Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH:15]1[CH2:22][CH2:21][CH2:20][CH:16]1[C:17]([OH:19])=[O:18]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([O:19][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)C1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
Benzyl bromide (2 eq.) and K2CO3 (2.5 eq) were added to a solution (0.6 M) of DL-proline in DMF. The reaction was stirred at 100° C. overnight. The solution was allowed to cool to RT and then diluted with EtOAc and washed with 1 N HCl, brine, before being dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by FC (PE/EtOAc 90:10) to afford the product (43%). (ES+) m/z 296 (M+H)+
Reaction SMILES: O1CCCC1.[CH3:6][C:7]1([CH3:19])[C:11]([CH3:13])([CH3:12])[O:10][B:9]([C:14]2[CH:15]=[N:16][NH:17][CH:18]=2)[O:8]1.[H-].[Na+].[CH3:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][O:26][CH2:27]Cl>O>[CH3:6][C:7]1([CH3:19])[C:11]([CH3:12])([CH3:13])[O:10][B:9]([C:14]2[CH:18]=[N:17][N:16]([CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:30])([CH3:29])[CH3:22])[CH:15]=2)[O:8]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OB(c2cnn(COCC[Si](C)(C)C)c2)OC1(C)C
Reaction time: 0.08 h
Yield: 45.7 %

Procedure:
Under argon atmosphere, to 20 ml of tetrahydrofuran solution containing 1.09 g (5.62 mmol) of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole was added 443 mg (11.1 mmol) of 60% sodium hydride under ice-cooling, and the mixture was stirred for 5 minutes. Then, 3 ml (17.0 mmol) of (2-trimethylsilylethoxy)methyl chloride was added dropwise to the mixture, and the mixture was reacted at room temperature for 2 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, and the solutions were washed successively with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 832 mg of the title compound as a colorless oil. (Yield: 46%)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:12]2[NH:16][C:15](=[O:17])[N:14]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:13]=2)[C:6]([CH:9]([F:11])[F:10])=[N:7][CH:8]=1.[CH:28]([S:31](Cl)(=[O:33])=[O:32])([CH3:30])[CH3:29]>C(Cl)Cl>[F:10][CH:9]([F:11])[C:6]1[N:7]=[CH:8][C:3]([CH2:2][NH:1][S:31]([CH:28]([CH3:30])[CH3:29])(=[O:33])=[O:32])=[CH:4][C:5]=1[C:12]1[NH:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][CH:19]=2)[N:13]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NCc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NCc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Yield: 12.9 %

Procedure:
The title compound was prepared by following the procedure as described in Example-108 by using 3-(5-(aminomethyl)-2-(difluoromethyl)pyridin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (step-1 of Example-186, 0.75 g, 0.19 mmol), isopropyl sulphonyl chloride (0.042 g, 0.29 mmol), TEA (0.059 g, 0.58 mmol), and DCM (10 mL) to afford 0.012 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 1.32 (s, 3H), 1.35 (s, 3H), 3.15 (m, 1H), 4.36 (s, 2H), 7.26-7.66 (m, 3H), 8.08-8.11 (m, 3H), 8.65 (s, 1H); MS (m/z): 492.08 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[C:12]=2[C:18]2[NH:19][C:20]3[C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=[CH:23][C:21]=3[N:22]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC1C=C(C=CC=1)CNC(C1C2NC(C3C(=O)NC=CC=3NC[C@@H](O)C3C=CC=CC=3)=NC=2C=CC=1)=O>CN(C=O)C>[CH2:30]([NH:37][C:27]([C:26]1[C:20]2[NH:19][C:18]([C:12]3[C:13](=[O:17])[NH:14][CH:15]=[CH:16][C:11]=3[NH:10][CH2:9][CH2:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[N:22][C:21]=2[CH:23]=[CH:24][CH:25]=1)=[O:29])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(O)c1cccc2nc(-c3c(NCCc4cccc(Cl)c4)cc[nH]c3=O)[nH]c12
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(NCc1cccc(F)c1)c1cccc2nc(-c3c(NC[C@@H](O)c4ccccc4)cc[nH]c3=O)[nH]c12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccccc1)c1cccc2nc(-c3c(NCCc4cccc(Cl)c4)cc[nH]c3=O)[nH]c12

