Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([N:10]1[CH2:23][CH2:22][CH2:21][C@H:11]1[C:12]([N:14]1[CH2:20][CH2:19][CH2:18][C@H:15]1[CH2:16][OH:17])=[O:13])=[O:9].C(N(CC)CC)C>CS(C)=O>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([N:10]1[CH2:23][CH2:22][CH2:21][C@H:11]1[C:12]([N:14]1[CH2:20][CH2:19][CH2:18][C@H:15]1[CH:16]=[O:17])=[O:13])=[O:9]
Reactant: O=C1CCCN1CC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1CO
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CN1CCCC1=O
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a solution of N-[(2-oxo-1-pyrrolidinyl)acetyl]-L-prolyl-L-prolinol (965 mg) in DMSO (5 ml) were added triethylamine (2.5 ml) and sulfur trioxide pyridine complex (1.89 g) under ice-cooling, and the mixture was stirred at a temperature of 10°-15° C. for 1 hour. The reaction mixture was concentrated at room temperature, and the residue was purified by silica gel column chromatography (chloroform-methanol) to give 663 mg of N-[(2-oxo-1-pyrrolidinyl)acetyl]-L-prolyl-L-prolinal.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]=[C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:24])=[CH:9][CH:8]=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]=[C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][C:16]3=[O:24])=[CH:9][CH:8]=2)[CH2:28][CH2:27]1
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(OCCCCI)cc1
Reactant: CN1CCNCC1
Product: CN1CCN(CCCCOc2ccc(NC=C3C(=O)Nc4ccccc43)cc2)CC1

Procedure:
In a manner similar to that described in Example 207, 3-{[4-(4-Iodo-butoxy)-phenylamino]-methylene}-1,3-dihydro-indol-2-one and N-methylpiperazine are converted to the named compound.
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[NH2:7][OH:8].O=[C:10]1[CH2:18][CH2:17][CH2:16][C:15]2[NH:14][CH:13]=[CH:12][C:11]1=2>O.C(O)C>[N:7](=[C:10]1[CH2:18][CH2:17][CH2:16][C:15]2[NH:14][CH:13]=[CH:12][C:11]1=2)[OH:8]
Reactant: O=C1CCCc2[nH]ccc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C1CCCc2[nH]ccc21

Procedure:
A solution of 6.08 g of sodium acetate, 5.15 g of hydroxylamine hydrochloride, and 5.25 g of 4-keto-4,5,6,7-tetrahydro indole in 12 mL of water and 36 mL of ethanol was heated at 50° C. for 3 hr, quenched in water, extracted with ethyl acetate and dried over magnesium sulfate. The solvents were removed in vacuo to give a mixture of oxime isomers which was characterized by NMR and Mass spectroscopy.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:16][C:17]([F:26])([C:22]([F:25])([F:24])[F:23])[C:18](I)([F:20])[F:19]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:18]([F:20])([F:19])[C:17]([F:26])([F:16])[C:22]([F:25])([F:24])[F:23])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: FC(F)(F)C(F)(F)C(F)(F)I
Reactant: CCC[C@H]1CC[C@H](C2CC=CCC2)CC1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(F)(F)C(F)(F)C(F)(F)F)CC2)CC1

Procedure:
A mixture of 0.1 mol of 4-(trans-4-propylcyclohexyl)-cyclohex-1-ene, 0.1 mol of heptafluoropropyl iodide, 10 mol % of tetrakis-(triphenylphosphine)-palladium and 200 ml of hexane is heated under reflux for 24 hours (compare T. Ishihara, Chemistry Letters (1986) 1895). The isomer mixture of the addition product thus formed is, after the catalyst has been filtered off, first heated with tributyl-tin hydride for 90 hours in toluene and reduced. The all-trans product, trans-4-(trans-4-propylcyclohexyl)-1-heptafluoropropylcyclohexane, is finally obtained by separating the thiourea inclusion compound from a solution in methanol.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2=[CH:17][S:18][CH:19]=[C:6]12)=[O:4].[CH3:20][N:21]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]1)[CH3:22]>C(#N)C>[CH3:20][N:21]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2=[CH:17][S:18][CH:19]=[C:6]12)=[O:4])[CH3:22]
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2cscc21
Reactant: CN(C)CC1CCCCN1
Solvent: CC#N
Product: CN(C)CC1CCCCN1CC(=O)N1c2ccccc2NC(=O)c2cscc21

