Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][N:5]([CH3:7])[CH:6]=1.FC1C=NN(C)C=1C(O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:54]1[C:62]2[C:57](=[C:58]([C:63]3[CH:64]=[C:65]([NH2:72])[C:66]4[CH:67]=[N:68][NH:69][C:70]=4[CH:71]=3)[CH:59]=[CH:60][CH:61]=2)[CH:56]=[CH:55]1>CN(C=O)C.CO>[F:1][C:2]1[C:3]([C:8]([NH:72][C:65]2[CH:64]=[C:63]([C:58]3[CH:59]=[CH:60][CH:61]=[C:62]4[C:57]=3[CH:56]=[CH:55][NH:54]4)[CH:71]=[C:70]3[C:66]=2[CH:67]=[N:68][NH:69]3)=[O:10])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: Cn1cc(F)c(C(=O)O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cn1ncc(F)c1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(F)c(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture 4-fluoro-1-methyl-1H-pyrazole-3-carboxylic acid and 4-fluoro-1-methyl-1H-pyrazole-5-carboxylic acid (45:55) (580 mg, 20% W/W), HATU (306 mg), and DIPEA (0.422 ml) in DMF (3 ml) was stirred at RT for 10 min. 6-(1H-Indol-4-yl)-1H-indazol-4-amine (100 mg) in DMF (3 ml) was then added and the mixture was stirred at RT overnight. The reaction mixture was added to a 20 g aminopropyl SPE cartridge which had been preconditioned with methanol. The reaction mixture was allowed to remain on the cartridge for 3 h before being eluted with methanol (4 column volumes) and then 10%-triethylamine in methanol (6 column volumes). The appropriate fractions were evaporated to give a brown oil which was partitioned between ethyl acetate (25 ml) and water (5 ml). The phases were separated and the organic phase was dried over anhydrous sodium sulphate and evaporated to a brown oil. This was dissolved in ethyl acetate (10 ml) and pre-adsorbed on silica (1.2 g) which was then added to the top of a 20 g silica SPE cartridge. The cartridge was eluted with a gradient of 0-100% ethyl acetate in cyclohexane over 60 min to give the title compound (65 mg) as a buff-coloured solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1)=O.[NH2:14][CH2:15][C:16]([N:18]([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[CH2:19][CH3:20])=[O:17]>>[CH3:24][N:23]([CH3:25])[CH2:22][CH2:21][N:18]([CH2:19][CH3:20])[C:16]([CH2:15][NH:14][CH2:1][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][N:4]=1)=[O:17]
Reactant: CCN(CCN(C)C)C(=O)CN
Reactant: CCOC(=O)c1ccnc(C=O)c1
Product: CCOC(=O)c1ccnc(CNCC(=O)N(CC)CCN(C)C)c1