Procedure:
2-{4-[2-(3-chloro-phenyl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazole-4-carboxylic acid benzylamide was synthesized from 2-{4-[2-(3-chloro-phenyl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazole-4-carboxylic acid, benzylamine, DIEA, HATU and DMF using a similar procedure as 2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazole-4-carboxylic acid 3-fluoro-benzylamide yielding 2-{4-[2-(3-chloro-phenyl)-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazole-4-carboxylic acid benzylamide. LC/MS calcd for C28H24ClN5O2 (m/e) 497.0, obsd 498 (M+H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[CH2:8][CH:9]=[CH2:10].[CH2:11]([O:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([OH:22])[CH:16]=1)[CH3:12]>CC(C)=O>[CH2:11]([O:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH2:10][CH:9]=[CH2:8])[CH:16]=1)[CH3:12]
Reactant: CCOC(=O)c1ccc(F)c(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(C(=O)OCC)ccc1F
Temperature: 25 °C

Procedure:
K2CO3 (96.9 mmol) and 3-bromo-1-propen (64.6 mmol) are added to a solution of 4-fluoro-3-hydroxy-benzoic acid ethyl ester (32.3 mmol) in acetone (50 mL). The mixture is heated to reflux for 16 h, filtered and cooled to RT. The solvents are removed in vacuo to give the desired product which is used without further purification. LC-MS: tR=1.01 min; [M+CH3CN+H]+=266.0.
Reaction SMILES: [BH4-].[Li+].C([O:5][C:6]([CH:8]1[CH:12]([OH:13])[CH2:11][N:10]([C:14](=[O:31])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:9]1)=O)C>O1CCCC1.CO.C(Cl)(Cl)Cl>[CH2:24]([O:23][C:21](=[O:22])[NH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]([N:10]1[CH2:9][CH:8]([CH2:6][OH:5])[CH:12]([OH:13])[CH2:11]1)=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)C1CN(C(=O)CCCCCNC(=O)OCc2ccccc2)CC1O
Agent: [BH4-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCCCCCC(=O)N1CC(O)C(CO)C1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To the solution of lithium borohydride (0.305 g, 13 mmol) in anhydrous tetrahydrofuran (25 mL) was added a solution of ethyl ester 62 (3.74 g, 9.2 mmol) in THF (25 mL) over a period of 30 mins at 0° C. After the addition the reaction mixture was brought to room temperature and stirred further under argon. The completion of the reaction was ascertained by TLC after 4 h. (Rf=0.4 in 10% MeOH/CHCl3). The reaction mixture was evaporated to dryness and cooled to 0° C. To the residue 3N HCl (40 mL) was added slowly. After stirring for 30 mins the product was extracted with dichloromethane (3×75 mL). The combined organic layer was washed with brine and dried over sodium sulfate. Organic layer was filtered and evaporated to dryness. Compound 63 was purified by column chromatography first by eluting with dichloromethane/methanol (5%) (3.2 g, 92%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:8])=[N:6][CH:7]=1.[I:9]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[Br:8][C:5]1[N:6]=[C:7]([I:9])[C:2]([NH2:1])=[CH:3][CH:4]=1
Reactant: Nc1ccc(Br)nc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1ccc(Br)nc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
5.0 g 5-Amino-2-bromopyridine were dissolved in 70 ml ethanol. 9.0 g silver sulfate and 7.33 g iodine were added. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue diluted with 500 ml ethyl acetate and filtered over a celite pad. The filtrate was washed with 200 ml saturated Na2S203 solution and water, dried over MgSO4 and then the solvent was removed in vacuo to obtain 7.7 g 6-Bromo-2-iodo-pyridin-3-ylamine.
Reaction SMILES: [Mg].[CH3:2][Si:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(Cl)Cl.[CH2:12]1[CH2:16]O[CH2:14][CH2:13]1.C=CC=C>CCOCC.C(O)(C)C>[CH3:2][Si:3]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:14][CH:13]=[CH:12][CH2:16]1
Reactant: C[Si](Cl)(Cl)c1ccccc1
Reactant: C1CCOC1
Agent: C=CC=C
Agent: [Mg]
Solvent: CCOCC
Solvent: CC(C)O
Product: C[Si]1(c2ccccc2)CC=CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
In a 500 mL two neck rb flask equipped with a reflux condenser, a Teflon covered magnetic stirring bar and a rubber septum was placed magnesium powder (9.6 g, 0.4 mol), methylphenyldichlorosilane (38.2 g, 0.2 mol) and THF (300 mL). The reflux condenser was connected to a refrigeration unit. Isopropyl alcohol cooled to -20° C. was circulated through the reflux condenser. 1,3-Butadiene (15.1 g, 0.28 mol) was condensed at -78° C. into a volumetric flask which was sealed with a rubber septum. The 1,3-butadiene was transferred into the reaction via a cannula. The reaction mixture was stirred at rt for 24 h. Ether (2×100 mL) was added. The organic solution was decanted from the magnesium chloride salts. These were transferred to a sintered glass funnel and were washed with ether (100 mL). The combined organic solution was washed with water (2×50 mL), dried over anhydrous magnesium sulfate, filtered and the volatile solvents removed by evaporation under reduced pressure. The residue was purified by distillation through a 10 cm vacuum jacketed Vigreux column. The expected compound (boiling point 85°-87° C. at 4 mm Hg, 22.6 g, 65 % yield) was collected.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.O.[C:24]1([S:30]([OH:33])(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[CH3:1][C:2]1[S:6][C:5]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)[C:4]=2[CH:3]=1.[S:30]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([O-:33])(=[O:32])=[O:31]
Reactant: O=S(=O)(O)c1ccccc1
Agent: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Solvent: CC(C)=O
Solvent: O
Product: O=S(=O)([O-])c1ccccc1

