Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH:4]([N:15]1[C:21](=[O:22])[CH2:20][CH2:19][N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH2:17][CH2:16]1)[CH2:5][CH2:6]O[Si](C(C)(C)C)(C)C.B(Br)(Br)[Br:35]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:33])[CH:4]([N:15]1[C:21](=[O:22])[CH2:20][CH2:19][N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH2:17][CH2:16]1)[CH2:5][CH2:6][Br:35]
Reactant: BrB(Br)Br
Reactant: COC(=O)C(CCO[Si](C)(C)C(C)(C)C)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Solvent: ClCCl
Product: COC(=O)C(CCBr)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 9.3 %

Procedure:
A solution of 1.03 g (2.12 mmol) of (rac)-4-(tert-butyl-dimethyl-silanyloxy)-2-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-butyric acid methyl ester in 6 ml of CH2Cl2 was treated at 0° C. with 2.33 ml (2.33 mmol, 1M in CH2Cl2) of boron tribromide and kept 2.5 h at this temperature. The solution was warmed to RT cooled (0° C.) and treated again with 2.33 ml (2.33 mmol, 1M in CH2Cl2) of boron tribromide. After 1 h at this temperature, the reaction was extracted with cold sat. aq. NaHCO3 and EtOAc solution (3×). The organic phases were washed with sat. aq. NaHCO3 solution, dried over Na2SO4 and evaporated to give 1.14 g of the crude compound. Purification by flash silica gel column ((n-heptane:EtOAc 95:5, 1:1 to EtOAc) gave 0.086 g (11%) of the title compound as light yellow oil, MS: 437.1 (MH+, 1Br) and
Reaction SMILES: O[CH2:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[N+:15]([O-])=O>[Pd].C(O)C>[CH3:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[NH2:15]
Reactant: COc1cc([N+](=O)[O-])c(CO)c(OC)c1OC
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)c(C)c(OC)c1OC

Procedure:
A mixture of 2-hydroxymethyl-1-nitro-3,4,5-trimethoxybenzene (200 mg, 0.82 mmol) and 10% palladium on carbon (100 mg) in ethanol (4 ml) was hydrogenated at 20 psi overnight. The mixture was filtered through a Celite pad and washed with ethanol. The combined filtrate and washings were evaporated in vacuo to dryness. The residue was chromatographed over a silica gel column (2×20 cm) using toluene/ethyl acetate (2:1, v/v) as the eluent to give 2-methyl-3,4,5-trimethoxyaniline as brown crystals (hexane), 130 mg (80%) with mp 49-51 ° C. 1H-NMR (CDCl3): δ2.01 (3H, s, Me), 3.49 (2H, b, exchangeable, NH2), 3.77, 3.78, and 3.82 (each 3H, s, 3×OMe), 6.07 (1H, s, H-6). Analyses: Calculated for C10H15NO3 : C, 60.90; H, 7.67; N, 7.10. Found: C, 61.05; H, 7.46; N, 7.00.
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:20])([F:19])[C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.[OH-].[Na+]>C(O)(=O)C.C(Cl)Cl>[Br:1][C:16]1[CH:17]=[CH:18][N:14]([S:11]([C:8]2[CH:7]=[CH:6][C:5]([C:4]([F:3])([F:19])[F:20])=[CH:10][CH:9]=2)(=[O:13])=[O:12])[CH:15]=1
Reactant: BrBr
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)n1cccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)n1ccc(Br)c1
Temperature: 100 °C
Yield: 75.6 %

Procedure:
Bromine (4.12 mL, 80.1 mmol) was added to a solution of 1-(4-(trifluoromethyl)phenylsulfonyl)-1H-pyrrole (111) (21 g, 76.2 mmol) in acetic acid (254 mL) and the resulting solution was heated to 100° C. for 1 h. The mixture was diluted with CH2Cl2 and poured slowly into ice cold aqueous sodium hydroxide (3 N). The solution was adjusted to pH 7 with aqueous sodium hydroxide (3 N), extracted with CH2Cl2. The organic phase was separated, dried (Na2SO4), filtered and concentrated under vacuum and purified on a silica gel column (eluant hexane/EtOAc, 4/1, v/v) to give compound 112 (20.4 g, 57.6 mmol, 75%). MS (ESI) 354.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.[C:10]1([Mg]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:7])=[CH:8][CH:9]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=Cc1ccc(Cl)nc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 95.8 %