Procedure:
The title compound is prepared analogously to Example 2 from 4-(chloroacetyl)-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2-[(dimethylamino)methyl]piperidine to give colorless crystals, Mp. 208°-209° C. (acetonitrile/activated charcoal).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:13]1[CH:14]=[CH:15][C:16]([CH3:38])=[C:17]([NH:19][C:20](=[O:37])[CH2:21][O:22][CH2:23][C:24]([NH:26][C:27]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:28]=2[C:29]([OH:31])=[O:30])=[O:25])[CH:18]=1>>[Cl:36][C:33]1[CH:34]=[CH:35][C:27]([NH:26][C:24](=[O:25])[CH2:23][O:22][CH2:21][C:20]([NH:19][C:17]2[CH:18]=[C:13]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:14]=[CH:15][C:16]=2[CH3:38])=[O:37])=[C:28]([CH:32]=1)[C:29]([OH:31])=[O:30]
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1ccc(Br)cc1NC(=O)COCC(=O)Nc1ccc(Cl)cc1C(=O)O
Product: COc1cccc(-c2ccc(C)c(NC(=O)COCC(=O)Nc3ccc(Cl)cc3C(=O)O)c2)c1

Procedure:
Using the same method as in Example 19-(ii), 3-methoxybenzene boronic acid was reacted with the 2-[((2-[(5-bromo-2-methylphenyl)amino]-2-oxoethoxy)acetyl)amino]-5-chlorobenzoic acid.methyl ester obtained in Example 38-(i) to give 5-chloro-2-[((2-[(3′-methoxy-4-methylbiphenyl-3-yl)amino]-2-oxoethoxy)acetyl)amino]benzoic acid.methyl ester (yield: 63%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:11][CH:12]=C)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].Cl.[N:15]1([C:21](=[O:34])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[N:32][N:31]=[N:30]3)=[CH:25][CH:24]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:11][CH2:12][N:18]2[CH2:17][CH2:16][N:15]([C:21](=[O:34])[CH2:22][C:23]3[CH:24]=[CH:25][C:26]([N:29]4[CH:33]=[N:32][N:31]=[N:30]4)=[CH:27][CH:28]=3)[CH2:20][CH2:19]2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: O=C(Cc1ccc(-n2cnnn2)cc1)N1CCNCC1
Reactant: C=CCc1ccc(C#N)c(OC)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(CCN2CCN(C(=O)Cc3ccc(-n4cnnn4)cc3)CC2)ccc1C#N
Temperature: -78 °C
Reaction time: 2 h

Procedure:
2-Methoxy-4-(prop-2-en-1-yl)benzonitrile (100 mg, 0.577 mmol) was dissolved in methanol (13 mL) and the resulting solution was cooled to −78° C. Ozone was bubbled through the solution until a blue color appeared (˜15 minutes). 1-(Piperazin-1-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone hydrochloride (178 mg, 0.577 mmol) was added, followed by sodium cyanoborohydride (363 mg, 5.77 mmol). After stirring the reaction mixture for ˜5 minutes 3 drops of acetic acid were added and the mixture was permitted to warm to rt and stir for 2 h. The reaction mixture was concentrated to dryness, dissolved in EtOAc (40 mL) and washed with brine, saturated NaHCO3 solution. The organic layer was dried over Na2SO4, filtered and concentrated to dryness. The residue was then purified by mass directed HPLC to afford the title compound. LC/MS: [(M+1)]+=432.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH2:27]([O:31][C:32]([O:34][CH:35](I)[CH3:36])=[O:33])[CH:28]([CH3:30])[CH3:29]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH:35]([O:34][C:32]([O:31][CH2:27][CH:28]([CH3:30])[CH3:29])=[O:33])[CH3:36])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CC(C)COC(=O)OC(C)I
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: CC(C)COC(=O)OC(C)OC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 74.1 %

