Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH:10]([CH3:11])[C:9]2[C:4](=[C:5]([CH3:13])[CH:6]=[CH:7][C:8]=2[CH3:12])[C:3]1=O.[CH3:15][Li].Cl.O>C(OCC)C>[CH3:15][CH:3]1[C:4]2[C:9](=[C:8]([CH3:12])[CH:7]=[CH:6][C:5]=2[CH3:13])[C:10]([CH3:11])=[C:2]1[CH3:1]
Reactant: [Li]C
Reactant: Cc1ccc(C)c2c1C(=O)C(C)C2C
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CC1=C(C)C(C)c2c(C)ccc(C)c21
Reaction time: 8 h
Yield: 44.8 %

Procedure:
In a 1 liter three necked round bottomed flask fitted with a magnetic stirring apparatus and a reflux condenser 2,3,4,7-tetramethyl-1-indanone (35) (19.52 g, 0.1 mol) was dissolved in dry diethyl ether (300 ml) under an argon atmosphere. The mixture was cooled with ice and methyllithium (45 ml, 3 M solution in diethoxymethane, 0.135 mol) was added dropwise via a syringe, then the mixture was refluxed for 3 h. When the yellow reaction mixture had cooled a mixture of concentrated HCl (20 ml) and H2O (60 ml) was added via an addition funnel. The resulting mixture was transferred to a separation funnel and extracted with diethyl ether (3×200 ml). The combined organic layers were stirred overnight with 15 ml concentrated HCl. After this time the reaction mixture was carefully adjusted to pH 7 with a saturated aqueous solution of sodium carbonate. The reaction mixture was transferred into a separation funnel. The organic layer was washed with H2O (3×100 ml), dried over MgSO4, filtered and the solvent removed under reduced pressure to give a yellow liquid. This residue was purified via column-chromatography [(SiO2, 25×9 cm) eluent: cyclohexane] to afford 1,2,3,4,7-pentamethylindene (38) (8.35 g, 44%) as a yellow liquid; then (35) (starting material) (9.60 g, 49%) (eluent: cyclohexane:ethylacetate (10:1)) as a yellow liquid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].ClCCl.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23].Cl>C1C=CC=CC=1.CCCCCC>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([NH:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)N
Agent: Cl
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)NC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
To a stirred solution of 13.43 g. (0.05 mole) of 3,5-di(t-butyl)-4-hydroxybenzoyl chloride in 50 ml. of dichloromethane is added dropwise 8.77 g. (0.12 mole) of t-butylamine. The mixture obtained is neutralized carefully with 10 percent hydrochloric acid and washed thrice with 200 ml. portions of water. The organic layer is dried, then evaporated under vacuum to provide a white residue. The residue is dissolved in hot benzene-hexane mixture and crystallized to provide 3,5-di(t-butyl)-4-hydroxy-N-t-butylbenzamide, m.p. 207°-208° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=2)[C:4](=[O:22])[CH:3]=1.[CH2:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C(Cl)Cl.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>[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[N:7]=[CH:6][N:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])=[C:10]([O:20][CH3:21])[CH:9]=3)[C:4](=[O:22])[CH:3]=2)=[CH:27][CH:26]=1)[CH3:24]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: COc1cc(-n2cnc(Cl)cc2=O)ccc1OCC(C)(C)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1ccc(-c2cc(=O)n(-c3ccc(OCC(C)(C)O)c(OC)c3)cn2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
A mixture of 6-chloro-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-pyrimidin-4(3H)-one Part A of Procedure 11 (11 mg, 0.03 mmol), 4-ethylphenylboronic acid (7.6 mg, 0.05 mmol), potassium phosphate tribasic (21.57 mg, 0.102 mmol), and PalladiumTetrakis (4 mg, 3.39 μmol) in DMF (0.5 mL) was stirred at 90° C. overnight. The reaction was diluted with CH2Cl2, filtered, and concentrated. The crude was purified using HPLC (Phen Luna Axia C18 5μ 10:90:0.1 to 90:10:0.1 MeOH—H2O-TFA) to afford the desired product 6-(4-ethylphenyl)-3-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyrimidin-4(3H)-one M-1 (9.93 mg, 0.02 mmol, 69.1% yield) as a light yellow solid. LC/MS 395 (M+H)+, tR 0.95 min (method 5). 1H NMR (500 MHz, CHLOROFORM-d) d ppm 8.25 (1H, s), 7.93 (2H, d, J=8.32 Hz), 7.34 (2H, d, J=8.32 Hz), 7.02 (1H, d), 6.91-6.96 (3H, m), 3.90 (3H, s), 3.89 (2H, s), 2.74 (2H, q), 1.38 (6H, s), 1.30 (3H, t, J=7.63 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH3:9])[C:5]([NH2:10])=[CH:4][C:3]=1[F:11].[F:12][C:13]([F:24])([F:23])[C:14]1[C:19]([C:20](O)=[O:21])=[CH:18][N:17]=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[C:3]([F:11])=[CH:4][C:5]([NH:10][C:20](=[O:21])[C:19]2[C:14]([C:13]([F:24])([F:12])[F:23])=[CH:15][CH:16]=[N:17][CH:18]=2)=[C:6]([NH:8][CH3:9])[CH:7]=1
Reactant: O=C(O)c1cnccc1C(F)(F)F
Reactant: CNc1cc(Cl)c(F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNc1cc(Cl)c(F)cc1NC(=O)c1cnccc1C(F)(F)F
Temperature: 80 °C