Procedure:
To a solution of 5.0 g of olanzapine in 150 ml acetone was slowly added a solution of 2.8 g benzenesulfonic acid monohydrate in 50 ml acetone at room temperature under stirring. The mixture was stirred 1 hour at room temperature and then at 4° C. overnight. Crystals were isolated by filtration, washed with 20 ml of acetone and 20 ml of ether and dried at 40° C. under vacuum overnight. Yield: 5.98 g (79%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][CH3:12])=[C:4]([CH3:13])[CH:3]=1.CC1(C)COB(B2OCC(C)(C)CO2)OC1.CC([O-])=O.[K+].ClCCl.Cl[C:39]1[N:44]=[C:43]([O:45][CH3:46])[C:42]([C@@:47]2([CH3:54])[CH2:52][CH2:51][CH2:50][NH:49][C:48]2=[O:53])=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH2:11]([N:8]1[C:9]2[C:5](=[C:4]([CH3:13])[CH:3]=[C:2]([C:39]3[N:44]=[C:43]([O:45][CH3:46])[C:42]([C@@:47]4([CH3:54])[CH2:52][CH2:51][CH2:50][NH:49][C:48]4=[O:53])=[CH:41][CH:40]=3)[CH:10]=2)[CH:6]=[N:7]1)[CH3:12]
Reactant: COc1nc(Cl)ccc1[C@@]1(C)CCCNC1=O
Reactant: CCn1ncc2c(C)cc(Br)cc21
Agent: CC(=O)[O-]
Agent: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCn1ncc2c(C)cc(-c3ccc([C@@]4(C)CCCNC4=O)c(OC)n3)cc21
Temperature: 110 °C
Yield: 94.5 %

