Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.Cl.Cl.[Cl:5][C:6]1[CH:7]=[C:8]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:9][NH:10][C:11]([NH:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[NH:15])=[NH:12].[CH3:29][C:30]([CH3:32])=O>>[ClH:5].[CH2:17]([NH:16][C:14]1[NH:13][C:11]([NH:10][CH2:9][C:8]2[CH:25]=[CH:26][C:27]([Cl:28])=[C:6]([Cl:5])[CH:7]=2)=[N:12][C:30]([CH3:32])([CH3:29])[N:15]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC(C)=O
Reactant: CCCCCCCCNC(=N)NC(=N)NCc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CO
Product: CCCCCCCCNC1=NC(C)(C)N=C(NCc2ccc(Cl)c(Cl)c2)N1

Procedure:
25 ml of methanol, 40 ml of acetone and 0.1 ml of concentrated hydrochloric acid were added to 1.8 g (4.4 mmol) of N1-(3′,4′-dichlorobenzyl)-N5-octyl-biguanide hydrochloride, and the mixture was refluxed for 24 hours. The solvent was distilled of f under reduced pressure, and the residue was dissolved in 80% aqueous acetonitrile. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.5 g of a colorless resinous solid (1) from the first main elution fraction with a mixture of chloroform and methanol (95:5), and 0.7 g of a colorless resinous solid (2) from the second main elution fraction.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.F[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[CH:27]=[N:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=34)[CH:23]=[CH:22][N:21]=2)=[C:12]([O:35][CH3:36])[CH:11]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([NH:19][C:20]3[N:25]=[C:24]([C:26]4[CH:27]=[N:28][N:29]5[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=45)[CH:23]=[CH:22][N:21]=3)=[C:12]([O:35][CH3:36])[CH:11]=2)[CH2:4]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Temperature: 140 °C
Yield: 79.2 %

Procedure:
(3R)—N,N-Dimethylpyrrolidin-3-amine (64 mg, 0.56 mmol), N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 127, 267 mg, 0.53 mmol) and DIPEA (0.186 mL, 1.07 mmol) were suspended in DMA (2 mL), sealed into a microwave tube and then heated to 140° C. for 1 h in a microwave reactor. After cooling to r.t. the mixture was part-purified by ion exchange chromatography, using an SCX column. The column was first washed with CH3OH and then eluted with 0.7M methanolic ammonia. Clean fractions were concentrated in vacuo to give crude material as an orange gum. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (201 mg, 79%) as a orange gum; 1H NMR (CDCl3): 1.89-1.98 (3H, m), 2.05-2.12 (2H, m), 2.16-2.23 (1H, m), 2.30 (6H, s), 2.78-2.87 (1H, m), 3.14-3.37 (5H, m), 3.54 (1H, td), 3.96 (3H, s), 4.20 (2H, t), 6.34 (1H, s), 6.85 (1H, d), 7.33 (1H, s), 7.95 (1H, s), 8.30 (1H, d), 8.95 (1H, s); m/z: ES+ MH+ 479.60.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:13])[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.[OH-].[Na+]>O>[CH2:1]([O:8][CH2:9][CH:10]1[O:13][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(CCl)COCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: c1ccc(COCC2CO2)cc1
Temperature: 5 °C
Yield: 91 %

Procedure:
