Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[C:13]2[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:16]([N:18]2[CH2:23][CH2:22][C:21]3([CH2:32][C:31](=[O:33])[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:34]5[NH:38][N:37]=[N:36][N:35]=5)[CH:29]=4)[O:24]3)[CH2:20][CH2:19]2)=[O:17])[CH:5]=1.[C:39]([O:45][CH2:46]Cl)(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]>CN(C=O)C.C(OCC)(=O)C>[C:39]([O:45][CH2:46][N:36]1[N:37]=[N:38][C:34]([C:28]2[CH:29]=[C:30]3[C:25](=[CH:26][CH:27]=2)[O:24][C:21]2([CH2:22][CH2:23][N:18]([C:16]([C:6]4[CH:5]=[C:4]([O:3][CH3:2])[C:13]5[C:8](=[C:9]([O:14][CH3:15])[CH:10]=[CH:11][CH:12]=5)[N:7]=4)=[O:17])[CH2:19][CH2:20]2)[CH2:32][C:31]3=[O:33])=[N:35]1)(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)nc2c(OC)cccc12
Reactant: CC(C)(C)C(=O)OCCl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn(COC(=O)C(C)(C)C)n4)ccc2O3)nc2c(OC)cccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of the sodium salt (105 mg) obtained in Example 18 in 1.0 mL of DMF, was added pivaloyloxymethyl chloride (35.6 μl), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with 20 mL of ethyl acetate, washed with water (4 times) and aqueous saturated sodium chloride solution, then dried over sodium sulfate, and concentrated. The residue was purified through silica gel column chromatography (0.7% methanol/chloroform) to obtain the 2-isomer and 1-isomer. 2-Isomer (major product): 1H-NMR (CDCl3) δ: 8.69 (1H, d, J=2.4 Hz), 8.32 (1H, dd, J=2.4, 8.8 Hz), 7.77 (1H, dd, J=1.0, 8.3 Hz), 7.47 (1H, dd, J=7.7, 8.3 Hz), 7.20 (1H, s), 7.16 (1H, d, J=8.8 Hz), 7.08 (1H, d, J=7.7 Hz), 6.50 (2H, s), 4.64-4.56 (1H, m), 4.24-4.17 (1H, m), 4.08 (3H, s), 4.03 (3H, s), 3.68-3.59 (1H, m), 3.40 (1H, td, J=12.9, 2.8 Hz), 2.88 (1H, d, J=16.6 Hz), 2.81 (1H, d, J=16.6 Hz), 2.28-2.20 (1H, m), 2.14-2.07 (1H, m), 2.01-1.88 (2H, m), 1.23 (9H, s). MS [M+H]+=615. 1-Isomer (minor product): 1H-NMR (CDCl3) δ: 8.30 (1H, d, J=2.4 Hz), 8.09 (1H, dd, J=8.8, 2.4 Hz), 7.78 (1H, dd, J=8.2, 1.0 Hz), 7.48 (1H, t, J=8.2 Hz), 7.25 (1H, d, J=8.2 Hz), 7.20 (1H, s), 7.08 (1H, d, J=8.8 Hz), 6.32 (1H, d, J=11.2 Hz), 6.29 (1H, d, J=11.2 Hz), 4.65-4.57 (1H, m), 4.28-4.20 (1H, m), 4.09 (3H, s), 4.04 (3H, s), 3.69-3.59 (1H, m), 3.40 (1H, td, J=12.8, 2.9 Hz), 2.90 (1H, d, J=16.6 Hz), 2.84 (1H, d, J=16.6 Hz), 2.28-2.21 (1H, m), 2.14-2.07 (1H, m), 2.06-1.89 (2H, m), 1.28 (9H, s). MS [M+H]+=615.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)C.Cl.[NH2:13][OH:14].[OH-].[Na+].Cl>O.C(O)C>[OH:14][N:13]=[CH:9][C:3]1[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=1[OH:1]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 2.0 grams (0.013 mole) of 1-(2,4-dihydroxyphenyl)ethan-1-one (commercially available) and 1.4 grams (0.019 mole) of hydroxylamine hydrochloride in 20 mL of water and 100 mL of ethanol was cooled to about 0° C. to 4° C. and 2.7 grams (0.068 mole) of sodium hydroxide was added. Upon completion of addition the reaction mixture was warmed to reflux where it stirred during a 30 minute period. After this time the reaction mixture was cooled to ambient temperature and 400 mL of aqueous 5% hydrochloric acid was added. The mixture was extracted with diethyl ether, and the extract was washed with water. The organic layer was dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, yielding 1.5 grains of the subject compound.