Procedure:
To a stirred solution of 6-chloronicotinaldehyde (1.0 g, 7.1 mmol) in anhydrous tetrahydrofuran (10 mL) was added phenylmagnesium bromide solution (3M in diethyl ether, 2.6 mL, 7.8 mmol) dropwise at −78° C. under argon. After the reaction mixture was stirred at −78° C. for 10 min and 0° C. for 20 min, saturated aqueous ammonium chloride solution (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3×10 mL). The combined ethyl acetate extracts were dried (Na2SO4) and concentrated to give (6-chloropyridin-3-yl)(phenyl)methanol (1.5 g, 6.8 mmol, 96% yield) as a yellow liquid. MS found: (M+H)+=220.09.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[S:8][CH:9]=[C:10]([CH3:12])[CH:11]=1)=O.O.[NH2:15]N>C(O)C>[CH3:12][C:10]1[CH:11]=[C:7]([C:5]2[CH:4]=[CH:3][NH:2][N:15]=2)[S:8][CH:9]=1
Reactant: Cc1csc(C(=O)C=CN(C)C)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1csc(-c2cc[nH]n2)c1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
A mixture of 3-(dimethylamino)-1-(4-methyl-2-thienyl)prop-2-en-1-one (72 mmol) and hydrazine hydrate (144 mmol) in 80 mL ethanol was refluxed for 18 h and then allowed to cool to room temperature. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was successively washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium bicarbonate solution and brine, dried over MgSO4, filtered and concentrated to afford 11.58 g (98% yield) 3-(4-methyl-2-thienyl)-1H-pyrazole which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([F:18])=[C:4](F)[C:3]=1[F:20].[CH3:21][O:22][C:23]1[C:24]([NH2:29])=[CH:25][CH:26]=[CH:27][CH:28]=1>>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:4]1[C:3]([F:20])=[C:2]([F:1])[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]=1[F:18]
Reactant: COc1ccccc1N
Reactant: O=C1c2ccccc2C(=O)c2c(F)c(F)c(F)c(F)c21
Product: COc1ccccc1Nc1c(F)c(F)c2c(c1F)C(=O)c1ccccc1C2=O
Reaction time: 4 h
Yield: 69.8 %