Procedure:
By General Procedure A from ethyl 2-formylpyridine-4-carboxylate and 2-amino-N-[2-(dimethylamino)ethyl]-N-ethylacetamide. 1H NMR (300 MHz, CDCl3), δ ppm: 3.47-3.32 (m, 4H), 3.27-3.20 (m, 2H), 2.44-2.35 (m, 2H), 2.22 (s, 6H), 1.53 (s, 2H), 1.15-1.06 (m, 3H).
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].[OH-].[Na+].ClOC(C)(C)C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1.[Br:75][C:76]1[CH:77]=[N:78][CH:79]=[C:80](/[CH:82]=[C:83](\[C:85]2[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=2)/[CH3:84])[CH:81]=1.BrC1C=NC=C(/C=C(/C2C=CC=CC=2)\C)C=1>C(O)CC.O>[Br:75][C:76]1[CH:81]=[C:80]([C@H:82]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[C@@H:83]([C:85]2[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=2)[CH3:84])[CH:79]=[N:78][CH:77]=1
Reactant: C/C(=C/c1cncc(Br)c1)c1ccccc1
Reactant: CC(C)(C)OC(N)=O
Agent: C/C(=C\c1cncc(Br)c1)c1ccccc1
Agent: CC(C)(C)OCl
Agent: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Solvent: O
Solvent: CCCO
Product: C[C@H](c1ccccc1)[C@@H](NC(=O)OC(C)(C)C)c1cncc(Br)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
To a solution of tert-butyl carbamate (1.907 g, 16.28 mmol) in propanol (4.6 mL) was added sodium hydroxide (0.641 g, 16.02 mmol) in water (8 mL) followed by tert-butyl hypochlorite (1.808 ml, 16.02 mmol). After 5 minutes, the solution was cooled to 0° C. and treated with a solution of (DHQD)2PHAL (0.245 g, 0.315 mmol) in propanol (4.6 mL). To this was added a solution of (Z)-3-bromo-5-(2-phenylprop-1-enyl)pyridine and (E)-3-bromo-5-(2-phenylprop-1-enyl)pyridine (1.440 g, 5.25 mmol) in propanol (7.8 mL), and potassium osmate dihydrate (0.077 g, 0.210 mmol) as a solid in one portion. The ice bath was removed and stirring continued overnight. The reaction was quenched by addition of a solution of sodium thiosulfate (1.84 g) in water (23 mL). After 30 minutes, the reaction was diluted with ether, washed with water, then brine, dried over MgSO4, and concentrated. Biotage purification (20%-50% EtOAc/Hex) gave title compound (1.18 g, 2.90 mmol, 55% yield) as colored semi-solid. Mass spec.: 407.0 (MH)+.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[CH3:21][N:22]([CH3:43])[C:23]([CH2:25][S:26][C:27]1[C:36]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)=[O:24].IC>CCCCCC.O1CCCC1.O.C(O)(=O)C>[CH3:21][N:22]([CH3:43])[C:23]([CH:25]([S:26][C:27]1[C:36]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1)[CH3:1])=[O:24]
Reactant: CN(C)C(=O)CSc1nc2ccccc2cc1-c1ccccc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(Sc1nc2ccccc2cc1-c1ccccc1)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of lithium di-isopropylamide [prepared from di-isopropylamine (6.2 ml.) and n-butyllithium (24.7 ml. of a 1.7 M solution in hexane) in dry tetrahydrofuran (100 ml.) at -78°. under argon] was added a solution of 2-(dimethylcarbamoylmethylthio)-3-phenylquinoline (6.6 g.) in dry tetrahydrofuran (50 ml.) at -60°. The mixture was then stirred for 15 min. at -60°. Iodomethane (2.7 ml.) was added and the mixture was allowed to warm up to ambient temperature. Glacial acetic acid (2.6 ml.) was then added, followed by water (200 ml.). The tetrahydrofuran phase was separated and retained, and the aqueous layer was extracted with ethyl acetate (2×30 ml.). The ethyl acetate and tetrahydrofuran phases were combined and dried (MgSO4). The solvent was evaporated and the residual oil was chromatographed on basic alumina (100 g. of Brockmann grade III) eluted with increasing concentrations of chloroform in petroleum ether. The eluate obtained with 20% v/v chloroform in petroleum ether on evaporation gave 2-[1-(dimethylcarbamoyl)ethylthio]-3-phenylquinoline as a viscous oil, which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Cu]>[CH3:8][C:5]1[CH:6]=[CH:7][C:2](=[O:1])[N:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:4]=1
Reactant: Cc1ccc(O)nc1
Reactant: Ic1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(=O)n(-c2ccccc2)c1
Temperature: 185 °C
Yield: 55.4 %

