Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH3:25])([CH3:24])[C:17](=[O:23])[N:18]2[CH2:21][CH3:22])=[CH:14][CH:13]=1>>[CH2:21]([N:18]1[C:19]2[C:15](=[CH:14][CH:13]=[C:12]([NH:11][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][N:9]=[CH:10][C:2]=3[F:1])[CH:20]=2)[C:16]([CH3:25])([CH3:24])[C:17]1=[O:23])[CH3:22]
Reactant: CCN1C(=O)C(C)(C)c2ccc(N)cc21
Reactant: O=C(O)c1ccncc1F
Product: CCN1C(=O)C(C)(C)c2ccc(NC(=O)c3ccncc3F)cc21

Procedure:
Prepared in analogy to example 26 from 3-fluoroisonicotinic acid and 6-amino-1-ethyl-3,3-dimethylindolin-2-one (G. Georges et al., US2006/142247 A1). The title compound was obtained as light yellow solid.
Reaction SMILES: O[C:2]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=[CH:13]2)([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClC(Cl)(Cl)Cl>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:2]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=[CH:13]3)=[CH2:3])[CH:5]=1
Reactant: COC(=O)c1ccc2cc(C(C)(O)c3cccnc3)ccc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: C=C(c1cccnc1)c1ccc2cc(C(=O)OC)ccc2c1
Yield: 86.4 %

Procedure:
0.3 g (1 mmol) of methyl 6-[1-hydroxy-1-(3-pyridyl)ethyl]-2-naphthoate and 0.68 g (2.6 mmol) of triphenylphosphine in 3 ml of tetrachloromethane are heated under reflux for 9 hours. After evaporation, the residue is taken up in 4 N HCL, and triphenylphosphine and triphenylphosphine oxide are extracted with ethyl acetate. The aqueous phase is then neutralized with sodium bicarbonate. After extraction with ethyl acetate, and drying and evaporation of the ethyl acetate phase in vacuo, 0.25 g (86%) of methyl 6-[1-(3-pyridyl)ethenyl]-2-naphthoate is obtained as an oil. RF (ethyl acetate/methanol 8:1): 0.59. 1H-NMR (CDCl3, 60 MHz) δ=4.0 (2, 3H; CH3), 5.7 (d, 2H; C=CH2), 7.0-8.7 (m, 10H; arom. H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: NCc1ccccc1
Product: c1ccc(CNc2nccc(-n3cnc4ccccc43)n2)cc1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with benzylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound.
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:3]1.[NH2-].[Na+].Cl[CH2:22][CH2:23][N:24]([CH3:28])[CH2:25][CH2:26]Cl>C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=3)[N:2]([N:1]3[CH2:26][CH2:25][N:24]([CH3:28])[CH2:23][CH2:22]3)[CH:3]=2)=[CH:13][CH:14]=1
Reactant: Cc1ccc2c(c1)c(-c1ccc(F)cc1)cn2N
Reactant: CN(CCCl)CCCl
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: Cc1ccc2c(c1)c(-c1ccc(F)cc1)cn2N1CCN(C)CC1
Temperature: 25 °C

Procedure:
To a mixture of 1-amino-3-(4-fluorophenyl)-5-methyl-1H-indole 19a (1 g) and toluene (20 ml) was added a 50% suspension of sodium amide in xylene (1.0 ml). After reaction for 15 min at room temperature a solution of N,N-bis(2-chloroethyl)methylamine (0.8 g) in toluene was added slowly and the mixture was refluxed for 3 h. After cooling to room temperature, the solvents were evaporated in vacuo and water (100 ml) was added. The mixture was extracted with ethyl acetate (2×50 ml) and the combined organic phases were dried (Na2SO4). Evaporation of the solvents in vacuo afforded the title compound, which was purified by column chromatography on silica gel (eluted with ethyl acetate/ethanol 4:1 containing 4% triethylamine) and crystallized from heptane. Yield: 0.5 g, mp 105°-107° C.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH2:7](O)[CH2:8][CH2:9][CH3:10]>>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)O
Reactant: CCCCO
Product: CCCCOC(=O)C(C)C

