Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]2[N:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:14][CH:15]=2)[CH2:4]1.Cl[C:24]1[N:29]=[CH:28][N:27]=[CH:26][CH:25]=1>CN(C=O)C>[N:27]1[CH:26]=[CH:25][CH:24]=[N:29][C:28]=1[N:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([NH:9][C:10]2[N:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:14][CH:15]=2)[CH2:4]1
Reactant: Clc1ccncn1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCCNC2)cn1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCCN(c3ncccn3)C2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.3 %

Procedure:
To a solution of ethyl (2E)-3-{5-[(3R)-3-piperidinylamino]-2-pyrazinyl)acrylate dihydrochloride (300 mg, 0.86 mmol) in DMF (6 mL) were added diiopropylethylamine (366 mg, 2.84 mmol) and 6-chloropyrimidine (128 mg, 1.11 mmol) at ambient temperature and the mixture was stirred at ambient temperature for 18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between water and EtOAc. The organic layer was separated, washed water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform-MeOH=95-5/hexane-EtOAc=1/4) to give ethyl (2E)-3-(5-{[(3R)-1-(2-pyrimidinyl)-3-piperidinyl]amino}-2-pyrazinyl)acrylate (141 mg, 46%) as an amorphous powder.
Reaction SMILES: CCO[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[F:16][C:17]([F:26])([F:25])[C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[F:16][C:17]([F:25])([F:26])[C:18]1[CH:24]=[C:23]2[C:21](=[CH:20][CH:19]=1)[N:22]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]2[OH:13]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(C(F)(F)F)cc2c1O

Procedure:
Using the procedure of Example 2, ethyl ethoxymethylene malonate and 4-trifluoromethyl-aniline were reacted and treated with phenyl oxide to obtain ethyl 6-trifluoromethyl-4-hydroxy-3-quinoline-carboxylate melting at >260° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2([C:13]([NH2:15])=[O:14])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[N:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][CH:23]=[CH:22]2.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:16]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C:9]2([C:13]([NH2:15])=[O:14])[CH2:12][CH2:11][CH2:10]2)=[N:7][C:2]=1[NH:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][CH:23]=[CH:22]2)#[N:17]
Reactant: N#Cc1ncc(NC2(C(N)=O)CCC2)nc1Cl
Reactant: Nc1ccc2ncccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: N#Cc1ncc(NC2(C(N)=O)CCC2)nc1Nc1ccc2ncccc2c1
Reaction time: 5 h
Yield: 32 %

Procedure:
A mixture of 1-(6-chloro-5-cyanopyrazin-2-ylamino)cyclobutanecarboxamide (22 mg, 0.087 mmol), 6-aminoquinoline (30 mg, 0.208 mmol), K2CO3 (90 mg, 0.652 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (15 mg, 0.066 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 5 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give 1-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)cyclobutanecarboxamide (10 mg).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[N:29]1([CH2:36][CH2:37][O:38][C:39]2[CH:40]=[CH:41][C:42]([C:45]([O-])=O)=[N:43][CH:44]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.[Na+]>>[N:29]1([CH2:36][CH2:37][O:38][C:39]2[CH:40]=[CH:41][C:42]([CH2:45][N:3]([CH2:1][CH3:2])[C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[CH:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[N:43][CH:44]=2)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: O=C([O-])c1ccc(OCCN2CCCCCC2)cn1
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Agent: [Na+]
Product: CCN(Cc1ccc(OCCN2CCCCCC2)cn1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 50.4 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (40 mg) and sodium 5-(2-azepan-1-ylethoxy)pyridine-2-carboxylate (120 mg) according to an analogous synthetic method to Example 152, the title compound (28 mg) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[CH:2].[C:13](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:22]1[CH:29]=[CH:28][C:25]([O:26][CH3:27])=[CH:24][CH:23]=1)[C:14]1[CH:21]=[CH:20][C:17]([O:18][CH3:19])=[CH:16][CH:15]=1>C(Cl)Cl>[CH3:27][O:26][C:25]1[CH:24]=[CH:23][C:22]([C:13]([C:14]2[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[CH:20][CH:21]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH:12][S:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[CH:2])=[CH:8][CH:7]=2)(=[O:10])=[O:11])=[CH:29][CH:28]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: C#Cc1ccc(S(N)(=O)=O)cc1
Solvent: ClCCl
Product: C#Cc1ccc(S(=O)(=O)NC(c2ccccc2)(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a stirring slurry of 4-ethynylbenzenesulfonamide (1.81 g, 10.0 mmol) and DMTr-Cl (4.07 g, 12.0 mmol) in DCM (100 mL) was added TEA (2.8 mL). The resulting solution was allowed to stir at room temperature for overnight. Silica gel (3 g) was added to the solution followed by rotary evaporation of solvent in vacuo. The sample was absorbed onto silica gel was then loaded onto a pre-equilibrated column (with 10% TEA in hexane). Flash chromatography using 0-30% EtOAc in hexane as the gradient eluents gave the product 5 as a yellow solid (4.8 g, 99%).
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][O:4][CH2:3]1.[CH:22]1([C:25]([NH2:33])([C:27]2[N:31]=[C:30]([CH3:32])[O:29][N:28]=2)[CH3:26])[CH2:24][CH2:23]1>>[CH:22]1([C:25]([NH:33][C:12]([C:9]2[CH:8]=[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])[C:6]([C:2]3([F:1])[CH2:5][O:4][CH2:3]3)=[CH:11][N:10]=2)=[O:14])([C:27]2[N:31]=[C:30]([CH3:32])[O:29][N:28]=2)[CH3:26])[CH2:24][CH2:23]1
Reactant: Cc1nc(C(C)(N)C2CC2)no1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1(F)COC1)C(F)(F)F
Product: Cc1nc(C(C)(NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3(F)COC3)cn2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3-fluorooxetan-3-yl)-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carboxylic acid (example 142b) and 1-Cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (CAN1155536-64-3) as starting materials and the mixture of epimers was isolated (72 mg, 40%). The mixture of epimers was separated into its epimers by preparative chiral HPLC (Chiralpak AD, ethanol/heptane) and the title compound was the first epimer collected and isolated as colorless oil; MS (ESI, m/z): 459.5 (M+H+).
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[N:8]([C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[CH2:7]1)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:12]([N:8]2[C:9](=[O:11])[CH2:10][C@@H:6]([CH:4]=[O:5])[CH2:7]2)[CH3:13])=[CH:15][CH:16]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H](C(=O)N(C)OC)CC2=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)N2C[C@H](C=O)CC2=O)cc1
Reaction time: 1 h

