Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:24]=[CH:23][C:13]([O:14][CH2:15][C:16](=[O:22])[C:17]([CH3:21])([CH3:20])[CH:18]=[CH2:19])=[CH:12][CH:11]=1>ClC(Cl)(Cl)Cl>[Br:1][CH:15]([O:14][C:13]1[CH:23]=[CH:24][C:10]([Cl:9])=[CH:11][CH:12]=1)[C:16](=[O:22])[C:17]([CH3:20])([CH3:21])[CH:18]=[CH2:19]
Reactant: C=CC(C)(C)C(=O)COc1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: C=CC(C)(C)C(=O)C(Br)Oc1ccc(Cl)cc1
Temperature: 5 °C
Yield: 103.5 %

Procedure:
12.5 g (0.07 mol) of N-bromosuccinimide were added to a solution of 16.7 g (0.07 mol) of 5-(4-chlorophenoxy)-3,3-dimethylpent-1-en-4-one and a pinch of azoisobutyronitrile in 200 ml of tetrachloromethane. The mixture was then heated at the boil for 8 hours, under UV irradiation. The mixture was then cooled to 5° C. and filtered off from the precipitated succinimide. The filtrate was concentrated in vacuo. 23 g of crude 5-bromo-5-(4-chlorophenoxy)-3,3-dimethylpent-1-en-4-one were obtained as an oil, which was directly reacted further. ##STR29##
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C:11]2[CH2:15][CH2:14][CH2:13][CH:12]=2)=[C:4](Cl)[N:3]=1.[I:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][NH2:22]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C:11]2[CH2:15][CH2:14][CH2:13][CH:12]=2)=[C:4]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[C:18]([I:17])[CH:19]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3=CCCC3)c2n1
Reactant: NCc1cccc(I)c1
Solvent: CCN(CC)CC
Product: Clc1nc(NCc2cccc(I)c2)c2ncn(C3=CCCC3)c2n1

Procedure:
2-Chloro-6-[(3-iodobenzyl)amino]-9-cyclopentenylpurine is prepared from 2,6-dichloro-9-cyclopentenylpurine, 3-iodobenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:30])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:22]4[CH2:27][CH2:26][NH:25][CH:24]([CH3:28])[CH2:23]4)=[C:17]([F:29])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])C.[OH-].[K+].C(O)(=O)C>C(O)C>[F:21][C:19]1[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH:24]([CH3:28])[CH2:23]2)=[C:17]([F:29])[C:11]2=[N:12][C:13]3[N:14]([CH3:16])[CH:15]=[C:6]([C:4]([OH:5])=[O:3])[C:7](=[O:30])[C:8]=3[CH:9]=[C:10]2[CH:20]=1
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCNC(C)C4)c(F)cc3cc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC1CN(c2c(F)cc3cc4c(=O)c(C(=O)O)cn(C)c4nc3c2F)CCN1
Yield: 64.3 %

Procedure:
A suspension of 1.5 g of (RS)-3-ethoxycarbonyl-7,9-difluoro-1-methyl-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine in 20 cm3 of ethanol and 20 cm3 of N aqueous potassium hydroxide solution is heated at a temperature close to 75° C. for 1 hour and a half. 12 g of a 10% aqueous solution of acetic acid is added to the solution obtained, at this latter temperature. The insoluble matter obtained is drained at about 75° C. and washed 3 times with 30 cm3 of water at about 20° C. After recrystallizing once from 100 cm3 of dimethylformamdide, 0.9 g of (RS)-7,9-difluoro-1-methyl-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid melting at 380°-382° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.[F:29][C:30]1[CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:34][C:35]=1[F:36].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[F:29][C:30]1[CH:31]=[C:32]([C:2]2[S:3][C:4]3[CH2:5][C:6]4[C:12]([C:13]5[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=5)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[C:7]=4[C:8]=3[CH:9]=2)[CH:33]=[CH:34][C:35]=1[F:36]
Reactant: CC1(C)OB(c2ccc(F)c(F)c2)OC1(C)C
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccc(F)c(F)c4)cc2-3)cc1
Temperature: 100 °C
Yield: 65 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.5 g, 0.1 mmol), 2-(3,4-Difluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.24 g, 0.1 mmol), Na2CO3 (2 M, 2.45 mL), and Pd(PPh3)2Cl2 (9.7 mg, 0.084 mmol) in toluene/ethanol (1:1, 8.0 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 2-(3,4-Difluoro-phenyl)-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as orange solid in 65% yield.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[S:13][C:12]([CH2:14][CH3:15])=[N:11][C:10]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[CH:6]=[CH:5][N:4]=1.[C-:23]#[N:24].[K+].C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:23]([CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[S:13][C:12]([CH2:14][CH3:15])=[N:11][C:10]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[CH:6]=[CH:5][N:4]=1)#[N:24]
Reactant: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(CCl)c2)s1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1nc(-c2cccc(C)c2)c(-c2ccnc(CC#N)c2)s1
Yield: 49.6 %

Procedure:
A suspension of 5-(2-chloromethyl-4-pyridyl)-2-ethyl-4-(3-methylphenyl)-1,3-thiazole (0.40 g, 1.2 mmol), potassium cyanide (0.095 g, 1.5 mmol), 18-crown-6 (0.14 g, 0.51 mmol) in acetonitrile (5 mL) was heated under reflux for 6 hours. After cooling, an aqueous potassium carbonate solution was added, and extracted with ethyl acetate. The extracts were washed with brine, then, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=2:1). The resulting crystal was washed with hexane-isopropyl ether to obtain a title compound (0.19 g, 48%).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:6][C:5]=1[OH:28].[CH2:30](Br)[CH:31]=[CH2:32]>>[CH2:32]([O:28][C:5]1[CH:6]=[C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)[CH:8]=[CH:9][C:4]=1[O:3][CH:2]([F:1])[F:29])[CH:31]=[CH2:30]
Reactant: C=CCBr
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Product: C=CCOc1cc(-c2nc(CNC(=O)c3ccccc3OCC)co2)ccc1OC(F)F

Procedure:
Using the compound obtained in Example 347 and allyl bromide, white powdery N-[2-(3-allyloxy-4-difluoromethoxy phenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following the procedure of Example 348.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:27][CH3:28])=[C:12]([C:14]3[C:15](=[O:26])[N:16]([CH3:25])[N:17]=[C:18]([CH3:24])[C:19]=3S(C)(=O)=O)[CH:13]=2)=[CH:4][CH:3]=1.CN1CCCC1=[O:35].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:27][CH3:28])=[C:12]([C:14]3[C:15](=[O:26])[N:16]([CH3:25])[N:17]=[C:18]([CH3:24])[C:19]=3[OH:35])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1-c1c(S(C)(=O)=O)c(C)nn(C)c1=O
Reactant: CN1CCCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1-c1c(O)c(C)nn(C)c1=O
Temperature: 70 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
To a 25 ml volume three-necked flask, 4-[5-(4-chlorophenyl)-2-ethylphenyl]-2,6-dimethyl-5-methylsulfonyl-2,3-dihydro-3-pyridazinone ((2-34)-(1)-67) (290 mg), N-methyl-2-pyrrolidone (890 mg), and aqueous sodium hydroxide solution (410 mg) were added under a nitrogen atmosphere, and stirred at 70° C. for 3 hours. After the reaction mixture was cooled to room temperature, toluene was added and washed. The organic layer was removed. To the resulting aqueous layer, 10 wt % of hydrochloric acid was added to adjust pH to less than 1, and extracted with ethyl acetate times. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (hexane:ethyl acetate=2:1) to give 157 mg of 4-[5-(4-chlorophenyl)-2-ethylphenyl]-5-hydroxy-2,6-dimethyl-2,3-dihydro-3-pyridazinone ((1-4)-(1)-67).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([O-])=O.[H][H]>[Ni].CCO>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1ccccc1C1(O)CCCCC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1ccccc1C1(O)CCCCC1

Procedure:
A suspension of 5.20 g (16.45 mmol) of 1-(2-nitrophenyl)cyclohexanol and 500 mg of Raney nickel in EtOH (70 mL) is hydrogenated at RT and under 3 bar hydrogen pressure for 4 hours. The catalyst is filtered off through CELITE® filter aid and the filtrate is evaporated down in vacuo. The residue is recrystallized from hexane. Yield: 1.53 g (49%); Rf=0.38 (silica gel, hexane/EtOAc 4:1); ESI-MS: [M+H−H2O]+=174.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[C:15]([Cl:16])=[N:14][C:13](Cl)=[CH:12][N:11]=1)=[O:9].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[OH:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:16][C:15]1[C:10]([C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[O:9])=[N:11][CH:12]=[C:13]([O:26][C:20]2[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=2[F:18])[N:14]=1
Reactant: Oc1ccc(F)cc1F
Reactant: O=C(c1ccccc1Cl)c1ncc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1Cl)c1ncc(Oc2ccc(F)cc2F)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a dimethylformamide, i.e., DMF, (25 mL) solution of (2-chlorophenyl)-(3,5-dichloropyrazin-2-yl)methanone (2.1 g, 7.3 mmol, 1.0 eq) under nitrogen was added 2,4-difluorophenol (0.7 mL, 7.3 mmol, 1.0 eq) and potassium carbonate (1.21 g, 8.76 mmol, 1.2 eq). The resulting mixture was stirred overnight at room temperature and then concentrated. The residue was dissolved in dichloromethane and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated to give a crude oil which was purified via a chromatography using dichloromethane/hexanes (1:1) as the eluent to give [3-chloro-5-(2,4-difluorophenoxyl)pyrazin-2-yl]-(2-chlorophenyl)methanone (2.46 g, 6.45 mmol, 88% yield). Mass spec., M+1=382.
Reaction SMILES: C(ONC([C:9]1[C:18]([CH3:19])=[C:17]2[C:12]([C:13]([CH3:22])=[CH:14][C:15]([CH3:21])([CH3:20])[NH:16]2)=[CH:11][CH:10]=1)=O)(C)(C)C.[NH2:23]C1C=C2C(C(C)=CC(C)(C)N2)=CC=1>>[NH2:23][C:9]1[C:18]([CH3:19])=[C:17]2[C:12]([C:13]([CH3:22])=[CH:14][C:15]([CH3:21])([CH3:20])[NH:16]2)=[CH:11][CH:10]=1
Reactant: CC1=CC(C)(C)Nc2cc(N)ccc21
Reactant: CC1=CC(C)(C)Nc2c1ccc(C(=O)NOC(C)(C)C)c2C
Product: CC1=CC(C)(C)Nc2c1ccc(N)c2C

Procedure:
Removal of the Boc protective group of 7-tert-butyloxycarbamoyl-1,2-dihydro-2,2,4,8-tetramethylquinoline (400 mg, 1.32 mmol) was effected in the manner similar to that described for 7-amino-1,2-dihydro-2,2,4-trimethylquinoline (EXAMPLE 13), affording 267 mg (quantitative) of the desired aniline as a light reddish oil. Data for 7-amino-1,2-dihydro-2,2,4,8-tetramethylquinoline: 1H NMR (400 MHz, CDCl3) 6.82 (d, 1H, J=8.2 Hz, 5-H), 6.08 (d, 1H, J=8.1 Hz, 6-H), 5.15 (d, 1H, J=1.2 Hz, 3-H), 3.56 (br s, 3H, NH2, NH), 1.95 (D, 3H, J=1.2 Hz, 4-CH3), 1.91 (s, 3H, 8-CH3), 1.27 [s, 6H, 2-(CH3)2].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](C=O)=[C:5]([O:11][CH3:12])[C:4]=1[O:13][CH3:14].[OH:15]S(O)(=O)=O.OO.CCOC(C)=O>CO>[CH3:12][O:11][C:5]1[C:4]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:10]=[CH:9][C:6]=1[OH:15]
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(C=O)c(OC)c1OC
Agent: OO
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(O)c(OC)c1OC
Yield: 98 %

Procedure:
Following a modified procedure by Tremblay et al.,17 2,3,4-trimethoxybenzaldehyde (16, 6.075 g, 31.0 mmol) was dissolved in MeOH (60.0 mL), and then H2SO4 (0.6 mL) and 35% aq. H2O2 (4.0 mL, ˜40 mmol) was added at room temperature. The reaction was then heated to reflux for 2 hrs and monitored by TLC (1:4 EtOAc:hexanes) for completion. When the reaction was complete the solution was cooled and extracted with ethyl acetate. The layers are separated and the organic layer was washed with brine, dried over MgSO4, and filtered. Flash chromatography (1:4 EtOAc:hexanes) provides 17 (5.564 g, 30.2 mmol, 98%) as a light red oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[O:23][C:24](=[O:36])[CH2:25][CH2:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[CH2:34]Br>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:34][C:28]2[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=2[CH2:26][CH2:25][C:24]([OH:36])=[O:23])[C@@H:12]2[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1cc(F)ccc1CBr
Reactant: CC1(C)CCNC(=O)[C@H](NS(=O)(=O)c2ccc(Cl)cc2)C1
Product: CC1(C)CCNC(=O)[C@H](N(Cc2ccc(F)cc2CCC(=O)O)S(=O)(=O)c2ccc(Cl)cc2)C1

Procedure:
4-Chloro-N-((R)-5,5-dimethyl-2-oxo-azepan-3-yl)-benzenesulfonamide was alkylated using 3-(2-bromomethyl-5-fluoro-phenyl)-propionic acid methyl ester analogous to Example 2c and then saponified to give 3-(2-{[(4-chloro-benzenesulfonyl)-((R)-5,5-dimethyl-2-oxo-azepan-3-yl)-amino]-methyl}-5-fluoro-phenyl)-propionic acid. MS: m/e=509.3 (MH−).
Reaction SMILES: C([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=[O:22])[C@H:10]2[F:23])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C>[C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH3:15])[C:11](=[O:22])[C@H:10]2[F:23])[CH2:7][CH2:8]1)([OH:5])=[O:3]
Reactant: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=O)[C@H]2F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H](c1ccccc1)N1C[C@H](C2(C(=O)O)CC2)[C@H](F)C1=O
Temperature: 40 °C
Reaction time: 6 h
Yield: 89.4 %

Procedure:
4-(S)-(1-ethoxycarbonylcyclopropyl)-3-(S)-fluoro-1-[1-(S)-phenylethyl]-2-pyrrolidone (12.56 g, 39.33 mmol) was dissolved in ethanol (120 ml) and a 1 N aqueous solution of sodium hydroxide (120 ml) was added dropwise thereinto. After stirring at 40° C. for 6 hours, ethanol was evaporated under reduced pressure. The residue was washed with chloroform (100 ml×2). Under ice cooling, the separated aqueous layer was acidified by adding dropwise 1 N hydrochloric acid thereinto and then extracted successively with chloroform (300 ml×2) and diethyl ether (300 ml). The combined organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 10.24 g (89.4%) of the title compound as colorless needles.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=O.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCCCCC>[C:10]1([N:9]=[CH:7][C:3]2[S:4][CH:5]=[CH:6][C:2]=2[CH3:1])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccsc1C=O
Solvent: CCCCCC
Product: Cc1ccsc1C=Nc1ccccc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 84.9 %

Procedure:
3-methylthiophene-2-aldehyde (103 g, 0.816 mol) was mixed with hexane (100 ml), to which aniline (74.4 ml, 0.816 mol) was added and stirred at room temperature for 7 hours. After separating deposited crystalline solids by filtration, and washing with hexane, 139.5 g (yield: 85%) of 3-methylthiophene-2-aldehyde phenylimine was obtained. After concentrating the liquid filtrate and stirring at room temperature for a further 12 hours, 7.30 g (yield: 4%) of 3-methylthiophene-2-aldehyde phenylimine was obtained by post treatment in the same manner as above. 1H-NMR spectra (chemical shift, ppm: in CDCl3); 2.47 (3H, s), 6.92 (1H, d, J=4.9 Hz), 7.15-7.30 (3H), 7.30-7.45 (3H), 8.61 (1H).
Reaction SMILES: C([O:5][C:6](=O)/[C:7](=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]2)=[C:22]([O:32][CH3:33])[CH:21]=1)/[CH2:8][CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][N:10]1[CH2:9][CH2:8]/[C:7](=[CH:19]\[C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]3)=[C:22]([O:32][CH3:33])[CH:21]=2)/[C:6]1=[O:5]
Reactant: COc1cc(/C=C(\CCNCc2cccc(F)c2)C(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(/C=C2\CCN(Cc3cccc(F)c3)C2=O)ccc1-n1cnc(C)c1
Yield: 60.8 %

Procedure:
To a methylene chloride (0.5 mL) solution of (E)-4-(3-fluorobenzylamino)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]butyric acid tert-butyl ester (4.50 mg), trifluoroacetic acid (500 μL) was added. After agitating reaction solution at room temperature for 1.5 hours and agitating that materials disappeared, reaction solution was concentrated under reduced pressure as it was. The residue was dissolved in DMF (0.5 mL), IPEA (17.0 μL), EDC (5.58 mg), and HOBT (3.93 mg) were added to the reaction solution one by one, and the reaction solution was agitated at room temperature for 1.5 hours. After confirming disappearance of the starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: ethyl acetate->ethyl acetate:ethanol=20:1), and 2.30 mg of the title compound was obtained.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[C:11]([C:13]([Cl:17])=[C:14]([Cl:16])[Cl:15])[CH:10]=[C:9]([C:18]([Cl:22])=[C:19]([Cl:21])[Cl:20])[CH:8]=1>C(Cl)Cl>[Cl:17][C:13]([C:11]1[CH:12]=[C:7]([OH:6])[CH:8]=[C:9]([C:18]([Cl:22])=[C:19]([Cl:20])[Cl:21])[CH:10]=1)=[C:14]([Cl:16])[Cl:15]
Reactant: COc1cc(C(Cl)=C(Cl)Cl)cc(C(Cl)=C(Cl)Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cc(C(Cl)=C(Cl)Cl)cc(C(Cl)=C(Cl)Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.153 g (0.6 mmol) of boron tribromide in 0.5 mL of CH2Cl2 was magnetically stirred at 0° C. with an external ice-water bath, while a solution of 0.093 g (0.25 mmol) of the product of Step C in 0.5 mL CH2Cl2 was added over a period of 5 min. The reaction mixture was stirred an additional 30 min at 0° C. then allowed to warm to room temperature and stirring was continued overnight. The reaction was again cooled to 0° C. and quenched by addition of 1.0 mL water. The organic layer was separated and then washed with 2 N NaOH. The aqueous extracts were acidified with 1 N HCl and extracted with ether. The organic extracts were combined, washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 5% EtOAc-hexane. Evaporation of the purified fractions and drying in vacuo afforded the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[N:14][CH:13]=[CH:12]3)[CH:8]=1)([O-])=O>[Pd].C1COCC1>[CH:15]1[C:16]2[C:11](=[CH:10][C:9]([N:7]3[CH:8]=[C:4]([NH2:1])[CH:5]=[N:6]3)=[CH:18][CH:17]=2)[CH:12]=[CH:13][N:14]=1
Reactant: O=[N+]([O-])c1cnn(-c2ccc3cnccc3c2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cnn(-c2ccc3cnccc3c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.1 %

Procedure:
A mixture of 6-(4-nitro-1H-pyrazol-1-yl)isoquinoline (367 mg, 1.53 mmol) and 10 wt. % palladium on activated carbon (163 mg, 153 μmol) in THF (15 mL) was stirred under an atmosphere of hydrogen at ambient temperature for 4 hours. The mixture was filtered through a Celite pad that was washed with THF (30 mL), and the combined filtrates were concentrated under reduced pressure. The resulting yellow solid was dissolved in MeOH/DCM, evaporated onto silica gel, and purified by flash chromatography (Biotage Si 40+M, 3% to 8% MeOH/DCM) to provide 1-(isoquinolin-6-yl)-1H-pyrazol-4-amine (264 mg, 82% yield) as a yellow solid. LCMS (API-ES) m/z (%): 211.2 (100%, M++H); 1H NMR (300 MHz, CDCl3) δ ppm 3.01 (br s, 2H), 7.48 (s, 1H), 7.62-7.69 (m, 2H), 7.93 (s, 1H), 7.96-8.06 (m, 2H), 8.52 (d, J=5.8 Hz, 1H), 9.22 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.C1(P([N:47]=[N+:48]=[N-:49])(C2C=CC=CC=2)=O)C=CC=CC=1>C(O)(C)C>[F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:47]=[N+:48]=[N-:49])=[O:20])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(-c2ccn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)c1ccc(-c2ccn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.2 %

Procedure:
To 4-(1-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-3-yl)benzoic acid (0.58 g, 1.67 mmol) in isopropanol (10.7 mL) was added triethylamine (0.30 mL, 2.17 mmol) and diphenylphosphoryl azide (0.47 mL, 2.17 mmol) and the reaction was stirred at room temperature for 16 hours. The orange precipitate that had formed was filtered through a fritted glass funnel, rinsed with isopropanol, and dried in a vacuum oven to provide 4-(1-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-3-yl)benzoyl azide as an orange solid (188 mg, 30%): 1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J=2.6 Hz, 1H), 8.17-8.11 (m, 2H), 8.09-8.04 (m, 4H), 7.57 (d, J=8.4 Hz, 2H), 7.24 (d, J=2.6 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) δ −56.97; ESIMS m/z 374 ([M+H]+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:35])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[CH:33]=[CH:32][N:31]=[N:30]2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:16])([F:18])[F:17])=[CH:10][C:9]2[NH:19][C:20](=[O:35])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[CH:33]=[CH:32][N:31]=[N:30]4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3ccnn3)c1)=N2

Procedure:
The title compound was prepared from {5-methyl-2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M53) (0.29 g, 0.58 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (143 mg, 64%).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[N:5][C:6]([N+:9]([O-])=O)=[CH:7][CH:8]=1.[H][H]>C(O)C.[Pd]>[CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[N:5][CH:4]=1
Reactant: CN(C)c1ccc([N+](=O)[O-])nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN(C)c1ccc(N)nc1
Yield: 93.9 %

Procedure:
A solution of dimethyl-(6-nitro-pyridin-3-yl)-amine (0.64 g, 3.83 mmol) in ethanol (45 mL) was treated with 10% palladium on activated carbon (203 mg). The reaction mixture was stirred under a positive pressure of hydrogen gas (balloon) at 25° C. and atmospheric pressure overnight. The catalyst was then filtered off through a pad of celite, and the celite pad was washed well with ethanol. The filtrate was concentrated in vacuo to afford N5,N5-dimethyl-pyridine-2,5-diamine (493.6 mg, 94%) as a dark red-purple oil: EI-HRMS m/e calcd for C7H11N3 (M+) 137.0953, found 137.0957.