Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5]([OH:7])=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=N[C:34]2[CH:35]=[CH:36][CH:37]=[N:38][C:33]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NCCC)C>CN(C=O)C>[CH2:33]([N:38]([CH2:37][CH2:36][CH3:35])[C:5]([C:4]1[CH:8]=[C:9]([CH:10]=[C:2]([I:1])[CH:3]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:7])[CH3:34]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)c1cc(I)cc(C(=O)O)c1
Agent: CCCNCC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CC)C(=O)c1cc(I)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Iodo-5-(methoxycarbonyl)benzoic acid (1 g, 3.3 mmol) is dissolved in DMF (10 mL), and diisopropylethylamine (1.7 mL, 9.8 mmol), HATU (1.5 g, 3.9 mmol), and N-ethylpropylamine (572 μL, 4.9 mmol) are added. The reaction stirred at room temperature 16 h. The reaction is partitioned between ethyl acetate and water. The organic layer is washed with saturated sodium bicarbonate, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 40% ethyl acetate/hexane) provides the title compound. ESI MS m/z 376.1 [M+H]+.
Reaction SMILES: [NH:1]1[N:5]2[CH2:6][CH2:7][CH2:8][CH:4]2[C:3](=O)O1.[C:10]([Sn:12]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH2:15][CH3:16])#C>>[CH2:21]([Sn:12]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:17][CH2:18][CH2:19][CH3:20])[C:10]1[CH:3]=[C:4]2[CH2:8][CH2:7][CH2:6][N:5]2[N:1]=1)[CH2:22][CH2:23][CH3:24]
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1ONN2CCCC12
Product: CCCC[Sn](CCCC)(CCCC)c1cc2n(n1)CCC2

Procedure:
The title compound was prepared from 5,6-dihydro-4H-pyrrolo [1,2-c][1,2,3]oxadiazolone (prepared by the method described in Tet Letters, 24, (10), 1067, 1983) and ethynyltributyltin by the procedure described in Example 5., Preparation 3; δH (CDCl3) 0.8-1.7 (27H, m), 2.62 (2H, q), 2.85 (2H, t), 4.17 (2H, t), 6.02 (1H, s).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[I:7][C:8]1[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[NH:11][CH:12]=1.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1O.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[I:7][C:8]1[CH:9]=[C:10]([C:13]([O:15][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[Br:16])=[O:14])[NH:11][CH:12]=1
Reactant: Oc1ccccc1Br
Reactant: O=C(O)c1cc(I)c[nH]1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1Br)c1cc(I)c[nH]1
Temperature: 18 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
Oxalyl chloride (203 mL, 2.32 mmol) was added to a magnetically stirred suspension of 4-iodopyrrole-2-carboxylic acid (8) (500 mg, 2.11 mmol) in dry CH2Cl2 (15.0 ml) containing dmf (1 drop). After stirring the resulting solution at 18° C. for 2 h it was added to a magnetically stirred solution of o-bromophenol (363 mg, 2.11 mmol), triethylamine (660 ml, 4.73 mmol) and 4-(N,N-dimethylamino)pyridine (dmap, several crystals) in CH2Cl2 (10 ml). After 1 h the reaction mixture was concentrated onto silica gel (5 g) and the residue subjected to flash chromatography (silica gel, 3:1 hexane/ether elution). Concentration of the appropriate fractions (Rf 0.2) then gave the title compound (761 mg, 92%) as a white crystalline solid, m.p. 126-127° C. (Found: C, 33.9; H, 1.7; Br, 20.4; I, 32.4; N, 4.0. C11H7BrINO2 requires C, 33.7; H, 1.8; Br, 20.4; I, 32.4; N, 3.6%). nmax (KBr) 3383, 2969, 1709, 1580, 1541, 1472, 1444, 1377, 1312, 1218, 1169, 1133, 1043 cm−1. 1H n.m.r. d 9.57, broad s, 1H; 7.65, dd, J 8.1 and 1.5 Hz, 1H; 7.37, td, J 8.1 and 1.5 Hz, 1H; 7.27, m, 2H; 7.18, td, J 8.1 and 1.5 Hz, 1H; 7.08, m, 1H. 13C n.m.r. d 158.0 (C), 148.3 (C), 134.0 (CH), 129.8 (CH), 129.1 (CH), 128.1 (CH), 124.4 (CH), 124.3 (CH), 123.6 (C), 116.9 (C), 62.9 (C). Mass spectrum m/z 393 (24%) 391 (22) (M+.); 220 (100) [(M−C6H4BrO)+.].
Reaction SMILES: [C:1]1([C@@H:7]2[NH:10][C:9](=[O:11])[C@@H:8]2[O:12][Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:29]([N:10]1[C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@@H:8]([O:12][Si:13]([CH2:16][CH3:17])([CH2:18][CH3:19])[CH2:14][CH3:15])[C:9]1=[O:11])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC[Si](CC)(CC)O[C@H]1C(=O)N[C@H]1c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC[Si](CC)(CC)O[C@H]1C(=O)N(C(=O)c2ccccc2)[C@H]1c1ccccc1
Reaction time: 0.08 h

Procedure:
To a stirred solution of (3R, 4S)-4-phenyl-3-triethylsilyloxy-2-azetidinone (LXXII) (1.000 g, 3.601 mmol) in dry CH2Cl2 (25 mL) was added N,N-diisopropylethylamine (0.689 mL, 3.961 mmol, 1.1 equiv) at 0° C. under an argon atmosphere. The solution was stirred for 5 min followed by the addition of benzoyl chloride (0.459 mL, 3.961 mmol, 1.1 equiv) and 4-dimethylaminopyridine (96.5 mg, 0.790 mmol, 0.20 equiv). The reaction mixture was stirred at room temperature for 1 h, then it was diluted with ethyl acetate (25 mL). The resulting solution was washed with brine, 10% NaHCO3, 10% HCl solution, dried (MgSO4), and concentrated to give a crude compound as an oil. The compound was further purified by silica gel flash chromatography (being eluted with 15% ethyl acetate in hexanes) which afforded 1.04 g (Y: 80%) of 8.07-8.00 (m, 2H) 7.59-7.45 (m, 3H) 7.37-7.31 (m, 5H) 5.41 (d, J=6.1 Hz, 1H) 0.83-0.77 (m, 9H) 0.54-0.42 (m, 6H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:25])([F:24])[C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[C:14]2[CH:15]=[N:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:7][N:6]=1.[Br:26][C:27]1[CH:34]=[C:33](F)[CH:32]=[CH:31][C:28]=1[C:29]#[N:30].O>CN(C)C=O>[Br:26][C:27]1[CH:34]=[C:33]([N:7]2[C:8]3=[N:9][CH:10]=[CH:11][C:12]([C:14]4[CH:15]=[N:16][C:17]5[C:22]([CH:23]=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[C:13]3[C:5]([C:4]([F:24])([F:3])[F:25])=[N:6]2)[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]
Reactant: N#Cc1ccc(F)cc1Br
Reactant: FC(F)(F)c1n[nH]c2nccc(-c3cnc4ccccc4c3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(-n2nc(C(F)(F)F)c3c(-c4cnc5ccccc5c4)ccnc32)cc1Br
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
Sodium hydride (0.183 g, a 55% dispersion in paraffin liquid) was added to a solution of compound (1d) (0.940 g) in N,N-dimethylformamide (hereinafter referred to as DMF, 6 mL) at room temperature, followed by stirring for 30 min. Subsequently, 2-bromo-4-fluorobenzonitrile (0.838 g) was added to the reaction solution, followed by stirring at 60° C. for 1 hr. After cooling, water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated saline in this order and was dried over anhydrous sodium sulfate. After distillation of the solvent, the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain compound (1e) (0.56 g, 380) as a white solid.
Reaction SMILES: Cl.[CH3:2][N:3]([CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[N+:24]([O-])([OH:26])=[O:25]>O>[CH3:2][N:3]([CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:24]([O-:26])=[O:25])[CH:21]=2)[CH2:16]1)[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=1
Reactant: CN(CCc1ccc([N+](=O)[O-])cc1)C1Cc2ccccc2C1
Reactant: O=[N+]([O-])O
Agent: Cl
Solvent: O
Product: CN(CCc1ccc([N+](=O)[O-])cc1)C1Cc2ccc([N+](=O)[O-])cc2C1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
2-[N-Methyl-N-(4-nitrophenethyl)amino]indane hydrochloride (1.2 g) was added portionwise over 10 minutes to fuming nitric acid (20 ml, density=1.5 g/ml) cooled to -5°. Stirring was continued for a further 2 minutes before the reaction mixture was poured into ice/water. The water-containing mixture was extracted with methylene chloride and the organic extract was washed with aqueous sodium bicarbonate, dried (MgSO4) and evaporated to dryness in vacuo. The residue was rectystallised from ethanol to give the title compound, yield 0.78 g, m.p. 138°-140°.
Reaction SMILES: O.O.Cl[Sn]Cl.[CH2:6]([C:13]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:14]=1[C:15]([NH:17][CH:18]([CH2:23][CH2:24][S:25][CH3:26])[C:19]([O:21][CH3:22])=[O:20])=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N.[C:35]([O:38][CH2:39][CH3:40])(=[O:37])[CH3:36]>>[C:35]([O:38][CH2:39][CH3:40])(=[O:37])[CH3:36].[CH3:14][CH2:13][CH2:6][CH:7]([CH3:12])[CH3:8].[NH2:31][C:29]1[CH:28]=[CH:27][C:14]([C:15]([NH:17][C@@H:18]([CH2:23][CH2:24][S:25][CH3:26])[C:19]([O:21][CH3:22])=[O:20])=[O:16])=[C:13]([CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:30]=1
Reactant: COC(=O)C(CCSC)NC(=O)c1ccc([N+](=O)[O-])cc1Cc1ccccc1
Agent: Cl[Sn]Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: O
Product: CCCC(C)C
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1Cc1ccccc1
Temperature: 25 °C

Procedure:
SnCl2.2H2O (2.5 g, 11.08 mmol) was added to a stirred solution of compound 30 (2.24 mmol) in ethyl acetate(50 mL) and the resulting mixture heated at reflux for 18 h. The reaction mixture was cooled to ambient temperature and treated with 0.880 SG NH3(aq) dropwise to pH8. The resulting precipitate was removed by filtration through diatomaceous earth (Celite®)(545). The filtrates were then evaporated and purified by chromatography (Mega Bond Elut,Silica), eluting with dichloromethane and then 50% ethyl acetate/i-hexane to give the desired compound 21.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]1([CH:12]([N:16]2[CH:20]=[C:19](B3OC(C)(C)C(C)(C)O3)[CH:18]=[N:17]2)[CH2:13][C:14]#[N:15])[CH2:11][CH2:10]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(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>[Cl:1][C:2]1[N:7]=[C:6]([C:19]2[CH:18]=[N:17][N:16]([CH:12]([CH:9]3[CH2:11][CH2:10]3)[CH2:13][C:14]#[N:15])[CH:20]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2cnn(C(CC#N)C3CC3)c2)OC1(C)C
Reactant: Clc1ccnc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: N#CCC(C1CC1)n1cc(-c2ccnc(Cl)n2)cn1
Temperature: 100 °C

Procedure:
A mixture of 2,4-dichloropyrimidine (2.8 g, 0.019 mol), 3-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile (4.50 g, 0.0157 mol), tetrakis(triphenylphosphine)palladium (1.0 g, 0.9 mmol), and potassium phosphate (0.1 g, 0.047 mol) in 1,4-dioxane (50 mL) and water (5 mL) was heated at 100° C. overnight. After cooling to room temperature, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified on silica gel, eluting with 0 to 100% EtOAc in hexanes, to give the desired product as racemic mixture (3.08 g, 71.81%). LCMS (M+H) 274.3.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+:20].[K+]>CO>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:14]#[N:15])=[CH:2][C:1]([O-:5])=[O:4])=[CH:9][CH:8]=1.[K+:20]
Reactant: O=CC(=O)O
Reactant: N#CCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N#CC(=CC(=O)[O-])c1ccc(Cl)cc1
Temperature: 35 °C
Reaction time: 6 h

Procedure:
133 g (0.9 mol) of 50% strength aqueous glyoxylic acid was added dropwise with stirring to 91.2 g (0.6 mol) of (4-chlorophenyl)acetonitrile and 210 g (1.5 mol) of potassium carbonate in 1.2 l of methanol such that the reaction temperature increased to 35° C. The mixture was stirred at room temperature for 6 h and then filtered, and the residue was washed with methylene chloride and dried under reduced pressure. At room temperature, the crude product was stirred with 3 l of water for 1.5 h, and the residue was filtered off, washed with water and dried. Yield: 138 g of a solid of m.p. 241-242° C.
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:9]([Mg]Br)=[CH2:10].[Cl-].[NH4+]>O1CCCC1.O>[CH:1]1([CH:7]([OH:8])[CH:9]=[CH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CC1CCCCC1
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC(O)C1CCCCC1
Temperature: -20 °C
Yield: 37.8 %

Procedure:
A solution of cyclohexanecarbaldehyde (4.79 mL, 39.8 mmol) in tetrahydrofuran (30 mL) was added dropwise to a solution of vinylmagnesium bromide (47.8 mL, 1 M in tetrahydrofuran, 47.8 mmol) stirring at −20° C. The solution was stirred for 30 minutes at −20° C. at which time saturated ammonium chloride solution (75 mL) was added and the reaction was allowed to warm to 25° C. The solution was diluted with water and extracted three times with ethyl acetate. The ethyl acetate layers were combined and washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, followed by 5% and 10% ethyl acetate in hexane to give the title compound (2.11 g, 38%). 1H NMR (300 MHz, CDCl3): δ ppm 1.40 (m, 11 H) 3.85 (m, 1H) 5.17 (m, 2 H) 5.86 (m, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[S:5][C:6]=1I.[F-:12].[K+].[F:14][C:15]([F:24])(S(F)(=O)=O)C(OC)=O>CN(C=O)C.CN(P(N(C)C)(N(C)C)=O)C.[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[S:5][C:6]=1[C:15]([F:24])([F:12])[F:14]
Reactant: COC(=O)c1cc(Br)c(I)s1
Reactant: [F-]
Reactant: COC(=O)C(F)(F)S(=O)(=O)F
Agent: [Cu]I
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)c1cc(Br)c(C(F)(F)F)s1
Temperature: 70 °C
Reaction time: 1 h
Yield: 197 %

Procedure:
To a solution of methyl 4-bromo-5-iodo-2-thiophenecarboxylate (500 mg, 1.44 mmol), copper (I) iodide (137 mg, 0.72 mmol) and potassium fluoride (251 mg, 4.32 mmol) in DMF/HMPA (5 ml/5 mL) was added methyl difluoro(fluorosulfonyl)acetate (1.1 g, 5.76 mmol). The mixture was heated at 70° C. under N2 in a sealed tube. After 1 h, the reaction was quenched with NH4Cl (sat'd) (2 mL), extracted with ether (5 mL×5) and washed with distilled water (5 mL×5). The combined organic phase was dried over Mg2SO4 and purified on silica (EtOAc/Hex, 20-50%) to afford the title compound (0.82 g) containing a 60% inseparable impurity: LC-MS m/z (ES) 290 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Br[CH2:32][C:33]([NH2:35])=[O:34].O>CN(C=O)C>[NH2:35][C:33](=[O:34])[CH2:32][N:13]1[CH:12]([NH:11][S:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)(=[O:9])=[O:10])[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14]1
Reactant: NC(=O)CBr
Reactant: COC(=O)c1ccc(NS(=O)(=O)c2ccc(C)cc2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1=CN(CC(N)=O)C(NS(=O)(=O)c2ccc(C)cc2)C=C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Compound 1B was prepared starting from compound 1A in three steps following an analogous method to that described in U.S. Pat. No. 6,358,971, which is incorporated by reference herein in its entirety. Specifically, a mixture of methyl 6-aminonicotinate (1A, 3 g, 19.7 mmol) and tosylchloride (4.5 g, 23.6 mmol) in pyridine (40 mL) was heated at 80° C. for 16 hrs. The reaction was cooled to room temperature and pyridine was removed in vacuo. The resulting residue was diluted with water and allowed to stir for 10 min. The resulting solid was filtered and dried under vacuum to