Procedure:
47 g isobutyric acid were esterified with excess n-butanol under conditions as in Example I and 67 g butyl isobutyrate were obtained. Butyl isobutyrate was oxidized with oxygen under conditions as in Example I.
Reaction SMILES: [CH:1]1([S:4]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)(=[N:6][C:7](=[O:12])[C:8]([F:11])([F:10])[F:9])=[O:5])[CH2:3][CH2:2]1>[Pd].C(O)C.C1COCC1>[NH2:19][C:16]1[CH:15]=[CH:14][C:13]([S:4]([CH:1]2[CH2:3][CH2:2]2)(=[N:6][C:7](=[O:12])[C:8]([F:11])([F:9])[F:10])=[O:5])=[CH:18][CH:17]=1
Reactant: O=C(N=S(=O)(c1ccc([N+](=O)[O-])cc1)C1CC1)C(F)(F)F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(S(=O)(=NC(=O)C(F)(F)F)C2CC2)cc1
Reaction time: 1 h
Yield: 93 %

Procedure:
1.4 g palladium on charcoal (10%/50% moisture) was added to a solution of 6.9 g (21.44 mmol) (RS)-S-cyclopropyl-S-(4-nitrophenyl)-N-(trifluoroacetyl)sulfoximide in 214 ml ethanol and 39 ml THF and was hydrogenated for 1 hour under normal pressure at 25° C. A further 1.4 g palladium on charcoal was added, and it was hydrogenated for a further 4.5 hours at normal pressure. The mixture was filtered, 1.4 g palladium on charcoal was added to the filtrate again and finally hydrogenated for 45 minutes. The mixture was filtered and concentrated by evaporation. 5.8 g (19.91 mmol; yield: 93%) of the product was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([O:19][CH2:20][CH2:21][CH2:22]Cl)[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:4]([F:26])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:33]1[CH:37]2[CH2:38][NH:39][CH2:40][CH:36]2[CH2:35][N:34]1[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:24][CH3:25])=[C:16]([O:19][CH2:20][CH2:21][CH2:22][N:39]4[CH2:38][CH:37]5[CH2:33][N:34]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:35][CH:36]5[CH2:40]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:4]([F:26])[CH:3]=1
Reactant: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OCCCCl
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OCCCN1CC2CN(C(=O)OC(C)(C)C)CC2C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a mixture of N-(4-bromo-2-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (1.25 g), K2CO3 (0.78 g) and a catalytic amount of KI in DMF (20 mL) was added tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.78 g) at room temperature. The reaction mixture was heated to 80° C. and stirred for 8 h, then diluted with water and extracted with CH2Cl2. The organic layer was dried over anhydrous Na2SO4 for 1 h and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 30:1 (v/v) DCM/MeOH) to give the title compound as a white solid (1.16 g, 66.50%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([O:10]C(=O)C)=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].O.Cl>CO>[OH:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([OH:10])=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15]
Reactant: CC(=O)Oc1cc(C(C)=O)c(O)c(C)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)c1cc(O)c(C)c(C)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
The phenylethanone of Step 2 (500 mg) was dissolved in MeOH (20 mL), and potassium carbonate (1 eq.) was added followed by water (1 mL). The mixture was stirred at room temperature for 1 h, and then was poured into water. The solution was acidified with HCl and a precipitate was formed. The precipitate was collected and air dried to give about 350 mg of 1-(2,5-dihydroxy-3,4-dimethyl-phenyl)-ethanone.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1)=O.[NH2:17][C:18]1[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][C:19]=1[OH:25]>>[O:13]=[C:11]1[NH:10][C:9](=[O:14])[C:8](=[CH:7][C:6]2[CH:15]=[CH:16][C:3]([C:1]3[NH:17][C:18]4[C:19]([OH:25])=[CH:20][CH:21]=[CH:22][C:23]=4[N:24]=3)=[CH:4][CH:5]=2)[S:12]1
Reactant: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1
Reactant: Nc1cccc(O)c1N
Product: O=C1NC(=O)C(=Cc2ccc(-c3nc4cccc(O)c4[nH]3)cc2)S1

Procedure:
2-[4-[(2,4-Dioxothiazolidin-5-ylidene)methyl]phenyl]-4-hydroxybenzimidazole was prepared from 5-(4-formylbenzylidene)-2,4-thiazolidinedione and 2,3-diaminophenol by following General Procedure 2.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[C:4]([CH3:11])[C:3]=1[C:12]1[C:13]([F:20])=[C:14]([OH:19])[CH:15]=[C:16]([F:18])[CH:17]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:25]=O.C(O)(=O)C>CCO>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]2[C:17]3[C:16]([F:18])=[CH:15][C:14]([OH:19])=[C:13]([F:20])[C:12]=3[C:3]3[C:4]([CH3:11])=[N:5][N:6]([C:7]([CH3:9])([CH3:10])[CH3:8])[C:2]=3[N:1]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1nn(C(C)(C)C)c(N)c1-c1cc(F)cc(O)c1F
Reactant: O=Cc1ccc(OCc2ccccc2)c(Cl)c1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nn(C(C)(C)C)c2nc(-c3ccc(OCc4ccccc4)c(Cl)c3)c3c(F)cc(O)c(F)c3c12
Temperature: 120 °C
Reaction time: 4.5 h
Yield: 46.6 %