Procedure:
A finely pulverized mixture of 2-hydroxy-5-methylpyridine (0.500 g, 4.58 mmol), anhydrous potassium carbonate (0.693 g, 6.41 mmol), copper powder (0.006 g, 0.09 mmol) and iodobenzene (1.68 g, 8.26 mmol) was heated at 180-190° C. for 7 hours. The mixture was cooled, and standard extractive workup was performed to afford a brown residue which was triturated with petroleum ether and recrystallized from hot water to yield the title compound as a white solid (0.470 g, 56%). m.p. 105-107° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.50 (s, 3H), 6.43 (d, J=9.3 Hz, 1H), 7.36-7.53 (m, 7H); IR (KBr) u 3045, 1675, 1611, 1531, 1270 cm−1; MS 186 (M+1).
Reaction SMILES: C[O:2][C:3]([C:7]1[CH:12]=[CH:11][N:10]2[C:13]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:14][N:15]=[C:9]2[N:8]=1)(OC)[CH3:4].CO.C(Cl)Cl.C([O-])(O)=O.[Na+]>Cl>[N:25]1[CH:24]=[CH:23][C:22]([C:18]2[N:17]=[C:16]([C:13]3[N:10]4[CH:11]=[CH:12][C:7]([C:3](=[O:2])[CH3:4])=[N:8][C:9]4=[N:15][CH:14]=3)[CH:21]=[CH:20][N:19]=2)=[CH:27][CH:26]=1
Reactant: COC(C)(OC)c1ccn2c(-c3ccnc(-c4ccncc4)n3)cnc2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1ccn2c(-c3ccnc(-c4ccncc4)n3)cnc2n1
Yield: 60.9 %

Procedure:
A solution of 7-(1,1-dimethoxyethyl)-3-[2-(pyridin-4yl)pyrimidin-4-yl]imidazo[1,2-α]pyrimidine (Example 60) (3 g, 8.3 mmol) in 2.5N HCl (60 ml) was heated at 50° C. for 4 h. To the cooled solution was added 5% MeOH/DCM (500 ml) then neutralized by portionwise addition of a saturated solution of NaHCO3. Organic layer was separated and the aqueous re-extracted twice with 5% MeOH/DCM. Combined organics washed with brine, dried (MgSO4) and concentrated in vacuo to give the crude residue. The crude was purified using 100 g silica bond elute cartridge, eluting with 1-2.5% MeOH/DCM, to afford 1-[3-(2-(pyridin-4-yl)pyrimidin-4-yl)imidazo[1,2-α]pyrimidin-7-yl]ethanone as a yellow solid (1.6 g, 61%): 1H NMR (400 MHz, d6DMSO) δ 2.74 (3H, s), 7.92 (1H, d, J 7.2), 8.23 (1H, d, J 5.5), 8.37 (2H, dd, J 1.6, 4.3), 8.83 (2H, dd, J 1.6, 4.3), 9.04 (1H, d, J 5.5), 9.15 (1H, s), 10.39 (1H, d, J 7.4); m/z (ES+) 317 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:10])=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C[O:12][C:13]1C=CC=C(N)[CH:14]=1>>[NH2:6][C:5]1[C:4]([CH3:10])=[C:3]([O:2][CH3:1])[CH:9]=[CH:8][C:7]=1[C:13](=[O:12])[CH3:14]
Reactant: COc1cccc(N)c1C
Reactant: COc1cccc(N)c1
Product: COc1ccc(C(C)=O)c(N)c1C
Yield: 23 %

Procedure:
Compound 201b was synthesized from 3-methoxy-2-methylaniline 215b as a yellow solid in 23% yield, according to the procedure as described for compound 215a. MS (ESI, EI+): m/z=180 (MH+).
Reaction SMILES: [CH2:1]([S:13]([N:16]1[CH2:21][CH2:20][CH2:19][S:18][C:17]1=[CH:22][N+:23]([O-:25])=[O:24])(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Br:26]N1C(=O)CCC1=O>>[CH2:1]([S:13]([N:16]1[CH2:21][CH2:20][CH2:19][S:18][C:17]1=[C:22]([Br:26])[N+:23]([O-:25])=[O:24])(=[O:14])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCS(=O)(=O)N1CCCSC1=C[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Product: CCCCCCCCCCCCS(=O)(=O)N1CCCSC1=C(Br)[N+](=O)[O-]

Procedure:
was prepared, as a yellow solid, m.p.: 70°-71° C., by treating (3A) with N-bromosuccinimide, according to the procedure described in Example 1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1.[O:39]1[CH2:44][CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH2:41][CH2:40]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[O:39]1[CH2:40][CH:41]=[C:42]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[C:5]3[C:17]2[N:22]=[C:21]([O:23][C@H:24]3[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:29][CH2:28][C:25]43[CH2:26][CH2:27]4)[CH:20]=[N:19][CH:18]=2)[CH2:43][CH2:44]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC2)[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(C5=CCOCC5)cc34)n2)C1
Temperature: 150 °C
Yield: 80.2 %