Reaction SMILES: O=[C:2]([CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([Cl:16])=[CH:11][C:10]=1[N+:17]([O-])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4]>CCO.C(O)(=O)C.[Fe]>[Cl:15][C:13]1[CH:14]=[C:9]2[C:10](=[CH:11][C:12]=1[Cl:16])[NH:17][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:8]2
Reactant: CCOC(=O)C(=O)Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2cc(Cl)c(Cl)cc2[nH]1
Yield: 92 %

Procedure:
A mixture of ethyl α-oxo-3-(2-nitro-4,5-dichlorophenyl)propanoate (100 g, 327 mmol) and iron powder (160 g) in EtOH (625 ml) and acetic acid (625 ml) was refluxed for two hours. After cooling, the resulting mixture was evaporated under vacuum and the solid residue was dissolved in THF (1000 ml) and chromatographed on Florisil (500 g) eluting with THF (5000 ml). Evaporation of the collected fractions gave pure title compound (77.5 g, 301 mmol, yield 92.0%) as a light brown powder, m.p. 215°-218° C.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:15][C:16]([F:34])([F:33])[C:17]1[N:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]3)[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1.O[C:36]1[CH:46]=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][CH:37]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:34][C:16]([F:15])([F:33])[C:17]1[N:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][CH:29]([O:32][C:36]4[CH:46]=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][CH:37]=4)[CH2:28][CH2:27]3)[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1
Reactant: OC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OC2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.8 %

Procedure:
DIAD (2.262 mL, 11.49 mmol) was added to 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (3 g, 10.44 mmol), ethyl 4-hydroxybenzoate (1.909 g, 11.49 mmol) and triphenylphosphine (3.01 g, 11.49 mmol) in THF (50 mL) under nitrogen. The resulting solution was stirred at ambient temperature for 4 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 2M ammonia in methanol. The crude solid was triturated with MeOH to give a solid which was collected by filtration and dried under vacuum to give ethyl 4-[[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]oxy]benzoate (2.220 g, 49%) as a solid.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][CH:9]=[C:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][O:18]2)[CH3:16])[CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CCCCCC>CO>[CH3:24][C:20]1([CH3:23])[CH2:19][O:18][CH:17]([CH:15]([C@@H:14]2[C@:25]3([CH3:34])[C@H:11]([C:10]4[C@H:28]([CH2:27][CH2:26]3)[C@:29]3([CH3:33])[C:7]([CH2:6][C@@H:5]([OH:4])[C@@H:31]5[O:32][C@@H:30]53)=[CH:8][CH:9]=4)[CH2:12][CH2:13]2)[CH3:16])[O:22][CH2:21]1
Reactant: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of 5 mg (0.0106 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate in 2 ml of dry methanol was added 7.3 mg (0.0528 mmole) of anhydrous potassium carbonate and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through a glass filter with the aid of Celite and the filtrate was concentrated under reduced pressure. Finally the concentrate was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1:5, v/v) to give 4 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-ol (yield: ca. 90%).
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=[CH2:11])=[CH:8][CH:7]=[CH:6][N:5]=1)([O-:3])=[O:2].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C(N(CC)CC)C>C(O)C>[N+:1]([C:4]1[C:9]([CH2:10][CH2:11][NH:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)=[CH:8][CH:7]=[CH:6][N:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: C=Cc1cccnc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(NCCc2cccnc2[N+](=O)[O-])CC1
Temperature: 90 °C
Yield: 48 %

Procedure:
2-Nitro-3-vinylpyridine (0.300 g, 2 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (0.601 g, 3.00 mmol), and ethanol (5 ml) were combined. Triethylamine (0.836 ml, 6.00 mmol) was added. The vial was capped and heated at 90° C. for 62 hours. More tert-butyl 4-aminopiperidine-1-carboxylate (0.601 g, 3.00 mmol), and triethylamine (0.836 ml, 6.00 mmol) were added and the mixture was heated at 90° C. for 20 hours. Mixture was concentrated by roto-vap. Silica gel chromatography eluting ethyl acetate-hexanes afforded the title compound as tan solid in 48% yield. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 8.38 (dd, J=4.58, 1.53 Hz, 1 H) 7.84 (dd, J=7.63, 1.53 Hz, 1 H) 7.49 (dd, J=7.63, 4.58 Hz, 1 H) 3.92 (s, 2 H) 2.85-2.98 (m, 3 H) 2.75 (t, J=11.75 Hz, 2 H) 2.50-2.62 (m, 1 H) 1.75 (d, J=12.51 Hz, 2 H) 1.40 (s, 9 H) 1.00-1.27 (m, 4 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3I)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(OC([N:29]1[CH2:37][CH:36]2[CH:31]([NH:32][CH2:33][CH2:34][CH2:35]2)[CH2:30]1)=O)(C)(C)C.[ClH:38]>>[Cl-:38].[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[N:29]2[CH2:37][CH:36]3[CH:31]([NH2+:32][CH2:33][CH2:34][CH2:35]3)[CH2:30]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC2CCCNC2C1
Reactant: O=S(=O)(c1cccc(F)c1)c1cnc2c(I)cccc2c1
Reactant: Cl
Product: O=S(=O)(c1cccc(F)c1)c1cnc2c(N3CC4CCC[NH2+]C4C3)cccc2c1
Product: [Cl-]

Procedure:
0.073 g of 6-(3-(3-fluorophenylsulfonyl)quinolin-8-yl)octahydro-1H-pyrrolo[3,4-b]pyridin-1-ium chloride were prepared by analogy to the methods of Examples 27 and 28 by coupling of 3-(3-fluorophenylsulfonyl)-8-iodoquinoline with commercially available octahydro-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester and subsequent deprotection of the tert-butyl-oxycarbonyl derivative with HCl in isoproanol.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]3)=[O:14])[N:10]=[C:9]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:37]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:16][CH2:17][CH:18]([NH:21][C:41]([CH:37]4[CH2:40][CH2:39][CH2:38]4)=[O:42])[CH2:19][CH2:20]3)=[O:14])[N:10]=[C:9]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[CH:8]=2)=[CH:28][CH:29]=1
Reactant: NC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Reactant: O=C(Cl)C1CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1)C1CCC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-amine (150 mg, 0.38 mmol) in DCM (4 mL) at room temperature was added triethylamine (56 μL, 0.40 mmol) followed by cyclobutanecarbonyl chloride (43 μL, 0.38 mmol) and the solution stirred for 10 minutes. The solution was then loaded directly onto a pre-wetted Biotage 25M column for flash chromatography and eluted with 2-8% MeOH/DCM to yield the title compound as a white solid, 138 mg, 76%. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.43-8.56 (2 H, m), 7.60-7.70 (3 H, m), 7.24-7.35 (2 H, m), 7.09-7.21 (2 H, m), 6.51 (1 H, s), 5.09-5.31 (2 H, m), 4.13 (1 H, d, J=13.39 Hz), 3.93 (2 H, s), 3.70-3.88 (2 H, m), 3.15 (1 H, t, J=11.37 Hz), 2.89-3.04 (1 H, m), 2.69-2.82 (1 H, m), 2.03-2.17 (2 H, m), 1.93-2.03 (2 H, m), 1.81-1.92 (1 H, m), 1.66-1.80 (3 H, m,) 1.29-1.48 (1 H, m), 1.13-1.27 (1 H, m); m/z (APCI+) for C27H30N5O2F 476.2 (M+H)+.
Reaction SMILES: C[C:2]1[C:3](=[CH:7][C:8](=[CH:12][CH:13]=1)[N:9]=[C:10]=[O:11])[N:4]=[C:5]=[O:6].[C:14]([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>C(C(CCCC)CO)C>[CH3:14][C:7]1[C:3]([N:4]=[C:5]=[O:6])=[CH:2][CH:13]=[CH:12][C:8]=1[N:9]=[C:10]=[O:11]
Reactant: CCCCCCCCCCCC(=O)[O-]
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Agent: CCCC[Sn+2]CCCC
Solvent: CCCCC(CC)CO
Product: Cc1c(N=C=O)cccc1N=C=O

Procedure:
In another reactor, a fully blocked diurethane of 80/20 2,4/2,6-toluene diisocyanate mixture was prepared by slowly adding 87.1 parts of 80/20 toluene diisocyanate to 142 parts of 2-ethylhexanol containing 1 drop of dibutyl tin dilaurate with external cooling to maintain the reaction mixture below 100° C.
Reaction SMILES: Br[C:2]1[N:3]([C:12]2[N:13]=[C:14]([NH2:20])[NH:15][C:16](=[O:19])[C:17]=2[N:18]=1)[C@@H:4]1[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[CH2:5]1.[C-:21]#[N:22].[Na+]>CN(C=O)C.[Pd].[H][H]>[NH2:22][CH2:21][C:2]1[N:3]([C:12]2[N:13]=[C:14]([NH2:20])[NH:15][C:16](=[O:19])[C:17]=2[N:18]=1)[C@@H:4]1[O:11][C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[CH2:5]1
Reactant: [C-]#N
Reactant: [H][H]
Reactant: Nc1nc2c(nc(Br)n2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Agent: [Pd]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NCc1nc2c(=O)[nH]c(N)nc2n1[C@H]1C[C@H](O)[C@@H](CO)O1

Procedure:
8-bromo-2'-deoxyguanosine is reacted with sodium cyanide in DMF. The resulting 8-position modified nucleoside is then reduced with Pd-hydrogen to give 8-aminomethyl-2'-deoxyguanosine This compound is then condensed with N-Fmoc-aminocaproic acid-pentafluorophenyl ester. This introduces a --CH2 --NH--CO--(CH2)5 --NH-Fmoc functionality at the 8-position of guanosine Further treatment with (CH3)3SiCl, isobutyric anhydride and NH4OH yielded N2 -isobutyryl protected 8-position functionalized guanosine. Treatment with dimethoxytrityl chloride and pyridine added a DMT blocking group at the 5'-position. Finally phosphitylation gave the desired phosphoramidite compound which is incorporated into oligonucleotides.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH:10]([N:12]1[C:25]2[CH:24]=[C:23]([C:26]#[N:27])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11].[SH2:28]>N1C=CC=CC=1>[OH:8][CH2:9][CH:10]([N:12]1[C:25]2[CH:24]=[C:23]([C:26](=[S:28])[NH2:27])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11]
Reactant: S
Reactant: CC(CO)N1c2ccccc2Sc2ccc(C#N)cc21
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(CO)N1c2ccccc2Sc2ccc(C(N)=S)cc21

Procedure:
Triethylamine (98.4 cc) is added to a solution of 10-[(1RS)-2-hydroxy-1-methylethyl]-2-phenothiazine-carbonitrile (197.7 g) in anhydrous pyridine (750 cc), and hydrogen sulphide is bubbled through for 6 hours 30 minutes at 25° C. while the mixture is kept stirred. The mixture is stirred for 16 hours at 25° C., then purged with a stream of nitrogen for 2 hours and poured into distilled water (3000 cc). The oil which forms is separated after settling has taken place, washed with distilled water (3×1000 cc) and dissolved in ethyl acetate (3000 cc). The solution obtained is washed with distilled water (7×1 liter), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give a yellow crystalline mass (225 g). This product is recrystallized in ethanol (1350 cc) to give 10-[(1RS)-2-hydroxy-1 -methylethyl]-2-phenothiazinecarbothioamide (158.4 g) in the form of yellow crystals, m.p. 152° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][CH2:12][CH2:13][OH:14].CCN(CC)CC.[CH3:22][NH:23][C:24](=[O:31])[CH2:25][CH2:26][CH2:27][N+:28]([O-:30])=[O:29]>ClCCl>[CH3:22][NH:23][C:24](=[O:31])[CH2:25][CH2:26][CH:27]([N+:28]([O-:30])=[O:29])[CH:13]([OH:14])[CH2:12][F:11]
Reactant: CNC(=O)CCC[N+](=O)[O-]
Reactant: OCCF
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)CCC(C(O)CF)[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
To a clear solution of oxalyl chloride (2.0 M oxalyl chloride in dichloromethane, 0.868 g, 6.84 mmol) at −74° C. was added anhydrous DMSO (1.06 mL, 14.9 mmol) dropwise over 10 minutes while maintaining the internal temperature <−60° C. The white suspension was stirred for 15 min, then 2-fluoroethanol (0.273 mL, 4.65 mmol) was added dropwise while maintaining the internal temperature <−65° C. The yellow suspension was stirred for 20 minutes and then diluted with dichloromethane (19.5 mL), followed by the addition of anhydrous Et3N (3.90 mL, 28.0 mmol). The reaction mixture was stirred for 15 min at −71° C. and then allowed to warm to 0° C. and stirred at 0° C. for 2 h. To the reaction mixture was added a solution of N-methyl-4-nitro-butyramide (0.570 g, 3.90 mmol) in dichloromethane (2.3 mL). The reaction mixture was stirred at 0° C. for 1 h and then stirred at room temperature overnight. The mixture was concentrated to a white residue, diluted with ethyl acetate (50 mL), and the organic layer was washed with water (25 mL). The aqueous layer was then extracted with ethyl acetate (2×40 mL) and the combined organic layers were dried over MgSO4, concentrated and the residue was purified by flash chromatography (silica gel, gradient elution with EtOAc:Hexanes, 1:1 to 4:1) to give 0.325 g (40%) of the titled product as a colorless viscous oil. 1H NMR (CDCl3): 6.88 (br s, NH, 1H), 6.31 (br s, NH, 1H), 5.20-4.20 (m, 5H), 2.40-2.15 (m, 4H).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:16]1[C:21]([CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([O:25][CH3:26])=[O:24])=[C:20]([CH3:30])[N:19]=[C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:17]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[N:1]1([C:16]2[C:21]([CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([O:25][CH3:26])=[O:24])=[C:20]([CH3:30])[N:19]=[C:18]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:17]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCCNCC1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1N1CCCCCC1
Temperature: 100 °C
Yield: 48.2 %

Procedure:
Azepane (0.113 mL; 1.00 mmol) and triethylamine (0.277 mL; 2.00 mmol) were added to a solution of methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.159 g; 0.5 mmol) in tetrahydrofuran (1.5 mL). The reaction vessel was sealed and heated at 100° C. for 18 h. The mixture was diluted with a saturated solution of sodium hydrogen carbonate and was extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.092 g (98%) of the title compound.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23]>[OH-].[Na+].C(Cl)Cl>[CH2:22]([N:24]([CH2:25][CH3:26])[C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=1)[CH3:23]
Reactant: CCNCC
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)c1ccc(C(=O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
A solution of 25 g (110 mmol) 4-benzoylbenzoic acid [611-95-0] and 20 mL SOCl2 was allowed to reflux for 2 h then allowed to cool. The excess SOCl2 was evaporated off and the resulting clear oil was dissolved in 10 mL CH2Cl2 then slowly added to 12 mL (116 mmol) diethylamine in a mixture of 10 mL 3N NaOH and 50 mL CH2Cl2. The mixture was allowed to stir for 30 min then partitioned between H2O and CH2Cl2. The organic layer was washed with brine, dried over K2CO3, filtered and concentrated. The product precipitated from EtOAc/hexane to give 29.6 g (105 mmol) white crystals. MS m/z (MH+) 282.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:22]([O-:24])=[O:23])=[CH:4][C:5]([Cl:21])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1.Cl[CH2:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.C[CH2:37][N:38](P1(N(C)CCCN1C)=NC(C)(C)C)[CH2:39]C.CNC>CN(C1C=CN=CC=1)C.C(#N)C.O>[Cl:21][C:5]1[CH:4]=[C:3]([N+:22]([O-:24])=[O:23])[C:2]([NH:1][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([CH2:26][N:38]([CH3:39])[CH3:37])=[CH:28][CH:29]=2)=[CH:7][C:6]=1[N:8]1[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:12][CH2:13]1
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(N)c([N+](=O)[O-])cc2Cl)CC1
Agent: CN(C)c1ccncc1
Agent: CNC
Solvent: CC#N
Solvent: O
Product: CN(C)Cc1ccc(C(=O)Nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)c(Cl)cc2[N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 58.9 %

Procedure:
A mixture of tert-butyl 4-(5-amino-2-chloro-4-nitrophenyl)piperazine-1-carboxylate (100 mg, 0.280 mmol), 4-(chloromethyl)benzoyl chloride (106 mg, 0.561 mmol), BEMP (154 mg, 0.561 mmol), and DMAP (34 mg, 0.28 mmol) in acetonitrile (2 mL) was heated overnight at 80° C. Cooled down, treated with 0.5 ml of dimethylamine in water (40%) for 2 h. HPLC purification gave tert-butyl 4-(2-chloro-5-(4-((dimethylamino)methyl)benzamido)-4-nitrophenyl)piperazine-1-carboxylate (94 mg, 0.165 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30](=[O:40])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=1.C(P(CCCC)CCCC)CCC.CN(C(/N=N/C(N(C)C)=O)=O)C>>[CH3:28][O:29][C:30](=[O:40])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:35][CH:34]=1
Reactant: COC(=O)COc1ccc(O)cc1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Product: COC(=O)COc1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c), (4-hydroxy-phenoxy)-acetic acid methyl ester (commercially available), tri-n-butylphosphin and N,N′,N′-tetramethylazodicarboxamide. The compound was purified by preparative HPLC (phenomenex gemini column) eluting with a gradient of acetonitril:water (50:50 to 95:5). Colorless oil. MS (Turbo Spray): m/z=555.2 [M+H].
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[NH:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(C)C>C(Cl)(Cl)Cl>[CH2:2]([O:9][N:10]1[C:12]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[CH:14][C:13]=2[N:22]=[C:23]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NOCc1ccccc1
Reactant: O=C(Nc1cnc2ccccc2c1Cl)c1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: c1ccc(COn2c(-c3ccccc3)nc3cnc4ccccc4c32)cc1
Temperature: 80 °C
Yield: 12.8 %

Procedure:
O-Benzylhydroxylamine hydrochloride (10.2 g, 63.7 mmol), N-(4-chloroquinolin-3-yl)benzamide (6.00 g, 21.2 mmol), and isopropanol (200 mL) were combined and heated at 80° C. After 18 hours the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane, and the solution was washed sequentially with saturated aqueous potassium carbonate and water and then concentrated under reduced pressure. This material was purified by column chromatography (320 g of silica gel, eluting with a gradient of 1-2% methanol in dichloromethane). The resulting solid was triturated with hexanes to provide a tan solid that was isolated by filtration. The solid was mixed with chloroform and isolated by filtration to provide 0.951 g of 1-(benzyloxy)-2-phenyl-1H-imidazo[4,5-c]quinoline as a reddish-brown solid. 2-Phenyl-1H-imidazo[4,5-c]quinolin-1-ol (2.39 g) was recovered from the aqueous washings.