Procedure:
To the solution of compound 5-chloro-4-fluoro-N1-methylbenzene-1 2-diamine (0.3 g, 0.00172 mol) and 4-trifluoromethylnicotinic acid (0.36 g, 0.00189 mol) in DMF (5 ml) was added EDC-HCl (0.27 g, 0.00206 mol) followed by HOBt (0.39 g, 0.00206 mol) and Et3N (0.047 g, 0.00344 mol). Reaction mixture was heated at 80° C. for 12 h. Reaction mass was quenched with ice water and layers were separated. The aqueous layer was extracted with EtOAc (3×10 ml). The combined organic extracts were washed with sat NaHCO3 solution and brine dried over Na2SO4 and concentrated to get crude product which was purified by column chromatography to provide N-(4-chloro-5-fluoro-2-(methyl amino)phenyl)-4-(tri-fluoromethyl)nicotinamide as a brown colored solid. 1H NMR (400 MHz, DMSO-d6), δ: 10.08 (s, 1H), 9.20 (s, 1H), 8.99-8.98 (d, J=4.8 Hz, 1H), 8.75-8.74 (d, J=4.8 Hz, 1H), 7.91-7.89 (d, J=5.2 Hz, 1H), 7.39-7.37 (d, J=10.4 Hz, 1H), 6.72-6.71 (d, J=7.2 Hz, 1H), 5.36 (bs, 1H), 2.74-2.73 (d, J=4.0 Hz, 3H). MS (M+1): 348.12.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8].[Na].[CH3:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([CH2:18]Cl)=[C:13]([CH3:20])[CH:12]=1>C(O)C>[CH3:20][C:13]1[CH:12]=[C:11]([CH3:10])[CH:16]=[C:15]([CH3:17])[C:14]=1[CH2:18][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:8]
Reactant: Cc1cc(C)c(CCl)c(C)c1
Reactant: [O-][n+]1ccccc1S
Agent: [Na]
Solvent: CCO
Product: Cc1cc(C)c(CSc2cccc[n+]2[O-])c(C)c1
Yield: 88.7 %

Procedure:
A mixture of 17 gms (0.05 mole) 2-mercaptopyridine N-oxide, sodium salt (40% aqueous solution) and 8.5 gms (0.05 mole) α2 chloroisodurene in 50 ml of ethanol is brought to reflux for 15 minutes. The volatiles are removed and the residue extracted with 150 ml of boiling chloroform, filtered and dried over sodium sulfate. Evaporation and trituration of the residue with a few drops of acetone induce crystallization. A yield of 11.5 gms of 2-(2,4,6-trimethylphenylmethylthio)pyridine N-oxide is obtained. Melting point 137° - 138° C. Structure confirmed by IR and NMR.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.O.Cl.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=1
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Yield: 71.9 %