Procedure:
An oven-dried 20 mL vial was charged with 6-bromo-1-ethyl-4-methyl-1H-indazole (345 mg, 1.4 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (591 mg, 1.7 mmol), oven dried KOAc (566 mg, 5.8 mmol), anhydrous dioxane (5 mL) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropaladium(II) complex with dichloromethane (56.8 mg, 0.072 mmol). The mixture was bubbled with nitrogen gas for 5 minutes, and the reaction vial was sealed and heated at 110° C. for 1 h. After being cooled to r.t., to the reaction mixture was added (R)-3-(6-chloro-2-methoxypyridin-3-yl)-3-methylpiperidin-2-one (294 mg, 1.2 mmol), an aqueous solution of sodium carbonate (2M, 1.8 mL, 3.6 mmol) and additional [1,1′-Bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (56.8 mg, 0.072 mmol). The reaction mixture was degassed with nitrogen, and heated at 100° C. for 75 min. The reaction mixture was cooled to r.t., diluted with EtOAc, filtered over Celite®, and the filtrate was concentrated. The crude residue was purified by silica gel column chromatography (0-10% EtOH/DCM, 40 g column) to afford (R)-3-(6-(1-ethyl-4-methyl-1H-indazol-6-yl)-2-methoxypyridin-3-yl)-3-methylpiperidin-2-one (429 mg, 79%) as an off-white solid. 1H NMR (600 MHz, CDCl3) δ 1.56 (t, 3H), 1.64-1.91 (m, 2H), 1.74 (s, 3H), 1.97-2.08 (m, 1H), 2.35-2.44 (m, 1H), 2.66 (s, 3H), 3.39-3.50 (m, 1H), 3.51-3.62 (m, 1H), 4.13 (s, 3H), 4.51 (q, 2H), 6.07 (brs, 1H), 7.43 (d, 1H), 7.55 (s, 1H), 7.68 (d, 1H), 7.89 (s, 1H), 8.01 (s, 1H). MS (AP+)(M+H) 379.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>O>[Br:7][C:4]1[S:3][C:2]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:5]=1
Reactant: Brc1cnc(Br)s1
Reactant: C1COCCN1
Solvent: O
Product: Brc1cnc(N2CCOCC2)s1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
2,5-Dibromo-1,3-thiazole (500 mg) was mixed with morpholine (2 ml), followed by stirring at 60° C. for 5 hours. Water was added to the reaction mixture, followed by stirring for 1 hour, and the resulting insoluble matter was collected by filtration, followed by washing with water, to obtain 4-(5-bromo-1,3-thiazol-2-yl)morpholine (475 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].C(N(CC)CC)C.[C:32](Cl)(=[O:48])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>ClCCl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][O:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:32](=[O:48])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)NCCOCCn1c(CCOC)nc2c(N)nc3ccccc3c21
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
Under a nitrogen atmosphere, a suspension of 1-[2-(2-aminoethoxy)ethyl]-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (140.5 mg, 0.428 mmol) in a mixture of dichloromethane (3.5 mL) and triethylamine (150 μL, 1.07 mmol) was cooled to 0° C. Palmitoyl chloride (130 μL, 0.428 mmol) was slowly added. The reaction mixture was allowed to stir at 0° C. for 2 hours at which time analysis by thin layer chromatography indicated that there was no starting material left. The reaction mixture was diluted with dichloromethane (30 mL), washed with saturated sodium bicarbonate solution (2×5 mL), dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (12 g of silica gel eluted with 2% methanol in dichloromethane) to provide 183 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)hexadecanamide as a white powder.
Reaction SMILES: [Se](=O)=[O:2].[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)(=[O:6])[CH3:5]>>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]([CH:5]=[O:2])=[O:6]
Reactant: O=[Se]=O
Reactant: CC(=O)c1ccccn1
Product: O=CC(=O)c1ccccn1
Yield: 72.2 %

Procedure:
2-Pyridylglyoxal (8.0 g, crude) was prepared from selenium dioxide (15 g, 135 mmol) and 2-acetyl pyridine (10 g, 82 mmol) according to the typical procedure used for Preparation 1.
Reaction SMILES: C[O-].[Na+:3].[CH3:4][C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH2:16][O:17][C:18]1[CH:38]=[CH:37][C:21]([CH2:22][O:23]/[N:24]=[C:25](/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)\[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:20][CH:19]=1>CO>[CH3:4][C:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:7][C:6]=1[CH2:16][O:17][C:18]1[CH:38]=[CH:37][C:21]([CH2:22][O:23]/[N:24]=[C:25](/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)\[CH2:26][CH2:27][C:28]([O-:30])=[O:29])=[CH:20][CH:19]=1.[Na+:3]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCC(=O)O)c2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCC(=O)[O-])c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
Sodium methoxide (108 mg) was added to a solution of E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyric acid (941 mg) in methanol (5 ml), which was stirred at room temperature for 1 hour and concentrated. The remaining crystals were recrystallized from methanol-diethyl ether to obtain sodium E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate (456 mg, yield 46%) as colorless crystals. m.p. 64-70° C.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[S:9]([CH2:19][CH2:20][CH2:21]S(C1C=CC(C)=CC=1)(=O)=O)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]>CN(C=O)C>[S:9]([CH2:19][CH2:20][CH2:21][C:6]1[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[NH:8][CH:7]=1)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: Cc1ccc(S(=O)(=O)CCCS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=[N+]([O-])c1ncc[nH]1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)CCCc2c[nH]c([N+](=O)[O-])n2)cc1
Temperature: 80 °C