Procedure:
2 g of 1,2,3,4-Tetrafluoroanthraquinone and 25 g of o-anisidine were charged in a 50 cc, four necked flask and then the reaction was carried out at 50° C. for about 4 hours. After completion of reaction, o-anisidine was distilled out from the reaction solution and then a column purification using a column with a silica gel was effected to give rise to 1.91 g of 2-(o-methoxyanilino)-1,3,4-trifluoroanthraquinone (Dye 6') (yield 69.8 mol %) and 0.85 g of 2,3,-bis(o-methoxyanilino-1,4-difluoroanthraquinone (Dye 19') (yield 24.5 mol %). The physical properties of Dye 6' and analytical values defining the compound are tabulated in Table 23 and the physical properties of Dye 19' and analytical values defining the compound are tabulated in Table 24.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=2)[CH2:2][CH3:3].[Sn](Cl)(Cl)(Cl)Cl.[CH3:22][O:23][CH2:24][C:25](Cl)=[O:26]>ClCCl>[CH3:22][O:23][CH2:24][C:25]([C:12]1[C:11]2[C:6](=[CH:7][C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:10]=2)[NH:5][C:4]=1[CH2:1][CH2:2][CH3:3])=[O:26]
Reactant: COCC(=O)Cl
Reactant: CCCc1cc2ccc(C(=O)OC)cc2[nH]1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCc1[nH]c2cc(C(=O)OC)ccc2c1C(=O)COC
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 2-propylindole-6-carboxylate (300 mg) in dichloromethane (10 ml) was added a 1M solution of tin(IV) chloride in dichloromethane (2.76 ml) at 20° C. The mixture was stirred at 20° C. for 30 minutes, then methoxyacetyl chloride (0.25 ml) was added. After stirred at 20° C. or 30 minutes, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:10-1:1) to give methyl 3-methoxyacetyl-2-propylindole-6-carboxylate (135 mg) as pale yellow crystals.
Reaction SMILES: C([O:8][C@@:9]1([C:36]([F:39])([F:38])[F:37])[CH2:33][C@H:13]2[CH2:14][CH2:15][CH2:16][C:17]3[C:18](=[CH:19][C:20]4[CH:21]=[N:22][N:23]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)[C:24]=4[CH:25]=3)[C@:12]2([C:34]#N)[CH2:11][CH2:10]1)C1C=CC=CC=1.CC(C[AlH]CC(C)C)C.[BH4-].[Na+].C1C[O:54]CC1>>[F:32][C:29]1[CH:28]=[CH:27][C:26]([N:23]2[C:24]3[CH:25]=[C:17]4[CH2:16][CH2:15][CH2:14][C@@H:13]5[CH2:33][C@:9]([C:36]([F:37])([F:38])[F:39])([OH:8])[CH2:10][CH2:11][C@@:12]5([CH2:34][OH:54])[C:18]4=[CH:19][C:20]=3[CH:21]=[N:22]2)=[CH:31][CH:30]=1
Reactant: C1CCOC1
Reactant: N#C[C@@]12CC[C@](OCc3ccccc3)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Agent: CC(C)C[AlH]CC(C)C
Agent: [BH4-]
Agent: [Na+]
Product: OC[C@@]12CC[C@](O)(C(F)(F)F)C[C@H]1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of (3R,4aR,12bS)-3-(benzyloxy)-9-(4-fluorophenyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazole-12b-carbonitrile (33, R1=4-Fluorophenyl, R3=Trifluoromethyl) (79 mg, 0.158 mmol) was dissolved in THF (2 mL) and cooled to about 0° C. under nitrogen. The mixture was treated dropwise with DIBAL-H (1M in cyclohexane, 0.90 mL, 0.90 mmol). The reaction was stirred at about 0° C. for about 2 h, then quenched by addition of 6% acetic acid in sat. aq. sodium acetate solution (3 mL). The reaction was concentrated to about 3 mL volume and extracted with DCM (2×20 mL). The organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Intermediate LC/MS, method 3, Rt=3.14 min, MS m/z 537 (M+H)+. The residue was dissolved in EtOH (3 mL) and treated with NaBH4 (18 mg, 0.47 mmol) at rt for about 1 h. The reaction was quenched with aq. NH4Cl solution (2 mL) and stirred about 15 min at rt. The mixture was further diluted with water (2 mL) and extracted with DCM (2×5 mL). The combined DCM layers were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure to yield (3R,4aR,12bS)-9-(4-fluorophenyl)-12b-(hydroxymethyl)-3-(trifluoromethyl)-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol), (37, R1=4-Fluorophenyl, R3=Trifluoromethyl) (85 mg, 100%) as a glass: LC/MS, method 3, Rt=3.02 min, MS m/z 539 (M+H)+. The residue was used in step #2 without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[CH2:17].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>ClCCl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:20]([O:19][C:15](=[O:18])[CH:16]=[CH:17][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:2]([F:1])[CH:7]=1)[CH3:21]
Reactant: C=CC(=O)OCC
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccc(-c2ccccc2)c(F)c1
Temperature: 25 °C

Procedure:
A solution of 2-fluoro-4-bromobiphenyl 12-1 (7.5 gm, 31.8 mmol), ethyl acrylate (4.3 mL), Pd(OAc)2 (0.714 gm, 3.2 mmol), tri-o-tolylphosphine (1.94 gm, 1.5 mmol), and triethylamine (12 mL) was heated to 100° C. in a sealed tube for 12 h. The reaction was cooled to room temperature and diluted with dichloromethane (40 mL). The organic solution was washed with 10% aq. citric acid (20 mL), satd. aq. NaHCO3, and brine (20 mL). The organic solution was dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography (95:5 to 90:10 hexanes/EtOAc) to give the acrylate ester 12-2 as a white solid.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[CH3:9][N:10]([CH:12](OC)OC)[CH3:11]>CC#N>[CH3:9][N:10]([CH:12]=[C:2]1[C:3](=[O:7])[CH2:4][CH2:5][CH2:6][C:1]1=[O:8])[CH3:11]
Reactant: O=C1CCCC(=O)C1
Reactant: COC(OC)N(C)C
Solvent: CC#N
Product: CN(C)C=C1C(=O)CCCC1=O

