:40][N:35]([CH2:36][CH2:37]3)[CH2:34]2)=[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.[CH:50](=O)[CH3:51].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C(F)(F)F>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:49])[CH:5]=[C:6]([Cl:48])[C:7]=1[CH2:8][C@H:9]([O:20][C:21]([C:23]1[S:24][C:25]([CH2:28][N:29]([CH2:50][CH3:51])[CH:30]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:31](=[O:41])[O:32][C@@H:33]2[CH:38]3[CH2:37][CH2:36][N:35]([CH2:40][CH2:39]3)[CH2:34]2)=[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: CC=O
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(CNC(C(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)s2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: OCC(F)(F)F
Product: CCN(Cc1ccc(C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC)c(OC)c2)s1)C(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 40 °C
Yield: 25.4 %

Procedure:
A suspension of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]5-[[[2-oxo-1-phenyl-2-[(3R)-quinuclidin-3-yl]oxy-ethyl]amino]methyl]thiophene-2-carboxylate (Example 42, 100 mg, 0.12 mmol) in trifluoroethanol (0.5 mL) was heated at 40 C for 5 min. Acetaldehyde (11 μL, 0.19 mmol) was added followed by acetic acid (7 μL, 0.12 mmol) and the reaction mixture was heated at 40° C. for 18 h. Sodium triacetoxyborohydride (52 mg, 0.25 mmol) was added and the mixture was heated at 40° C. for 2 h. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (1 mL) and water (1 mL). 0.2N aqueous HCl was added to adjust pH=1. The acidic aqueous phase was washed with ethyl acetate (3×1 mL), sodium chloride (1 g) was added to the aqueous phase that was extracted with chloroform (3×1 mL), the combined chloroform extracts were filtered through a phase separator and the solvent was removed in vacuo. The combined ethyl acetate washes were extracted with 0.2N HCl (1 mL), water (1 mL). The aqueous phases were combined, saturated with solid sodium chloride and extracted with chloroform (3×1 mL). The crude product from both extractions was combined and purification by preparative HPLC gave the title compound as an off-white solid (23 mg, 24%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([F:24])[CH:19]=3)=[N:16][CH:17]=2)=[O:9])=[N:6][CH:7]=1.[CH3:25][N:26]([CH3:36])[C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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.C(O)C>[CH3:25][N:26]([CH3:36])[C:27]1[N:32]=[CH:31][C:30]([C:2]2[CH:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][C:12]3[CH:13]=[CH:14][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[C:20]([F:24])[CH:19]=4)=[N:16][CH:17]=3)=[O:9])=[CH:4][CH:3]=2)=[CH:29][CH:28]=1
Reactant: CN(C)c1ccc(B(O)O)cn1
Reactant: O=C(NCc1ccc(-c2ccnc(F)c2)nc1)c1ccc(Br)cn1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN(C)c1ccc(-c2ccc(C(=O)NCc3ccc(-c4ccnc(F)c4)nc3)nc2)cn1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
To a tube was added 5-bromo-N-((2′-fluoro-2,4′-bipyridin-5-yl)methyl)picolinamide 38-4 (38 mg, 0.10 mmol), 6-(dimethylamino)pyridin-3-ylboronic acid 38-5 (33 mg, 0.20 mmol), Pd(PPh3)4 (11 mg, 0.01 mmol), toluene (0.4 mL), ethanol (0.1 mL) and 2M Na2CO3 (0.15 mL). The reaction mixture was bubbled with nitrogen for 2 minutes and stirred at 90° C. for 10 hours with the tube sealed. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated NaHCO3 aqueous solution, H2O and brine. The organic phase was dried over Na2SO4 and concentrated to dryness by rotary evaporation. The crude product was purified with reverse phase HPLC to give 6′-(dimethylamino)-N-((2′-fluoro-2,4′-bipyridin-5-yl)methyl)-3,3′-bipyridine-6-carboxamide 38 as a white powder. MS m/z 429.20 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 9.52 (t, 1H, J=6.4 Hz), 8.94 (d, 1H, J=2.4 Hz), 8.73 (d, 1H, J=2.0 Hz), 8.60 (d, 1H, J=2.4 Hz), 8.35 (d, 1H, J=5.2 Hz), 8.22 (m, 1H), 8.15 (d, 1H, J=8.0 Hz), 8.06-7.93 (m, 4H), 7.80 (s, 1H), 6.78 (d, 1H, J=9.2 Hz), 4.60 (d, 2H, J=6.4 Hz), 3.09 (s, 6H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:20]1([NH:23][C:24](=[O:44])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([N:32]3[C:41](=[O:42])[C:40]4[C:35](=[CH:36][CH:37]=[C:38](I)[CH:39]=4)[N:34]=[CH:33]3)[CH:26]=2)[CH2:22][CH2:21]1.[C:45]([O:49][CH3:50])(=[O:48])[CH:46]=[CH2:47].C(N(CC)CC)C>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:20]1([NH:23][C:24]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([N:32]3[C:41](=[O:42])[C:40]4[C:35](=[CH:36][CH:37]=[C:38](/[CH:47]=[CH:46]/[C:45]([O:49][CH3:50])=[O:48])[CH:39]=4)[N:34]=[CH:33]3)[CH:26]=2)=[O:44])[CH2:22][CH2:21]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(I)cc2c1=O
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc2ncn(-c3cc(C(=O)NC4CC4)ccc3C)c(=O)c2c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Palladium acetate (0.02 g) and triphenylphosphine (0.038 g) was added to a stirred mixture N-cyclopropyl-3-(6-iodo-4-oxoquinazolin-3(4H)-yl)-4-methylbenzamide (0.20 g), methyl acrylate (0.4 ml) and triethylamine (0.63 ml) in anhydrous tetrahydrofuran (15 ml) under an argon atmosphere. The mixture was heated to 60° C. and stirred for 2 hours. The reaction mixture was evaporated, dissolved in ethyl acetate (100 ml) and washed with water (100 ml) and brine (100 ml). The organic phase was dried (magnesium sulphate) and evaporated and the residue purified by column chromatography on a silica column using initially iso-hexane and then a 1:1 mixture of iso-hexane and ethyl acetate as eluent. There was thus obtained the title compound (0.14 g); NMR Spectrum: (DMSOd6) 0.57 (m, 2H), 0.70 (m, 2H), 2.17 (s, 3H), 2.86 (m, 1H), 3.76 (s, 3H), 6.80 (d, 1H), 7.55 (m, 2H), 7.63 (m, 1H), 7.86 (m, 2H), 8.31 (m, 1H), 8.37 (s, 1H), 8.45 (m, 2H); Mass Spectrum: M+H+ 404.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N+:6]([O-:11])[CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[S:12]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([C:22]#[N:23])[CH:16]=1)(=[O:14])=[O:13].[N+:24]([O-])([OH:26])=[O:25].CCOCC>C(O)(=O)C>[Br:1][C:2]1[C:10]2[C:5](=[N+:6]([O-:11])[CH:7]=[C:8]([N+:24]([O-:26])=[O:25])[CH:9]=2)[S:4][C:3]=1[S:12]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([C:22]#[N:23])[CH:16]=1)(=[O:13])=[O:14]
Reactant: N#Cc1cc(F)cc(S(=O)(=O)c2sc3c(ccc[n+]3[O-])c2Br)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CCOCC
Product: N#Cc1cc(F)cc(S(=O)(=O)c2sc3c(cc([N+](=O)[O-])c[n+]3[O-])c2Br)c1

Procedure:
3-Bromo-2-(3-cyano5-fluorobenzenesulfonyl)-thieno[2,3-b]pyridin-N-oxide (prepared as described in WO 2007/072095) (7.97 g, 19.3 mmol) was boiled at 120° C. with 66% nitric acid (1.22 ml) in acetic acid (25 ml) for 4 hours. The reaction mixture was evaporated and the residue was purified by chromatography (Kieselgel 60, chloroform:methanol=5:0.1). First the starting material was isolated (3.7 g, 47%), than a yellow solid, which was treated with ether (5 ml). After filtration the title compound was isolated (0.72 g, 8.3%). LC-MS: (M+H)+ 459.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=2)[C:10]2[CH:15]=[CH:14][C:13]([N:16]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)[C:17]3[CH:34]=[CH:33][C:20]([O:21][CH2:22][CH2:23][CH2:24][P:25](=[O:32])([O:29]CC)[O:26]CC)=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.Br[Si](C)(C)C>ClCCl>[CH3:50][O:49][C:46]1[CH:47]=[CH:48][C:43]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:10]2[CH:11]=[CH:12][C:13]([N:16]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)[C:17]3[CH:34]=[CH:33][C:20]([O:21][CH2:22][CH2:23][CH2:24][P:25](=[O:26])([OH:32])[OH:29])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)=[CH:44][CH:45]=1
Reactant: CCOP(=O)(CCCOc1ccc(N(c2ccc(OC)cc2)c2ccc(N(c3ccc(OC)cc3)c3ccc(OC)cc3)cc2)cc1)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: COc1ccc(N(c2ccc(OC)cc2)c2ccc(N(c3ccc(OC)cc3)c3ccc(OCCCP(=O)(O)O)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a dry 25 mL round bottom flask under nitrogen was added diethyl 3-(4-((4-(bis(4-methoxyphenyl)amino)phenyl)(4-methoxyphenyl)amino)phenoxy)propylphosphonate (0.500 g, 0.718 mmol) and the flask was purged with nitrogen. Dichloromethane (1.00 mL) and bromotrimethylsilane (0.199 g, 2.30 mmol) were added under nitrogen and the mixture was allowed to stir at room temperature overnight. Upon disappearance of the starting material the solvent was removed through nitrogen purge. Residual solvent was removed in vacuo. Anhydrous methanol (8.00 mL) was added to the flask and allowed to stir at room temperature overnight. White solid was filtered from methanol through cannula filtration. Solid was washed using 3×5 mL anhydrous methanol and dried in vacuo. The product was collected under nitrogen atmosphere as a green solid (0.185 g, 40.2%). 1H NMR (400 MHz, (CD3)2SO) δ 9.87 (s, 2H), 6.89 (m, 8H), 6.83 (m, 8H), 6.71 (s, 4H), 3.91 (m, 2H), 3.69 (s, 9H), 1.84 (m, 2H), 1.51 (m, 2H). 13C{1H} NMR (400 MHz, (CD3)2S, δ): 154.98, 154.40, 142.17, 140.91, 140.77, 125.27, 125.19, 122.72, 122.68, 115.37, 114.82, 68.35 (m), 55.24, 23.62 (m). 31P NMR (400 MHz, (CD3)2S, δ): 25.05. HRMS-EI (m/z): [M]+ calcd for C36H37N2O7P, 640.23. found, 640.1). Anal. Calcd for C36H37N2O7P: C, 67.49; H, 5.82; N, 4.37. Found: C, 67.09; H, 6.16; N, 3.99.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6](S)[N:7]([C:9]3[CH:10]=[CH:11][C:12]([F:21])=[C:13]([CH:20]=3)[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])[CH:8]=2)[CH2:3][CH2:2]1.[N+]([O-])(O)=O>O>[CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[CH:10]=[CH:11][C:12]([F:21])=[C:13]([CH:20]=3)[C:14]([O:16][CH:17]([CH3:18])[CH3:19])=[O:15])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: CC(C)OC(=O)c1cc(-n2cc(C3CC3)nc2S)ccc1F
Solvent: O
Solvent: O=[N+]([O-])O
Product: CC(C)OC(=O)c1cc(-n2cnc(C3CC3)c2)ccc1F
Temperature: 100 °C
Yield: 44 %

Procedure:
Isopropyl 5-(4-cyclopropyl-2-mercapto-1H-imidazol-1-yl)-2-fluorobenzoate (0.776 g, 2.43 mmol) was suspended in a water (16 ml) and fuming nitric acid (4 ml) mixture. The mixture was stirred under nitrogen at 100° C. while monitoring by LC/MS. When the reaction was complete heat was removed and ammonium hydroxide was added to bring the pH to neutral. The solvent was removed under reduced pressure and the residue purified by column chromatography to afford isopropyl 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluorobenzoate. (0.306 g, 1.06 mmol). 44% yield. 289 (M+1).
Reaction SMILES: C[O:2][C:3]1(OC)[CH:8]2[CH2:9][CH2:10][CH:4]1[CH2:5][N:6]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:7]2>Cl>[CH3:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:6]2[CH2:5][CH:4]3[C:3](=[O:2])[CH:8]([CH2:9][CH2:10]3)[CH2:7]2)=[CH:17][CH:16]=1
Reactant: COc1ccc(CN2CC3CCC(C2)C3(OC)OC)cc1
Agent: Cl
Product: COc1ccc(CN2CC3CCC(C2)C3=O)cc1
Temperature: 25 °C

Procedure:
8,8-Dimethoxy-3-(4-methoxy-benzyl)-3-aza-bicyclo[3.2.1]octane (4.88 g, 0.0167 mol) was dissolved in 1N HCl (50 mL) then heated to reflux 2 h (or until judged complete by TLC). The reaction was cooled to room temperature, washed with ether (1×50 mL), then the aqueous layer was made alkaline with 1 N NaOH and saturated aqueous NaHCO3 solution. The product was extracted with EtOAc (4×70 mL) then CH2Cl2 (1×50 mL), washed with saturated aqueous NaCl solution (200 mL), dried over Na2SO4, filtered then concentrated to yellow oil (3.88 g, 94%). (TLC 50% EtOAc/hexanes Rf 0.55); 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J=8.3 Hz, 2H), 6.83 (d, J=8.3 Hz, 2H), 3.77 (s, 3H), 3.49 (s, 2H), 2.92 (dd, J=11.4, 3.9 Hz, 2H), 2.46 (d, J=10.8 Hz, 2H), 2.12 (br s, 2H), 2.00 (dd, J=12.7, 4.6 Hz, 2H), 1.83 (m, 2H); GCMS m/z 245 (M)+.
Reaction SMILES: C([O:8][C:9](=[O:44])[C@@H:10]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[CH2:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[S:20]2(=[O:35])=[O:34])[CH:13]=1)C1C=CC=CC=1.[H][H]>CCOC(C)=O.CCO.[Pd]>[C:40]([O:39][C:37]([NH:36][C@@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[CH2:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[S:20]2(=[O:34])=[O:35])[CH:13]=1)[C:9]([OH:44])=[O:8])=[O:38])([CH3:41])([CH3:43])[CH3:42]
Reactant: [H][H]
Reactant: COc1ccc(CN2C(=O)CN(Cc3cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc4ccccc4)c3)S2(=O)=O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(CN2C(=O)CN(Cc3cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c3)S2(=O)=O)cc1
Reaction time: 0.5 h

Procedure:
The title D compound, (S)-2-t-butoxycarbonylamino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-propionic acid benzyl ester (127 mg, 0.20 mmol) is dissolved in EtOAc/EtOH (50:50) (56 mL) and 10% palladium on carbon (35 mg) is added and the mixture is treated with 45 psi of hydrogen on a Parr shaker apparatus. After two 90 min runs, starting material is not completely consumed, so another aliquot of 10% palladium on carbon (35 mg) is added and after shaking at 45 psi hydrogen for 30 min, the reaction is complete. The mixture is filtered through celite, the filtrate is concentrated and dried to give (S)-2-t-butoxycarbonylamino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-phenyl}-propionic acid as a white foam: [M+1]+=534.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.Br[CH:20]([CH3:28])[C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1COCC1>[CH3:28][C:20]1[N:3]2[C:2]([C:7]3[O:8][CH2:9][CH2:10][N:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:6]=3[CH:5]=[CH:4]2)=[N:1][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C(=O)C(C)Br