A 2,000 mL, 3-necked flask equipped with a mechanical stirrer and thermometer was charged with 3-benzyloxy-2-hydroxypropyl chloride (353 g, 1.76 mol) and dichloromethane (1,000 mL). This mixture was stirred and cooled in an ice bath to ca. 5° C. Aqueous 50% NaOH (176 g) was added in portions while the temperature was kept under 30° C. After addition was complete, the reaction mixture was stirred 4 hours at 25° C. Water (1,000 mL) was added to dissolve the salts. The organic phase was separated from the aqueous phase, washed with ice water (3×500 mL), dried and reduced in vacuo to yield 263 g (92%) of pure 3-benzyloxy-1,2-epoxypropane.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[F:7][C:8]1[CH:34]=[CH:33][C:11]([O:12][C:13]2[C:27]([CH:28]3[CH2:32][CH2:31][CH2:30][NH:29]3)=[CH:26][C:16]3[NH:17][C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[N:19][C:15]=3[CH:14]=2)=[CH:10][CH:9]=1>[Zn].C1C=CC=CC=1>[F:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[C:27]([CH:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:2]([O:4][CH2:5][CH3:6])=[O:3])=[CH:26][C:16]3[NH:17][C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[N:19][C:15]=3[CH:14]=2)=[CH:33][CH:34]=1
Reactant: Fc1ccc(Oc2cc3nc(-c4ccccn4)[nH]c3cc2C2CCCN2)cc1
Reactant: CCOC(=O)Cl
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.2 mg of zinc powder and 0.006 ml of ethyl chloroformate were added in order to a benzene (1 ml) solution of 20 mg of 5-(4-fluoro-phenoxy)-2-pyridin-2-yl-6-pyrrolidin-2-yl-1H-benzimidazole obtained in Example 168, and the reaction liquid was stirred overnight at room temperature. The reaction solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=10/1) to obtain the entitled compound as a white solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].O=[C:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[C:18]#[N:19]>C(O)C>[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:18]([NH2:19])=[C:13]2[C:12]([CH2:17][CH2:16][CH2:15][CH2:14]2)=[N:10]1
Reactant: Cc1ccccc1NN
Reactant: N#CC1CCCCC1=O
Agent: Cl
Solvent: CCO
Product: Cc1ccccc1-n1nc2c(c1N)CCCC2
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of (2-methylphenyl)hydrazine hydrochloride (464 mg, 2.92 mmol) in ethanol (2 mL) was added 2-oxocyclohexanecarbonitrile (300 mg, 2.44 mmol), and the mixture was heated to 60° C. and stirred for 16 h. The flask was then cooled to rt and the solvent was evaporated to give a solid. The crude residue of 2-(2-methylphenyl)-4,5,6,7-tetrahydro-2H-indazol-3-amine hydrochloride (449 mg, 70%) was used in the next step with no further purification. ES-MS m/z 228.2 (MH+); HPLC RT (min) 1.22.
Reaction SMILES: C([N:4]1[C@@H:9]([C:10]([O:12]CC)=[O:11])[C@H:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:7]2[CH:22]=[C:23](Br)[S:24][C:6]=2[C:5]1=[O:26])C=C.[CH3:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[CH:30][N:29]=1.O1CCOCC1.O.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C@H:8]2[C@H:9]([C:10]([OH:12])=[O:11])[NH:4][C:5](=[O:26])[C:6]3[S:24][C:23]([C:32]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:27])[CH:33]=4)=[CH:22][C:7]2=3)=[CH:20][CH:19]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: C=CCN1C(=O)c2sc(Br)cc2[C@@H](c2ccc(Cl)cc2)[C@@H]1C(=O)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2cc3c(s2)C(=O)N[C@@H](C(=O)O)[C@@H]3c2ccc(Cl)cc2)ccn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