Procedure:
A MeCN solution of cyclohexane-1,3-dione 2.24 g (0.02 mol) i and DMF-DMA 11.9 g (0.1 mol) was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the product was used for the next step with no purification.
Reaction SMILES: [C:1]1([C@@H:7]([N:9]2[C:13]3[CH2:14][O:15][C:16](=[O:17])[C:12]=3[NH:11][C:10]2=[O:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.[Pd]>[C:1]1([C@@H:7]([N:9]2[C@H:13]3[CH2:14][O:15][C:16](=[O:17])[C@H:12]3[NH:11][C:10]2=[O:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](c1ccccc1)n1c2c([nH]c1=O)C(=O)OC2
Agent: [Pd]
Solvent: CC(=O)O
Product: C[C@@H](c1ccccc1)N1C(=O)N[C@@H]2C(=O)OC[C@@H]21
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.6 %

Procedure:
A solution of 3.7 g (15.16 mmol) of 1-[(S)-(1-phenylethyl)]-1H-furo[3,4-d]-imidazol-2,4 (3H,6H)-dione in 100 ml of acetic acid is placed in a 250-ml autoclave and 0.4 g of palladium on activated carbon (5 percent) was added. Then the autoclave was flushed twice successively with hydrogen and filled to 50 bars. This mixture was stirred for 15 hours at room temperature. The catalyst was then filtered off. The solvent was evaporated at 20 mbars and the residue was chromatographed over silica gel with ethyl acetate. 2.0 g (54 percent yield) of the title product was eluted. Recrystallization in methanol yields white needles. Concerning the product:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5](=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)[OH:6].[CH:13]([O-])=[O:14].[Na+]>C(O)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][CH:13]=[O:14])[C:5]=1[OH:6]
Reactant: O=C[O-]
Reactant: COC(=O)c1cccc(N)c1O
Agent: [Na+]
Solvent: O=CO
Product: COC(=O)c1cccc(NC=O)c1O

Procedure:
To a solution of methyl-3-aminosalicylate (3.34 grams, 20 mmol) in concentrated formic acid (20 mL) was added solid sodium formate (1.36 grams, 20 mmol, 1 eq.) and the resulting suspension stirred under reflux for 2 hours. The precipitate was filtered at room temperature and washed with water until neutral. After drying on air, 3.595 grams (92%) light brown crystals were collected. M+196, M−194.
Reaction SMILES: [F:1][CH:2]([F:14])[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:5]=2[N:4]=1.[Cl:15][C:16]1[N:21]=[C:20](Cl)[N:19]=[C:18]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:15][C:16]1[N:17]=[C:18]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[N:19]=[C:20]([N:7]2[C:6]3[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:5]=3[N:4]=[C:3]2[CH:2]([F:1])[F:14])[N:21]=1
Reactant: COc1cccc2[nH]c(C(F)F)nc12
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reaction time: 3 h
Yield: 85.9 %