Procedure:
In the same manner as in Example 81, 334 mg of the title compound was prepared from 346 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate prepared in Example 41 and 278 mg of 1-(isobutyloxycarbonyloxy)ethyl iodide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>ClCCl>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N2CCOCC2)nc1
Temperature: 25 °C
Yield: 95 %

Procedure:
In a round-bottom flask, to a dichloromethane (125 mL) solution of 2-bromo-5-nitropyridine (5 g, 24.6 mmol), morpholine (5.4 mL, 61.5 mmol) was added. The reaction was refluxed for 4 hr, then cooled to room temperature. The solution was subsequently washed with saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried (Na2SO4), filtered, and the solvent was removed in vacuo. 4-(5-Nitropyridin-2-yl)morpholine, a yellow solid, was obtained: 4.9 g (95% yield); 1H NMR (300 MHz, DMSO) δ 8.95 (d, J=2.7, 1H), 8.22 (dd, J=2.7, 9.6, 1H), 6.92 (d, J=9.6, 1H), 3.74-3.65 (m, 8H); LCMS (M+) m/z 210.34.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5](=[NH:8])[NH:6][OH:7].[N+:10]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[NH:20][C:19]([C:22](O)=[O:23])=[CH:18]2)([O-:12])=[O:11]>>[CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5](=[N:6][OH:7])[NH:8][C:22]([C:19]1[NH:20][C:21]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[N+:10]([O-:12])=[O:11])=[O:23]
Reactant: COC(=O)CC(=N)NO
Reactant: O=C(O)c1cc2cccc([N+](=O)[O-])c2[nH]1
Product: COC(=O)CC(=NO)NC(=O)c1cc2cccc([N+](=O)[O-])c2[nH]1

Procedure:
2-(N-hydroxycarbamimidoyl)-acetic acid methyl ester prepared in Step A and 7-nitro-1H-indole-2-carboxylic acid prepared in Step A of Preparation 101 were reacted according to the same procedure as Step B of Preparation 101 to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:10][C:11]([NH2:15])=[C:12]([NH2:14])[CH:13]=1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[S:23].C(N(CC)CC)C>C1COCC1>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[C:12]2[NH:14][C:22](=[S:23])[NH:15][C:11]2=[N:10][C:9]=1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Fc1cnccc1-c1cc2[nH]c(=S)[nH]c2nc1-c1cccnc1
Reaction time: 6 h
Yield: 88.3 %

Procedure:
A solution of 3″-fluoro-3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 1, 2 g, 7.11 mmol), 1,1′-thiocarbonyldiimidazole (2.54 g, 14.22 mmol) and triethylamine (2 mL, 14.22 mmol) in THF (30 mL) was heated at 80° C. in a sealed tube. After 6 hours, the mixture was cooled and the solid was filtered, washed with NH4Cl aq. and water and dried to give the title compound (2.03 g, 88%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[Cl:12].[CH3:13][NH2:14]>CN(C=O)C>[Cl:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([NH:14][CH3:13])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1F
Reactant: CN
Solvent: CN(C)C=O
Product: CNc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,2-Dichloro-4-fluoro-5-nitrobenzene (5.00 g, 23.8 mmol) in DMF (5.0 mL) was added to methylamine (10% in toluene, 80.0 g, 258 mmol) and stirred at rt overnight. The reaction mixture was filtered through a pad of ALOX B, washed with DMF/MeOH and concentrated to give the sub-title compound.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28](=N)[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:26][N:27]=[C:28]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: N=C(NO)c1cccnc1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(-c3cccnc3)no2)CC1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-nicotinamidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.57 min; Mass spectrum (ESI+): m/z=457 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=2[O-])[CH:5]=[CH:6][CH:7]=1.COS(OC)(=O)=O.[C-:24]#[N:25].[Na+]>CC(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]2[N:11]=[C:12]([C:24]#[N:25])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: [O-][n+]1ccccc1C=Cc1cccc(F)c1
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)O
Product: N#Cc1cccc(C=Cc2cccc(F)c2)n1

Procedure:
Following the general method described in example 2b, 2-[2-(3-fluoro-phenyl)-vinyl]-pyridine 1-oxide was reacted first with dimethylsulfate and then with NaCN. After extraction and crystallization the title compound was obtained as a beige crystalline material. Mp. 111-112° C. (iPrOH), MS: m/e=224 (M+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[C:15]([CH3:17])[N:16]=2)=[CH:8][CH:7]=1.[Br:22]N1C(=O)CCC1=O>C(#N)C>[Br:22][C:7]1[CH:8]=[C:9]([C:12]2[S:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[C:15]([CH3:17])[N:16]=2)[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1sc(-c2ccc(OCCCCl)cc2)nc1C
Solvent: CC#N
Product: COC(=O)c1sc(-c2ccc(OCCCCl)c(Br)c2)nc1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
A solution of methyl 2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylate ax60 (2 g, 6.15 mmol, 1 eq) in acetonitrile (50 ml) is treated with a solution of N-bromosuccinimide (1.8 g, 10 mmol, 1.5 eq) in acetonitrile (10 ml) and the resulting solution is stirred 2 h at room temperature and 2 h at 60° C. After cooling, the mixture is concentrated to dryness. The residue is taken up with ethyl acetate, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. Purification of the residue over silicagel (eluent: dichloromethane/benzine) affords 0.6 g of methyl 2-[3-bromo-4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylate i91.
Reaction SMILES: O1CCCC1.[CH:6]([O:9][C:10](=[O:33])[C@H:11]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=1)[NH:12][C:13](=[O:22])[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])([CH3:8])[CH3:7].[S].[H][H]>[Pt].CC(O)C>[CH:6]([O:9][C:10](=[O:33])[C@H:11]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=1)[NH:12][C:13](=[O:22])[C:14]1[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=1[Cl:20])([CH3:8])[CH3:7]
Reactant: CC(C)OC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: [H][H]
Agent: [Pt]
Agent: [S]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)OC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 10 °C

Procedure:
To 80 mL of tetrahydrofuran, there was added 31.3 g (content: about 50 wt %) of the wet crystals of Nα-(2,6-dichlorobenzoyl)-4-nitro-L-phenylalanine isopropyl ester at room temperature in a nitrogen gas atmosphere and the mixture was then stirred. To the mixture, there were added 80 mL of 2-propanol and 0.86 g of 3% Pt—S/C (wet product, obtained by applying platinum onto carbon and then poisoning the same with sulfur), hydrogen gas was then introduced into the reaction system and the reaction system was stirred at ordinary pressure. The reaction system was stirred at room temperature overnight as it was, and then the catalyst was removed from the reaction solution by filtration through Celite after the confirmation of the progress of the reaction according to HPLC. The resulting filtrate (initial amount of 178 g) was concentrated by distilling the solvent off under reduced pressure till the amount of the filtrate reached 91 g and 40 mL of 2-propanol was added to the concentrate to thus adjust the concentration of the condensate. To this liquid whose concentration had been adjusted, there was dropwise added 150 mL of water at room temperature to thus separate out a crystalline solid and the resulting suspension was maintained at a temperature of not higher than 10° C. overnight. The resulting crystals were filtered off, washed with 100 mL of water and the resulting wet crystals were dried at 60° C. under reduced pressure to thus give 13.16 g of the title compound as a white crystalline solid (overall yield of these two steps: 86%).
Reaction SMILES: CO[CH:3]=[CH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1)([O-:13])=[O:12]>C(O)C.Cl>[N+:11]([C:14]1[CH:15]=[CH:16][C:17]([NH:20][N:21]=[CH:3][CH2:4][C:5]2[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=2)=[CH:18][CH:19]=1)([O-:13])=[O:12]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: COC=Cc1cccnc1
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])c1ccc(NN=CCc2cccnc2)cc1
Yield: 81.8 %

Procedure:
A solution of 3-(2-EZ-methoxyethenyl)pyridine (3.43 g) in ethanol (15 ml) and 2N hydrochloric acid (25 ml) was heated under reflux for 1 hour and then cooled. 4-nitrophenylhydrazine (3.89 g) was added portionwise with stirring to give a solution which deposited a yellow solid. The mixture was cooled in ice and the solid was filtered off, washed with isopropanol,ether and then dried to give the title compound (5.32 g), m.p. 212°-214° C. Found: C,53.54; H,4.51; N,19.00. C13 H12N4O2 requires: C,53.34; H,4.48; N,19.14%.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].Cl.[Br:35][C:36]1[C:37]([F:44])=[C:38]([CH2:42][NH2:43])[CH:39]=[CH:40][CH:41]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Br:35][C:36]1[C:37]([F:44])=[C:38]([CH2:42][NH:43][C:26]([C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[CH:24]=2)=[O:27])[CH:39]=[CH:40][CH:41]=1
Reactant: NCc1cccc(Br)c1F
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(Br)c2F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (210 mg, 0.466 mmol), [(3-bromo-2-fluorophenyl)methyl]amine hydrochloride (123 mg, 0.513 mmol), HBTU (194 mg, 0.513 mmol) and diisopropyl ethyl amine (0.5 mL) in DCM (10 mL) was stirred at room temperature for about 5 h. It was concentrated, mixed with EtOAc (25 mL), washed with aqueous NaHCO3 (25 mL) and then NH4Cl (25 mL). The organic layer was collected, dried and concentrated to afford the desired product as a crude mixture (330 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[O:14][C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[C:20](=NO)[CH2:19][CH2:18]4)=[C:12]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[CH:11]=2)[CH2:6][CH2:5]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:50]1CCCC1>O>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[O:14][C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:50])[CH2:19][CH2:18]4)=[C:12]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[CH:11]=2)[CH2:6][CH2:5]1
Reactant: C1CCOC1
Reactant: OCCN1CCC(c2cc(-c3ccncc3)c(-c3ccc4c(c3)CCC4=NO)o2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: O=C1CCc2cc(-c3oc(C4CCN(CCO)CC4)cc3-c3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
A solution of the product of Step 1 (0.135 g, 0.26 mmol) in dry tetrahydrofuran (5 ml) was cooled to 0° C. and treated dropwise with tetrabutylammonium fluoride (1.0M solution in tetrahydrofuran, 0.078 ml, 0.78 mmol) and allowed to warm to room temperature. After stirring for 2 hours, the reaction mixture was diluted with water, extracted with dichloromethane. The organic layer was then washed with saturated aqueous brine, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 0.880 ammonia/methanol/dichloromethane (0.5:4.5:95) to afford the title compound (0.027 g, 26%); MS(ES+) m/e 403 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH2:11])[C:3]=1I.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH2:11])[C:3]=1[C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13]
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ncc([N+](=O)[O-])c(Cl)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1c(N)ncc([N+](=O)[O-])c1Cl
Temperature: 60 °C
Yield: 16.1 %

Procedure:
To a solution of 4-chloro-3-iodo-5-nitropyridin-2-amine (5.30 g, 17.7 mmol) in THF (90 mL) was added TEA (15.0 mL, 108 mmol). The reaction mixture was degassed and purged with nitrogen 3 times. Bis(triphenylphosphine)-palladium(II) dichloride (0.62 g, 0.88 mmol, Strem), copper(I) iodide (0.17 g, 0.89 mmol), and trimethylsilylacetylene (5.4 mL, 39 mmol) were added to the reaction mixture, degassed, and purged 3 times with nitrogen. The reaction was heated at about 60° C. for about 16 h. The reaction mixture was cooled to ambient temperature. The reaction mixture was filtered and washed with THF (200 mL). The filtrate was concd under reduced pressure. DCM (100 mL) was added to the residue and the precipitate that formed was filtered and collected to give 4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine (0.77 g). The remaining filtrate was concd under reduced pressure and the crude material was purified by flash chromatography on silica gel eluting with a gradient of 0-100% EtOAc in DCM. The purified material was combined with the 0.77 g of precipitate to afford 4-chloro-5-nitro-3-((trimethylsilyl)ethynyl)pyridin-2-amine (2.22 g, 47%) as a yellow solid: LC/MS (Table 1, Method c) Rt=1.62 min; MS m/z 268 (M−H)−.