To a solution of ethyl rel-(4R,5R)-6-allyl-2-bromo-4-(4-chlorophenyl)-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-carboxylate (505.0 mg, 1.11 mmol) and 2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (486 mg, 2.22 mmol) in 1,4-dioxane (14.6 mL, 187 mmol) and water (1.9 mL, 110 mmol) were added tetrakis(triphenylphosphine)palladium(0) (64.2 mg, 0.055 mmol) and cesium carbonate (1.08 g, 3.33 mmol). The mixture was stirred at 80° C. for 16 hr. After the reaction was completed, the solvent was evaporated and the obtained residue was purified by column chromatography (SiO2, elution with 0-100% [(60/20/20/20) EA/ACN/MeOH/water)]/EA to give the title compound as a yellow solid (428.7 mg, 73% yield). LCMS: (AA) ES+ , 399/401. 1H NMR (400 MHz, DMSO) δ 8.72 (d, J=6.1 Hz, 1H), 8.45 (d, J=6.6 Hz, 1H), 8.30 (d, J=4.4 Hz, 1H), 8.13 (s, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.43 (t, J=10.0 Hz, 2H), 7.21 (dd, J=24.7, 7.7 Hz, 3H), 4.98-4.59 (m, 1H), 4.32 (d, J=2.9 Hz, 1H), 2.69 (s, 3H).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][C:10]([Cl:22])([Cl:21])[C:11]([CH:13]=[C:14]1[CH2:18][O:17]C(C)(C)O1)=[O:12]>>[OH:17][CH2:18][C:14]1[CH2:13][C:11]([C:10]([Cl:22])([Cl:21])[Cl:9])([OH:12])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: CC1(C)OCC(=CC(=O)C(Cl)(Cl)Cl)O1
Reactant: NNc1ccccc1
Product: OCC1=NN(c2ccccc2)C(O)(C(Cl)(Cl)Cl)C1

Procedure:
The procedure is as described in example 2 but using phenylhydrazine and 1,1,1-trichloro-3-(2,2-dimethyl-1,3-dioxolan-4-ylidene)acetone.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[C:12]([CH3:13])=[N:11][NH:10][C:9]=2[OH:14])[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:22]([CH3:34])[C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[CH3:33])=[O:24]>CN(C=O)C>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[C:12]([CH3:13])=[N:11][NH:10][C:9]=2[O:14][CH:22]([CH3:34])[C:23]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=2[CH3:33])=[O:24])[N:3]=1
Reactant: COc1ccc(C(=O)C(C)Br)c(C)c1
Reactant: Cc1nc(C)n(-c2c(C)n[nH]c2O)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)C(C)Oc2[nH]nc(C)c2-n2nc(C)nc2C)c(C)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 4-(3,5-dimethyl-[1,2,4]triazol-1-yl)-5-methyl-2H-pyrazol-3-ol (1 g, 5.18 mmol) (Intermediate A) in DMF (25 ml) was added Cs2CO3 (1.771 g, 5.43 mmol). The mixture was left to stir at 50° C. for 30 minutes and then treated with of 2-bromo-1-(4-methoxy-2-methyl-phenyl)-propan-1-one (Intermediate B) (1.397 g, 5.43 mmol) in DMF (10 ml). The mixture was stirred at 50° C. for 1 hour and concentrated in vacuo. The residue was dissolved in water (300 ml) and extracted with EtOAc (3×150 ml). The combined organic extracts were washed with NaHCO3, water, dried (MgSO4) and concentrated in vacuo to yield a pale yellow solid. Purification of the solid by chromatography on silica eluting with 20-100% EtOAc in iso-hexane afforded the title compound as a white solid; LC-MS Rt 1.03 mins; MS m/z 370.3 [M+H]+; Method 2minLC—30_v002.
Reaction SMILES: [F:1][C:2]([C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=1)([C:7]([F:10])([F:9])[F:8])[C:3]([F:6])([F:5])[F:4].CN(C=O)C.[Br:27]N1C(=O)CCC1=O>O>[Br:27][C:16]1[CH:17]=[C:11]([C:2]([F:1])([C:3]([F:6])([F:5])[F:4])[C:7]([F:10])([F:9])[F:8])[CH:12]=[C:13]([C:18]([F:19])([F:20])[F:21])[C:14]=1[NH2:15]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
100 g (0.273 mol) of 4-(heptafluoropropan-2-yl)-2-(trifluoromethyl)aniline was charged to 500 ml of DMF, and 52.1 g (0.287 mol) of N-bromosuccinimide was charged in separate portions thereto over 30 minutes. After stirring at 60° C. for 2 hours, and then cooling to room temperature, the mixture was discharged to 2000 ml of water. The mixture was extracted with ethyl acetate, then washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent solvent; hexane:ethyl acetate=20:1) to prepare 89.0 g (yield 80%) of a target compound.