Procedure:
A mixture of 3.96 g (20 mmol) of 2-difluoromethyl-4-methoxy-1H-benzimidazole, 4.70 g (20 mmol) of 2,4-dichloro-6-(4-morpholinyl)-1,3,5-triazine, and 22 g (80 mmol) of powdered K2CO3 in 150 mL of DMF was stirred rapidly for 3 hrs, and then diluted with water. The resulting precipitate was collected, washed with water and then with cold ethanol, and dried to give 6.82 g (86%) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole: mp (CHCl3/EtOH) 263-266° C.; 1H NMR (CDCl3) δ 7.99 (d, J=8.4 Hz, 1H), 7.48 (t, JHF=53.4 Hz, 1H), 7.40 (t, J=8.3 Hz, 1H), 6.86 (d, J=8.1 Hz, 1H), 4.05 (s, 3H), 3.96 (m, 4H), 3.82 (m, 4H); Anal. Calcd. for C16H15ClF2N6O2: C, 48.4; H, 3.8; N, 21.2. Found: C, 48.3; H, 3.8; N, 21.1%.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:14]2)=[CH:9][CH:8]=1>FC(F)(F)C(O)=O>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:24])[C:20]([F:21])([F:22])[F:23])[CH2:14]2)=[CH:9][C:8]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C2CCCN(C(=O)C(F)(F)F)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2CCCN(C(=O)C(F)(F)F)C2)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
2.24 ml of fuming nitric acid were added dropwise with stirring to 14.3 g of the product of Step C in 50 ml of trifluoroacetic acid at 0° C. The temperature was allowed to return to ambient and the mixture was stirred for 1 hour. After pouring the mixture on ice, extracting with methylene chloride, washing with water, drying, evaporating to dryness under reduced pressure, and purifying by chromatography over silica (eluent benzene - ethyl acetate 9-1), 12.3 g of 3-(4-methoxy-3-nitrophenyl)-1-(trifluoroacetyl)-piperidine were obtained which after crystallization from isopropyl ether melted at 96° C.
Reaction SMILES: C=O.[O:3]=[C:4]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]2[CH2:15][CH2:16][N:17]([C:19](OC(C)(C)C)=O)[CH2:18][CH:6]2[CH2:5]1>C(O)=O>[CH3:19][N:17]1[CH2:16][CH2:15][N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[NH:10][C:4](=[O:3])[CH2:5][CH:6]2[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN2c3ccccc3NC(=O)CC2C1
Agent: C=O
Solvent: O=CO
Product: CN1CCN2c3ccccc3NC(=O)CC2C1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
Formalin solution (0.3 mL, 3.92 mmol) was added to a solution of the product of Example 22D (150 mg, 0.473 mmol) in 88% formic acid (4 mL), and the solution was stirred at 100° C. under nitrogen for 30 minutes. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by chromatography (SiO2, eluted with CH2Cl2-methanol-15 M NH4OH, 90:10:1) to provide the title compound: 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 2.05 (d, J=12.8 Hz, 1H), 2.66 (dd, J=13.6, 7.2 Hz, 1H), 2.90 (s, 3H), 3.08-3.19 (m, 2H), 3.32-3.39 (m, 2H), 3.53 (t, J=11.0 Hz, 2H), 3.57-3.67 (m, 1H), 7.00-7.04 (m, 1H), 7.08-7.13 (m, 1H), 7.13-7.18 (m, 1H), 7.18-7.24 (m, 1H); MS (DCI) m/z 232 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[N:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1>CS(C)=O>[S:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:15]1[C:12]1[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=1
Reactant: O=Cc1ccncc1
Reactant: Nc1ccccc1S
Solvent: CS(C)=O
Product: c1ccc2sc(-c3ccncc3)nc2c1
Yield: 84.8 %

