Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:13][S:14][S:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[N+:27]([C:30]1[C:31]([S:36]Cl)=[N:32][CH:33]=[CH:34][CH:35]=1)([O-:29])=[O:28]>ClCCl>[CH2:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][S:36][C:31]1[C:30]([N+:27]([O-:29])=[O:28])=[CH:35][CH:34]=[CH:33][N:32]=1)[CH2:13][S:14][S:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cccnc1SCl
Reactant: CC(C)(C)SSC[C@H](N)C(=O)NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)SSC[C@H](NSc1ncccc1[N+](=O)[O-])C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.6 %

Procedure:
(R)-2-amino-N-benzyl-3-(tert-butyldisulfanyl)propanamide (Compound tk93) (60 mg, 0.201 mmol) and triethylamine (0.034 ml, 0.241 mmol) were dissolved in dichloromethane (1 ml), and the solution was cooled to 0° C. 3-Nitro-2-pyridinesulfenyl chloride (46.0 mg, 0.241 mmol) was added and the mixture was stirred at 0° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (R)—N-benzyl-3-(tert-butyldisulfanyl)-2-(((3-nitropyridin-2-yl)thio)amino)propanamide (Compound tk94) (87 mg, 96%).
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1Br>O1CCOCC1.C(OCCO)C.C(=O)([O-])[O-].[Na+].[Na+].C1(P([Pd-4](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)C=CC=CC=1>[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:16]1[CH:17]=[CH:18][C:19]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: Brc1ccccc1Br
Reactant: OB(O)c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCCO
Product: Brc1ccccc1-c1ccc2c(c1)c1ccccc1n2-c1ccccc1

Procedure:
1.1 g (1 mmol) of tetrakis(triphenylphosphino)palladium(0) are added to a mixture of 28.7 g (100 mmol) of N-phenylcarbazole-3-boronic acid, 36.1 ml (300 mmol) of 1,2-dibromobenzene in 150 ml of dioxane, 100 ml of 2-ethoxyethanol and 250 ml of 2 N sodium carbonate solution, and the mixture is heated under reflux for 16 h. After cooling, the organic phase is separated off, 500 ml of toluene are added, and the mixture is washed three times with 500 ml of water, dried over magnesium sulfate, filtered through silica gel and then freed from toluene and excess 1,2-dibromobenzene in vacuo. The residue is washed by stirring three times with hot ethanol. Yield: 26.7 g (67 mmol), 67.1%, purity 97% according to
Reaction SMILES: F[C:2](F)(F)[C:3]1[N:4]=[C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)[S:6][CH:7]=1.C(NC1C=CC([C@@H](C)C(OC)=O)=CC=1)(=S)N.ClCC(=O)C>>[CH3:2][C:3]1[N:4]=[C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C@@H:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:13][CH:14]=2)[S:6][CH:7]=1
Reactant: C[C@@H](C(=O)O)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Agent: CC(=O)CCl
Agent: COC(=O)[C@H](C)c1ccc(NC(N)=S)cc1
Product: Cc1csc(Nc2ccc([C@@H](C)C(=O)O)cc2)n1
Yield: 75 %

Procedure:
The acid was obtained following the same procedure described for (2R)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid and starting from methyl (2R)-2-[4-(carbamothioylamino)phenyl]propanoate (2.0 g, 8.40 mmol) and chloro-2-propanone (0.67 ml, 8.40 mmol). The following acid hydrolysis afforded the pure (2R)-2-{4-[(4-methyl-1,3-thiazol-2-yl)amino]phenyl}propanoic acid (1.65 g, 6.30 mol) as a yellow oil (75%). 1H-NMR (CDCl3): δ 8.15 (bs, 1H, NH), 7.40 (d, 2H, J=7 Hz), 7.20 (d, 2H, J=7 Hz), 6.35 (s, 1H), 3.75 (q, 1H, J=7 Hz), 2.18, (s, 3H), 1.50 (d, 3H, J=7 Hz).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([CH3:12])=[CH:10][C:9]([Br:13])=[CH:8][N:7]=1)=O)C.[NH3:14].CO>>[Br:13][C:9]1[CH:10]=[C:11]([CH3:12])[C:6]([C:4]([NH2:14])=[O:3])=[N:7][CH:8]=1
Reactant: N
Reactant: CCOC(=O)c1ncc(Br)cc1C
Solvent: CO
Product: Cc1cc(Br)cnc1C(N)=O

Procedure:
5-Bromo-3-methyl-pyridine-2-carboxylic acid ethyl ester (2.44 g, 10 mmol) was dissolved in NH3/MeOH (50 ml) and heated to reflux for 3 days. The reaction mixture was concentrated to give the desired product as a pink solid (2.05 g, 9.6 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](OS(C3C=CC(C)=CC=3)(=O)=O)=[N:13][C:12]=12.C(N(CC)CC)C.[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]>CN(C)C=O.O>[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:11]3[N:10]=[N:9][C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[C:12]3[N:13]=2)[CH2:48][CH2:47]1)=[O:45])([CH3:42])([CH3:40])[CH3:41]
Reactant: Cc1ccc(S(=O)(=O)Oc2nc3c(-c4ccccc4F)nnn3c3ccccc23)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2nc3c(-c4ccccc4F)nnn3c3ccccc23)CC1
Yield: 87.9 %

Procedure:
A solution of 3-(2-fluorophenyl)-5-(4-methylbenzenesulfonyloxy)-[1,2,3]triazolo[1,5-α]quinazoline (0.33 g, 0.71 mmol), triethylamine (0.3 ml, 2.1 mmol) and piperazine-1-carboxylic acid tert-butyl ester (0.26 g, 1.4 mmol) in dry N,N-dimethylformamide (6 ml) was stirred at 50° C. under nitrogen for 18 h. The mixture was cooled, then diluted with water (30 ml) and extracted with EtOAc (2×75 ml). The combined organic extracts were washed with brine, dried over MgSO4 and evaporated to give a brown oil. Purification by flash column chromatography eluting with CH2Cl2:MeOH (93:7) gave 4-[3-(2-fluorophenyl)-[1,2,3]triazolo[1,5-α]quinazolin-5-yl]piperazine-1-carboxylic acid tert-butyl ester as a white solid (0.28 g, 88%). δH (400 MHz; CDCl3) 1.50 (9H, s), 3.59-3.62 (4H, m), 3.69-3.72 (4H, m), 7.19-7.30 (2H, m), 7.32-7.37 (1H, m), 7.63 (1H, ddd, J=8, 8 and 1), 7.91 (1H, ddd, J=8, 8 and 1), 8.02 (1H, d, J=8), 8.11 (1H, ddd, J=7, 7 and 2), 8.70 (1H, dd, J=8 and 1).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]([NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=O)=O)=CC=1.[C-:31]#[N:32].[K+].C1OCCOCCOCCOCCOCCOC1.[I-].[K+]>CN(C=O)C>[CH2:24]([O:23][C:21]([NH:20][C@H:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:12][C:31]#[N:32])=[O:22])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](NC(=O)OCc2ccccc2)c2ccccc2)cc1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC[C@H](NC(=O)OCc1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
60.5 g of (R)-2-benzyloxycarbonylamino-2-phenylethyl 4-methylphenylsulfonate (142.2 mmol) were dissolved in 675 ml of DMF. 13.9 g of potassium cyanide (213.3 mmol), 5.64 g of 18-crown-6 (21.33 mmol) and 520 mg of potassium iodide (3.13 mmol) were added and the mixture was stirred at 50° C. for 20 hours. The reaction solution was poured into 500 ml of ice water and then stirred at 0° C. for 5 hours. The precipitate was filtered off with suction and dissolved in ethyl acetate. The organic phase was washed three times with water, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether, filtered off with suction, washed with diethyl ether and dried over phosphorus pentoxide. Yield: 25.3 g (63.5%).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12](O)=[O:13])[C:3]1=[O:15].C(Cl)(=O)C([Cl:19])=O.CN(C)C=O>ClCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([Cl:19])=[O:13])[C:3]1=[O:15]
Reactant: Cn1c(=O)c(C(=O)O)cc2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(=O)c(C(=O)Cl)cc2ccccc21
Temperature: 40 °C
Reaction time: 1 h

Procedure:
0.76 g (3.7 mmol) of 1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid was dissolved in dichloromethane (50 mL), and 1.0 mL (12 mmol) of oxalyl chloride was added to the above solution. Two droplets of N,N-dimethylformamide were added to this mixture, and the resulting mixture was stirred for 1 hour at 40° C. The reaction solution was concentrated under reduced pressure, and thus 1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid chloride was obtained. The acid chloride thus obtained was dissolved in acetonitrile (30 mL), and this solution was added to an acetonitrile (50 mL) solution of 0.46 g (4.1 mmol) of 1,3-cyclohexanedione and 0.63 mL (4.5 mmol) of triethylamine under ice cooling. The mixture was stirred overnight at room temperature. This reaction mixture was poured into water and was extracted with ethyl acetate. The organic phase was washed with water, an aqueous solution of sodium hydrogen carbonate, and water in this order, and then was dried and concentrated. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:4 to 1:0), and thus 0.48 g (yield: 43%) of the title compound was obtained as a pale yellow powder.
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:14])[CH2:4][CH2:5][CH:6]=[C:7]([CH3:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl>[Br:1][CH2:2][C:3](=[O:14])[CH2:4][CH2:5][CH:6]1[O:23][C:7]1([CH3:13])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCC(C)=CCCC(=O)CBr
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCCC1(C)OC1CCC(=O)CBr
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 95.9 %

Procedure:
1-Bromo-6-methyl-2-oxo-undec-5-ene (10.4 g, 0.04 mole) is dissolved in methylene chloride (100 ml). The solution is cooled to 0° C. and m-chloroperbenzoic acid (7.9 g, 0.04 mole of 85% pure substance) in methylene chloride (180 ml) is added while stirring at +5°-10° C. within 25 minutes. After stirring for 3 hours at 0° C., the reaction mixture is stored at +5° C. for 16 hours. It is then filtered through a sintered glass funnel, and the filtrate is washed first with saturated aqueous sodium bicarbonate, and then 5 times with sodium sulfite (60 g in 500 ml of H2O). The solution is washed with saturated aqueous sodium chloride, dried with sodium sulfate, filtered, and evaporated in vacuo to give 1-bromo-5,6-epoxy-6-methyl-undecan-2-one (10.63 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C@H:5]([NH:6][C:7]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][N:10]=[C:9](S(C)(=O)=O)[N:8]=2)[CH2:4][C@@H:3]1[OH:21].Cl.Cl.[F:25][C:26]([C:29]1[C:34]([CH2:35][NH2:36])=[CH:33][N:32]=[CH:31][N:30]=1)([CH3:28])[CH3:27]>O1CCOCC1>[F:25][C:26]([C:29]1[C:34]([CH2:35][NH:36][C:9]2[N:8]=[C:7]([NH:6][C@@H:5]3[CH2:4][C@H:3]([OH:21])[C:2]3([CH3:22])[CH3:1])[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][N:10]=2)=[CH:33][N:32]=[CH:31][N:30]=1)([CH3:27])[CH3:28]
Reactant: CC(C)(F)c1ncncc1CN
Reactant: CC1(C)[C@@H](O)C[C@H]1Nc1nc(S(C)(=O)=O)ncc1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(F)c1ncncc1CNc1ncc(C(F)(F)F)c(N[C@@H]2C[C@H](O)C2(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
A solution of (1S,3R)-2,2-Dimethyl-3-((2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)amino)cyclobutanol (1.0 equiv.) and (4-(2-fluoropropan-2-yl)pyrimidin-5-yl)methanamine dihydrochloride (1.3 equiv.) were combined in dioxane (0.4 M) and stirred at ambient temperature. After 1 h, the solution was heated to 75° C. After 16 h, the solution was concentrated under reduced pressure and after standard work-up the title compound (50.9% yield) was obtained. The absolute stereochemistry was determined, using the chiral intermediate, as described herein for other compounds. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.01 (s, 1H), 8.47-8.67 (m, 1H), 7.94-8.14 (m, 1H), 7.78 (br. s., 1H), 6.07 (d, J=7.81 Hz, 1H), 4.66-4.91 (m, 2H), 3.35 (br. s., 1H), 1.96-2.22 (m, 1H), 1.62-1.82 (m, 6H), 0.54-1.23 (m, 6H); MS(ESI) m/z 429.3[M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH:4]([O:31][CH3:32])[CH:5](O)[C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:8][CH:7]=1.CCC(CCCCC(NC(C(NC(C(NC(C(NC1C(=O)NC(CCN)C(=O)NC(CC2C=CC=CC=2)C(=O)NC(CC(C)C)C(=O)NC(CCN)C(=O)NC(CCN)C(=O)NC(C(O)C)C(=O)NCC1)=O)CCN)=O)C(O)C)=O)CCN)=O)C.OS(O)(=O)=O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:33])/[C:4](/[O:31][CH3:32])=[CH:5]/[C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[C:9]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:8][CH:7]=1
Reactant: COC(=O)C(OC)C(O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12
Agent: CCC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(Cc2ccccc2)NC(=O)C(CCN)NC1=O)C(C)O
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Product: COC(=O)/C(=C/c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)OC
Temperature: 100 °C
Reaction time: 15 h
Yield: 90.3 %

Procedure:
2.50 g of 3-hydroxy-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid methyl ester (5.25 mmol, syn/anti mixture of 1:4) was dissolved at room temperature in 25 ml of DMF. After the addition of 0.59 ml of conc. sufuric acid (10.5 mmol), the brown solution was stirred at 100° C. for 15 h. During cooling the reaction solution to r.t., the product crystallized. Under stirring, 15 ml of methanol were added at r.t. and the suspension stirred for 1 h at 0° C. The white crystals were filtered off, washed with 25 ml of cold (−15° C.) methanol in two portions and dried to constant weight (20° C./5 mbar/16h) to afford 2.13 g (90%) of the title compound with a purity of 99.5% (GC area).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:17](N)=[O:18]>C1(C)C(C)=CC=CC=1>[CH2:1]([N:8]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:14]2[N:15]=[C:17]1[OH:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccnc1NCc1ccccc1
Reactant: NC(N)=O
Solvent: Cc1ccccc1C
Product: Oc1nc2cccnc2n1Cc1ccccc1
Temperature: 25 °C

Procedure:
Grams 10 2-benzylamino-3-amino pyridine and 3 g urea in 50 ml xylene are heated under reflux for 3 hours. The reaction mixture is then cooled to room temperature, the undissolved product filtered and washed with toluene; the solid dried in vacuo at 80° C. gives 5.1 g 3-benzyl-2-hydroxy-3H-imidazo[4,5-b]pyridine which, recrystallized from absolute ethyl alcohol, melts at 177°-179° C.
Reaction SMILES: C[O:2][C:3]([CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[C:12]2[CH2:16][CH:17]([NH:19][CH2:20][C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)[OH:22])[CH3:18])=[O:4].[OH-].[Na+]>CO>[C:3]([CH2:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[C:12]2[CH2:16][CH:17]([NH:19][CH2:20][C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)[OH:22])[CH3:18])([OH:4])=[O:2]
Reactant: COC(=O)COc1cccc2c(CC(C)NC[C@H](O)c3cccc(Cl)c3)c[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(Cc1c[nH]c2c(OCC(=O)O)cccc12)NC[C@H](O)c1cccc(Cl)c1

Procedure:
The compound obtained in Example 14 and sodium hydroxide are added to an aqueous methanol solution (methanol/water=2:1), and the mixture is treated in the same manner as in Example 13 to give the desired compound.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:25]=[N:26][CH:27]=2)[C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24])=[O:9])=C.Cl>CO>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:25]=[N:26][CH:27]=2)[C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=1[F:24])=[O:9]
Reactant: C=COCCONC(=O)c1ccc2cncn2c1Nc1ccc(I)cc1F
Agent: Cl
Solvent: CO
Product: O=C(NOCCO)c1ccc2cncn2c1Nc1ccc(I)cc1F
Temperature: 45 °C
Yield: 91.7 %

Procedure:
To a suspension of 5-(2-fluoro-4-iodophenylamino)-imidazo[1,5-a]pyridine-6-carboxylic acid (2-vinyloxyethoxy)-amide (58.36 g, 0.12 mol) in methanol (600 mL) was added aqueous hydrochloric acid (242 mL, 1M, 0.242 mol). The reaction mixture was stirred and warmed to 45° C. for 1 hr during which time the solids dissolved. The reaction mixture was then cooled to room temperature, and concentrated in vacuo to remove the methanol. The resultant residue was treated with aqueous saturated sodium hydrogen carbonate and stirred at room temperature for 1 hr before collecting crude product by filtration, and drying at 55° C. over phosphorus (V) oxide under vacuum for 24 hr. The crude product was crystallized from IPA:H2O (1:1, v/v) (800 mL) with slow cooling and mechanical stirring. The product was collected by filtration and washed cold IPA:H2O (1:1, v/v) (100 mL) before being dried in vacuo at 55° C. to yield the title compound as a light brown solid (50.2 g, 90%). LCMS (Method A): RT=5.58 min, [M+H]+=457. 1H NMR (DMSO-d6, 400 MHz) 8.05 (1 H, s), 7.58 (1 H, dd, J=10.69, 1.92 Hz), 7.43 (1 H, s), 7.39 (1 H, d, J=9.33 Hz), 7.31-7.28 (1 H, m), 6.89 (1 H, d, J=9.31 Hz), 6.34 (1 H, t, J=8.68 Hz), 4.64 (1 H, s), 3.64 (2 H, t; J=4.78 Hz), 3.46 (2 H, m).
Reaction SMILES: CN(C)C=O.[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C(=O)([O-])N.[CH2:16]([NH:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:38](N4CCC(N5CCCC5)CC4)=[O:39])[CH:32]=3)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1)=[O:20])[CH3:17]>C(OCC)C>[CH2:16]([NH:18][C:19]([N:21]1[C:29]2[C:24](=[CH:25][C:26]([O:30][C:31]3[CH:36]=[CH:35][N:34]=[C:33]([NH:37][C:38]([N:6]4[CH2:11][CH2:10][O:9][CH2:8][CH2:7]4)=[O:39])[CH:32]=3)=[CH:27][CH:28]=2)[CH:23]=[CH:22]1)=[O:20])[CH3:17]
Reactant: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(N5CCCC5)CC4)c3)ccc21
Reactant: C1COCCN1
Agent: NC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCOCC4)c3)ccc21
Reaction time: 8 h

Procedure:
N,N-Dimethylformamide (5 ml) and morpholine (0.326 ml, 3.73 mmol) were added to a mixture (0.401 g) of phenyl N-(4-(1-(ethylamino)carbonyl)-1H-5-indolyl)oxy-2-pyridyl)carbamate and phenyl N-(4-(1-(ethylamino)carbonyl-1H-5-indolyl)oxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate obtained in Example 77; the reaction mixture was stirred overnight; the reaction mixture was partitioned between ethyl acetate and water; the organic layer was concentrated; and the obtained solid was washed with a solvent mixture of hexane:diethyl ether=1:1 to yield the title compound (255 mg, 0.62 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9]2[C:10]3[N:11]([C:15]([NH:18]C(=O)OC(C)C)=[N:16][N:17]=3)[CH:12]=[CH:13][N:14]=2)=[CH:4][CH:3]=1.[OH-].[K+].Cl>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:25])[C:9]2[C:10]3[N:11]([C:15]([NH2:18])=[N:16][N:17]=3)[CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)Nc1nnc2c(N(C)c3ccc(F)cc3)nccn12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN(c1ccc(F)cc1)c1nccn2c(N)nnc12
Temperature: 125 °C

Procedure:
The crude isopropyl (8-((4-fluorophenyl)(methyl)amino)-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)carbamate was treated with 5N KOH aq (1 mL) and dioxane (2 mL). The mixture was heated to 125° C. for 48 hours then treated with 5N HCl (1 mL). The solvent was removed under reduced pressure to afford N8-(4-fluorophenyl)-N8-methyl-[1,2,4]triazolo[4,3-a]pyrazine-3,8-diamine which could be purified by reverse phase column chromatography. LCMS: 245 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[C:10]([C:19]([NH:21][CH:22]3[CH2:24][CH2:23]3)=[O:20])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>CS(C)=O.[Cu]I>[CH:22]1([NH:21][C:19]([C:10]2[C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[N:14][C:13]=3[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:26]#[C:25][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:3]=3)[N:9]=2)=[O:20])[CH2:24][CH2:23]1
Reactant: O=C(NC1CC1)c1nn(-c2cccc(Br)c2)c2ncccc2c1=O
Reactant: C#Cc1cccnc1
Agent: [Cu]I
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(NC1CC1)c1nn(-c2cccc(C#Cc3cccnc3)c2)c2ncccc2c1=O
Yield: 18.9 %

Procedure:
To 1-(3-Bromophenyl)-N-cyclopropyl-4-oxo-1,4-dihydropyridino[2,3-c]pyridazine-3-formamide (1 g, 2.6 mmol) in 50 mL DMSO was successively added 3-ethynyl-pyridine (0.34 g, 3.3 mmol), bistriphenylphosphine palladium dichloride (0.53 g, 0.76 mmol), CuI (0.14 g, 0.74 mmol), triethylamine (0.63 g, 6.25 mmol), reacted in a microwave reactor at 100° C. for 90 min. After reaction was complete, extraction was performed with H2O/DCM, and organic phase was purified by preparation chromatography column to obtain product 0.2 g.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH:11]=[CH:12]\[CH:13]=[CH:14]\[C@@H:15]1[O:17][C@H:16]1[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22].C(O)C(N)(CO)C[OH:27].Cl.[OH-].[Li+].CCCCC[C@H](O)/C=C/C1CCC(=O)C=1C/C=C\CCCC(O)=O>C(O)C>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][C@@H:9]([OH:27])/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[CH:14]=[CH:15]\[C@@H:16]([OH:17])[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: NC(CO)(CO)CO
Reactant: CCCCC/C=C\C/C=C\C=C\C=C\[C@@H]1O[C@H]1CCCC(=O)O
Agent: CCCCC[C@H](O)/C=C/C1=C(C/C=C\CCCC(=O)O)C(=O)CC1
Agent: Cl
Agent: [Li+]
Solvent: CCO
Product: CCCCC/C=C\C[C@@H](O)/C=C/C=C/C=C\[C@@H](O)CCCC(=O)O
Reaction time: 0.02 h

Procedure:
Leukotriene A4 hydrolase is determined by a direct enzyme assay of cytosolic fraction of cells treated with antisense oligonucleotides, as described by Ohishi et al. (J. Biol. Chem., 262:10200-10205, 1987). Briefly, HL-60 cells treated with antisense oligonucleotides are disrupted by sonication and cytosolic fraction isolated by centrifugation at 100,000× g for 1 hour. The reaction mixture contains 100 mM Tris-HCl buffer (pH=7.8) and enzyme in a total volume of 50 μL. After preincubating the enzyme for 3-4 minutes at 37° C., leukotriene A4 in ethanol containing lithium hydroxide was added to a final concentration of 75 μM and a final ethanol concentration of 2%. The enzyme was incubated for 1 minute at 37° C. and the reaction terminated by the addition of 100 μL of acetonitrile/methanol/acetic acid, 150:50:3 (v/v/v) containing 0.3 nmol prostaglandin B2 as an internal standard. Protein is precipitated by incubation at -20° C. for 30 minutes followed by centrifugation at 10,000× g for 10 minutes. A 120 μL aliquot of the supernatant was removed and 20 μL of 0.35% disodium EDTA is added. The amount of leukotriene B4 formed in 50 μL aliquot of the resulting solution is determined by reverse phase HPLC using a C18 column. Samples are eluted isocratically with solvent containing acetonitrile/methanol/water/acetic acid (3:1:3:0.006, v/v/v/v, 0.05% disodium EDTA). The absorbance at 270 nm is monitored to quantitate the amount of leukotriene B4 formed.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:10]([O:12]C)=O)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[CH2:14]([NH2:17])[CH:15]=[CH2:16]>CO>[CH2:14]([NH:17][C:10]([C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([S:8][CH3:9])[N:4]=1)=[O:12])[CH:15]=[CH2:16]
Reactant: COC(=O)c1nc(SC)ncc1Br
Reactant: C=CCN
Solvent: CO
Product: C=CCNC(=O)c1nc(SC)ncc1Br
Temperature: 90 °C
Yield: 89.6 %

Procedure:
A solution of methyl 5-bromo-2-(methylthio)pyrimidine-4-carboxylate (Preparation 30, 1.00 g, 3.80 mmol) was dissolved in methanol (16 mL), treated with allylamine (3.00 mL, 40.0 mmol) and heated to 90° C. for 18 hours. The mixture was concentrated in vacuo and the residue purified by silica gel column chromatography eluting with 0 to 5% EtOAc in cyclohexanes to give the title compound (981 mg, 90%).