Procedure:
To a solution of (R)-N-methoxy-1-((R)-1-(4-methoxyphenyl)ethyl)-N-methyl-5-oxopyrrolidine-3-carboxamide 1.02 (260 mg, 0.85 mmol) in THF (6 mL) at 0° C. was added a solution of LAH in THF (1M, 430 μL, 0.43 mmol). The reaction was stirred for 1 hour and quenched by the addition of KHSO4 (sat aq, 15 mL). The mixture was stirred for 5 minutes and Et2O (20 mL) was added. The layers were separated and the aqueous layer was extracted with Et2O (3×20 mL). The combined organics were dried (MgSO4), filtered and concentrated to afford (R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carbaldehyde 1.07.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[N:5]([CH3:7])[CH:6]=1.C[N:12](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH2:12])=[O:10])[N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(Br)cc1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(Br)cc1C(N)=O
Yield: 46 %

Procedure:
4-Bromo-1-methyl-1H-pyrrole-2-carboxylic acid (122 mg, 0.60 mmol), HATU (274 mg, 0.72 mmol) and DIEA (194 mg, 1.50 mmol) were dissolved in DMF (5 mL). The reaction mixture was stirred at room temperature with ammonia gas bubbled through continuously overnight. The reaction mixture was diluted with 100 mL of DCM, and then washed with water (50 mL). The aqueous layer was extracted with DCM (20 mL×2). All organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 6/1) to give 4-bromo-1-methyl-1H-pyrrole-2-carboxylic acid amide (56 mg, yield 46%). 1H NMR (300 MHz, CDCl3): δ 6.74 (d, J=1.8 Hz, 1H), 6.59 (d, J=1.8 Hz, 1H), 3.92 (s, 3H). LC-MS calcd for C6H7BrN2O (m/e) 201.97, obsd 203 and 205 [M+1]+.
Reaction SMILES: Cl[CH:2]([N:10]1[CH:13]([S:14][CH2:15][C:16]#[C:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:12]([NH:25][C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:11]1=[O:45])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:46]1([P:52]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.N1C=CC=CC=1>O1CCCC1.O1CCOCC1>[C:6]([O:5][C:3]([C:2]([N:10]1[CH:13]([S:14][CH2:15][C:16]#[C:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH:12]([NH:25][C:26]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:11]1=[O:45])=[P:52]([C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:4])([CH3:7])([CH3:9])[CH3:8]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)C(Cl)N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#Cc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(N1C(=O)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1SCC#Cc1ccc(F)cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
1-(1-Chloro-1-t-butoxycarbonylmethyl)-3-(triphenylmethylamino)-4-(3-p-fluorophenylprop-2-ynylthio)azetidin-2-one (570mg) was dissolved in a 1:1 mixture of dry tetrahydrofuran and dioxan (20ml) under nitrogen. Triphenylphosphine (495mg) and dry pyridine (150mg) were added and the mixture heated at 49° for 16 hours. The reaction mixture was filtered the filtrate evaporated. The residue was triturated with toluene and the soluble portion re-evaporated. Chromatography on silica afforded 1-(1-t-butoxycarbonyl-1-triphenylphosphoranylidenemethyl)-3-(triphenylmethylamino)-4-(3-p-fluorophenylprop-2-ynylthio) azetidin-2-one, as a white solid (418mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]([OH:14])[C:10]([NH:12][CH3:13])=[O:11].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N:9]([O:14][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]([NH:12][CH3:13])=[O:11]
Reactant: CNC(=O)N(O)c1cc(Cl)ccc1Cl
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)ON(C(=O)NC)c1cc(Cl)ccc1Cl

