Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([F:21])=[C:8]2[O:12][C:11]([N:13]([CH3:15])[CH3:14])=[N:10][C:9]2=[C:16]([C:19]#[N:20])[C:17]=1[CH3:18])=[CH2:5])C.O.[Br:23]N1C(=O)CCC1=O>O1CCCC1>[Br:23][CH2:3][C:4]([C:6]1[C:7]([F:21])=[C:8]2[O:12][C:11]([N:13]([CH3:15])[CH3:14])=[N:10][C:9]2=[C:16]([C:19]#[N:20])[C:17]=1[CH3:18])=[O:5]
Reactant: C=C(OCC)c1c(C)c(C#N)c2nc(N(C)C)oc2c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)CBr)c(F)c2oc(N(C)C)nc2c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
6-(1-Ethoxyvinyl)-2-(dimethylamino)-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-169) (0.51 g, 1.76 mmol) was dissolved in tetrahydrofuran (10 ml), then water (1.0 ml), N-bromosuccinimide (0.30 g, 1.69 g) were added. After stirring at room temperature for 30 minutes, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane to dichloromethane:methanol=100:1) to obtain a pale brown solid (0.60 g, 100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:11][CH2:12][OH:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].O[N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26]>>[C:1]([O:5][C:6](=[O:14])[N:7]([CH2:11][CH2:12][O:13][N:16]1[C:20](=[O:21])[C:19]2[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]1=[O:26])[CH:8]([CH3:10])[CH3:9])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)N(CCO)C(=O)OC(C)(C)C
Product: CC(C)N(CCON1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Yield: 57 %

Procedure:
Reaction of (2-hydroxyethyl)isopropylcarbamic acid tert-butyl ester with N-hydroxyphthalimide following the procedure described for Reference Example 14, except purification by column chromatography (silica gel, 75:25 hexanes/EtOAc to 50:50 hexanes/EtOAc), gave tert-butyl[2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]ethyl]isopropylcarbamate (960 mg, 57%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 1.15-1.20 (6H, br s), 1.43 (9H, s), 3.48-3.50 (2H, s), 4.08-4.15 (1H, m), 4.25-4.28 (2H, m), 7.74-7.85 (4H m).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([OH:15])=O)[CH2:7][CH2:6]1)=[O:4].CN(C)C=O.C(Cl)(=O)C([Cl:24])=O>ClCCl>[CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([Cl:24])=[O:15])[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)N1CCC(CCC(=O)O)CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)N1CCC(CCC(=O)Cl)CC1

Procedure:
To a solution of 49.5 gm (0.23 mol) of the compound of step c), in dichloromethane, was added 0.25 mL of dimethylformamide and 21 mL of oxalyl chloride (0.25 mol). After gas evolution subsided, formation of the title compound was complete. The resulting solution was used directly into the next step.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]([CH3:22])[CH2:17][C:18](=[O:21])[NH:19][N:20]=2)=[CH:11][C:10]=1[N+:23]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C1COCC1.[Ni]>[NH2:23][C:10]1[CH:11]=[C:12]([C:15]2[CH:16]([CH3:22])[CH2:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:13]=[CH:14][C:9]=1[NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CC(=O)NN=C1c1ccc(NCc2ccccc2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: CC1CC(=O)NN=C1c1ccc(NCc2ccccc2)c(N)c1

Procedure:
6-(4-Benzylamino-3-nitro-phenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one E-4.1′ (662 mg; 1.96 mmol) is solved in 200 ml THF, a scoop of Raney Nickel is then added. The mixture is placed in the hydrogenation apparatus and stirred at RT for 1.5 hours under 4 bar hydrogen pressure. The Raney Nickel is filtered off and the reaction solution evaporated to dryness.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)=[CH:6][C:5]=1[C:27]([F:30])([F:29])[F:28].[OH-].[Na+]>CO.O>[Cl:26][C:21]1[CH:20]=[C:19]([C:13]2([C:15]([F:17])([F:16])[F:18])[O:12][N:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:31])=[O:2])=[C:5]([C:27]([F:30])([F:28])[F:29])[CH:6]=3)[CH2:14]2)[CH:24]=[C:23]([Cl:25])[CH:22]=1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.5 %

