Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16]C)=[O:15])[C:9]2=[O:18])=[CH:4][CH:3]=1.[Li+].[OH-]>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[C:9]2=[O:18])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccn(-c2ccc(F)cc2)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
To a solution of methyl 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (10.0 g, 0.04 mol) in MeOH (150 mL) and water (50 mL) is added LiOH (1.9 g, 0.08 mol). The resulting reaction mixture is stirred at RT for 0.5 hour. After most of the MeOH is removed, the mixture is acidified with concentrated aqueous HCl until a white solid precipitates. The solid is collected by filtration and washed with water (5 mL) to give the desired product (8.7 g, 93% yield). MS (m/z): 234.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].Cl[C:10]([CH3:18])([CH2:12][CH2:13][C:14](Cl)([CH3:16])[CH3:15])[CH3:11].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[F:1][C:2]1[C:3]([CH3:8])=[CH:4][C:5]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][C:10]([CH3:18])([CH3:11])[C:6]=2[CH:7]=1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: Cc1ccccc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc2c(cc1F)C(C)(C)CCC2(C)C
Temperature: 25 °C
Yield: 86.1 %

Procedure:
To a solution of 15 g (136 mmol) of 2-fluorotoluene and 24.9 g (136 mmol) of 2,5-dichloro-2,5-dimethylhexane in 120 mL dichloromethane was added 1.82 g (13.6 mmol) of aluminum chloride and the solution heated at reflux. After 18 hours the reaction mixture was cooled to room temperature and 5% aqueous HCl was added. This was partitioned between hexane and water. The aqueous phase was washed once with hexane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 25.8 g (86%) of 2-fluoro-3-methyl-5 ,5 ,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (m.p.=90.0-91.8° C.).
Reaction SMILES: [Cl:1][C:2]1[C:9]([C:10]#[C:11][Si](C)(C)C)=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:17][CH:18]([CH2:23][CH3:24])[C:19]([CH3:22])([OH:21])[CH3:20].C([O-])([O-])=O.[K+].[K+].CN1C(=O)CCC1>O>[Cl:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[C:8]2[C:9]=1[CH:10]=[CH:11][N:17]2[CH:18]([CH2:23][CH3:24])[C:19]([OH:21])([CH3:22])[CH3:20]
Reactant: CCC(N)C(C)(C)O
Reactant: C[Si](C)(C)C#Cc1c(F)ccc(C#N)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCC(n1ccc2c(Cl)c(C#N)ccc21)C(C)(C)O
Temperature: 60 °C
Reaction time: 18 h
Yield: 42.5 %

Procedure:
A mixture of 2-chloro-4-fluoro-3-((trimethylsilyl)ethynyl)benzonitrile (Example 32B) (0.163 g, 0.647 mmol), 3-amino-2-methylpentan-2-ol (0.091 g, 0.776 mmol), and K2CO3 (0.179 g, 1.294 mmol) in anhyd NMP (3 mL) was stirred in a heating block at 60° C. under N2. After 18 h, the mixture was subjected to microwave heating (140° C.) for 15 min. Upon cooling the mixture was poured into water and extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) affording 4-chloro-1-(2-hydroxy-2-methylpentan-3-yl)-1H-indole-5-carbonitrile (0.0761 g, 43% yield) as a yellow gum: 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J=2.2 Hz, 1H), 7.42 (d, J=8.6 Hz, 1H), 7.35 (d, J=8.7 Hz, 1H), 6.77 (d, J=3.3 Hz, 1H), 4.07 (dd, J=11.6, 3.6 Hz, 1H), 2.09 (m, J=3.6 Hz, 2H), 1.44 (s, 1H), 1.35 (s, 3H), 1.08 (s, 3H), 0.65 (t, J=7.3 Hz, 3H); MS (LCMS ES+) m/z 277 ([M+H]+, 70%), 318 ({[M+H]+MeCN}+, 100%).
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[CH:10]=[C:11]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]([F:14])=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.Cl[C:41]([O:43][CH:44]([Cl:46])[CH3:45])=[O:42]>C(Cl)(Cl)Cl>[CH2:2]([N:3]1[C:9]2[C:8](=[CH:13][C:12]([F:14])=[C:11]([N:15]3[CH2:20][CH2:19][N:18]([C:41]([O:43][CH:44]([Cl:46])[CH3:45])=[O:42])[CH2:17][CH2:16]3)[CH:10]=2)[C:6](=[O:7])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:1]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClC(Cl)Cl
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C(=O)OC(C)Cl)CC3)cc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Norfloxacin (6.4 g) was suspended in 300 ml of chloroform and 4.3 g of proton sponge® was added to it. The suspension was cooled in an ice bath and 4.0 g of 1-chloroethyl chloroformate was added. A clear solution resulted in half an hour. The reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated in vacuum to about 150 ml. The crystals formed were filtered and washed with chloroform. The pure product weighed 5.3 g.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15](O)=O)=O)(C)(C)C.[F:18][C:19]1[CH:20]=[C:21]([NH2:27])[C:22]([NH2:26])=[CH:23][C:24]=1[F:25].C(=O)([O-])[O-].[K+].[K+]>>[F:18][C:19]1[C:24]([F:25])=[CH:23][C:22]2[NH:26][C:15]([CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[N:27][C:21]=2[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: Nc1cc(F)c(F)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1cc2nc(CC3CCCCN3)[nH]c2cc1F
Temperature: 140 °C
Yield: 69.3 %

Procedure:
A mixture of 2-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (Beckett et al., J. Med. Chem., 563,1969) (10.0 g, 41 mmol) and 4,5-difluoro-benzene-1,2-diamine (5.95 g, 41 mmol) in polyphosphoric acid (140 g) was heated at 140° C. for 7 h. The cooled reaction mixture was poured onto excess solid potassium carbonate and crushed ice. The resulting basic, aqueous solution was extracted with ethyl acetate (2×) and the combined organics were washed with brine, dried (Na2SO4) and the solvent removed in vacuo. The residue was triturated with diethyl ether, ethyl acetate and pentane to afford the title compound as a light brown solid (7.14 g, 69%).
Reaction SMILES: [C:1]1(=[O:22])[N:5]([CH2:6][C:7]2[N:8]=[C:9]([N:12]3[CH2:15][CH:14]([OH:16])[CH2:13]3)[S:10][CH:11]=2)[C:4](=[O:17])[C:3]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:2]12.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C.C(OCC)C>C(Cl)Cl>[C:4]1(=[O:17])[N:5]([CH2:6][C:7]2[N:8]=[C:9]([N:12]3[CH2:13][CH:14]([O:16][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:15]3)[S:10][CH:11]=2)[C:1](=[O:22])[C:2]2=[CH:21][CH:20]=[CH:19][CH:18]=[C:3]12
Reactant: CS(=O)(=O)Cl
Reactant: O=C1c2ccccc2C(=O)N1Cc1csc(N2CC(O)C2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CS(=O)(=O)OC1CN(c2nc(CN3C(=O)c4ccccc4C3=O)cs2)C1
Reaction time: 1 h
Yield: 67.3 %

Procedure:
To a solution of 1-(4-phthalimidomethyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (864 mg, 2.74 mmol) (obtained as described in Reference Example 68(2)) in methylene chloride (35 ml) were added methanesulfonyl chloride (0.25 ml, 3.29 mmol) and triethylamine (0.46 ml, 3.29 mmol) in an ice bath and the mixture was stirred for 1 hour. After checking the completion of the reaction, the mixture was added to diethyl ether and stirred for 30 minutes. The mixture was then filtered and the solid was collected by filtration and washed with diethyl ether to afford 1-(4-phthalimidomethyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (726 mg, yield 67%) as a white solid.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:37]=[CH:36][C:27]([O:28][CH2:29][CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH2:16][CH2:15][C@@H:2]([OH:1])[C@@H:3]([O:4][C:5]2[CH:10]=[CH:9][C:8]([C:24]3[CH:25]=[CH:26][C:27]([O:28][CH2:29][CH2:30][N:31]4[CH2:32][CH2:33][CH2:34][CH2:35]4)=[CH:36][CH:37]=3)=[CH:7][CH:6]=2)[CH3:14])[CH:18]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: Brc1ccc(OCCN2CCCC2)cc1
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
Product: C[C@H](Oc1ccc(-c2ccc(OCCN3CCCC3)cc2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 68.9 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.190 g, Example 33), 1-[2-(4-bromophenoxy)ethyl]pyrrolidine (0.27 g), 2M aqueous sodium carbonate (0.75 ml) and tetrakis(triphenylphosphine)palladium (0) (0.025 g) in ethanol (2 ml). The reaction mixture was heated at 90° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure, taken up in ethanol and concentrated again (twice). The residue was triturated with acetone and then filtered through silica gel. The filtrate was concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give an oil which crystallised under high vacuum over 24 hours. Trituration with diethyl ether resulted in isolation of the title compound as a foam (0.194 g).
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([NH:7][C:8]([C:10]1[N:19]2[C:13]([CH2:14][N:15]([C:24](=[O:38])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]=4)=[C:27]([CH3:37])[CH:26]=3)[C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[CH2:18]2)=[CH:12][CH:11]=1)=[O:9])[CH2:5][OH:6].[OH-].[Na+].Cl>CC(C)=O>[C:31]1([C:28]2[CH:29]=[CH:30][C:25]([C:24]([N:15]3[C:16]4[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=4[CH2:18][N:19]4[C:10]([C:8]([NH:7][C@@H:4]([CH2:5][OH:6])[C:3]([OH:39])=[O:2])=[O:9])=[CH:11][CH:12]=[C:13]4[CH2:14]3)=[O:38])=[CH:26][C:27]=2[CH3:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]=1
Reactant: COC(=O)[C@H](CO)NC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3=CCCCC3)c(C)c1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N[C@@H](CO)C(=O)O)n3Cc3ccccc32)ccc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
(2S)-2-{[10-(4-Cyclohex-1-en-1-yl-3-methyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carbonyl]-amino}-3-hydroxy-propionic acid methyl ester of Example 12 (0.260 g, 0.493 mmol), was dissolved in acetone (3.3 mL), followed by addition of 2.5 N sodium hydroxide (0.590 mL, 1.48 mmol). The reaction was stirred at room temperature overnight, acidified with 1 N hydrochloric acid and extracted with diethyl ether. The combined ether phases were extracted with 1 N sodium hydroxide and the basic extracts acidified with 2 N hydrochloric acid. The acidified extracts were extracted with diethyl ether and the combined extracts dried over anhydrous magnesium sulfate, filtered and concentrated to afford 0.210 g of the title compound as a white powder.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18]C(=O)OC(C)(C)C)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[ClH:26]>O1CCOCC1>[ClH:26].[F:1][C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH2:18])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of tert-butyl N-[(1S,2S)-2-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]carbamate (2.57 g, 7.08 mmol) in 1,4-dioxane (25 ml) was added HCl in 1,4-dioxane (4 M, 20 ml, 80 mmol). The reaction was stirred at room temperature for 20 hours. The reaction mixture was concentrated in vacuo and azeotropically distilled with toluene to afford the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([OH:10])=[O:9].Cl.[CH3:12][C:13]1[CH:22]=[C:21]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1>>[CH3:12][C:13]1[CH:22]=[C:21]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([NH:1][C@H:2]3[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]3[C:8]([OH:10])=[O:9])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: N[C@H]1CCCC[C@H]1C(=O)O
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Agent: Cl
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CCCC[C@H]3C(=O)O)cc2)c2ccccc2n1
Yield: 28.5 %

Procedure:
According to the procedure of Example 10, Step 1, the reaction of 429.6 mg (3 mmol) of cis-2-amino-1-cyclohexane-carboxylic acid with 1.15 g of 4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl chloride hydrochloride provided 387.9 mg of cis-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohexanecarboxylic acid in 28% yield. MS: 455.1 (M+H)+
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:6]#[N:7].C1C(=O)N([Br:21])C(=O)C1>CN(C=O)C.CC(N=NC(C#N)(C)C)(C#N)C.O>[Br:21][C:8]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:3]([NH:2][CH3:1])=[CH:4][C:5]=1[C:6]#[N:7]
Reactant: CNc1cc(C#N)ccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CN(C)C=O
Solvent: O
Product: CNc1cc(C#N)c(Br)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 3-(methylamino)-4-nitrobenzonitrile (0.9 g, 0.005 mol) and NBS (0.9 g, 0.005 mol) in DMF (15 ml), AIBN (catalytic) was carefully added and the resulting solution was stirred at 80° C. for 3 h. The reaction was diluted with H2O and extracted with dichloromethane (3×30 ml). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum to afford the title compound 2-bromo-5-(methylamino)-4-nitrobenzonitrile as a yellow solid. 1H NMR (400 MHz, CDCl3), δ: 8.44 (s, 1H), 8.04 (bs, 1H), 7.18 (s, 1H), 3.05 (s, 3H). MS (M+1): 256.12.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9]1[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=1)[C:4]1[CH:8]=[CH:7][S:6][CH:5]=1.Br[CH2:16][C:17]1[N:22]=[C:21]([N:23]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=[O:33])[CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C>[CH3:14][N:13]1[C:9]([C:3](=[N:2][O:1][CH2:16][C:17]2[N:22]=[C:21]([N:23]3[C:24](=[O:33])[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:31]3=[O:32])[CH:20]=[CH:19][CH:18]=2)[C:4]2[CH:8]=[CH:7][S:6][CH:5]=2)=[CH:10][N:11]=[CH:12]1
Reactant: O=C1c2ccccc2C(=O)N1c1cccc(CBr)n1
Reactant: Cn1cncc1C(=NO)c1ccsc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: Cn1cncc1C(=NOCc1cccc(N2C(=O)c3ccccc3C2=O)n1)c1ccsc1
Temperature: 25 °C
Reaction time: 28 h
Yield: 65.2 %

Procedure:
To a solution of N-hydroxy-1-(1-methyl-1H-imidazol-5-yl)-1-(3-thienyl)methanimine (4.96 g, 23.9 mmol) and 2-[6-(bromomethyl)pyridin-2-yl]-1H-isoindole-1,3(2H)-dione (8.35 g, 26.3 mmol) in acetonitrile (100 mL) were added cesium carbonate (16.4 g, 50.3 mmol) and potassium iodide (397 mg, 2.39 mmol). After stirring at room temperature for 28 h, the reaction mixture was filtered, the insolubles washed with ethyl acetate, and the combined filtrates concentrated in vacuo. Purification on silica gel afforded 2-{6-[({[(1-methyl-1H-imidazol-5-yl)(3-thienyl)methylene]amino}oxy)methyl]pyridin-2-yl}-1H-isoindole-1,3(2H)-dione [6.91 g, yield 62%; HPLC/MS: m/z=444 (M+H); log P(HCOOH)=1.73].
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[O:18]1[C:22]2([CH2:27][CH2:26][CH:25]([NH:28][C@@H:29]([C:31]([O:33][CH3:34])=[O:32])[CH3:30])[CH2:24][CH2:23]2)[O:21][CH2:20][CH2:19]1>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:28]([CH:25]2[CH2:26][CH2:27][C:22]3([O:18][CH2:19][CH2:20][O:21]3)[CH2:23][CH2:24]2)[C@@H:29]([C:31]([O:33][CH3:34])=[O:32])[CH3:30])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: COC(=O)[C@@H](C)NC1CCC2(CC1)OCCO2
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.6 %

Procedure:
To a stirred mixture of 2,4-dichloro-5-nitropyrimidine (4, 12 g, 62.1 mmol), potassium carbonate (11.7 g, 84.78 mmol) in acetone (100 mL) was added methyl N-1,4-dioxaspiro[4.5]dec-8-yl-D-alaninate (13.8 g, 62.1 mmol) at rt. The reaction mixture was stirred for 16 h at rt. The bulk of solvent was removed under reduced pressure to give a residue, which was diluted with ethyl acetate (100 mL), washed with water, dried over sodium sulfate. The solvent was evaporated to give a crude material, which was then purified by silica gel flash chromatography (eluent: ethyl acetate-hexane mixture (v:v=5:95)) to afforded the desired product (10.1 g). 1HNMR (300 MHz, CDCl3): δ 1.55-1.64 (m, 3H), 1.70-1.99 (m, 6H), 2.05-2.20 (m, 3H), 3.06-3.15 (m, 1H), 3.75 (s, 3H), 3.99 (t, 4H), 8.61 (s, 1H).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([C:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].CO>C(OCC)(=O)C>[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:24]3[CH2:23][CH:22]=[C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:26][CH2:25]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: C1=C(c2ccccc2)CCNC1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2ccccc2)CC1

Procedure:
The title compound was prepared according to Example 1 from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-phenyl-1,2,3,6-tetrahydropyridine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 60% overall yield as a white foam. FDMS m/e=348 (M+ of free base). α[D]589 =-17.09 (c=0.49, methanol).
Reaction SMILES: O.O.[Sn](Cl)Cl.CN(C)C=O.[CH2:11]([O:18][C:19]1[C:24]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])=[CH:23][C:22]([NH:33][C:34]([C:36]2[CH:41]=[N:40][CH:39]=[CH:38][N:37]=2)=O)=[C:21]([N+:42]([O-])=O)[CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)(=O)C>[CH2:11]([O:18][C:19]1[C:24]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[F:32])=[CH:23][C:22]2[NH:33][C:34]([C:36]3[CH:41]=[N:40][CH:39]=[CH:38][N:37]=3)=[N:42][C:21]=2[CH:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Nc1cc(Oc2ccccc2F)c(OCc2ccccc2)cc1[N+](=O)[O-])c1cnccn1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccccc1Oc1cc2[nH]c(-c3cnccn3)nc2cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3.72 g of tin(II) chloride dihydrate was added to a dimethylformamide (16 ml) suspension of 1.52 g of N-(4-benzyloxy-5-(2-fluorophenoxy)-2-nitrophenyl)pyrazinecarboxamide, and the reaction liquid was stirred overnight at 80° C. The reaction liquid was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate, water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was washed with a mixed solvent of ethyl acetate and hexane to obtain the entitled compound as a yellow solid.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[CH:10]=[C:9]([CH3:11])[NH:8][C:7]=1[C:12]([NH2:14])=[O:13])[CH2:4][CH3:5])[CH3:2].N.CN.C1([NH2:21])CC1>>[NH2:21][N:8]1[C:9]([CH3:11])=[CH:10][C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[C:7]1[C:12]([NH2:14])=[O:13]
Reactant: CCC(CC)c1cc(C)[nH]c1C(N)=O
Reactant: NC1CC1
Agent: CN
Agent: N
Product: CCC(CC)c1cc(C)n(N)c1C(N)=O

Procedure:
By the same procedure as a reaction of Example 5, using 3-(1-ethylpropyl)-5-methyl-1H-pyrrole-2-carboxamide (which was provided by the same procedure as a reaction of Example 4, using a saturated aqueous solution of ammonia instead of an aqueous solution of 40% methylamine) instead of the compound prepared in Example 4, using cyclopropylamine instead of 40% aqueous solution of methylamine, and using the corresponding aldehydes instead of the compound prepared in Example 7, the title compound (1.988 g) having the following physical data was obtained.
Reaction SMILES: [N:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]([O:13][C:14]([NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>ClCCl>[C:9]([O:13][C:14]([NH:16][CH:17]1[CH2:18][CH2:19][N:20]([C:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:7])[CH2:21][CH2:22]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: O=C(Cl)N1CCCC1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)N2CCCC2)CC1
Reaction time: 72 h

Procedure:
1-Pyrrolidine carbonylchloride (1.10 g, 9.99 mmol) was dissolved in 400 ml if dichloromethane under N2. (Tert-butoxy)-N-(4-piperidyl)carboxamide (2.0 g, 9.99 mmol) and triethyl amine (1.40 mL, 9.99 mmol) were added and the reaction mixture was stirred for three days. The reaction was quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic phases were dried over MgSO4 and the solvent evaporated to give the product as a white solid. (2.63 g, 8.84 mmol, 89%).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])=[N:24][CH:25]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)CC)C>ClCCl>[C:27]([N:26]([CH3:30])[C:23]1[N:24]=[CH:25][C:20]([NH:19][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:21][CH:22]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)N(C)c1ccc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(C)c1ccc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (260 mg, 1 mmol), N-(5-amino-pyridin-2-yl)-N-methyl-acetamide (165 mg, 1 mmol), bromo-tri-pyrrolidino-phosphonium hexafluorophosphate (470 mg, 1 mmol), and triethylamine (202 mg, 2 mmol) in anhydrous dichloromethane (5 mL) was stirred at room temperature overnight. After the reaction was complete, the solvent and excess triethylamine were removed by evaporation. Flash chromatography (Merck silica gel 60, 230-400 mesh, 0%-40% ethyl acetate in hexane for 20 min) gave 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(acetyl-methyl-amino)-pyridin-3-yl]-amide as a yellow solid. LCMS calcd for C19H15F3N4O3 (m/e) 404, obsd 405 (M+H).