Procedure:
A solution of 1-(2,5-dichlorophenyl)-1-hydroxy-3-methylurea (22 grams; 0.09 mol) in 2 N sodium hydroxide (50 ml) was charged into a glass reaction flask equipped with a mechanical stirrer. Ethyl chloroformate (9.6 ml; 0.1 mol) was added to the flask at a temperature of about 10° to 15°C. After the addition the reaction mixture was stirred for a period of about one-half hour, during which time a precipitate was formed. The precipitate was recovered by filtration and was recrystallized from isopropyl alcohol to yield 1-(2,5-dichlorophenyl)-1-ethoxycarbonyloxy-3-methylurea having a melting point of 130° to 132°C and having the following elemental analysis as calculated for C11H12Cl2N2O4 :
Reaction SMILES: [Br:1]Br.[CH:3]1([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:16][CH:15]=3)=[CH:12][C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>CC(O)=O>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:9]([CH:3]3[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]3)[N:10]=[C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:12]=2[Br:1])=[CH:15][CH:16]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrBr
Reactant: CCOC(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(C2CCCCC2)c(-c2ccc(OCc3ccccc3)cc2)c1Br
Temperature: 25 °C
Reaction time: 17 h
Yield: 61.4 %

Procedure:
Bromine (82 μL, 1.61 mmol) was added to pyrazole 1.3 (500 mg, 1.24 mmol) in AcOH (5 ml) at 0° C. and the reaction mixture was stirred at rt for 17 h. Upon concentration, the crude product was purified by SiO2 chromatography (stepwise gradient: 20 to 25% EtOAc/hexanes) to afford 368 mg (62%) of bromide 8.1. MS (ESI) 483.4 (MH+).
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([CH2:12][CH3:13])([CH:8]([OH:11])[CH2:9][CH3:10])[CH2:4][O:3]1.O>CO>[CH2:12]([C:5]([CH2:6][OH:7])([CH:8]([OH:11])[CH2:9][CH3:10])[CH2:4][OH:3])[CH3:13]
Reactant: CCC(O)C1(CC)COC(C)(C)OC1
Solvent: CO
Solvent: O
Product: CCC(O)C(CC)(CO)CO
Reaction time: 3 h
Yield: 74.8 %

Procedure:
2,2-Dimethyl-5-ethyl-5-(1-hydroxypropyl)-1,3-dioxane (10 g.) and Dowex 50×8-200 ion exchange resin (H+ form) (1.0 g.) in methanol (200ml) containing water (40 ml) was refluxed with stirring for three hours. The mixture was filtered and the filtrate was evaporated in vacuo. 2-Ethyl-2-hydroxymethyl-pentan-1,3-diol (6.0 g.) was obtained as a colourless viscous oil.
Reaction SMILES: C(CCC1C=C(/[C:12](/[CH:37]=[CH:38]/[C:39]2[C:40]([CH3:57])([CH3:56])[C:41]3[C:42]([N:55]=2)=[N+:43]([CH2:48][CH2:49][CH2:50][S:51]([O-:54])(=[O:53])=[O:52])[CH:44]=[C:45]([Cl:47])[CH:46]=3)=[CH:13]\[CH:14]=[C:15]2\[N:16]([CH2:30][CH2:31][CH2:32][S:33]([O-:36])(=[O:35])=[O:34])[C:17]3[C:22]([C:23]\2([CH3:25])[CH3:24])=[CH:21][C:20]([S:26]([O-:29])(=[O:28])=[O:27])=[CH:19][CH:18]=3)C=CC=1)(O)=O.[Na+:58].[Na+].[C:60]([CH2:63][CH2:64][C:65]1[CH:70]=[CH:69][C:68](B(O)O)=[CH:67][CH:66]=1)([OH:62])=[O:61]>>[C:60]([CH2:63][CH2:64][C:65]1[CH:70]=[CH:69][C:68](/[C:12](/[CH:37]=[CH:38]/[C:39]2[C:40]([CH3:57])([CH3:56])[C:41]3[C:42]([N:55]=2)=[N+:43]([CH2:48][CH2:49][CH2:50][S:51]([O-:54])(=[O:53])=[O:52])[CH:44]=[C:45]([Cl:47])[CH:46]=3)=[CH:13]\[CH:14]=[C:15]2\[N:16]([CH2:30][CH2:31][CH2:32][S:33]([O-:36])(=[O:35])=[O:34])[C:17]3[C:22]([C:23]\2([CH3:25])[CH3:24])=[CH:21][C:20]([S:26]([O-:29])(=[O:27])=[O:28])=[CH:19][CH:18]=3)=[CH:67][CH:66]=1)([OH:62])=[O:61].[Na+:58].[Na+:58]
Reactant: O=C(O)CCc1ccc(B(O)O)cc1
Reactant: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2cccc(CCC(=O)O)c2)=Nc2c1cc(Cl)c[n+]2CCCS(=O)(=O)[O-]
Agent: [Na+]
Product: CC1(C)C(/C=C/C(=C/C=C2/N(CCCS(=O)(=O)[O-])c3ccc(S(=O)(=O)[O-])cc3C2(C)C)c2ccc(CCC(=O)O)cc2)=Nc2c1cc(Cl)c[n+]2CCCS(=O)(=O)[O-]

Procedure:
Compound 12 is prepared analogously to compound 10 (Example 10), except that 4-(2-carboxyethyl)phenylboronic acid is used as a starting material.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].Cl.[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[CH:30]([OH:35])[C:31](=N)OC>C(O)C.O>[NH2:1][C:2]1[C:3]2[N:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[C:31]([CH:30]([C:24]3[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:23]=3[Cl:22])[OH:35])=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=N)C(O)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)NCCCNc1c(N)cccc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCCCn1c(C(O)c2ccc(Cl)cc2Cl)nc2cccc(N)c21
Reaction time: 14 h
Yield: 84.6 %

Procedure:
To a stirred solution of tert-butyl {3-[(2,6-diaminophenyl)amino]propyl}carbamate (5.47 g, 19.5 mmol) in ethanol (39 mL) was added methyl 2-(2,4-dichlorophenyl)-2-hydroxyethanimidoate hydrochloride (5.80 g, 19.5 mmol) at room temperature. After 14 h, the reaction mixture was diluted with water. The resultant precipitate was collected by filtration and washed with water and ethyl acetate to give the title compound as a colorless solid (7.67 g, 16.5 mmol, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].I[CH2:25][CH2:26][F:27]>C1COCC1>[F:27][CH2:26][CH2:25][N:21]1[CH2:20][CH2:19][N:18]([CH:15]2[CH2:14][CH2:13][N:12]([C:5]3[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:17][CH2:16]2)[CH2:23][CH2:22]1
Reactant: COc1cc(N2CCC(N3CCNCC3)CC2)ccc1[N+](=O)[O-]
Reactant: FCCI
Solvent: C1CCOC1
Product: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 85 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
To a solution of 1-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}piperazine (18.03 g, 56.10 mmol and 2.23 g, 6.96 mmol from separate batches) in THF was added 1-iodo-2-fluoroethane (7.38 mL, 90.79 mmol). The reaction was stirred at 85° C. overnight. The solution was transferred to a sealed tube. Upon addition of 1-iodo-2-fluoroethane (7.38 mL, 90.79 mmol), the reaction was stirred at 85° C. for an additional 5 h. The solvent was removed in vacuo and the residue was taken up in H2O and extracted with DCM (×3), dried with MgSO4, filtered and concentrated. Purification by flash chromatography provided the title compound of step D (15.94 g, 43.50 mmol, 69%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (qd, J=11.9, 3.7 Hz, 2H), 1.79 (d, J=10.8 Hz, 2H), 2.32-2.42 (m, J=7.0, 3.7 Hz, 9H), 2.52 (dt, JHF=28.6 Hz, J=4.9 Hz, 2H), 2.86-2.95 (m, 2H), 3.85 (s, 3H), 3.99 (d, J=13.4 Hz, 2H), 4.46 (dt, JHF=47.8 Hz, J=4.9 Hz, 2H), 6.45 (d, J=2.4 Hz, 1H), 6.54 (dd, J=9.5, 2.6 Hz, 1H), 7.82 (d, J=9.3 Hz, 1H).
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20]/[CH:21]=[CH:22]/[C@@H:23]([NH:28][P:29]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:30])[CH2:24][CH:25]([CH3:27])[CH3:26])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:18][CH2:19][CH2:20]/[CH:21]=[CH:22]/[C@@H:23]([NH:28][P:29]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:30])[CH2:24][CH:25]([CH3:26])[CH3:27]
Reactant: CC(C)C[C@@H](/C=C/CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NP(=O)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)C[C@@H](/C=C/CCO)NP(=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the TBDPS-protected alcohol 8c (700 mg, 0.983 mmol, crude) in dry THF (8 mL) at 0° C. was added TBAF (1.0M/THE, 1.23 mL, 1.23 mmol), and the reaction mixture was allowed to warm to rt while stirring under argon. As completion was not reached after 4 h, 0.75 eq of TBAF (0.75 mL) was added at 0° C. The reaction mixture was stirred further at rt for 3 h, then quenched with sat. aq. NH4Cl and diluted with EtOAc. The aqueous phase was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography (SiO2, 95:5, EtOAc/MeOH) afforded 272 mg (77%, 2 steps) of the title compound as a white solid. mp 124.0-124.2° C.; [α]D23-12.1 (c 1.0, DCM); 1H NMR (300 MHz, CDCl3) δ 8.00-7.83 (m, 4 H), 7.58-7.35 (m, 6 H), 5.52 (dd, 1 H, J=15.3, 9.0 Hz), 5.24 (m, 1 H), 4.58 (bs, 1H), 3.78-3.47 (m, 3 H), 2.80 (appdd, 1 H, J=9.2, 3.8 Hz), 2.16 (m, 2 H), 1.68 (bs, 1 H), 1.55-1.43 (m, 1 H), 1.43-1.31 (m, 1 H), 0.87 (dd, 6 H, J=8.6, 6.4 Hz); HRMS (ESI) m/z calcd for C21H28NO2PNa 380.1755. found 380.1725.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:6]=1[CH2:21]Br)=[O:4].[CH3:23][O:24][C:25](=[O:38])[CH2:26][NH:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[C:6]=1[CH2:21][N:27]([CH2:26][C:25]([O:24][CH3:23])=[O:38])[S:28]([C:31]1[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=1)(=[O:30])=[O:29])=[O:4]
Reactant: COC(=O)c1cc(Br)c(=O)n([C@H](C)c2ccccc2)c1CBr
Reactant: COC(=O)CNS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN(Cc1c(C(=O)OC)cc(Br)c(=O)n1[C@H](C)c1ccccc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.8 %

Procedure:
A mixture of (R)-5-bromo-2-bromomethyl-6-oxo-1-(1-phenyl-ethyl)-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (3.48 g, 8.11 mmol), (toluene-4-sulfonylamino)-acetic acid methyl ester (1.87 g, 7.71 mmol), sodium iodide (2.43 g, 16.2 mmol) and potassium carbonate (2.24 g, 16.2 mmol) in DMF (50 mL) was stirred at r.t. for 16 h. Brine (100 mL) was added, and the resulting suspension was extracted with EtOAc. The organic layer was washed with water and brine, and dried over MgSO4. After the solvent was evaporated in vacuo, the crude product was chromatographed (0-50% EtOAc/hexanes) to give 3.5 g of the title compound as a yellow viscous oil. MS: (+) m/z 613, 615 (M+Na, 79/81Br).
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][CH3:6])[CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=1>C(OCC)(=O)C>[CH:1]1([C:4]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]3[C:5]=2[CH3:6])[CH2:3][CH2:2]1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: CCC(=O)C1CC1
Solvent: CCOC(C)=O
Product: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12

Procedure:
Operations similar to Production Example 1-(1) were conducted using 1-cyclopropyl-1-propanone, and successively those of Production 1-(2) were conducted using 2-amino-5-nitropyridine. The solid whereupon obtained was suspended in ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution and purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to provide the title compounds as yellow crystals.
Reaction SMILES: [CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2].Br[CH2:15][CH:16]=[CH:17][CH2:18][CH3:19]>>[CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]([CH2:15][CH:16]=[CH:17][CH2:18][CH3:19])[C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2]
Reactant: CCC=CCBr
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Product: CCC=CCn1c(C)c(C)c(C=O)c1C(=O)OC

Procedure:
The title compound (trans) was prepared as a yellow-orange oil in 85.1% yeild in a similar procedure to that described in Referential Example 9 by using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 1-bromo-2-pentene (trans).