Procedure:
To 3-[5-amino-1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-4-yl]-2,5-difluorophenol (0.050 g, 0.178 mmol) and 3-chloro-4-[(phenylmethyl)oxy]benzaldehyde (0.044 g, 0.178 mmol) was added acetic acid (1 mL). The mixture was stirred at 120° C. for 4.5 h and then concentrated in vacuo to afford a residue which was co-evaporated with EtOH (2×) to afford a film which was purified by column chromatography (ether-dichloromethane 1:20) to afford 5-{3-chloro-4-[(phenylmethyl)oxy]phenyl}-3-(1,1-dimethylethyl)-6,9-difluoro-1-methyl-3H-pyrazolo[3,4-c]isoquinolin-8-ol as a light brown foam (0.042 g, 0.083 mmol, 47% yield). 1H NMR (400 MHz, CDCl3): 7.63 (t, 1H), 7.55-7.51 (m, 2H), 7.46-7.34 (m, 5H), 7.06 (d, 1H), 6.86 (dd, 1H), 5.25 (s, 2H), 2.81 (d, 3H), 1.84 (s, 9H); MS (EI) for C28H24ClF2N3O2: 508 (MH+).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([I:11])[CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>C(Cl)Cl>[Br:10][C:8]1[CH:7]=[C:6]([I:11])[CH:5]=[C:4]([CH:9]=1)[CH2:3][OH:2]
Reactant: COC(=O)c1cc(Br)cc(I)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Product: OCc1cc(Br)cc(I)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To methyl 5-bromo-3-iodobenzoate (Step A above) (5.01 g, 0.015 mole) in anhydrous methylene chloride (100 mL) at -78° C., was added dropwise minutes, diisobutylaluminum hydride (5.50 mL, 0.03 mole). The mixture was stirred for 1 hour then allowed to warm to 0° C. The reaction solution was poured into 600 mL, chilled 3N HCl and extracted 3× with methylene chloride (150 mL). The organic layers were combined, dried over MgSO4 and concentrated under vacuum to yield 5-bromo-3-iodobenzyl alcohol (4.54 g) as a white solid. MP=110-112° C. MS and NMR were consistent with the desired structure.
Reaction SMILES: CNC1N=C(C2C=CC=CN=2)C=C(C2C=NC=C(C3C=CC=C(O[CH2:28][CH2:29][N:30]4[CH2:34]CC[CH2:31]4)C=3)C=2)C=1.C1(O)C=CC=CC=1.[CH2:42]([NH:49][C:50]1[N:55]=[C:54]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=2)[CH:53]=[C:52]([C:62]2[CH:63]=[N:64][CH:65]=[C:66]([C:68]3[CH:69]=[C:70]([OH:74])[CH:71]=[CH:72][CH:73]=3)[CH:67]=2)[CH:51]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH2:42]([NH:49][C:50]1[N:55]=[C:54]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=2)[CH:53]=[C:52]([C:62]2[CH:63]=[N:64][CH:65]=[C:66]([C:68]3[CH:73]=[CH:72][CH:71]=[C:70]([O:74][CH2:28][CH2:29][N:30]([CH3:34])[CH3:31])[CH:69]=3)[CH:67]=2)[CH:51]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Oc1cccc(-c2cncc(-c3cc(NCc4ccccc4)nc(-c4ccccn4)c3)c2)c1
Reactant: CNc1cc(-c2cncc(-c3cccc(OCCN4CCCC4)c3)c2)cc(-c2ccccn2)n1
Solvent: Oc1ccccc1
Product: CN(C)CCOc1cccc(-c2cncc(-c3cc(NCc4ccccc4)nc(-c4ccccn4)c3)c2)c1

Procedure:
This compound is prepared analogously to Methyl-{5″-[3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[2,2′;4′,3″]terpyridin-6′-yl}-amine (Example 2.189) by replacing methylamino-[2,2′;4′,3″]terpyridin-5″-yl)-phenol (example 2.189 step 1) with 3-(6′-Benzylamino-[2,2′;4′,3″]terpyridin-5″-yl)-phenol (Example 2.143) and by replacing 1-(2-Chloro-ethyl)-pyrrolidine with 2-Dimethyl-aminoethyl chloride.
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=O)[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2.[CH3:22][C:23]1([NH2:26])[CH2:25][CH2:24]1>>[CH3:22][C:23]1([N:26]=[C:10]2[CH2:9][CH2:8][C@H:7]3[C@H:6]4[C@H:5]([CH2:4][CH2:3][C@:2]23[CH3:1])[C@:15]2([CH3:21])[C:14]([CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16]2)=[CH:13][CH2:12]4)[CH2:25][CH2:24]1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC1(N)CC1
Product: CC1(N=C2CC[C@H]3[C@@H]4CC=C5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]23C)CC1

Procedure:
Reaction of dehydroepiandrosterone with 1-methylcyclopropylamine according to the procedure described in Example 1 gives 17-(1-methylcyclopropylimino)androst-5-en-3β-ol. This is then reduced with sodium borohydride according to the procedure in Example 2 to give 17β-(1-methylcyclopropylamino)androst-5-en-3β-ol.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:33][C@H:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)[CH3:35].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[N:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C@@H:34]([NH:33][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:32])([F:1])[F:31])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:29])[CH3:35]
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: C[C@H](N)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with (S)-1-amino-1-(2-pyridyl)-ethane (51 mg, 0.41 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide a residue. This material was purified by preparative thin-layer-chromatography on silica eluting with ethyl acetate. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 76 mg of the title compound. Optical Rotation [α]D=+63.90° (c=0.39 mg/ml; CH3OH)
Reaction SMILES: N[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N+:5]([O-:12])=[N:4][N:3]=1.N([O-])=[O:14].[Na+].Cl>>[OH:14][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N+:5]([O-:12])=[N:4][N:3]=1
Reactant: Nc1nn[n+]([O-])c2ccccc12
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: [O-][n+]1nnc(O)c2ccccc21

Procedure:
The amino-benzotriazine N-oxide (16) is diazotized with NaNO2/HCl and the intermediate diazonium salt (not shown) is hydrolysed to form the hydroxybenzotriazine N-oxide compound (17). Reaction of the hydroxybenzotriazine N-oxide compound (17) with phosphorus oxychloride in the presence of a non-interfering base such as N,N-dimethylaniline gives the chlorobenzotriazine N-oxide compound (18). The chlorination reaction is typically carried out with heating, for example at reflux temperatures.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[CH3:21]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].CI>O>[CH3:21][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:13])[F:14])[CH:7]=2)[C:2](=[O:1])[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4]1
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: CCOC(=O)c1cn(C)c2cc(C(F)(F)F)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 105 %

Procedure:
A slurry of ethyl 4-hydroxy-7-(trifluoromethyl)quinoline-3-carboxylate (10.0 g, 35.1 mmol), DMF (50 mL), potassium carbonate (12.11 g, 88.00 mmol), and methyl iodide (11.00 ml, 175.0 mmol) was heated to 90° C. After 20 minutes, the dark solution was cooled to room temperature and water (25 mL) was added slowly, keeping the temperature <40° C. The reaction mixture was cooled to ambient temperature, and the brown slurry was filtered and washed with 2:1 DMF/water (20 mL×2) and water (20 mL×2). The solids were partially dried on the frit giving the title compound (11.0 g, 36.8 mmol, 105% yield), which was used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[N:6][C:5]=1Cl.[C:13]([Cu])#[N:14]>CN1C(=O)CCC1.O.Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[N:6][C:5]=1[C:13]#[N:14]
Reactant: N#C[Cu]
Reactant: COC(=O)c1c(C)ccnc1Cl
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1c(C)ccnc1C#N
Temperature: 180 °C
Reaction time: 16 h

Procedure:
A suspension of 2-chloro-4-methyl-nicotinic acid methyl ester (2.64 g, 14.3 mmol) and CuCN (6.4 g, 71 mmol) in NMP (5.3 mL) was heated to 180° C. for 30 min. The reaction mixture was then cooled to room temperature and diluted with water (80 mL). After vigorous stirring for 16 h, the suspension was centrifuged and the precipitate suspended in a solution of FeCl3.6H2O (5.8 g, 21 mmol) in aqueous HCl (4 M, 80 mL). After vigorous stirring for 1 h, the suspension was extracted with DCM (3×70 mL). The organic layer was dried over Na2SO4/Na2CO3, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with EA/DCM 1:10) to give the title compound. MS (m/z): 177.0 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[N+:14]([O-])([O:16]C(C)C)=[O:15].S(=O)(=O)(O)O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[OH:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CC(C)O[N+](=O)[O-]
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(O)c(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 41.9 %