provide methyl 6-(4-methylphenylsulfonamido)nicotinate which was used without further purification. To a suspension of methyl 6-(4-methylphenylsulfonamido)nicotinate (5.3 g, 17.3 mmol) in anhydrous DMF was sequentially added DIEA (3.31 mL, 19.03 mmol) and then 2-bromoacetamide (2.63 g, 19.03 mmol). The reaction was stirred at ambient temperature for 24 hrs and then poured into water. The resulting solid was filtered and dried under vacuum to provide methyl 1-(2-amino-2-oxoethyl)-6-(4-methylphenylsulfonamido)-1,6-dihydropyridine-3-carboxylate which was used without further purification. To a suspension of methyl 1-(2-amino-2-oxoethyl)-6-(4-methylphenylsulfonamido)-1,6-dihydropyridine-3-carboxylate (1.0 g, 2.8 mmol) in DCM (20 mL) was added TFAA (8.0 mL, 57.5 mmol) dropwise at ambient temperature. The reaction was refluxed for 2 hrs, cooled to ambient temperature, and then concentrated in vacuo. The resulting residue was suspended in saturated sodium bicarbonate and stirred for 15 min. The resulting solid was filtered and dried under vacuum to provide methyl 2-(2,2,2-trifluoroacetamido)imidazo[1,2-a]pyridine-6-carboxylate (1B) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[O:17][CH3:18].[OH-].[K+].O>CS(C)=O>[CH3:18][O:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1
Reactant: Cc1c[nH]cn1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc([N+](=O)[O-])ccc1-n1cnc(C)c1
Temperature: 110 °C
Yield: 20.5 %

Procedure:
Step D (1): A mixture of 4-methyl-1H-imidazole (18.0 g, 53.5 mmol), 1-chloro-2-methoxy-4-nitrobenzene (10.0 g, 53.5 mmol), and potassium hydroxide (4.5 g, 80.3 mmol) in DMSO (50 mL) was heated at 110° C. for 24 h. The reaction mixture was allowed to cool to rt and was poured into 1000 mL of water. The aqueous mixture was extracted with dichloromethane (3×250 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude reaction mixture was purified using silica gel chromatography (330 g silica cartridge, 0-2% MeOH/chloroform, linear gradient over 72 min, flow 25 mL/min) to afford 1-(2-methoxy-4-nitrophenyl)-4-methyl-1H-imidazole (2.56 g, 20% yield) as a yellow/orange solid. LC-MS (M+H)+=234.1. 1H NMR (500 MHz, chloroform-d) δ ppm 7.97-8.00 (m, 1 H) 7.93-7.97 (m, 2 H) 7.45 (d, J=8.85 Hz, 1 H) 7.02 (s, 1 H) 4.02 (s, 3 H) 2.35 (s, 3 H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][N:4]([CH2:20][CH3:21])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[S:14][C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=2)=[CH:7][CH:6]=1.[CH3:22][N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1>C(#N)C>[Br-:1].[CH3:18][C:16]1[N:17]=[C:13]([N:12]=[N:11][C:8]2[CH:9]=[CH:10][C:5]([N:4]([CH2:20][CH3:21])[CH2:3][CH2:2][N:25]3[CH:26]=[CH:27][N+:23]([CH3:22])=[CH:24]3)=[CH:6][CH:7]=2)[S:14][C:15]=1[CH3:19]
Reactant: CCN(CCBr)c1ccc(N=Nc2nc(C)c(C)s2)cc1
Reactant: Cn1ccnc1
Solvent: CC#N
Product: CCN(CCn1cc[n+](C)c1)c1ccc(N=Nc2nc(C)c(C)s2)cc1
Product: [Br-]
Temperature: 80 °C
Yield: 80.1 %

Procedure:
0.5 g N-(2-bromoethyl)-4-[(4,5-dimethyl-1,3-thiazol-2-yl)diazenyl]-N-ethylaniline is dissolved in 10 ml acetonitrile followed by subsequent addition of 5.3 g 1-methyl-1H-imidazole. The reaction mixture is heated at 80° C. overnight. After cooling to room temperature, the formed precipitate is filtered off, washed with acetonitrile, and dried under vacuum at 40° C. 0.49 g of 1-{2-[{4-[(4,5-dimethyl-1,3-thiazol-2-yl)diazenyl]phenyl}(ethyl)amino]ethyl}-3-methyl-1H-imidazol-3-ium bromide are obtained as a red crystals.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:7][CH:8]=1)(O)=[O:2].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>C1COCC1.CO>[OH:2][CH2:1][C:4]1[N:5]=[C:6]([CH2:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:7][CH:8]=1
Reactant: CCOC(=O)CC(Cc1nc(C(=O)O)co1)c1ccccc1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)CC(Cc1nc(CO)co1)c1ccccc1
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
To a solution of ethyl (±)-4-(4-carboxy-1,3-oxazol-2-yl)-3-phenylbutanoate (500 mg, 1.65 mmole) in dry THF (8 mL) was added 4-methylmorpholine (0.22 mL, 1.99 mmole) then ethyl chloroformate (0.19 mL, 1.99 mmole) at 0° C. After 10 min, NaBH4 (249 mg, 6.59 mmole) was added all at once, then MeOH (8 mL) was added dropwise. After 30 min, the mixture was quenched with H2O (20 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel (80% EtOAc/hexanes) to give the title compound (371 mg, 78%) as a yellow oil: MS (ES) m/e 290 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH3:12])[C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:11]=1.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:12][N:4]1[C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:11]=[C:3]1[CH2:2][O:1][C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1
Reactant: Cn1c(CO)nc2cnccc21
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cnccc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 1.94 g of 2-hydroxymethyl-1-methylimidazo[4,5-c]pyridine (prepared as described in Preparation 73), 5.71 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 3.1 ml of tributylphosphine, 3.09 g of 1,1'-(azodicarbonyl)dipiperidine and 50 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1:0 to 10:1 by volume as the eluent, to give 3.55 g of the title compound having Rf=0.08 (on silica gel thin layer chromatography using ethyl acetate as the developing solvent).
Reaction SMILES: C([O-])=O.[NH4+].C([CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])C1C=CC=CC=1>C(O)C.C(O)(=O)C>[CH2:14]([NH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH3:12]
Reactant: CCOC(=O)CNCCCCc1ccccc1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCNCC(=O)OCC
Temperature: 80 °C

Procedure:
Ammonium formate (2 g, 31 mmol) was added to a solution of ethyl 2-[benzylpropylamino]acetate (1.05 g, 4.47 mmol) in ethanol (15 mL) and acetic acid (1 mL). The reaction vessel was then carefully flushed with nitrogen gas. Palladium on carbon (10%, 300 mg) was added in one portion, and the resulting mixture was heated at 80° C., under nitrogen for 3 h. The reaction mixture was allowed to cool to room temperature, and filtered through celite filteraid. The filtrate was concentrated in vacuo, (azeotroping with toluene (20 mL) to remove the acetic acid), to give ethyl 2-(propylamino)acetate as a yellow oil (quantitative crude yield). 1H NMR (CDCl3) δ 4.14 (q, J=7.1 Hz, 2H), 3.30 (s, 2H), 2.60 (dd, J=7.4 Hz, 2H), 1.50 (m, 2H), 1.26 (t, J=7.2 Hz, 3H), 0.89 (t, J=7.4 Hz, 3H).