Procedure:
A mixture of (4R)-tert-butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (260 mg, 0.445 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (140 mg, 0.667 mmol), potassium phosphate (283 mg, 1.334 mmol), and PdCl2(Amphos) (31.5 mg, 0.044 mmol) in dioxane (4044 μL) and water (404 μL) was heated in the microwave for 10 min at 150° C. The crude was purified via automated flash chromatography (silica gel) with 100% hexanes to 40% EtOAc/hexanes to give (4R)-tert-butyl 4-(6-(5-(3,6-dihydro-2H-pyran-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (210 mg, 0.357 mmol, 80% yield) as a colorless oil. MS (ESI, pos. ion) m/z: 588.2 (M+1).
Reaction SMILES: [CH2:1]([N:3](C(C)C)C(C)C)[CH3:2].[O:10]=[C:11]([S:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:12][C@H:13]([NH:17][C:18](=[O:23])[CH2:19][CH2:20][CH:21]=[CH2:22])[C:14]([OH:16])=[O:15].[Cl-].[NH4+]>BrCC#N>[O:10]=[C:11]([S:24][CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:12][C@H:13]([NH:17][C:18](=[O:23])[CH2:19][CH2:20][CH:21]=[CH2:22])[C:14]([O:16][CH2:2][C:1]#[N:3])=[O:15]
Reactant: CCN(C(C)C)C(C)C
Reactant: C=CCCC(=O)N[C@@H](CC(=O)SCCc1ccccc1)C(=O)O
Agent: N#CCBr
Agent: [Cl-]
Agent: [NH4+]
Product: C=CCCC(=O)N[C@@H](CC(=O)SCCc1ccccc1)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
N-Ethyl-N-isopropylpropan-2-amine (0.187 ml, 1.07 mmol) was added to a solution of ((S)-4-oxo-2-(pent-4-enamido)-4-(phenethylthio)butanoic acid (Compound 1f-IE) (300 mg, 0.894 mmol) in 2-bromoacetonitrile (1.87 ml), and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution (5 ml) was added to the reaction mixture, after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over magnesium sulfate. Following concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→60/40) to afford (S)-cyanomethyl 4-oxo-2-(pent-4-enamido)-4-(phenethylthio)butanoate (Compound 1g-IE) (295 mg, 88%).
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7](=[O:32])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C@@H:19](/[CH:20]=[CH:21]/[C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][CH2:17][CH2:16][C:15]1=[O:31]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:32])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:15](=[O:31])[CH2:16][CH2:17][CH2:18][C@@H:19]1/[CH:20]=[CH:21]/[CH:22]([OH:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)CCCCCCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CCCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.5 %

Procedure:
Sodium borohydride (35 mg, 0.93 mmol), followed by MeOH (0.25 mL), was added to a solution of 7-[(R)-2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-heptanoic acid methyl ester (36 mg, 0.093 mmol) in CH2Cl2 (0.75 mL) at 0° C. The mixture was allowed to warm to rt. After 3 h at rt, the reaction was quenched with aqueous HCl (0.5 M, 5 mL) and extracted with EtOAc (3×10 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by preparative thin layer chromatography (silica, 5% MeOH/CH2Cl2) afforded 20 mg (55%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.N1CCCCC1.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1>CO>[Cl:17][C:18]1[CH:26]=[C:25]2[C:21](/[C:22](=[CH:5]\[C:4]3[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[C:3]=3[F:10])/[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1
Reactant: O=Cc1cccc(Cl)c1F
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C\c1cccc(Cl)c1F
Reaction time: 8 h
Yield: 96.1 %

