Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=[O:27])[NH:14][CH2:15][CH:16]1[CH2:19][N:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:17]1)(C)(C)C.[C:28]1([C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([S:43]([C:46]3[CH:54]=[CH:53][C:49](C(O)=O)=[CH:48][CH:47]=3)(=[O:45])=[O:44])[CH:35]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1>[F:26][C:23]1[CH:22]=[CH:21][C:20]([N:18]2[CH2:17][CH:16]([CH2:15][NH:14][C:13](=[O:27])[C:49]3[CH:48]=[CH:47][C:46]([S:43]([N:36]4[C:37]5[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=5)[C:34]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:35]4)(=[O:45])=[O:44])=[CH:54][CH:53]=3)[CH2:19]2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NCC1CN(c2ccc(F)cc2)C1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC1CN(c2ccc(F)cc2)C1)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Reaction time: 16 h
Yield: 11.9 %

Procedure:
Add trifluoroacetic acid (2 mL) to [1-(4-fluoro-phenyl)-azetidin-3-ylmethyl]-carbamic acid tert-butyl ester (135 mg, 0.482 mmol) causing much gas evolution. Rotary evaporate the reaction solution (40° C.; azeotroping 3× with CH2Cl2). Dissolve this material in anhydr CH2Cl2 (3 mL). Add 4-(3-Phenyl-indole-1-sulfonyl)-benzoic acid (200 mg, 0.53 mmol, 1.1 equiv), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC; 140 mg, 0.73 mmol, 1.5 equiv), and 4-(dimethylamino)pyridine (DMAP; 270 mg, 2.3 mmol, 4.7 equiv). After stirring 16 h, transfer the reaction solution to a column of silica gel (80 mm×20 mm dia.) and elute (10-45% EtOAc/hex) to yield 31 mg (12%) of N-[1-(4-fluoro-phenyl)-azetidin-3-ylmethyl]-4-(3-phenyl-indole-1-sulfonyl)-benzamide as a light-yellow foam. MS (m/e): 539.99 (M+1); 538.16 (M−1).
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C@@H:5]1[CH2:10][CH:9]([C@H:11]([NH:17][C:18]([O:20][CH3:21])=[O:19])[C:12]([O:14]CC)=[O:13])[CH2:8][C@@H:7]([CH3:22])[O:6]1>O.C1COCC1>[CH3:4][C@@H:5]1[CH2:10][CH:9]([C@H:11]([NH:17][C:18]([O:20][CH3:21])=[O:19])[C:12]([OH:14])=[O:13])[CH2:8][C@@H:7]([CH3:22])[O:6]1
Reactant: CCOC(=O)[C@@H](NC(=O)OC)C1C[C@@H](C)O[C@H](C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N[C@H](C(=O)O)C1C[C@@H](C)O[C@H](C)C1
Temperature: 5 °C
Reaction time: 0.67 h
Yield: 104.1 %

Procedure:
Lithium hydroxide hydrate (8.51 g, 203 mmol) in H2O (270 mL) was added dropwise to a stirred solution of (S)-ethyl 2-((2R,6R)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-2-(methoxycarbonyl-amino)acetate (27.7 g, 101 mmol) in THF (405 mL) over 65 min, while maintaining an internal temperature<5° C. The reaction mixture was stirred in an ice bath for 40 min and then in a water bath at RT for 5 h. The reaction mixture was partially concentrated to remove the THF and then partitioned between water (250 mL) and DCM (250 mL). The aqueous layer was adjusted to pH=2 with 1 N HCl (205 mL), and then extracted with isopropyl acetate (7×250 mL). The combined extracts were washed with brine (1×600 mL), dried (MgSO4), filtered and concentrated. The resulting viscous oil was treated with toluene (100 mL) and ether (75 mL), evaporated and dried in vacuo to afford Cap-2 (25.8 g, with 0.33 eq. of toluene) as a white foam. Chiral SFC purity>99.9% (Chiralpak AD-H (25×0.46 cm, 5 μm) 5% EtOH in CO2, 3 mL/min, 35° C., 220 nm, 100 bar). HPLC purity 95.6% (Column: Sunfire C8 75×4.6 mm ID; 2.5 μm; 40° C.; Mobile Phase: A=Water w/0.1% Formic Acid; B═CH3CN w/0.1% Formic Acid). LC/MS (ES+) 228.1 (M+H−H2O)+. By 1H-NMR the material contained about 0.33 eq. of toluene. 1H-NMR (400 MHz, CDCl3) δ 5.29 (d, J=8.6 Hz, 1H), 4.46-4.25 (m, 2H), 3.82 (dd, J=9.7, 5.9 Hz, 1H), 3.74 (s, 3H), 2.46-2.30 (m, 1H), 1.76-1.55 (m, 2H), 1.51-1.35 (m, 1H), 1.29 (d, J=6.8 Hz, 3H), 1.18 (d, J=6.2 Hz, 3H), 1.18-1.06 (m, 1H). 13C-NMR (101 MHz, CDCl3) δ 174.1, 156.7, 68.3, 64.4, 57.5, 52.2, 35.8, 32.6, 30.3, 21.6, 16.7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)=[O:8].N1CCCCC1.C(O)(=O)[CH2:30][C:31]([OH:33])=[O:32].C(=O)=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[CH:30][C:31]([OH:33])=[O:32])=[CH:14][CH:13]=1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)NCCc1ccc(C=O)cc1
Reactant: O=C(O)CC(=O)O
Agent: O=C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(C=CC(=O)O)cc1

Procedure:
31.75 g. 4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-benzaldehyde (m.p. 115°-116° C.) and 1 ml. piperidine are added to 11.5 g. malonic acid in 100 ml. anhydrous pyridine. The reaction mixture is heated on a waterbath until the evolution of carbon dioxide is finished. After cooling, the reaction mixture is poured on to ice/concentrated hydrochloric acid and the precipitate formed is filtered off with suction, whereafter it is recrystallized from ethanol. There are obained 23.4 g. (about 65% of theory) 4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-cinnamic acid; m.p. 197°-198° C.
Reaction SMILES: F[C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16]([CH2:22][C:23]([OH:25])=[O:24])[CH2:17][C:18](=[O:21])[NH:19][OH:20])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[I:28]C1C=CC(OC2C=CC(S(N(CC(O)=O)CC(O)=O)(=O)=O)=CC=2)=CC=1>>[I:28][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16]([CH2:22][C:23]([OH:25])=[O:24])[CH2:17][C:18](=[O:21])[NH:19][OH:20])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CN(CC(=O)O)S(=O)(=O)c1ccc(Oc2ccc(I)cc2)cc1
Reactant: O=C(O)CN(CC(=O)NO)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Product: O=C(O)CN(CC(=O)NO)S(=O)(=O)c1ccc(Oc2ccc(I)cc2)cc1

Procedure:
Compound 6e was prepared following the procedure described for 6b with reagent quantities adapted to the amount of starting material 5e (500 mg, 1.02 mmol). Yield: 305 mg, 0.60 mmol, 59%. 1H NMR (D2O): δ 7.72 (d, 3J=8.2 Hz, 2H, ArH), 7.52 (d, 3J=8.8 Hz, 2H, ArH), 7.03 (d, 3J=8.8 Hz, 2H, ArH), 4.01 (s, 4H, CH2COOH). ESI-MS calcd for C16H15IN2O7S 505.97 [M-H]−, obsd 507.0.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH:12]([OH:16])[CH2:13][CH:14]=[CH2:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:17](Br)[CH:18]=[CH2:19]>C1COCC1>[CH2:19]([O:16][CH:12]([CH2:13][CH:14]=[CH2:15])[CH2:11][O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:18]=[CH2:17]
Reactant: C=CCC(O)COCc1ccccc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC(CC=C)COCc1ccccc1
Temperature: 25 °C

Procedure:
NaH (4.8 g, 120 mmol) was added portion wise to a stirred solution of 1-(benzyloxy)pent-4-en-2-ol (11) (15.3 g, 79.6 mmol) in THF (100 mL) at 0° C. After addition, the mixture was warmed to room temperature and stirred for another hour before it was cooled to 0° C. Allyl bromide (9 mL, 103.5 mmol) was added to the reaction and the resulting mixture was warmed to room temperature and then heated to 50° C. overnight. After cooling to room temperature, the mixture was quenched with saturated NH4Cl and worked up under standard conditions. The residue was purified over silica using Et2O and hexane to give ((2-(allyloxy)pent-4-enyloxy)methyl)benzene (12).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[CH:8][N:7]=[C:6]2[C:10]2[S:11][C:12]3[CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22](Br)[CH:21]=[CH:20][C:17]=4[C:18]=3[N:19]=2)[CH2:2]1.[CH3:25][C:26]([OH:43])([CH3:42])[CH2:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1>[Pd]>[NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[CH:8][N:7]=[C:6]2[C:10]2[S:11][C:12]3[CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([C:31]5[CH:30]=[N:29][N:28]([CH2:27][C:26]([CH3:42])([OH:43])[CH3:25])[CH:32]=5)[CH:21]=[CH:20][C:17]=4[C:18]=3[N:19]=2)[CH2:2]1
Reactant: Brc1ccc2c(c1)OCCc1sc(-c3nccn3C3CNC3)nc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4nccn4C4CNC4)nc2-3)cn1

Procedure:
Following the procedure for 355, 2-(1-Azetidin-3-yl-1H-imidazol-2-yl)-8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene and 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol were reacted under Suzuki palladium conditions to give 411. MS: (ESI+)=463.2. 1H NMR (400 MHz, DMSO) δ 8.36 (d, J=8.2 Hz, 1H), 8.15 (s, 1H), 7.94 (s, 1H), 7.84 (s, 1H), 7.45 (dd, J=8.3, 1.7 Hz, 1H), 7.28 (d, J=1.7 Hz, 1H), 7.14 (s, 1H), 6.16-6.06 (m, 1H), 4.72 (s, 1H), 4.36 (t, J=5.0 Hz, 2H), 4.04 (s, 2H), 3.98 (t, J=8.2 Hz, 2H), 3.82-3.76 (m, 2H), 1.10 (s, 6H)
Reaction SMILES: [H-].[Na+].[Na+].[I-].C[C:6]1([CH3:13])[O:10][CH:9]([CH2:11][OH:12])[CH2:8][O:7]1.S(C1C=CC(C)=CC=1)(O[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]CC)(=O)=O>CN(C=O)C.O>[CH2:6]([O:7][CH2:8][CH:9]([CH2:11][OH:12])[OH:10])[CH2:13][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CC1(C)OCC(CO)O1
Reactant: CCCCCCCC/C=C\CCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCC/C=C\CCCCCCCCOCC(O)CO
Reaction time: 72 h

Procedure:
To a mixture of NaH (4.8 g, 120 mmol) and NaI (0.2 g) in dry DMF (20 mL) was added solketal (5.0 mL, 40 mmol) dropwise over a 30 min period. Once the effervescence had stopped, oleyl tosylate (Compound 13) (16.9 g, 40 mmol) was added and the reaction mixture was left for 3 days at 50° C. Then, H2O (10 mL) was added and the mixture was extracted with diethyl ether (2×100 mL), the combined organic phases were dried (MgSO4) and evaporated to dryness. The residue was taken up in THF (150 mL), 2M HCl was added until the solution turned turbid and the reaction was left to stir for 16 hours. The mixture was concentrated and subjected to silica-gel column chromatography [eluent: ethyl acetate/hexane, 50/50, v/v] to give 1-O-oleyl-rac-glycerol (Compound 20) as an oil.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[F:11][C:12]1[CH:13]=[C:14]([S:19]([C:22]([C:25]2[CH:30]=[C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]3[CH3:37])[N:28]=[C:27]([C:38]3[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=3)[N:26]=2)([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH:15]=[C:16]([F:18])[CH:17]=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[F:18][C:16]1[CH:15]=[C:14]([S:19]([C:22]([C:25]2[CH:30]=[C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]3[CH3:37])[N:28]=[C:27]([C:38]3[CH:39]=[CH:40][C:41]([NH:42][C:2](=[O:3])[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:43][CH:44]=3)[N:26]=2)([CH3:23])[CH3:24])(=[O:20])=[O:21])[CH:13]=[C:12]([F:11])[CH:17]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2cc(F)cc(F)c2)nc(-c2ccc(N)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2cc(F)cc(F)c2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
Phenyl chloroformate (0.413 mL, 3.29 mmol) was added to 4-[4-[2-(3,5-difluorophenyl)sulfonylpropan-2-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (1.46 g, 2.99 mmol) and sodium hydrogen carbonate (0.377 g, 4.48 mmol) in dioxane (25 mL). The resulting slurry was stirred at RT for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic solution was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was chromatographed on silica, eluting with 25%-80% ethyl acetate in isohexane, to give a colourless gum. This material was triturated with diethyl ether to give the desired material as a colourless crystalline solid (1.808 g).
Reaction SMILES: C1(NC(C)C)CCCCC1.C([Li])CCC.[C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH3:17].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]([CH2:42][CH2:43][CH2:44][O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[CH2:40]I)(=[O:33])=[O:32])=[CH:27][CH:26]=1>O1CCCC1.CCCCCC.CN(C)P(N(C)C)(N(C)C)=O>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([S:31]([NH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]([CH2:42][CH2:43][CH2:44][O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[CH2:40][CH2:17][C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])(=[O:32])=[O:33])=[CH:29][CH:30]=1
Reactant: O=S(=O)(NCCCCC(CI)CCCOC1CCCCO1)c1ccc(Cl)cc1
Reactant: CC(=O)OC(C)(C)C
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.11 mL cyclohexyl-isopropylamine (0.68 mmol) in 1 mL dry tetrahydrofuran at 0° C. is added dropwise 0.23 mL (0.57 mmol) of a 2.5 M solution of n-butyllithium in hexane. The mixture is allowed to stir for 15 minutes at 0° C. The reaction mixture is then cooled to -78° C. and 0.077 mL (0.57 mmol) t-butyl acetate is added and the mixture is stirred at -78° C. for 0.5 hour. Then a solution of 0.12 g (0.22 mmol) of 6-(p-chlorophenylsulfonamido)-2-[3-(tetrahydropyranyloxy)propyl]-1-iodohexane in 0.5 mL hexamethylphosphoramide is added followed by 1 ml dry tetrahydrofuran. The reaction temperature is raised to -23° C. and allowed to warm to 0° C. over a period of 1 hour. The reaction is then quenched by the addition of 5 mL saturated aqueous ammonium chloride solution and extracted with ether. The organic layer is washed with water (3×25 mL) and brine, dried, filtered, and concentrated to give a yellow oil which is chromatographed using 3:7 ethyl acetate, hexane to yield t-butyl 8-(p-chlorophenylsulfonamido)-4-[3-(tetrahydropyranyloxy)propyl]-octanoate; NMR (CDCl3): delta 2.2 (t,2H), 1.6 (s,9H); IR (neat): 1721 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([O:14][CH3:15])[C:11]([N+:16]([O-])=O)=[C:10]([NH:19][C:20]([C:22]2[N:23]([CH3:32])[N:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=2[Cl:27])=O)[CH:9]=1.CCOC(C)=O>CC(O)=O.CCOCC.[Fe]>[C:28]([C:25]1[C:26]([Cl:27])=[C:22]([C:20]2[NH:16][C:11]3[C:12]([O:14][CH3:15])=[N:13][C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[CH:9][C:10]=3[N:19]=2)[N:23]([CH3:32])[N:24]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: COc1nc(-c2ccccc2Cl)cc(NC(=O)c2c(Cl)c(C(C)(C)C)nn2C)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1nc(-c2ccccc2Cl)cc2nc(-c3c(Cl)c(C(C)(C)C)nn3C)[nH]c12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [6-(2-chloro-phenyl)-2-methoxy-3-nitro-pyridin-4-yl]-amide (9.10 g, 32.6 mmol, prepared as described in the previous step above) in AcOH (50 mL) was treated with iron powder (6.80 g, 122 mmol) and heated to 100° C. for 3 h. The resulting mixture was cooled to room temperature and treated with EtOAc (100 mL). The resulting mixture was then filtered through a pad of diatomaceous earth and the filtrate was concentrated in vacuo. The residue was purified on silica (0:100-100:0 EtOAc/hexane) to yield a white solid. The solid obtained was dissolved in Et2O (200 mL) with heating and sonication. Hexanes (50 mL) were added and the resulting mixture was concentrated until a precipitate started to form. The solution was left at room temperature overnight and the solid formed was collected by suction filtration to yield 2-(5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl)-6-(2-chloro-phenyl)-4-methoxy-3H-imidazo[4,5-c]pyridine. 1H-NMR (400 MHz, CD3OD) δ: 7.76-7.58 (m, 1H), 7.49 (m, 2H), 7.39 (m, 2H), 4.16 (s, 3H), 4.04 (s, 3H), 1.44 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calculated for C21H21N5OCl2: 430.1 (M+H), Measured: 430.2.
Reaction SMILES: C(OCC)C.[CH3:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])=[O:8].[Br-].CO.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>>[Cl:16][C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[C:7](=[O:8])[CH2:6][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: c1c[nH]cn1
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Agent: [Br-]
Solvent: CO
Solvent: CCOCC
Product: O=C(Cn1ccnc1)c1ccc(Cl)cc1Cl
Reaction time: 1 h
Yield: 80 %

Procedure:
A 300 ml solution of diethyl ether containing 100 g (0.53 mole) of 2,4-dichloroacetophenone was cooled to 0°-5° C., and treated with 85.0 g (0.53 mole) of bromide and stirred one hour. The organic layer was washed with 3×500 ml portions of saturated sodium bicarbonate solution followed by 3×500 ml portions of water. The aqueous layer was removed and the organic layer treated with a 200 ml portion of methanol containing 108.0 g (1.6 mole) of imidazole and stirred in the cold overnight. The solution was concentrated, poured into 1600 ml of H2O with separation of an oil, the aqueous layer decanted, and the oil extracted 2×300 ml of methylene chloride. The combined organic phase was washed 2×300 ml of H2O, dried over magnesium sulfate and concentrated to give 108.8 g (80%) of a red oil. The nitrate salt was formed by treatment of the oil in acetone/ether solution with excess nitric acid, m.p. 161°-163° C. The free base obtained by neutralization was recrystallized from ethanol/water, m.p. 80°-82° C.
Reaction SMILES: [C:1]([C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([N:6]3C(OC(C)(C)C)=O)[CH2:4]1)[CH2:10]2)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH:7]12[CH2:12][C:3]3([C:1]#[N:2])[CH2:10][CH:9]([CH2:11][CH:5]([CH2:4]3)[NH:6]1)[CH2:8]2
Reactant: CC(C)(C)OC(=O)N1C2CC3CC1CC(C#N)(C3)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC12CC3CC(C1)NC(C3)C2
Temperature: 0 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
A 50 mL RB flask fitted with magnetic stirrer was charged with tert-butyl 5-cyano-2-azatricyclo[3.3.1.13,7]decane-2-carboxylate, Intermediate-13 (0.5 g, 1.98 mmol) in DCM (5 mL). Then reaction mixture was cooled to 0° C. and trifluoroacetic acid (1.1 g, 9.54 mmol) was added and stirred for 4 hours. After completion of the reaction (reaction was monitored by LCMS) the reaction mixture was concentrated followed by the process of trituration with mixture of hexane:ether (1:1) to give Intermediate-14 (0.5 g, yield=97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5][CH2:6][NH:7][C:8](=O)[O:9]CC.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O=P(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[Cl:16])[C:8](=[O:9])[NH:7][CH2:6][CH2:5]2
Reactant: CCOC(=O)NCCc1ccc(Cl)c(Cl)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1NCCc2cc(Cl)c(Cl)cc21
Yield: 20.3 %

Procedure:
Using an analogous procedure and workup as described for the preparation of intermediate I-1d above, ethyl 3,4-dichlorophenethylcarbamate (I-55c: 6 g, 22.989 mmol) in POCl3 (60 mL) was reacted with P2O5 (6.52 g, 45.977 mmol) at 120° C. for 1 hour to afford the crude product. Purification by column chromatography on silica gel (30% ethylacetate in hexane) afforded 1.01 g of the product. LCMS: 53.61%, m/z=216.0 (M+1)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-])=O.C(=O)([O-])O.[Na+].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH2:33])[CH:28]=1.[H][H]>C(O)C.[C].[Pd].O1CCCC1.O>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([NH:33][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[N:12]=3)=[CH:4][C:3]=2[NH2:17])[CH:30]=[CH:31][CH:32]=1
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Reactant: [H][H]
Reactant: COc1cccc(N)c1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1cccc(Nc2ccc(-c3nc4ccccc4o3)cc2N)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 15.2 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (300 mg, 1.16 mmol) in ethanol (5 mL) was added sodium hydrogen carbonate (195 mg, 2.32 mmol) and m-anisidine (357 mg, 2.90 mmol), and this was heated to reflux with stirring for 4 hours. After the reaction was complete, this was cooled to room temperature, water was added, and this was extracted with chloroform. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. The crystals obtained were added to a tetrahydrofuran (5 mL) solution containing 10% palladium-carbon (50 mg), a hydrogen atmosphere was substituted in the flask and this was stirred at room temperature for 8 hours. After the reaction was complete, this was filtered through Celite and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (58.5 mg, 15% yield) as a pale yellow oil.
Reaction SMILES: [N:1]1[C:6]([CH3:7])=[CH:5][C:4]([CH3:8])=[CH:3][C:2]=1[CH3:9].[Br:10][CH:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].N>O1CCCC1>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:8][C:4]1[CH:5]=[C:6]([CH3:7])[N:1]=[C:2]([CH3:9])[CH:3]=1
Reactant: Cc1cc(C)nc(C)c1
Reactant: CCCCCC(Br)Br
Agent: N
Solvent: C1CCOC1
Product: Cc1cc(CCCCCCCBr)cc(C)n1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Sodium amide was formed from sodium (1.0 g, 43.5 mmol) in liquid ammonia (100 ml) according to Example 1. Collidine (1) (5.0 g, 41.3 mmol) dissolved in tetrahydrofuran (5 ml) was added dropwise and after 45 min a well-cooled solution of dibromohexane (51.2 g, 210 mmol) in THF (100 ml) was added quickly. The reaction mixture was stirred for 1 h at -40° C. and then left stirring overnight during which times ammonia evaporated.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-])=O)[CH:11]=1)[NH:8][CH2:7][CH:6]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:5]2>C(O)C.[Pd]>[CH2:19]([N:15]([CH2:16][CH2:17][CH3:18])[CH:6]1[CH2:5][C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=[CH:2][CH:3]=2)[NH:8][CH2:7]1)[CH2:20][CH3:21]
Reactant: CCCN(CCC)C1CNc2c(cc(Br)cc2[N+](=O)[O-])C1
Agent: [Pd]
Solvent: CCO
Product: CCCN(CCC)C1CNc2c(N)cccc2C1
Reaction time: 18 h
Yield: 101.3 %

Procedure:
A mixture of 6-bromo-1,2,3,4-tetrahydro-8-nitro-N,N-dipropyl-3-quinolinamine (2.7 g) and 10% palladium charcoal (0.5 g) in ethanol (150 mL) was hydrogenated for 18 hours. The solution was filtered and the ethanol evaporated to give 1.9 g of 1,2,3,4-tetrahydro-N3, N3 -dipropyl-3,8-quinolinediamine as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19](=O)[CH:20]=[CH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:6][N:7]=1.Cl.[CH:30]([NH2:32])=[NH:31].[OH-].[Na+]>>[CH2:17]([S:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:4]=[C:3]([C:19]3[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:32]=[CH:30][N:31]=3)[C:2]([NH2:1])=[N:7][CH:6]=2)[CH2:9][CH2:10]1)(=[O:16])=[O:15])[CH3:18]
Reactant: N=CN
Reactant: CCS(=O)(=O)N1CCN(c2cnc(N)c(C(=O)C=Cc3ccccc3)n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3cc(-c4ccccc4)ncn3)n2)CC1
Temperature: 25 °C
Yield: 153 %

Procedure:
A mixture of 1-(3-amino-6-(4-(ethylsulfonyl)piperazin-1-yl)pyrazin-2-yl)-3-phenylprop-2-en-1-one (45 mg, 0.1121 mmol), formamidine hydrochloride (9.026 mg, 0.1121 mmol) and NaOH (4.932 mg, 0.1233 mmol) were heated at reflux for 1 hour. The reaction mixture was allowed to cool to ambient temperature and the solvent removed in vacuo. The resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B, (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound (73 mg, 4% Yield). 1H NMR (400.0 MHz, DMSO) d 1.25 (t, 3H), 3.12 (q, 2H), 3.36-3.38 (m, 4H), 3.56-3.59 (m, 4H), 7.15 (br s, 2H), 7.60-7.61 (m, 3H), 8.25-8.26 (m, 3H), 8.76 (s, 1H) and 9.31 (s, 1H) ppm; MS (ES+) 426.0