Procedure:
To a solution of ethyl 3,4-dihydroxybenzoate (9.5 g, 52.2 mmol), isopropyl nitrate (13.5 g, 130.5 mmol), and tetrabutylammonium hydrogensulfate (0.884 g, 2.61 mmol) in DCM (100 mL), was added sulfuric acid (14.25 g, 145.6 mmol) slowly at 0° C. The reaction mixture was warmed to room temperature and stirred for 45 min, then quenched with ice/water (150 mL), and extracted with DCM (150 mL×2). The extracts were combined, and the solvent removed under vacuum. The product was purified by silica gel column (20% v/v EtOAc in PE) to give ethyl 3,4-dihydroxy-2-nitrobenzoate (4.97 g, 40% yield). ESI MS: m/z 228 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[S:7][C:6]([C:8]([NH2:10])=[NH:9])=[CH:5][CH:4]=1.O=[C:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17](OCC)=[O:18].C[O-].[Na+]>C(O)C>[Cl:2][C:3]1[S:7][C:6]([C:8]2[NH:10][C:17](=[O:18])[C:13]3[CH2:14][CH2:15][CH2:16][C:12]=3[N:9]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1CCCC1=O
Reactant: N=C(N)c1ccc(Cl)s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]c(-c2ccc(Cl)s2)nc2c1CCC2
Temperature: 25 °C
Yield: 71 %

Procedure:
A 50-mL round bottomed flask was charged with 5-chlorothiophene-2-carboxamidine HCl salt (400 mg, ˜2 mmol, 1 eq.), ethyl 2-oxocyclopentanecarboxylate (320 mg, 2 mmol, 1 eq.), and ethanol (10 ml). To the mixture was added sodium methoxide (25 w % in methanol, 540 mg, 2.5 mmol, 1.25 eq.). The resulting mixture was stirred under reflux for 20 hr. After cooling to room temperature, the mixture was evaporated under reduced pressure to dryness and the residue was treated with 1N HCl (6 ml). Solid was collected by filtration and washed water followed by ether. The product thus obtained was forwarded to the next step without any further purification (360 mg, 71% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:3]=1.Cl.[CH3:18][NH:19][CH3:20].C(N(CC)CC)C>CN(C=O)C>[CH3:18][N:19]([CH3:20])[C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: CNC
Reactant: Cc1ccc(Nc2cc(Cl)nc(N)n2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(Nc2cc(N(C)C)nc(N)n2)cc1
Temperature: 170 °C
Yield: 38.5 %

Procedure:
A mixture of 6-chloro-N4-(4-methylphenyl)-2,4-pyrimidinediamine (1.5 g, 6.4 mmol), and N,N-dimethylamine hydrochloride (0.56 g, 7 mmol) and triethylamine (1.4 g, 14 mmol) in DMF (2 mL), was heated at 170° C. for 16 h. The product was filtered out and the organic layer was treated with saturated NaHCO3 (50 mL) and extracted with EtOAC (3×50 mL). The organic layer washed with brine (2×100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica using hexane/EtOAc (1:3), giving the desired product (0.6 g, 40%).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[OH:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[C:22](=[O:24])[CH3:23].[F:25][C:26]([F:37])([F:36])[C:27]1[C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=[CH:29][N:28]=1.Cl>N1C=CC=CC=1>[OH:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:14]=1[C:22](=[O:24])[CH2:23][C:33]([C:32]1[C:27]([C:26]([F:37])([F:25])[F:36])=[N:28][CH:29]=[CH:30][CH:31]=1)=[O:34]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1O
Reactant: O=C(Cl)c1cccnc1C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(CC(=O)c1cccc([N+](=O)[O-])c1O)c1cccnc1C(F)(F)F
Temperature: 70 °C
Reaction time: 12 h
Yield: 38.1 %

Procedure:
DBU (334 mg, 2.2 mmol) was added to a solution of 1-(2-Hydroxy-3-nitrophenyl)ethanone 1 (181 mg, 1 mmol) and 2-(trifluoromethyl)pyridine-3-carbonyl chloride 25 (1.1 mmol) in pyridine (3 ml). The mixture was stirred at 70° C. for 12 h, poured into 2N HCl (20 ml) and extracted with EtOAc. The organic layers were dried over Na2SO4, concentrated and purified by preparative TLC (CH2Cl2/EtOAc, 10:1) to give 26 as a yellow solid (135 mg, 38% yield).