Reactant: CC(C)(C)OC(=O)N1CCOc2c1ccnc2N
Solvent: C1CCOC1
Product: CCOC(=O)c1nc2c3c(ccn2c1C)N(C(=O)OC(C)(C)C)CCO3
Yield: 25 %

Procedure:
To a solution of tert-butyl 5-amino-2,3-dihydropyrido[3,4-b][1,4]oxazine-1-carboxylate (2.1 g, 8.37 mmol) in 100 mL of THF was added ethyl 3-bromo-2-oxobutanoate (3.482 g, 16.74 mmol). The mixture was stirred under reflux overnight. After removal of the solvent, the crude product was purified by silica gel column chromatography (EtOAc/PE v/v 2:1) to give 10-tert-butyl 4-ethyl 5-methyl-13-oxa-3,6,10-triazatricyclo[7.4.0.0{2,6}]trideca-1(9),2,4,7-tetraene-4,10-dicarboxylate (757 mg, 25% yield).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[CH2:35][C:36]([OH:38])=O.CCN(C(C)C)C(C)C.[CH3:48][C:49]1[N:50]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][C:64]=2C)[C:51]([CH:54]([NH2:62])[CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[N:52][N:53]=1>CN(C=O)C>[OH:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][CH:30]=[C:29]2[CH2:35][C:36]([NH:62][CH:54]([C:51]1[N:50]([C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[C:49]([CH3:48])=[N:53][N:52]=1)[CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)=[O:38]
Reactant: O=C(O)Cc1c[nH]c2ccc(O)cc12
Reactant: Cc1ccccc1-n1c(C)nnc1C(N)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nnc(C(Cc2ccccc2)NC(=O)Cc2c[nH]c3ccc(O)cc23)n1-c1ccccc1
Reaction time: 0.17 h

Procedure:
HATU (40 mg, 0.105 mmol) was added to a solution of 2-(5-hydroxy-1H-indol-3-yl)acetic acid (19.2 mg, 0.1 mmol) and DIPEA (0.02 mL, 0.12 mmol) in DMF (0.3 mL). After 10 minutes, 10F (29.2 mg, 0.1 mmol) in 0.2 mL of DMF was added to the reaction. The reaction was stirred for 2 hours. LC/MS shows desired product with a small amount of acid. Purified reaction mixture on prep reverse phase HPLC using 20-80% B over 20 min. (A=0.1% TFA/H2O; B=0.1% TFA/Acetonitrile). Combined pure fractions as determined by LC/MS and lyophilized to provide) to provide the desired product. 1H NMR (400 MHz, DMSO) δ 10.44 (s, 1H), 8.64-8.42 (m, 1H), 7.50-7.19 (m, 3H), 7.17-6.93 (m, 6H), 6.81 (dd, J=53.1, 21.8 Hz, 4H), 6.54 (d, J=8.8 Hz, 1H), 3.39-3.22 (m, 3H), 3.09-2.85 (m, 2H), 2.01 (d, J=15.7 Hz, 3H). MS (m/z) 452 [M+H]+.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([O:9]C)=[CH:5][C:4]=1[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][C:15]=1F)=[O:13].Cl>>[OH:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[O:13][C:3]3[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=3[CH:11]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(C(=O)Cc2cc(OC)ccc2OC)c(F)c1
Agent: Cl
Product: Oc1ccc(-c2cc3cc(O)ccc3o2)cc1

Procedure:
A solution of 3-Fluoro anisole (2 g, 16 mmol) and 2,5-dimethoxyphenacetyl chloride in dichloroethane (50 mL) was treated with AlCl3 (2.3 g, 18 mmol) and stirred at rt until TLC analysis indicated reaction was complete. The reaction was worked up by adding a 2 N HCl aq solution to the reaction (slowly) and washing with saturated NaHCO3 aq, brine and drying over MgSO4. After filtering, the EtOAc was concentrated and chromatographed on silica gel (EtOAc/hexanes 1:4) to yield 1 gram of the acylated intermediate 76 as well as an isomer as an oily solid that was used as is for the next reaction step. All of 76 from the previous step (1 g, 3.3 mmol) was heated with pyr-HCl at 180° C.-200° C. until TLC indicated reaction completion. The reaction was worked up by partitioning between 2 N HCl aq and EtOAc and washing the EtOAc with saturated NaHCO3, brine, and drying over MgSO4. The solution was filtered, concentrated and chromatographed on silica gel to yield 0.48 g of impure pdt 77. The product thus obtained was recrystallized from EtOAc/hexanes to yield desired product plus a small amt of unidentified impurity: Mp=218-222° C.; 1H NMR (DMSO-d6) δ 10.39 (s, 1 H), 9.20 (s, 1 H), 7.74 (t, 1 H, J=8.7 Hz), 7.37 (d, 1 H, J=8.8 Hz), 6.96-6.94 (m, 2 H), 6.79-6.70 (m, 3 H); MS 243 (M−H)−.
Reaction SMILES: Br.[NH2:2][C:3]1[N:12]=[C:6]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][N:5]2[N:4]=1.[CH:13]1([C:16](Cl)=[O:17])[CH2:15][CH2:14]1>CN(C)C(=O)C.O>[OH:11][C:9]1[CH:8]=[CH:7][C:6]2[N:5]([N:4]=[C:3]([NH:2][C:16]([CH:13]3[CH2:15][CH2:14]3)=[O:17])[N:12]=2)[CH:10]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1nc2ccc(O)cn2n1
Agent: Br
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(Nc1nc2ccc(O)cn2n1)C1CC1
Yield: 172.7 %

Procedure:
To a solution of 2-amino[1,2,4]triazolo[1,5-a]pyridin-6-ol hydrobromide (1.50 g, 4.22 mmol) in N,N-dimethylacetamide (5 mL) was added cyclopropanecarbonyl chloride (1.15 mL, 12.7 mmol) with stirring under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration, and washed with ethyl acetate-hexane to give the title compound (1.59 g, 89%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:36]2[CH2:35][CH2:34][N:33]([C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=3)[CH2:38][CH2:37]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc4ccccc4nc3OC)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate(148 mg, 0.5 mmol) and 1-(3,5-dimethoxyphenyl)piperazine(112 mg, 0.5 mmol) were dissolved in anhydrous tetrahydrofuran and DBU(117 mg, 0.75 mmol) was added. The solution was stirred at room temperature for 2 hours. The mixture was concentrated under the reduced pressure to remove tetrahydrofuran and purified by column chromatography(hexane:ether=5:1) to obtain the titled compound.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:14])[C:11]=1[O:12]C)[C:6]([OH:8])=[O:7].Cl.N1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[OH:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH3:14])[C:11]=1[OH:12])[C:6]([OH:8])=[O:7]
Reactant: COc1cc(C(=O)O)cc(C)c1OC
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: Cc1cc(C(=O)O)cc(O)c1O

Procedure:
Under a nitrogen atmosphere 50.0 g (0.25 mol) 3,4-dimethoxy-5-methyl-benzoic acid and 170 g pyridine-hydrochloride were stirred for 2 h at a bath temperature of 160° C. The reaction mixture was poured onto 1 L citric acid solution and extracted with 1 L EtOAc. The organic phase was washed with 1 L water, dried and evaporated down i.vac.