Procedure:
Beginning with 4.0 gm (29.6 mMol) 5-fluoro-1H-indole and 9.13 gm (59.0 mMol) 4-piperidone hydrochloride monohydrate, 4.60 gm (72%) of the title compound were recovered as a white solid.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][N:18](COCC[Si](C)(C)C)[CH:19]=3)[N:12]3[CH:28]=[CH:29][N:30]=[C:11]3[CH:10]=2)[CH:6]=[N:5]1)([CH3:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]([N:4]1[CH:8]=[C:7]([C:9]2[N:14]=[C:13]([C:15]3[CH:16]=[N:17][NH:18][CH:19]=3)[N:12]3[CH:28]=[CH:29][N:30]=[C:11]3[CH:10]=2)[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cc(-c2cc3nccn3c(-c3cnn(COCC[Si](C)(C)C)c3)n2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)n1cc(-c2cc3nccn3c(-c3cn[nH]c3)n2)cn1
Yield: 53 %

Procedure:
To a solution of 7-(1-isopropyl-1H-pyrazol-4-yl)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (0.191 g, 0.451 mmol) in 2.5 mL of DCM was added 2,2,2-trifluoroacetic acid (1.5 mL, 19.5 mmol) slowly at ambient temperature with stirring under an inert atmosphere. After 4 hours the reaction mixture was concentrated under reduced pressure and then allowed to dry on high vacuum over the weekend. The crude residue was taken up in 5 mL of 1M NaOH and stirred for 10 minutes before solid sodium chloride was added in sufficient amount to saturate the aqueous. The aqueous was then extracted with chloroform and then extracted with 10% MeOH in DCM (50 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was dissolved in DCM in preparation for silica gel chromatography and a short time later a large amount of precipitate was observed. This solid was collected by means of vacuum filtration and the solid was rinsed with DCM to afford 7-(1-isopropyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (0.070 g, 0.239 mmol, 52.9% yield). MS (apci) m/z=294.1 (M+H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].C1(C)C=CC=CC=1.[OH-].[Na+].[C:16](Cl)([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17]>O>[O:6]=[C:2]1[CH2:3][CH2:4][CH2:5][N:1]1[C:16]([O:18][CH2:19][CH:20]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=2[C:27]2[C:32]1=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:17]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: O=C1CCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
Into a 500 mL four neck flask were added 2-pyrrolidone (8.51 g) [mw. 85.10, 100 mmol] and toluene (170 mL), and the mixture was dissolved. Powder sodium hydroxide (4.00 g) [mw. 40.00, 100 mmol] was added thereto, Dean-Stark trap was set, and the mixture was subjected to dehydration reflux for 4 hr. After cooling to 0° C., Fmoc-Cl (25.70 g) [mw. 258.70, 99 mmol] was added at not more than 5° C., the mixture was stirred at 25° C. for 2 hr, and water (43 mL) was added to allow for partitioning. The organic layer was washed with 5 w/w aqueous potassium hydrogen sulfate solution (43 mL), and further washed twice with water (43 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Pale-yellow oil, 30.56 g, yield 99.4%, 1H-NMR (500 MHz, CDCl3, TMS) δ 1.13 (d, J=6.3 Hz, 1H), 2.04 (quin, J=7.7 Hz, 2H), 2.57 (t, J=8.2 Hz, 2H), 3.75-3.82 (m, 2H), 4.49 (d, J=7.6 Hz, 2H), 7.30-7.36 (m, 2H), 7.37-7.45 (m, 2H), 7.70-7.79 (m, 4H). 13C-NMR (125 MHz, CDCl3, CDCl3) δ 17.56, 32.87, 46.41, 46.72, 68.59, 119.97, 125.35, 127.22, 127.87, 141.31, 143.53, 151.75, 173.79.
Reaction SMILES: [CH3:1]N.[N+:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[N+:15]([O-])=O)[C:9]([OH:11])=[O:10])([O-:5])=[O:4]>CCO>[CH3:1][NH:15][C:14]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[N+:3]([O-:5])=[O:4]
Reactant: CN
Reactant: O=C(O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Solvent: CCO
Product: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]