Procedure:
In a solution of 0.40 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-trifluoromethyl benzoic acid methyl ester in 5 ml of methanol, a solution of 0.10 g of sodium hydroxide in 2 ml of water was added, and stirred at room temperature for 18 hours. After the completion of the reaction, 10 ml of water was added in the reaction mixture, washed with 5 ml of toluene, aqueous phase was collected, adjusted to pH 1 to 2 with concentrated hydrochloric acid and then extracted with ethyl acetate (20 ml×2). The organic phase was washed with water, dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 0.34 g of the aimed product as pale yellow resinous substance. The resulting product was used as such without purification for the next step.
Reaction SMILES: [CH2:1]([C@@H:8]([NH:25][CH3:26])[CH2:9][N:10]1[CH2:15][CH2:14][C:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])=[CH:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][C:35]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>ClCCl>[CH2:1]([C@@H:8]([N:25]([CH3:26])[C:41]([C:35]1([CH3:34])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:42])[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])[CH2:12][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN[C@H](Cc1ccccc1)CN1CC=C(c2cc(F)ccc2OC)CC1
Reactant: CC1(C(=O)Cl)CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1C1CCN(C[C@@H](Cc2ccccc2)N(C)C(=O)C2(C)CCCCC2)CC1
Reaction time: 8 h
Yield: 55.2 %

Procedure:
Under a N2 atmosphere, a solution of {(1R)-1-benzyl-2-[4-(5-fluoro-2-methoxy-phenyl)-1,2,5,6-tetrahydropyridine-1-yl]-ethyl}-methyl-amine (0.18 g, 0.49 mmole) and triethylamine (0.14 mL, 1.0 mmole) in dichloromethane (10 mL) was cooled to 0° C. To the solution, 1-methyl-1-cyclohexanecarboxylic acid chloride (0.10 g, 0.59 mmole) in 1 mL dichloromethane was added and the resulting mixture was stirred at 0° C. to room temperature (ice melt) overnight. The solvent was evaporated and the residue dissolved in EtOAc (50 mL) and water (50 mL). The layers were separated and the organics washed with water (50 mL), brine (25 mL) and dried over Na2SO4, filtered and concentrated. Flash chromatography (elution with 1:4 EtOAc-hexane) gave 0.13 g (55% yield) of the titled compound. An ethanolic solution of the product was heated to gentle reflux and 1 equivalent of fumaric acid in hot ethyl alcohol solution was added to afford the fumarate salt of the titled compound as a white solid. m.p. 146-151° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]#[N:12])([O-:3])=[O:2].[H-].[Na+].[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19](S(C)(=O)=O)[N:18]=1.Cl>CN(C)C=O.O>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([CH:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[C:11]#[N:12])[N:18]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: N#CCc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(C(C#N)c2ccccc2[N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
50 g (0.31 M) of 2-(2-nitrophenyl)acetonitrile was dissolved in 500 ml of dimethylformamide. Thereto was added 24.7 g (0.62 M) of 60% sodium hydride. The mixture was stirred at room temperature for 2 hours. Then, 68 g (0.31 M) of 4,6-dimethoxy-2-methanesulfonylpyrimidine was added. The mixture was stirred at 80° C. for 1 hour to give rise to a reaction. The reaction mixture was poured into water, followed by neutralization with dilute hydrochloric acid. The mixture was subjected to extraction with ethyl acetate. The extract was washed with water, dried and subjected to vacuum distillation to remove the solvent. The residue was recrystallized from ethanol to obtain 73.3 g (yield: 79%) of 2-(4,6-dimethoxypyrimidine-2-yl)-2-(2-nitrophenyl)acetonitrile as a white powder (melting point: 88 to 89° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.I[CH2:17][CH3:18].[H-].[Na+]>CN(C=O)C>[CH2:17]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=2)[C:2]([CH3:15])([CH3:1])[CH2:3][CH2:4]1)[CH3:18]
Reactant: CCI
Reactant: CC1(C)CCNc2cc([N+](=O)[O-])ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCC(C)(C)c2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydro-quinoline (0.48 g, 2.33 mmol), iodoethane (0.21 ml, 2.56 mmol), and NaH (60%, 0.10 g, 2.5 mmol) in 10 ml of DMF was stirred at RT overnight, and partitioned between EtOAc and H2O. The combined organic portions were washed with brine, dried with MgSO4, filtered, and condensed. The crude compound was purified by flash column chromatography (5 to 10% of CH2Cl2 in hexanes). The titled compound was obtained as a yellow oil. MS (ES+): 235.3 (M+H)+. Calc'd for C13H18N2O2—234.29.
Reaction SMILES: Cl.[C:2]([N:10]1[CH2:15][CH2:14][CH:13]([C:16](=O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[NH2:23])[CH2:12][CH2:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:25]#[C:26][NH2:27].C(=O)([O-])O.[Na+]>O>[NH2:27][C:26]1[N:25]=[C:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:2](=[O:9])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:11][CH2:12]2)[C:17]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:23]=1
Reactant: Nc1ccccc1C(=O)C1CCN(C(=O)c2ccccc2)CC1
Reactant: N#CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1nc(C2CCN(C(=O)c3ccccc3)CC2)c2ccccc2n1
Yield: 97.6 %