Procedure:
3-Chloro-2-fluorobenzaldehyde (6.24 g, 39.4 mmol) was added to a solution of piperidine (3.88 mL, 39.4 mmol) and 6-chlorooxindole (6.0 g, 35.8 mmol) dissolved in methanol (100 mL). After stirring overnight, the resulting solid was filtered and washed with methanol and hexanes to give 10.6 g of (E)-6-chloro-3-(3-chloro-2-fluorobenzylidene)indolin-2-one (3) as a green solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]([CH2:17][OH:18])[CH:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.[S:27](Cl)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28].CCN(CC)CC.CNC1C=CC=C(NC)N=1>C(OCC)(=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]([CH2:17][O:18][S:27]([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH:12]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(C2C(CO)c3ccc(OC)cc3C3CCCCC32)cc1
Agent: CNc1cccc(NC)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(C2C(COS(=O)(=O)c3ccc(C)cc3)c3ccc(OC)cc3C3CCCCC32)cc1
Reaction time: 18 h
Yield: 94.8 %

Procedure:
Combine [6-methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthren-9-yl]-methanol (1.45 g, 3.81 mmol), TosCl (0.80 g, 4.19 mmol), Et3N (1.2 mL, 8.38 mmol), 2,6-dimethylaminopyridine (140.0 mg, 1.14 mmol), and methylene chloride (30 mL), and stir under nitrogen atmosphere at room temperature. After 18 hours, concentrate reaction under vacuum and add ethyl acetate. Wash with water and then brine. Dry the organic phase with anhydrous sodium sulfate and concentrate to yield the titled compound (1.83 g, 95%) as a yellowish-white solid. TLC Rf=0.30 in 2:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 7.53 (d, 2H, J=8.4 Hz), 7.22 (d, 2H, J=8.4 Hz), 7.16 (d, 1H, J=8.8 Hz), 7.06 (d, 2H, J=8.8 Hz), 6.92 (d, 1H, J=2.2 Hz), 6.83 (d, 2H, J=8.4 Hz), 6.66 (dd, 1H, J=8.8, 2.6 Hz), 4.34 (dd, 1H, J=9.7, 2.6 Hz), 4.03 (dd, 1H, J=9.7, 4.0 Hz), 3.85 (s, 6H), 3.48 (d, 1H, J=11.9 Hz), 3.20 (s, 1H), 3.09 (dd, 1H, J=12.1, 3.3 Hz), 2.46 (s, 3H), 1.89 (m, 1H), 1.61 (m, 3H), 1.41 (d, 2H, J=9.7 Hz), 1.14 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12](Cl)[C:11]=2[N+:18]([O-:20])=[O:19])=[N:6][CH:7]=1.[CH3:22][NH:23][CH3:24].O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([N:23]([CH3:24])[CH3:22])[C:11]=2[N+:18]([O-:20])=[O:19])=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)cc(Cl)c1[N+](=O)[O-]
Reactant: CNC
Solvent: O
Solvent: CS(C)=O
Product: CN(C)c1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
Into a solution of N-(5-chloropyridin-2-yl)-2-nitro-3,5-dichlorobenzamide (4.0 g, 12 mmol) in dimethyl sulfoxide (60 mL) was bubbled an excess of dimethyl amine gas. The mixture was sealed in a pressure tube and heated at 50° C. After 3 hours, the mixture was cooled to ambient temperature, then poured into water, and extracted with methylene chloride. The combined organic extracts were dried over MgSO4, and concentrated in vacuo to afford 3.8 g (93% yield) of N-(5-chloropyridin-2-yl)-2-nitro-3-dimethylamino-5-chlorobenzamide; NMR (CDCl3) 9.6 (s, 1), 8.2 (d, 1), 7.8 (d, 1), 7.7 (dd, 1), 7.1 (d, 1), 6.9 (d, 1), 2.8 (s, 6) ppm.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[NH:13][C:5]2[N:6]=[C:7]([S:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.Br[CH2:17][CH:18]1[CH2:22][CH2:21][O:20][CH2:19]1>CN(C=O)C>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH2:17][CH:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[C:5]2[N:6]=[C:7]([S:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1
Reactant: BrCC1CCOC1
Reactant: CSc1nc(C)c2cc(Br)c(=O)[nH]c2n1
Solvent: CN(C)C=O
Product: CSc1nc(C)c2cc(Br)c(=O)n(CC3CCOC3)c2n1
Temperature: 70 °C
Reaction time: 7 h
Yield: 61.3 %

Procedure:
To a mixture of 6-bromo-4-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (900 mg, 3.15 mmol) and 3-(bromomethyl)-tetrahydrofuran (571 mg, 3.46 mmol) in DMF was added CsCO3 (1.13 g, 3.46 mmol). After stirred at 70° C. for 7 h and the mixture was quenched with water and extracted with t-butyl ethyl ether (4 times) and concentrated. The crude mixture was purified by flash chromatography, using 0-2% MeOH/CHCl3, to give the title compound (715 mg, 61%).
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][N:18]([C:21](OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[CH:11][N:10]=2)=[CH:5][C:4]=1[F:30])#[N:2].[CH2:31]([C:36]1[CH:37]=[N:38]C(Br)=[N:40][CH:41]=1)[CH2:32][CH2:33][CH2:34][CH3:35]>>[C:1]([C:3]1[CH:29]=[CH:28][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]4[N:40]=[CH:41][C:36]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:37][N:38]=4)[CH2:17][CH2:16]3)=[CH:11][N:10]=2)=[CH:5][C:4]=1[F:30])#[N:2]
Reactant: CCCCCc1cnc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(COc3ccc(C#N)c(F)c3)nc2)CC1
Product: CCCCCc1cnc(N2CCC(c3ccc(COc4ccc(C#N)c(F)c4)nc3)CC2)nc1

Procedure:
The title compound was prepared from tert-butyl 4-[2-(4-cyano-3-fluorophenoxymethyl)pyridin-5-yl]piperidine-1-carboxylate (Example 13) (33 mg, 0.08 mmol) and 5-pentyl-2-bromopyrimidine (27 μL, 0.16 mmol) following a procedure analogous to that in Example 48 as a white crystal (24 mg, yield 65%).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:17]([O-])([OH:19])=[O:18]>O>[N+:17]([C:8]1[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-:19])=[O:18]
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Reactant: O=[N+]([O-])O
Solvent: O
Product: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Temperature: 45 °C
Reaction time: 0.3 h

Procedure:
A mixture of 208 g of anthraquinone and 763 g of 99% strength nitric acid (molar ratio 1:12) is stirred at 45°C for 18 minutes and then diluted to an acid content of approx. 90% with 51 ml of water. 193 G of 98% strength nitric acid are then distilled off in vacuo, resulting in an acid content of approx. 87%, and a molar ratio of approx. 8:1, in the sump. The product which precipitates is filtered off, washed until neutral and dried. Fractional distillation of the product at 6 mm Hg and a head temperature of 267°C gives 165 g of a 99.4% pure 1-nitroanthraquinone (65% of theory).
Reaction SMILES: COC1C=CC(C[N:8]2[C:16]3[CH:15]=[C:14]([NH:17][C:18]4[N:19]=[CH:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=4)[N:13]=[CH:12][C:11]=3[N:10]=[CH:9]2)=CC=1.C(O)(C(F)(F)F)=O>>[NH:8]1[C:16]2[CH:15]=[C:14]([NH:17][C:18]3[N:19]=[CH:20][C:21]([C:24]#[N:25])=[N:22][CH:23]=3)[N:13]=[CH:12][C:11]=2[N:10]=[CH:9]1
Reactant: COc1ccc(Cn2cnc3cnc(Nc4cnc(C#N)cn4)cc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cnc(Nc2cc3[nH]cnc3cn2)cn1
Yield: 98.6 %

Procedure:
5-(1-(4-Methoxybenzyl)-1H-imidazo[4,5-c]pyridin-6-ylamino)pyrazine-2-carbonitrile (10.6 mg, 30 μmol) was treated with TFA at 80° C. over 30 minutes. Isolation by SPE on a MP-TsOH cartridge, eluting with 2N ammonia in methanol, followed by concentration, gave the title compound as a white solid (7.02 mg, 100%). 1H NMR (d6-DMSO, 400 MHz) δ 12.79 (br s, 1H), 10.85 (br s, 1H), 8.76 (s, 2H), 8.75 (s, 1H), 8.35 (s, 1H), 8.26 (s, 1H). LCMS (2) Rt=1.36 min; m/z (ESI+) 238 (MH+), (ESI−) 236 (M−H).