Procedure:
TEA (13 mL) and methylamine (2 M in MeOH, 35 mL, 70 mmol) was added to 3,4-dinitrobenzoic acid (10 g, 47.2 mmol) in EtOH (50 mL) at rt. After 24 h at rt the mixture was concentrated and H2O was added to the residue. The mixture was filtered and acidified with AcOH. The solids were collected and dried to give the sub-title compound. Yield: 7.5 g (81%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:16][CH:17]3[O:21][C:20](=[O:22])[NH:19][CH2:18]3)[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.I[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl.CCOC(C)=O>CS(C)=O.CCOC(C)=O.[Cu]I>[Br:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:16][CH:17]3[O:21][C:20](=[O:22])[N:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:18]3)[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3
Reactant: O=C1NCC(Cn2c3ccc(Br)cc3c3cc(Br)ccc32)O1
Reactant: Ic1ccccn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C1OC(Cn2c3ccc(Br)cc3c3cc(Br)ccc32)CN1c1ccccn1
Temperature: 130 °C
Yield: 79.4 %

Procedure:
A mixture of 5-((3,6-dibromo-9H-carbazol-9-yl)methyl)oxazolidin-2-one (0.0195 g, 0.0460 mmol), 2-iodopyridine (0.0209 g, 0.102 mmol), CuI (0.0009 g, 0.00460 mmol), and K2CO3 (0.0058 g, 0.0418 mmol) in 0.5 mL of DMSO was sealed tightly in a vial and heated at 130° C. for 12 hours. The reaction mixture was cooled and diluted with 20 mL EtOAc and washed with water 5×10 mL. The organic layer was dried over anhydrous Na2SO4 and evaporated to afford the crude product, which was subjected to silica gel chromatography using CH2Cl2/EtOAc as elute to afford 0.0183 g white solid as product, yield 79.4%.
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([C:32]#[C:33][CH2:34][OH:35])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>[Pt]=O>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[C:15]([CH2:32][CH2:33][CH2:34][OH:35])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1cccc(-c2nc(C#CCO)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Agent: O=[Pt]
Product: CCCCCCc1cccc(-c2nc(CCCO)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1

Procedure:
In analogy to the procedure described for example 14, [2-(3-hexyl-phenyl)-5-(3-hydroxy-prop-1-ynyl)-3-methyl-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 31) was hydrogenated using platinum oxide as catalyst to give the title compound as yellow oil. MS: 481.4 (MH+).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:20]([CH:21]([C:23]4[C:28]([F:29])=[CH:27][CH:26]=[C:25]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])[C:24]=4[F:37])[OH:22])=[CH:19][NH:18][C:15]3=[N:16][CH:17]=2)=[CH:8][N:7]=1)=[O:5])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CN(C)C=O>O1CCCC1>[CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:20]([C:21](=[O:22])[C:23]4[C:28]([F:29])=[CH:27][CH:26]=[C:25]([NH:30][S:31]([CH2:34][CH2:35][CH3:36])(=[O:33])=[O:32])[C:24]=4[F:37])=[CH:19][NH:18][C:15]3=[N:16][CH:17]=2)=[CH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(-c4ccc(C(=O)NCC)nc4)cc23)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(C(=O)NCC)nc4)cc23)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
To 5-(3-{[2,6-difluoro-3-(propane-1-sulfonylamino)-phenyl]-hydroxy-methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)-pyridine-2-carboxylic acid ethylamide (73, 50 mg, 0.094 mmol) dissolved in 0.76 mL of tetrahydrofuran, Dess-Martin periodinane (48 mg, 0.113 mmol) was added, followed by 1 mL of dimethylformamide. The reaction was allowed to stir at room temperature for 1 hour, then quenched with water and the aqueous layer extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to provide the desired compound (P-2151, 30.6 mg). MS (ESI) [M+H+]+=528.2.
Reaction SMILES: [CH:1]1([N:4]2[C:8](=[O:9])[C:7]3=[CH:10][C:11]([N+:14]([O-])=O)=[CH:12][CH:13]=[C:6]3[C:5]2=[O:17])[CH2:3][CH2:2]1.O.O.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[CH:1]1([N:4]2[C:8](=[O:9])[C:7]3=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=[C:6]3[C:5]2=[O:17])[CH2:3][CH2:2]1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1C1CC1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)C(=O)N(C1CC1)C2=O
Temperature: 0 °C

Procedure:
N-Cyclopropyl-4-nitrophthalimide (10.0 g, 43.0 mmol) was dissolved in ethanol (200 mL). Tin (II) chloride dihydrate (49.0 g, 215 mmol) was added, and the mixture was heated to reflux overnight. After cooling, the mixture was poured over crushed ice (1.0 L), and pH adjusted to 6.5 using 1 N NaOH. The mixture was passed through a small bed of celite, and the filtrate was subsequently extracted with ethyl acetate (1.2 L). The organic phase was dried using anhydrous MgSO4, and solvent was removed by rotary evaporation in vacuo, to afford crystalline N-cyclopropyl-4-aminophthalimide. Yield: 6.0 g (69%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15]C)=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[N:10][C:11]=2[NH2:17].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[NH2:17][C:11]1[N:10]=[C:9]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[N:8]=[C:7]2[C:12]=1[NH:13][C:14](=[O:15])[N:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COc1nc2c(N)nc(OC3CCCC3)nc2n1CCCCCl
Reactant: C1CCNCC1
Product: Nc1nc(OC2CCCC2)nc2c1[nH]c(=O)n2CCCCN1CCCCC1

Procedure:
Prepared similarly to Example 29 from 9-(4-chlorobutyl)-2-(cyclopentyloxy)-8-(methyloxy)-9H-purin-6-amine and piperidine.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[C:13]2[S:12][C:11]3[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:10]=3[NH:9][C:8](=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:26].O>N1C=CC=CC=1>[F:1][C:2]([F:24])([F:23])[C:3]1[C:13]2[S:12][C:11]3[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:10]=3[NH:9][C:8](=[S:26])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1Nc2cc(C(F)(F)F)ccc2Sc2c1cccc2C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: FC(F)(F)c1ccc2c(c1)NC(=S)c1cccc(C(F)(F)F)c1S2
Reaction time: 8 h
Yield: 50.8 %

Procedure:
4,8-Bis(trifluoromethyl)-10,11-dihydrodibenzo[b,f][1,4]thiazepin-11-one (0.54 g) was dissolved in pyridine (15 ml). Phosphorus pentasulphide (0.60 g) was added to the solution and the whole was stirred under reflux for 6 hours, then cooled and left overnight. Addition of water (40 ml) and cooling gave a yellow solid which was filtered off, washed with water and recrystallised from ethanol to give the product as yellow needles (0.26 g, m/s. M- =379).
Reaction SMILES: [O:1]=[C:2]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=[C:18]2[CH2:17]1)[CH2:3][C:4](=O)[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14].C([O-])(=O)C.[NH4+:33].N>CO>[O:1]=[C:2]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=[C:18]2[CH2:17]1)[CH:3]=[C:4]([NH2:33])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14]
Reactant: O=C(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: N
Solvent: CO
Product: NC(=CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 55 °C
Reaction time: 6 h
Yield: 75 %

Procedure:
A mixture of 7-(1,3-dioxo-4-(2,4,5-trifluorophenyl)-butyl)-3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine (22.1 g), ammonium acetate (25 g), methanol (220 mL), and aqueous ammonia (22 mL) are heated to about 55° C. and stirred for about 6 hours. The reaction mass is then cooled to 30° C. and the undissloved particles are filtered off. The filterate is distilled off completely under vaccum. To the residue, ethanol (25 mL) is charged and the mixture is stirred at about 30° C. for about 30 minutes. The solid is filtered, washed with ethanol (5 mL), and dried to afford the title compound. (Yield: 75%; purity by HPLC: 96.7%)
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C[O:17][C:18]1C=CC=[CH:20][C:19]=1N1CCN(CCCO)CC1>>[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:20][CH2:19][CH2:18][OH:17])[CH2:12][CH2:11]1
Reactant: COc1ccccc1N1CCN(CCCO)CC1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: Cl
Product: OCCCN1CCN(c2cccc(Cl)c2Cl)CC1
Yield: 82 %

Procedure:
3-[4-(2,3-Dichloro-phenyl)-piperazin-1-yl]propan-1-ol (36A) is prepared from 1-(2,3-dichloro-phenyl)-piperazine hydrochloride as described for 29A.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[C:3]=1[CH2:4]O.C(N(CC)CC)C.S([Cl:25])(C)(=O)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[C:3]=1[CH2:4][Cl:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Nc1cccc(C)c1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cccc(C)c1CCl
Reaction time: 0.5 h

Procedure:
To a suspension of 2-methyl-6-acetamidobenzyl alcohol (30 g) and triethylamine (46.54 ml) in methylene chloride (300 ml) was added dropwise mesyl chloride (14.25 ml) below 8° C. The mixture was stirred under ice cooling for 30 minutes and then at room temperature for 20 minutes. The reaction mixture was washed with 1N-hydrochloric acid solution, water and saturated sodium bicarbonate aqueous solution, dried over magnesium sulfate and evaporated in vacuo. The residue was suspended in n-hexane and the precipitates were collected by filtration and dried to give 2-methyl-6-acetamidobenzyl chloride (19.28 g).
Reaction SMILES: [Cl:1][C:2]([N:13]([CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][OH:17])([C:9]([F:12])([F:11])[F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O[C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[O:38])=[CH:35][CH:34]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]([N:13]([CH2:18][CH:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH2:14][CH2:15][CH2:16][O:17][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[O:38])=[CH:35][CH:34]=1)([C:9]([F:11])([F:12])[F:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: OCCCN(CC(c1ccccc1)c1ccccc1)C(Cl)(c1ccccc1)C(F)(F)F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=Cc1ccc(OCCCN(CC(c2ccccc2)c2ccccc2)C(Cl)(c2ccccc2)C(F)(F)F)cc1
Yield: 43 %

Procedure:
To a solution of 3-[(Chloro-trifluoromethyl-benzyl)-diphenylethyl-amino]-propan-1-ol (0.500 g, 1.12 mmol) in toluene (4 ml) at ambient temperature was added 4-Hydroxy-benzaldehyde (0.213 g, 1.74 mmol) under Argon with stirring. The mixture was treated with polymer bound PPh3 (0.594 g, 1.782 mmol). After 15 minutes of stirring, the mixture was treated with DIAD (0.273 mL, 1.387 mmol) and was stirred at ambient temperature overnight. The reaction mixture was filtered then concentrated, in-vacuo, to dryness. The oil was dissolved in DMSO and was purified via reverse-phase HPLC to yield the title compound (0.266 g, 43%); MS (ES+) m/e 553 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[Cl:7][CH2:8][C:9](Cl)=[O:10]>C1COCC1>[Cl:7][CH2:8][C:9]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)=[O:10]
Reactant: Cn1cccc1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Product: Cn1cccc1C(=O)CCl
Yield: 106.4 %

Procedure:
A solution of 15 g (0.186 mole) N-methylpyrrole and 19.2 mL (0.186 mole) chloroacetyl chloride in 600 mL dry THF was heated under reflux overnight with a nitrogen stream bubbling through the reaction mixture. After cooling, the organics were washed with water, 1N NaOH, water, brine and dried (MgSO4). Evaporation of the solvent gave 31.2 g of a green solid: mp (decomp.)280° C.; NMR 300 MHz (CDCl3) d 7.05 (d, 1 H); 6.95 (s, 1 H); 6.2 (m, 1 H); 4.5 (s, 2 H); 3.9 (s, 3 H).