Procedure:
The titled compound was prepared by warming a mixture of 1-benzoyl-4-(2-aminobenzoyl)piperidine hydrochloride (17 g, 0.049 mol) and cyanamide (4.12 g, 0.098 mol). At about 50° C., vigorous exothermic reaction occurred. After the reaction was finished, the reaction mixture was cooled, water was added to the reaction mixture, and then added sodium hydrogencarbonate to make the mixture basic. The mixture was then extracted with dichloromethane. The organic layer was washed with aqueous solution of saturated sodium chloride, and then dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the titled compound (15.9 g) as a foam.
Reaction SMILES: [F:1][C:2]([F:9])([CH2:6][CH:7]=[CH2:8])[C:3]([OH:5])=[O:4].[CH2:10](O)[CH3:11]>>[F:1][C:2]([F:9])([CH2:6][CH:7]=[CH2:8])[C:3]([O:5][CH2:10][CH3:11])=[O:4]
Reactant: CCO
Reactant: C=CCC(F)(F)C(=O)O
Product: C=CCC(F)(F)C(=O)OCC

Procedure:
Analogously to Example 1, 38.5 g (0.28 mol) of 2,2-difluoro-4-pentenoic acid are esterified with ethanol. Yield: 41.3 g (89%) of a colourless oil of boiling point 55°-57° C./52 mbar, 1H-NMR (60 MHz, CDCl3): 6.1-5.0 (m, 3H); 4.30 (qa, J=7 Hz, 2H); 2.85 (d x t, J=16 Hz, 2H); 1.35 (t, J=7 Hz, 3H).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1([C:13](Cl)=[O:14])[CH2:12][CH2:11]1.[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:35][CH2:34][C:33]3[S:32][C:31]([CH3:36])=[N:30][C:29]=3[C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)=[O:25])=[CH:20][C:19]=1[CH3:41]>ClCCl>[CH3:41][C:19]1[CH:20]=[C:21]([C:24]([N:26]2[CH2:35][CH2:34][C:33]3[S:32][C:31]([CH3:36])=[N:30][C:29]=3[C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)=[O:25])[CH:22]=[CH:23][C:18]=1[CH2:17][NH:16][C:13]([CH:10]1[CH2:12][CH2:11]1)=[O:14]
Reactant: O=C(Cl)C1CC1
Reactant: Cc1nc2c(s1)CCN(C(=O)c1ccc(CN)c(C)c1)c1ccccc1-2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc2c(s1)CCN(C(=O)c1ccc(CNC(=O)C3CC3)c(C)c1)c1ccccc1-2
Temperature: 25 °C
Reaction time: 20 h
Yield: 46 %

Procedure:
DIEA (0.02 ml, 0.115 mmol) and cyclopropanecarbonyl chloride (0.008 ml, 0.088 mmol) were added to a solution of (4-aminomethyl-3-methyl-phenyl)-(2-methyl-4,5-dihydro-3-thia-1,6-diaza-benzo[e]azulen-6-yl)-methanone from E124.2 (20 mg, 0.055 mmol) in dichloromethane (5 ml) at 0° C. The mixture was stirred for 20 h at room temperature then concentrated in vacuo and purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% di-chloromethane) to give a white powder identified as the title compound (11 mg, 46%).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[CH:14]=[CH:13][O:12][N:11]=2)=[CH:8][C:7]([C:15]2[N:20]=[C:19]([OH:21])[CH:18]=[CH:17][N:16]=2)=[N:6]1.[S:26]([Cl:30])(=O)(=[O:28])[OH:27]>C(OCC)(=O)C>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[CH:14]=[CH:13][O:12][N:11]=2)=[CH:8][C:7]([C:15]2[N:20]=[C:19]([OH:21])[C:18]([S:26]([Cl:30])(=[O:28])=[O:27])=[CH:17][N:16]=2)=[N:6]1
Reactant: O=S(=O)(O)Cl
Reactant: Oc1ccnc(-c2cc(-c3ccon3)n(Cc3ccccc3F)n2)n1
Solvent: CCOC(C)=O
Product: O=S(=O)(Cl)c1cnc(-c2cc(-c3ccon3)n(Cc3ccccc3F)n2)nc1O

Procedure:
A solution of 2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-ol Compound I-160 (56 mg, 1 equiv) and sulfurochloridic acid (552 μl) in a sealed vial was heated to 100° C. for 30 min. The mixture was diluted in ethyl acetate (50 ml) and washed with water (50 ml). The organic layer was dried, filtered and evaporated to give 79 mg of crude 2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)-4-hydroxypyrimidine-5-sulfonyl chloride as a white solid. The solid was combined with morpholine (47.4 μl, 3.3 equiv) and stirred at 25° C. for 30 min. The mixture was diluted in ethyl acetate (100 ml) and washed with water (50 ml). The organic layer was dried, filtered and evaporated to give crude oil. Purification by column chromatography (0 to 10% methanol in dichloromethane) gave 40 mg of the desired product (45%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 9.11 (d, 1H), 8.01 (bs, 1H), 7.74-7.67 (m, 1H), 7.66 (s, 1H), 7.51 (t, 1H), 7.35-7.30 (m, 1H) 7.22 (s, 1H), 6.33 (bs, 1H), 5.97 (s, 2H), 3.52-3.46 (m, 4H), 2.67-2.59 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:38]=[CH:37]C3C4C(CCOC=3C=2)=CN(C2N(C3C=CC(F)=CC=3F)N=CN=2)N=4)C1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:40]1[CH:61]=[CH:60][C:43]2[C:44]3[N:48]([CH2:49][CH2:50][O:51][C:42]=2[CH:41]=1)[CH:47]=[C:46]([C:52]1[N:53]([CH:57]([CH3:59])[CH3:58])[N:54]=[CH:55][N:56]=1)[N:45]=3>>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][CH:12]([C:40]2[CH:61]=[CH:60][C:43]3[C:44]4[N:48]([CH2:49][CH2:50][O:51][C:42]=3[CH:41]=2)[CH:47]=[C:46]([C:52]2[N:53]([CH:57]([CH3:59])[CH3:58])[N:54]=[CH:55][N:56]=2)[N:45]=4)[CH2:38][CH2:37]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc3c(c2)OCCc2cn(-c4ncnn4-c4ccc(F)cc4F)nc2-3)C1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc1OCC2
Yield: 31 %

Procedure:
4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared similarly to 3-{2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-8-yl}-azetidine-1-carboxylic acid tert-butyl ester from 8-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (3.0 g, 8.0 mmol) and 4-piperidine-1-carboxylic acid tert-butyl ester zinc iodide (12 mmol) (prepared similarly to 3-azetidine-1-carboxylic acid tert-butyl ester zinc iodide) to give 4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.2 g, 31%). LCMS: RT=5.06 min, M+H+=479
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]=[CH:10][C:11]1[S:15][C:14]([CH3:16])=[C:13]([C:17]2[S:18][CH:19]=[C:20]([C:22]3[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=3)[O:25][CH2:26][C:27](O)=[O:28])[N:21]=2)[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2C=CC=1.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][N:9]=[CH:10][C:11]1[S:15][C:14]([CH3:16])=[C:13]([C:17]2[S:18][CH:19]=[C:20]([C:22]3[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=3)[O:25][CH2:26][C:27]([N:53]3[CH2:54][CH2:55][N:50]([C:48]([O:47][C:43]([CH3:46])([CH3:44])[CH3:45])=[O:49])[CH2:51][CH2:52]3)=[O:28])[N:21]=2)[CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1sc(C=NNC(=O)OC(C)(C)C)cc1-c1nc(-c2cccc(OCC(=O)O)c2)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: Cc1sc(C=NNC(=O)OC(C)(C)C)cc1-c1nc(-c2cccc(OCC(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c2)cs1
Yield: 46.4 %

Procedure:
A stirred solution of 40 mg (0.084 mmol) of 2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetic acid dissolved in dry dimethylformamide (5 mL) was treated with hydroxybenzotriazole (23 mg, 0.17 mmol), 32 mg (0.17 mmol) of N-tert-butoxycarbonyl-piperazine (Lancaster, Windham, N.H., USA), 65 mg (0.17 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) at room temperature for 20 h. The mixture was partitioned between dichloromethane (50 mL) and brine (50 mL). The aqueous layers were extracted twice with dichloromethane (50 mL) and the combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate. The solvents were removed in vacuo. Purification preparative thin layer chromatography eluting with dichloromethane:methanol 95/5 (v:v) gave tert-butyl 4-(2-{3-[2-(5-{[(tert-butoxy)carbonylamino]iminomethyl}-2-methyl-3-thienyl)-1,3-thiazol-4-yl]phenoxy}acetyl)piperazinecarboxylate (25 mg, 46%) as a white solid. 1H-NMR (DMSO-d6; 300 MHz) δ9.13 (br s, 2H), 8.50 (s, 1H), 8.20 (s, 1H), 7.63 (m, 2H), 7.39 (m, 1H), 6.95 (m, 1H), 4.93 (s, 2H), 3.47-3.34 (m, 8H), 2.82 (s, 3H), 1.45 (s, 9H), 1.42 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C31H39N5O6S2 642.3 (M+H), 542.3 ((M-BOC)+H), 442.3 ((M-2 BOC)+H), found 642.0, 542.2, 442.3.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[Cl:7][C:8]([Cl:20])([Cl:19])[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)O.O>C(Cl)Cl>[CH3:18][O:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:9]([Cl:2])[C:8]([Cl:20])([Cl:19])[Cl:7])[CH:12]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1cccc(C(O)C(Cl)(Cl)Cl)c1
Solvent: ClCCl
Solvent: O
Product: COc1cccc(C(Cl)C(Cl)(Cl)Cl)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of 2.4 g (11.0 mmol) of phosphorous pentachloride in 7.0 mL of CH2Cl2 was added a solution of 2.28 g (9.0 mmol) of the product of Step A in 5.0 mL of CH2Cl2. The reaction mixture became homogenous while it was stiffed at room temperature for 3 h. The reaction mixture was then cooled to 0° C. with an external ice-water bath and ice and water were added. The reaction mixture was allowed to warm to room temperature while stirring for 1 h, and was then extracted with CH2Cl2. The organic layers were combined, dried (Na2SO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 5-20% EtOAc-hexane. Evaporation of the purified fractions afforded the title compound as a colorless oil.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:12][C:13]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:14]=1[C:15]#[N:16]>>[Cl:12][C:13]1[CH:20]=[CH:19][C:18]([O:21][C:2]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1cc(O)ccc1Cl
Reactant: N#Cc1cc(C=O)ccc1F
Product: N#Cc1cc(Oc2ccc(C=O)cc2C#N)ccc1Cl

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 2-chloro-5-hydroxybenzonitrile.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21](=[O:31])[CH2:22][C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:32]1[CH2:34][C@@H:33]1[CH2:35][O:36][C:37]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:38]=1[CH:39]=[CH:40][CH:41]=[N:42]2>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21](=[O:31])[CH2:22][C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH2:34][C@@H:33]([OH:32])[CH2:35][O:36][C:37]3[CH:46]=[CH:45][CH:44]=[C:43]4[C:38]=3[CH:39]=[CH:40][CH:41]=[N:42]4)[CH2:27][CH2:26]2)=[O:24])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CC(=O)N1CCNCC1)NC(CCCc1ccccc1)CCCc1ccccc1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Solvent: CCO
Product: O=C(CC(=O)N1CCN(C[C@@H](O)COc2cccc3ncccc23)CC1)NC(CCCc1ccccc1)CCCc1ccccc1
Temperature: 25 °C

Procedure:
3-(Piperazin-1-yl)-3-oxopropionic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (38) (209.5 mg; 0.497 mmol) is dissolved in ethanol (12 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added, then the mixture is refluxed for 15 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (neat ethyl acetate, then 50%→100% acetone in hexanes, then 5% ethanol in acetone) affording the desired product as a solid. ESMS: MH− 623.4
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7](=O)[NH:8][CH:9]=1)([O-:3])=[O:2]>O>[N+:1]([C:4]1[CH:5]=[C:6]2[N:11]=[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:19][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(Nc1cc([N+](=O)[O-])c[nH]c1=O)c1ccccc1
Solvent: O
Product: O=[N+]([O-])c1cnc2oc(-c3ccccc3)nc2c1
Temperature: 165 °C
Yield: 3.2 %

Procedure:
To polyphosphoric acid at 165° C. was added N-(5-nitro-2-oxo-1,2-dihydropyridin-3-yl)benzamide (300 mg, 1.16 mmol). The resulting mixture was then heated to 165° C. for 30 min. The solution was then poured into water. The resulting precipitate was collected by filtration, dissolved in diethyl ether, filtered through alumina and evaporated to afford 9 mg (3%) of the title compound.