Reaction SMILES: [O:1]1CCCC1.[CH3:6][O:7][C:8]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([CH2:16][CH2:17][C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])[CH2:22][CH2:21]2)=O)=[C:10]([N:34]2[CH:38]=[CH:37][CH:36]=[CH:35]2)[CH:9]=1.O.[ClH:40]>C(O)C>[OH2:1].[ClH:40].[ClH:40].[CH3:6][O:7][C:8]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([CH2:16][CH2:17][CH2:18][N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])[CH2:22][CH2:21]2)=[C:10]([N:34]2[CH:38]=[CH:37][CH:36]=[CH:35]2)[CH:9]=1.[CH3:6][O:7][C:8]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([CH2:16][CH2:17][CH2:18][N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])[CH2:22][CH2:21]2)=[C:10]([N:34]2[CH:38]=[CH:37][CH:36]=[CH:35]2)[CH:9]=1.[ClH:40].[ClH:40]
Reactant: C1CCOC1
Reactant: COc1cc(CCC(=O)N2CCN(c3ccccc3OC)CC2)c(-n2cccc2)cc1OC
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(CCCN2CCN(c3ccccc3OC)CC2)c(-n2cccc2)cc1OC
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To 100 ml of tetrahydrofuran were added 18 ml of 1.0M borane-tetrahydrofuran complex and 1.14 g of 1-(3-(4,5-dimethoxy-2-(1-pyrrolyl)phenyl)-1-oxopropyl)-4-(2-methoxyphenyl)piperazine at room temperature, and the mixture was heated under reflux for 27 hours. Since it was found that the reaction had not completed, 10 ml of the borane-tetrahydrofuran complex was further added, and the refluxing was continued for additional 9 hours. After cooling to room temperature, 10 ml of water was added to the reaction mixture, and the solvent was removed under reduced pressure. To the residue was added 35 ml of 5% hydrochloric acid, followed by heating at 50° to 60° C. for 2 hours. The reaction mixture was dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform) to yield 780 mg of a pale yellow oily substance, which was dissolved in 15 ml of ethanol, 1.0 ml of concentrated hydrochloric acid was added thereto, and the solvent was removed under reduced pressure. Recrystallization of the residue from ethanol-ethyl ether yielded 500 mg of the title compound as a colorless prism crystal.
Reaction SMILES: [N:1]#[C:2]Br.[N+:4]([C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([NH:11][NH2:12])=[O:10])([O-:6])=[O:5]>C(#N)C>[N+:4]([C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]1[O:10][C:2]([NH2:1])=[N:12][N:11]=1)([O-:6])=[O:5]
Reactant: NNC(=O)c1ccccc1[N+](=O)[O-]
Reactant: N#CBr
Solvent: CC#N
Product: Nc1nnc(-c2ccccc2[N+](=O)[O-])o1

Procedure:
4 ml of a 5M cyanogen bromide solution in acetonitrile were added dropwise to the solution of 3.6 g of 2-nitrobenzoic hydrazide in 20 ml of acetonitrile. This resulted first in a clear solution, then a solid precipitated out which was filtered off with suction after continuing to stir for a short time, washed again with acetonitrile and dried under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C@H:4](O)[CH3:5].C1(P([N:25]=[N+:26]=[N-:27])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1COCC1>[N:25]([C@H:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Br:1])[CH3:5])=[N+:26]=[N-:27]
Reactant: C[C@@H](O)c1ccccc1Br
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H](N=[N+]=[N-])c1ccccc1Br
Temperature: 50 °C
Yield: 84.3 %

Procedure:
To a solution of (R)-(+)-2-bromo-α-methylbenzyl alcohol (402 mg, 2.0 mmol) and diphenylphosphoryl azide (0.692 ml, 3.2 mmol) in THF (10 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.466 ml, 3.2 mmol). The mixture was heated at 50° C. for overnight, partitioned with H2O and AcOEt, and then adjusted to pH 7 by adding 1M HCl. The organic layer was dried with MgSO4, filtered and evaporated. The residue was purified by silica gel column chromatography [eluting with n-hexane/AcOEt=95/5] to give the title compound (381 mg, 84%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[N:20]=[C:19]([CH:21]=[O:22])[C:18]([F:23])=[CH:17][CH:16]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:18]1[CH:17]=[CH:16][C:15]([C:6]2[CH:7]=[N:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[N:20][C:19]=1[CH:21]=[O:22]
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Reactant: O=Cc1nc(Br)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: O=Cc1nc(-c2ccc(C(F)(F)F)nc2)ccc1F
Temperature: 80 °C
Yield: 69.5 %

Procedure:
Nitrogen was bubbled through a mixture of 6-(trifluoromethyl)pyridin-3-ylboronic acid (3.74 g, 19.61 mmol), 6-bromo-3-fluoropicolinaldehyde (4.0 g, 19.61 mmol), Pd(Ph3P)4 (0.340 g, 0.294 mmol) was added and nitrogen was bubbled for 10 minutes, and the reaction mixture was heated overnight at 80° C. EtOAc (300 mL) was added and the mixture was washed with water (300 mL) and brine (300 mL), dried over Na2SO4, filtered, and concentrated. The residue was chromatographed on a Grace Reveleris 80 g column, eluted with 0-40% EtOAc in Heptane (30 mL/min) to provide the title compound (3.681 g, 13.62 mmol, 69.5% yield). MS (ESI+) m/z 303.0 (M+H+MeOH); 1H NMR (300 MHz, DMSO-d6) δ 10.15 (s, 1H), 9.50 (d, J=2.0, 1H), 8.82-8.75 (m, 1H), 8.58 (dd, J=8.9, 3.7, 1H), 8.23-8.13 (m, 1H), 8.10 (d, J=8.3, 1H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:14])[C:6]([Cl:13])=[CH:7][C:8]=2[Cl:12])[N:3]=1.[CH3:15][NH2:16]>C(O)C>[Cl:12][C:8]1[CH:7]=[C:6]([Cl:13])[C:5]([OH:14])=[C:4]2[C:9]=1[CH:10]=[CH:11][C:2]([NH:16][CH3:15])=[N:3]2
Reactant: Oc1c(Cl)cc(Cl)c2ccc(Cl)nc12
Reactant: CN
Solvent: CCO
Product: CNc1ccc2c(Cl)cc(Cl)c(O)c2n1

Procedure:
2,5,7-Trichloro-8-hydroxyquinoline 10 (200 mg, 0.805 mmol) and a solution of methylamine in ethanol (12 mL of a 33% solution) were heated in a sealed vessel at 90° C. for 26 h, and cooled. The precipitate was then isolated via filtration and washed with diethyl ether. This provided pure 5,7-dichloro-2-methylamino-8-hydroxyquinoline (PBT 1047) as a pale yellow solid (186 mg, 95%). 1H NMR (DMSO-d6, 400 MHz): δ 8.80 (br, 1 H), 7.98 (d, J=9.1, 1 H), 7.48 (br, 1 H), 7.25 (s, 1 H), 6.90 (d, J=9.1, 1 H), 2.98 (d, J=4.8, 3 H); mass spectrum: m/z 243, 245 (M++1, 100 and 66%, respectively).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[NH:10]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[N:11]1>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:15]([C:12]3[CH:13]=[CH:14][NH:10][N:11]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: O=Cc1cc[nH]n1
Product: Brc1cnc2[nH]c(-c3cc[nH]n3)nc2c1

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine and pyrazole-3-carbaldehyde.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][C:7]([C:13]([F:16])([F:15])[F:14])=[C:6]([O:17][CH3:18])[CH:5]=1)[CH3:2].[C:19](OCC)(=O)[CH3:20]>[Pt]=O.C(O)C>[CH2:1]([N:3]1[C:4]2[CH:5]=[C:6]([O:17][CH3:18])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:8][C:9]=2[N:10]=[C:19]1[CH3:20])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCNc1cc(OC)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCO
Product: CCn1c(C)nc2cc(C(F)(F)F)c(OC)cc21

Procedure:
A solution of 24.4 g. (0.09 mole) of N-ethyl-3-methoxy-6-nitro-4-trifluoromethylaniline in 200 ml. of ethyl acetate, plus 100 ml. of ethanol, was hydrogenated in the presence of 0.2 g. of platinum oxide at room temperature. The theoretical amount of hydrogen was absorbed in 19 hours of shaking at 60 psi. The catalyst was removed by filtration and the solvent evaporated at reduced pressure. The solid residue was dissolved in 200 ml. of absolute ethanol and 12.58 g. (0.10 mole) of ethyl methylcarboximidate hydrochloride added. The mixture was stirred overnight at room temperature and the solvent removed at reduced pressure. Trituration of the brown residue with 200 ml. of chloroform, filtration, and evaporation of solvent from the filtrate left the crude residual product. Crystallization from hexane-CCl4 (3:1) gave 18.1 g. (76%) of brown, shiny needles. Recrystallization from hexane gave the pure product, m.p. 127° - 129.5°C. whose structure was confirmed by an NMR spectrum.
Reaction SMILES: [OH-].[K+].[C:3]([C:7]1[CH:8]=[C:9]([CH3:12])[CH2:10][CH:11]=1)([CH3:6])([CH3:5])[CH3:4].[Cl:13][C:14]1[CH:28]=[CH:27][C:17]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=O)=[CH:16][CH:15]=1.Cl>C(OCC)C.C(COC)OC>[C:3]([C:7]1[CH:8]=[C:9]([CH3:12])[C:10](=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[C:17]2[CH:27]=[CH:28][C:14]([Cl:13])=[CH:15][CH:16]=2)[CH:11]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CC1=CC(C(C)(C)C)=CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CCOCC
Product: CC1=CC(C(C)(C)C)=CC1=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 0.65 g of powdery potassium hydroxide (13.0 mmol) and 70 ml of dehydrated dimethoxy ethane were added in a nitrogen atmosphere. To the suspension, 1.24 g of 3-tert-butyl-1-methyl-cyclopentadiene (9.11 mmol) was added dropwise at room temperature and then 2.40 g of 4,4′-dichloro-benzophenone (9.58 mmol) was added and stirred under reflux for 3 days. To a 30 ml of a hydrochloric acid aqueous solution (1N) set in an ice bath, the reaction mixture was gradually added dropwise and stirred for some time. Diethyl ether was added to the mixed solution to separate an organic phase. The organic phase was washed with a saturated sodium bicarbonate aqueous solution, water and saturated brine. The organic phase was dried with anhydrous magnesium sulfate, thereafter the drying agent was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give a reddish-orange solid. The solid was purified with a column chromatography using 110 g of silica gel (developing solvent: n-hexane) and the developing solvent was distilled off under reduced pressure, and thereby the aimed compound was obtained in an amount of 2.79 g (7.56 mmol) as a red solid (yield: 83%).
Reaction SMILES: [C:1]([N:5]([CH3:34])[C:6]([C:8]1[N:12]2[CH2:13][CH2:14][C:15]3[C:20]([C:11]2=[C:10]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[C:9]=1[CH2:32][OH:33])=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[C:17]([O:25][CH3:26])[CH:16]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:38].O>C1COCC1>[C:1]([N:5]([CH3:34])[C:6]([C:8]1[N:12]2[CH2:13][CH2:14][C:15]3[C:20]([C:11]2=[C:10]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[C:9]=1[CH2:32][O:33][CH3:38])=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[C:17]([O:25][CH3:26])[CH:16]=3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(cc1OC(C)C)-c1c(-c3cccs3)c(CO)c(C(=O)N(C)C(C)(C)C)n1CC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCc1c(-c2cccs2)c2n(c1C(=O)N(C)C(C)(C)C)CCc1cc(OC)c(OC(C)C)cc1-2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the product of example 40 (20 mg), sodium hydride (3.3 mg, 60% dispersion in oil) and iodomethane (13 μl) in THF (2.5 ml) was stirred for 18 h at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layers were combined, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel in heptane/ethyl acetate [1/0→1/1 (v/v)] as eluent.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.[O:17]=[N+:18]=[O:19]>C(#N)C.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[C:9]([N+:18]([O-:19])=[O:17])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(C)(C)C)cc1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CC#N
Product: Cc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
To a solution of 4-tert-butyl toluene (5 g, 33.7 mmol) in acetonitrile (150 mL) at 0° C. was added nitronium tetrafluoroborate (5.83 g, 40.5 mmol). After 30 min at room temperature, the reaction was diluted with water (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine and dried (MgSO4). Removal of the volatiles in vacuo left a residue which was purified by flash chromatography using 10% methylene chloride in petroleum ether as eluent. Concentration in vacuo of the product rich fractions provided 3.8 g of 4-tert-butyl-2-nitrotoluene.