Procedure:
2-Aminothiophenol (6.3 g, 0.05 mol) and 4-pyridinecarboxaldehyde (5.4 g, 0.05 mol) were dissolved in dimethylsulfoxide (35 ml) and heated until vapours distilled off at 180°-186° C. The distillation residue on cooling was partitioned between ethyl acetate and saturated ammonium chloride solution. The combined organic layers were washed with water (100 ml), dried (MgSO4) and concentrated. The solid was triturated with ether to afford the title compound as a pale brown solid (9 g, 85%). δH (CDCl3), 7.42 (1H, m, ArH), 7.51 (1H, m, ArH), 7.93 (3H, m, ArH), 8.13 (1H, d, J 8.7Hz, ArH), 8.78 (2H, m, ArH). m/z (ES+) 213 (M+1)+.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[N:15]=1.[NH2:40][C:41]1[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[N:45][CH:46]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:21]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C:16]2[N:17]=[C:18]([CH3:20])[N:19]=[C:14]([C:3]3[CH:4]=[CH:5][C:6]([C:8]4[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=4)=[N:7][C:2]=3[NH:40][C:41]3[CH:46]=[N:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[N:15]=2)=[CH:24][CH:25]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccc(-c4cccnc4)nc3F)n2)cc1
Reactant: COc1ccc(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3ccc(-c4cccnc4)nc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-(6-fluoro-2,3′-bipyridin-5-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (230 mg, 0.440 mmol) and 5-amino-2-methoxypyridine (0.082 mL, 0.660 mmol) (Aldrich) in THF (6.0 mL) was cooled to 0° C. in an ice bath and treated with 1 M LiHMDS (1.320 mL, 1.320 mmol) (Aldrich) resulting in a deep purple solution which was stirred at 0° C. for 30 min. The reaction was quenched by the addition of a saturated solution of NH4Cl and extracted with EtOAc (20 mL), washed with brine and dried over MgSO4, filtered and concentrated. The crude material was used in the next step without further purification. m/z (ESI, +ve ion) 627.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.89 (1H, s); 9.25 (1H, d, J=1.6 Hz); 8.91 (1H, d, J=8.2 Hz); 8.64 (1H, dd, J=4.8, 1.7 Hz); 8.37 (1H, d, J=2.5 Hz); 8.31 (1H, dt, J=8.0, 2.0 Hz); 8.01 (1H, dd, J=8.9, 2.6 Hz); 7.66 (1H, d, J=2.7 Hz); 7.39 (1H, dd, J=7.8, 4.7 Hz); 7.18-7.25 (4H, m); 7.03 (1H, dd, J=8.6, 2.9 Hz); 6.82-6.91 (4H, m); 4.85 (4H, s); 3.86 (3H, s); 3.81 (3H, s); 3.79 (3H, s); 2.60 (3H, s).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:12])[CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([CH3:30])[CH:24]=1>CN(C=O)C>[CH2:1]([NH:8][C:9](=[O:12])[CH2:10][NH:27][C:26]1[CH:28]=[CH:29][C:23]([F:22])=[CH:24][C:25]=1[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)NCc1ccccc1
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)ccc1NCC(=O)NCc1ccccc1
Temperature: 100 °C
Reaction time: 40 h

Procedure:
A mixture of N-benzyl-2-chloroacetamide (17.8 g), DIPEA (19.5 mL) and 4-fluoro-2-methyl-aniline (10.6 mL) in anhydrous DMF (174 mL) was stirred at 100° C. for 40 hours under a Nitrogen atmosphere. After cooling to r.t., the dark solution was partitioned between AcOEt (200 mL) and water (200 mL). The separated aqueous phase was extracted with further AcOEt (3×200 mL). The combined organic extracts were washed with water (200 mL), dried and concentrated in vacuo. The residue was purified by flash chromatography (CH/AcOEt 2:8) to give a dark solid, which was triturated with CH to give the title compound as a beige solid (16.2 g).
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:9][C:10]1([CH3:27])[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]2[CH:15]=[C:14](/[C:22](/[CH3:26])=[CH:23]\[CH2:24][OH:25])[CH:13]=[CH:12][C:11]1=2.N1C=CN=C1>CN(C=O)C>[C:4]([Si:1]([CH3:3])([CH3:2])[O:25][CH2:24]/[CH:23]=[C:22](\[C:14]1[CH:13]=[CH:12][C:11]2[C:10]([CH3:27])([CH3:9])[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=2[CH:15]=1)/[CH3:26])([CH3:7])([CH3:6])[CH3:5]
Reactant: C/C(=C/CO)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C/C(=C/CO[Si](C)(C)C(C)(C)C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.4 %

Procedure:
tert-Butyldimethylsilyl chloride (2.7 g, 17.5 mmol) was added to the solution of Intermediate 2 (3 g, 11.6 mmol) and imidazole (1.6 g, 23.2 mmol) in 10 mL of DMF. The mixture was then stirred for 16 h at room temperature. After quenching with water, the mixture was extracted with ether (3×10 mL), washed with brine (1×10 mL), dried (MgSO4) and concentrated to give a crude brown oil. The crude product was purified by flash chromatography using 10% EtOAc in hexane to give the title compound (3 g, 70% yield) as a colorless oil: