Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9](B(O)O)[CH:8]=1.Br[C:17]1[CH:26]=[CH:25][C:20]([CH:21]=[CH:22][CH:23]=[O:24])=[CH:19][CH:18]=1>CO.C1(C)C=CC=CC=1.ClCCl.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:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:17]2[CH:26]=[CH:25][C:20]([CH:21]=[CH:22][CH:23]=[O:24])=[CH:19][CH:18]=2)[CH:8]=1
Reactant: OB(O)c1cccnc1
Reactant: O=CC=Cc1ccc(Br)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: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=CC=Cc1ccc(-c2cccnc2)cc1

Procedure:
2M aq. Na2CO3 (1 mL) and a solution of 3-pyridinylboronic acid (148 mg, 1.20 mmol) in methanol (1 mL) were added to a solution of 4-bromocinnamaldehyde (211 mg, 1.00 mmol, prepared as described in Tetrahedron 1998, 54, 10761) and tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.030 mmol) in toluene (2 mL) and the mixture was heated to reflux for 36 h. The cooled reaction mixture was diluted with dichloromethane, washed with sat. aq. NaHCO3 and brine, dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 1:1 hexane/ethyl acetate) yielded the title compound. MS 210 (M+H)+.
Reaction SMILES: N[C@@H]1[C:8](=[O:9])[N:7]2[C@@H]1S[C@](C(O)=O)(N1CCN(N=CC3C=CC(C)=CC=3)C1=O)C2.[NH2:28][C@@H:29]1[C:35](=[O:36])[N:34]2[C@@H:30]1[S:31][C@@:32]([N:40]1[CH2:44][CH2:43][N:42]([N:45]=CC3C=CC=C(OC)C=3)[C:41]1=[O:55])([C:37]([OH:39])=[O:38])[CH2:33]2>>[NH2:28][C@@H:29]1[C:35](=[O:36])[N:34]2[C@@H:30]1[S:31][C@:32]([C:37]([OH:39])=[O:38])([N:40]1[CH2:44][CH2:43][N:42]([NH:45][C:8]([NH2:7])=[O:9])[C:41]1=[O:55])[CH2:33]2
Reactant: COc1cccc(C=NN2CCN([C@]3(C(=O)O)CN4C(=O)[C@@H](N)[C@H]4S3)C2=O)c1
Reactant: Cc1ccc(C=NN2CCN([C@]3(C(=O)O)CN4C(=O)[C@@H](N)[C@H]4S3)C2=O)cc1
Product: NC(=O)NN1CCN([C@]2(C(=O)O)CN3C(=O)[C@@H](N)[C@H]3S2)C1=O

Procedure:
(3R,5R,6R)-6-amino-3-carboxy-3-[3-(p-methylbenzylideneamino)-2-oxoimidazolidin-1-yl-]-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane and (3R,5R,6R)-6-amino-3-(3-anisylideneamino-2-oxoimidazolidin-1-yl)-3-carboxy-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane were treated in the same manner to obtain (3R,5R,6R)-6-amino-3-carboxy-7-oxo-3-(2-oxo-3-ureidoimidazolidin-1-yl)-4-thia-1-azabicyclo[3.2.0]heptane. The physical property (IR) of this product were identical with that obtained above.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH:10]=2)=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.ClC1C=CC=CC=1Cl.Cl.Cl[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]Cl.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:3]([C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH:10]=2)=[C:4]([N:8]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:5]=[CH:6][CH:7]=1
Reactant: ClCCNCCCl
Reactant: Cc1cccc(N)c1C1=CC(C)(C)CC(C)(C)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cc1cccc(N2CCNCC2)c1C1=CC(C)(C)CC(C)(C)C1
Temperature: 200 °C
Reaction time: 0.83 h
Yield: 73.5 %

Procedure:
To a mixture of 3-methyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenylamine (663 mg, 2.72 mmol) produced in Example (71b) and 1,2-dichlorobenzene (3 mL) was added bis(2-chloroethyl)amine hydrochloride (632 mg, 3.54 mmol), followed by stirring for 5 hours and 50 minutes at an external temperature of 200° C. under a nitrogen atmosphere. During the reaction, a nitrogen stream was passed through the reactor several times. The reaction mixture was cooled to room temperature, chloroform and saturated solution of sodium hydrogencarbonate were added, and the filtrate obtained by filtration through Celite was extracted with chloroform. The separated organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 625 mg of the title compound as a yellow solid.
Reaction SMILES: Cl.[CH:2]([N:5]([C:7]([C:9]1[S:10][C:11]2[CH2:12][CH2:13][O:14][C:15]3[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1)=[O:8])[NH2:6])([CH3:4])[CH3:3].[CH3:24][O:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl>[CH:2]([N:5]([C:7]([C:9]1[S:10][C:11]2[CH2:12][CH2:13][O:14][C:15]3[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1)=[O:8])[NH:6][C:27](=[O:28])[CH2:26][O:25][CH3:24])([CH3:4])[CH3:3]
Reactant: CC(C)N(N)C(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: COCC(=O)NN(C(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2)C(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a mixture of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid N-isopropyl-hydrazide hydrochloride (3.5 g, 8.4 mmol) and TEA (4.07 mL, 29.3 mmol) in DCM (35 mL) at 0° C. was added methoxy-acetyl chloride (1.53 mL, 16.7 mmol) dropwise and the reaction mixture was stirred at 0° C. for 0.75 h then 18 h at RT. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution and the phases separated. The aqueous phase was extracted with DCM (×2) before the combined organic extracts were washed with 10% citric acid solution, followed by brine then dried (Na2SO4) and concentrated in vacuo to give a yellow brown solid. The solid was triturated with diethyl ether to give the title compound as an off white solid (2.66 g, 5.86 mmol, 70%). LCMS RT=4.64 min, [M+H]+=454/456.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]1[C:8]2([CH3:12])[C:9]([CH3:11])=[CH:10][CH:5]([CH:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7]2)[N:4]1CC1C=CC=CC=1>[Pd].C(O)C>[ClH:1].[CH3:2][CH:3]1[C:8]2([CH3:12])[CH:9]([CH3:11])[CH2:10][CH:5]([CH:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7]2)[NH:4]1
Reactant: CCOC(=O)C1CC2(C)C(C)=CC1N(Cc1ccccc1)C2C
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CC2(C)C(C)CC1NC2C
Reaction time: 3.5 h

Procedure:
A mixture of ethyl 3,4,8-trimethyl-2-(phenylmethyl)-2-azabicyclo[2.2.2]oct-7-ene-6-carboxylate hydrochloride (26.2 g, mmol), 10% palladium on carbon (2.6 g) and ethanol (200 mL) were placed on a Parr hydrogenator at 50 psi for 3.5 hours. The catalyst was removed by filtration and the solvent was removed in vacuo to afford crude ethyl 3,4,8-trimethyl-2-azabicyclo[2.2.2]octane-6-carboxylate hydrochloride as a yellow oil, which was used directly in the next step.
Reaction SMILES: C[O:2][C:3]1[CH2:8][CH:7]=[C:6]([C:9]([OH:12])([CH3:11])[CH3:10])[CH2:5][CH:4]=1.[CH3:13][C:14]([C:22]1[CH:23]=[C:24](O)[CH:25]=[C:26]([CH:28]=1)[OH:27])([CH3:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].B(F)(F)F.CCOCC.Cl>C1C=CC=CC=1>[OH:27][C:26]1[C:25]2[C@H:5]3[CH2:4][C:3](=[O:2])[CH2:8][CH2:7][C@H:6]3[C:9]([CH3:11])([CH3:10])[O:12][C:24]=2[CH:23]=[C:22]([C:14]([CH3:13])([CH3:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:28]=1
Reactant: CCCCCCC(C)(C)c1cc(O)cc(O)c1
Reactant: COC1=CCC(C(C)(C)O)=CC1
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)[C@@H]1CCC(=O)C[C@H]21
Temperature: 24 °C
Reaction time: 5 h

Procedure:
A solution of 504 mg. of 1-methoxy-4-(1-hydroxy-1-methylethyl)-1,4-cyclohexadiene and 708 mg. of 5-(1,1-dimethylheptyl)resorcinol in 25 ml. of benzene was stirred at 24° C. while 5 ml. of boron trifluoride diethyl etherate was added in one portion. The reaction mixture was stirred at 24° C. for five hours. The reaction mixture then was added to 20 ml. of 6N hydrochloric acid solution. After allowing the benzene solvent to evaporated from the aqueous acid solution, the solution was extracted several times with diethyl ether. The ethereal extracts were combined, washed with water and with aqueous sodium bicarbonate solution, and dried. Evaporation of the solvent under reduced pressure provided an oil, which was crystallized from hexane to afford dl-cis-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-one.
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:14]([O-])=[CH:15][C:16](=O)[C:17]([O:19]CC)=[O:18])[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.Cl.[Cl:48][C:49]1[N:54]=[CH:53][C:52]([NH:55][NH2:56])=[CH:51][CH:50]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:14]2[N:55]([C:52]3[CH:53]=[N:54][C:49]([Cl:48])=[CH:50][CH:51]=3)[N:56]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:11])([F:12])[F:13])[CH:8]=1
Reactant: NNc1ccc(Cl)nc1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC(F)(F)F)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccc(Cl)nc2)n1

Procedure:
280 mg (0.72 mmol) of the compound of Example 5A is reacted analogously to the synthesis of the compound of Example 20A with 171 mg (0.79 mmol) of 6-chloropyridin-3-yl-hydrazine dihydrochloride. After hydrolysis, 202 mg (61% of theory) of the title compound is obtained.
Reaction SMILES: [C:1]1(=[O:13])[N:6]([CH:7]([CH3:11])C(O)=O)[C:5](=[O:12])[CH2:4][CH:2]1O.[B-](F)(F)(F)F.CN([C:22]([O:26][N:27]1[C:32](=[O:33])[CH2:31][CH2:30][C:28]1=[O:29])=[N+](C)C)C.CCN(C(C)C)C(C)C.C1C[O:46]CC1>>[O:29]=[C:28]1[CH2:30][CH2:31][C:32](=[O:33])[N:27]1[O:26][C:22](=[O:46])[CH2:11][CH2:7][N:6]1[C:1](=[O:13])[CH:2]=[CH:4][C:5]1=[O:12]
Reactant: C1CCOC1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C(=O)O)N1C(=O)CC(O)C1=O
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCN1C(=O)C=CC1=O)ON1C(=O)CCC1=O
Temperature: 25 °C

Procedure:
Malimidopropionic acid (500 mg) was dissolved in dry THF (15 ml). TSTU (790 mg) and DIPEA (0.62 ml) was added. The mixture was stirred at room temperature under nitrogen over night. The yellow thick suspension was concentrated. The residue was dissolved in DCM and extracted with 0.1 N HCl (2×) and brine (1×). The organic layer was dried (Na2SO4) and concentrated to give a white solid. LC-MS, M/z: 267.26 (M+1).
Reaction SMILES: F[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C[N:12]([CH:14]=O)C.[CH2:16]1COCC1>O>[CH2:14]([NH:12][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[CH3:16]
Reactant: O=[N+]([O-])c1ncccc1F
Reactant: CN(C)C=O
Reactant: C1CCOC1
Solvent: O
Product: CCNc1cccnc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
Ice cold ethylamine (0.55 mL) was added to a solution of 3-fluoro-2-nitropyridine (400 mg, 2.8 mmol; prepared according to N. Plé and G. Quéguiner, J. Heterocyclic Chem, 1989, 26, 475-476) in 2:1 DMF:THF (6 mL) at ambient temperature, and the mixture stirred for 0.75 h. Water was added, then extracted 2× with ethyl acetate. The combined organic layers were washed with water then with saturated aqueous sodium chloride, dried (MgSO4), and concentrated to give 3-ethylamino-2-nitro-pyridine as a gold solid. 1H NMR (CDCl3): δ 7.87 (d, 1h0, 7.43 (dd, 1H), 7.35 (d, 1H), 3.38 (pentet, 2H), 1.4 (t, 3H). LCMS: 121.1(MH+-NO2).
Reaction SMILES: C(O[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[N:19]=2)=[CH:7][CH:6]=1)C=C.C([O-])(=O)/[CH:21]=[CH:22]/[C:23]([O-])=[O:24]>>[CH2:23]([O:24][C:10]1[CH:9]=[C:8]([C:11]2[NH:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[N:19]=2)[CH:7]=[CH:6][CH:5]=1)[CH:22]=[CH2:21]
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: C=CCOc1ccc(-c2nc3cnccc3[nH]2)cc1
Product: C=CCOc1cccc(-c2nc3cnccc3[nH]2)c1

Procedure:
2-(p-Allyloxyphenyl)imidazo(4,5-c)pyridine, fumarate, m.p. 215°.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([CH:34]([C:36]2[CH:41]=[CH:40][C:39](SC)=[CH:38][CH:37]=2)[CH3:35])=[CH:4][N:3]=1.Cl[C:45]1C=C(C=CC=1)C(OO)=O.C(=O)(O)[O-].[Na+].[S:60]([O-:64])([O-])(=[O:62])=S.[Na+].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[N:9]=2)=[CH:6][C:5]([CH:34]([C:36]2[CH:37]=[CH:38][C:39]([S:60]([CH3:45])(=[O:64])=[O:62])=[CH:40][CH:41]=2)[CH3:35])=[CH:4][N:3]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)c4ccc(SC)cc4)cnc3F)n2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)c4ccc(S(C)(=O)=O)cc4)cnc3F)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(2-Fluoro-5-(1-(4-(methylthio)phenyl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.797 g, 3.016 mmol) was dissolved in DCM (30 mL) and the reaction flask was cooled in an ice water bath under nitrogen. Then, 3-chlorobenzoperoxoic acid (1.668 g, 9.666 mmol) was added as a solution in DCM (52 mL), and the reaction was warmed to room temperature and stirred. After 30 min, the reaction was cooled in an ice water bath and treated with a mixture of saturated sodium bicarbonate (50 mL) and saturated sodium thiosulfate (15 mL). The biphasic mixture was warmed to room temperature and stirred. After 1 h, the layers were separated, and the aqueous phase was extracted with DCM. The organic phases were combined, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel filter (150 mL fritted filter with about 2 inches of silica gel; DCM to 100:1 DCM/MeOH to 50:1 DCM/MeOH). The fractions with product were collected, concentrated, and dried under high vacuum to give 4-(2-fluoro-5-(1-(4-(methylsulfonyl)phenyl)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.517 g). 1H NMR (CDCl3, 400 MHz) δ 8.34 (dd, J=8.90 Hz, 2.45 Hz, 1H), 8.17 (s, 1H), 7.88 (d, J=8.41 Hz, 2H), 7.42 (d, J=8.22 Hz, 2H), 7.21 (d, J=8.02 Hz, 4H), 6.86 (t, J=8.90 Hz, 4H), 4.82 (s, 2H), 4.78 (s, 2H), 4.34 (q, J=7.69 Hz, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.02 (s, 3H), 2.54 (s, 3H), 1.74 (d, J=7.24 Hz, 3H). m/z (ESI, pos. ion) 628 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>>[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:4]2[C:5]3[C:10](=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)[C:2]([CH3:1])=[N:3]2)=[CH:29][CH:28]=1
Reactant: Cc1n[nH]c2ccc([N+](=O)[O-])cc12
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(C)c3cc([N+](=O)[O-])ccc32)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-methyl-5-nitro-1H-indazole (1.0 g, 5.6 mmol) was dissolved in DMF (11.2 mmol) and cesium carbonate (2.0 g, 6.2 mmol) added. The slurry was cooled to 0° C. and p-methoxy benzyl chloride (0.97 g, 6.2 mmol) added to vigorously stirred slurry drop wise. The slurry was stirred at 0° C. for 1 hour, the cooling bath removed and the mixture stirred at RT for 3 h. The mixture was diluted with 4:1 water:saturated sodium bicarbonate (200 ml), extracted with EtOAc (3×50 ml), the organic fractions combined, washed with brine, dried over Na2SO4, filtered and the volatiles removed in vacuum. The product was purified by chromatography on SiO2 eluting with 30% acetone:hexanes to give the titled compound.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[Li]CCCC.[C:12]([C:16](OCC)=O)([F:15])([F:14])[F:13].B(F)(F)F.O(CC)CC.[NH2:30][NH2:31]>C1COCC1>[CH2:4]([C:5]1[NH:31][N:30]=[C:16]([C:12]([F:13])([F:14])[F:15])[CH:6]=1)[CH2:3][CH2:2][CH3:1]
Reactant: C#CCCCC
Reactant: NN
Reactant: CCOC(=O)C(F)(F)F
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCc1cc(C(F)(F)F)n[nH]1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-Hexyne (3.37 mL, 29.4 mmol) in THF (30 mL) was added n-BuLi (2.78 M, 10.2 mL, 29.4 mmol). The solution was stirred at −78° C. for 30 minutes then CF3CO2Et (3.5 mL, 29.35 mL) and BF3—OEt2 were added successively. The reaction was further stirred at −78° C. for 2 h and was quenched with satd. NH4Cl. It was then warmed up to the room temperature. The THF was removed, the residue taken into ether, washed with saturated brine solution, dried over Na2SO4 and reduced. The crude product was then dissolved in benzene (25 mL) and hydrazine (29.4 mmol) was added. The reaction mixture was refluxed overnight, then cooled, the solvent evaporated, and the residue taken into CH2Cl2 (30 mL), washed with brine, dried over Na2SO4 and concentrated to give the title compound as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:12]=[C:11]([N:13]3[C:21]4[CH:20]=[CH:19][N:18]=[CH:17][C:16]=4[N:15]=[CH:14]3)[S:10][C:9]=2[C:22]([O:24]C)=O)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH3:32]>CO>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:12]=[C:11]([N:13]3[C:21]4[CH:20]=[CH:19][N:18]=[CH:17][C:16]=4[N:15]=[CH:14]3)[S:10][C:9]=2[C:22]([NH2:32])=[O:24])=[C:4]([C:28]([F:30])([F:29])[F:31])[CH:3]=1
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccc(F)cc1C(F)(F)F
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccc(F)cc1C(F)(F)F

Procedure:
In a similar manner as described for example 33, 45.5 mg of methyl 3-{[4-fluoro-2-(trifluoromethyl)benzyl]oxy}-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate and 5 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:9]=[C:8](Cl)[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].Cl.[C:17]([NH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:19])[CH3:18].C(=O)([O-])[O-].[Na+].[Na+].C(N(CC)CC)C>CN1CCCC1=O.C(OCC)C>[CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:9]=[C:8]([N:24]2[CH2:25][CH2:26][CH:21]([NH:20][C:17](=[O:19])[CH3:18])[CH2:22][CH2:23]2)[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(=O)NC1CCNCC1
Reactant: COC(OC)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: COC(OC)c1cc(N2CCC(NC(C)=O)CC2)ccc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
12 Grams of 2-nitro-5-chlorobenzaldehyde dimethyl acetal, 16.3 g of 4-acetylaminopiperidine hydrochloride, 13.7 g of sodium carbonate and 13 ml of triethylamine in 150 ml of N-methylpyrrolidone solution were mixed together and reacted by heating at 120° C for 12 hours with stirring under nitrogen gas stream. After the reaction was completed, the solvent was removed by evaporation and thus obtained residue was added with water and extracted with dichloromethane, then the extract was washed with water and with an aqueous solution saturated with sodium chlor:de, then dried with anhydrous sodium sulfate. The solvent was removed by evaporation and the residue thus obtained was added with diethyl ether, then the crystals formed were collected by filtration to yield 11.2 g of 2-nitro-5-(4-acetylamino-1-piperidyl)benzaldehyde dimethylacetal.
Reaction SMILES: C(CC[O:5][P:6]([O-])([O-:8])=[O:7])#N.[N:10]([C@@H:13]1[C@@H:17]([CH2:18][OH:19])[O:16][C@@H:15]([N:20]2[CH:27]=[CH:26][C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:14]1)=[N+:11]=[N-:12].C1(N=C=NC2CCCCC2)CCCCC1.O>N1C=CC=CC=1.[OH-].[K+]>[P:6]([O:19][CH2:18][C@H:17]1[O:16][C@@H:15]([N:20]2[CH:27]=[CH:26][C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:14][C@@H:13]1[N:10]=[N+:11]=[N-:12])([OH:8])([OH:7])=[O:5]
Reactant: N#CCCOP(=O)([O-])[O-]
Reactant: [N-]=[N+]=N[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: [N-]=[N+]=N[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 73 %

Procedure:
A freshly prepared pyridinium salt of 2-cyanoethylphosphate (8.05 g, 23.64 mmol) was added to a solution of 3'-azido-2',3'-dideoxyuridine (2.50 g, 9.7 mmol) in dry pyridine (50ml) and evaporated to dryness at 30° C. The concentrated residue was dissolved in pyridine (50 ml) and the solution again evaporated to dryness. The process was repeated twice and then the residue obtained was dissolved in dry pyridine (50 ml). Dicyclohexylcarbodiimide (8.08 g, 39.1 mmol) was added to the solution. The reaction mixture was stirred for 48 hours at room temperature. Water (10 ml) was added and the solution was then filtered to remove dicyclohexylurea. The clear solution was evaporated to dryness. The residue obtained was then dissolved in 1N KOH (250 ml) and heated for 15 minutes at 100° C. The cold solution was passed through a column of acidic Dowex 50 (H+), the effluent brought to pH 9 and passed through a column of Dowex (1×4 Cl-). A linear gradient elution of 0.015N HCl to 0.15N HCl afforded 3'-azido-2',3'-dideoxyuridine-5'-monophosphate in 73% yield.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[C@H:3]([O:12][CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH2:4][NH:5][C@H:6]([C:8]([O:10]C)=O)[CH3:7].[NH2:22][CH:23]1[C:29](=[O:30])[N:28]([CH3:31])[C:27]2[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=2[N:25]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:24]1=[O:42]>>[CH3:21][CH:2]([CH3:1])[C@H:3]([O:12][CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH2:4][NH:5][C@H:6]([C:8]([C:23]1([NH2:22])[C:29](=[O:30])[N:28]([CH3:31])[C:27]2[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=2[N:25]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:24]1=[O:42])=[O:10])[CH3:7]
Reactant: CN1C(=O)C(N)C(=O)N(c2ccccc2)c2ccccc21
Reactant: COC(=O)[C@H](C)NC[C@@H](OCOCC[Si](C)(C)C)C(C)C
Product: CC(C)[C@@H](CN[C@@H](C)C(=O)C1(N)C(=O)N(C)c2ccccc2N(c2ccccc2)C1=O)OCOCC[Si](C)(C)C

Procedure:
Following General Procedure II-A, Method B and using N-(3-methyl-2-(S)-(2-trimethylsilylethyloxy)methyloxybutyl)-L-alanine, methyl ester (Intermediate A, Step C; 1 eq), the free acid was prepared. The residue was used, following General Procedure D, and using 3-amino-2,4-dioxo-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (CAS No. 131604-75-6) to prepare the title intermediate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[C:12]([O:16][C:17](=[O:29])[NH:18][C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=1)([CH3:21])[CH3:20])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:12]([O:16][C:17](=[O:29])[NH:18][C:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[N+:8]([O-:10])=[O:9])[CH:23]=1)([CH3:21])[CH3:20])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(C)(C)c1cccc(Oc2cc(Cl)ccc2[N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 69.1 %

Procedure:
A mixture of 4-chloro-2-fluoronitrobenzene (2.57 g, 14.6 mmols), tert-butyl[1-(3-hydroxyphenyl)-1-methylethyl]carbamate (3.21 g, 12.8 mmols), potassium carbonate (2.02 g, 14.6 mmols) and N,N-dimethylformamide (20 ml) was stirred at 100° C. for 2 hours. The reaction mixture was cooled, then poured into water, and extracted with ethyl acetate. The extract was washed with water and brine, and then dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The residue was purified through silica gel column chromatography to give a crystal of tert-butyl[1-[3-(5-chloro-2-nitrophenoxy)phenyl]-1-methylethyl]carbamate (3.6 g, 69%).