Procedure:
To a stirred mixture containing 2-nitroimidazole (1 g, 8.34 mmol) and Cs2,CO3 (2.9 g, 8.90 mmol) in dimethylformaide (DMF, 50 ml), 1,3-ditosylpropane (3.84 g, 9.99 mmol) was added. The reaction was heated at 80° C. for 3 hours. The solvent was evaporated under vacuum and the residue was suspended in ethylacetate. The solid was filtered, the solvent was concentrated, loaded on a silica gel-packed column and eluted with hexane:ethylacetate (1:1). The product, 3-tosylpropyl-(2-nitroimidazole), was isolated (1.67 g, 57.5%) with m.p. 108-111° C. 1H-NMR (CDCl3) δ 2.23 (m, 2H), 2.48 (S, 3H), 4.06 (t, 2H, J=5.7 Hz), 4.52 (t, 2H, J=6.8 Hz), 7.09 (S, 1H), 7.24 (S, 1H), 7.40 (d, 2H, J=8.2 Hz), 7.77 (d, 2H, J=8.2 Hz).
Reaction SMILES: [CH2:1]([C:5]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)([C:11]([O:13]CC)=[O:12])[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[K+]>O.CO>[CH2:1]([C:5]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)([C:11]([OH:13])=[O:12])[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(CC1CCCCC1)(C(=O)OCC)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCC(CC1CCCCC1)(C(=O)O)C(=O)O
Temperature: 0 °C

Procedure:
A mixture of diethyl 2-n-butyl-2-(cyclohexylmethyl)malonate (1.8 g) and potassium hydroxide (10 g) in water (10 ml) and methanol (10 ml) were heated under reflux for 4 hours. The methanol was evaporated under reduced pressure and the residue treated with water (50 ml), cooled to 0° C., and acidified with concentrated hydrochloric acid. The product was extracted with ethyl acetate and the extracts washed with brine, dried (MgSO4) and evaporated to give 2-n-butyl-2-(cyclohexylmethyl)malonic acid. Without further purification the acid was heated to about 160° until the evolution of carbon dioxide ceased, and cooled to give 2-(cyclohexylmethyl)hexanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:21]([O:23]CC)=[O:22])=[CH:5][CH:4]=1.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:21]([OH:23])=[O:22])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1nc(Nc2ccccc2)oc1-c1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-c2oc(Nc3ccccc3)nc2C(=O)O)cc1
Temperature: 55 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a stirred solution of ethyl 5-(4-methoxyphenyl)-2-(phenylamino)oxazole-4-carboxylate in MeOH (5 mL) at 55° C. was added 1M aqueous potassium hydroxide solution (2.075 mL, 2.08 mmol) and the reaction mixture stirred at 55° C. overnight. The reaction was cooled to room temperature and the MeOH removed in vacuo. The remaining solution was diluted with water and washed with DCM. The aqueous phase was acidified with 2M aqueous HCl (2 mL) and extracted with EtOAc. The combined organic phase was washed with brine, dried over MgSO4 and the solvent removed in vacuo to afford 5-(4-methoxyphenyl)-2-(phenylamino)oxazole-4-carboxylic acid (0.012 g, 0.039 mmol, 48%) as a white solid which was used without further purification. LCMS (1) Rt: 1.44 min; m/z (ES+) 311.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:17])[CH:3]=1.C(Cl)CCl.C1C=C[C:25]2N(O)N=[N:28][C:26]=2[CH:27]=1.CCN(C(C)C)C(C)C.C1(N)CC1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([NH:28][CH:26]3[CH2:27][CH2:25]3)=[O:16])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:17])[CH:3]=1
Reactant: O=C(O)c1cnccc1-c1ccc(Cl)cc1F
Reactant: On1nnc2ccccc21
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(NC1CC1)c1cnccc1-c1ccc(Cl)cc1F
Reaction time: 0.08 h
Yield: 83 %

Procedure:
To a solution of 4-(4-chloro-2-fluorophenyl)nicotinic acid (500 mg, 1.987 mmol) (prepared as in Ex. 2, Part A) in DMF (6 mL) cooled to 0° C. was added EDC (571 mg, 2.98 mmol) and HOBT (609 mg, 3.97 mmol) and the mixture was stirred for 5 min. To the resultant solution DIPEA (1.04 mL, 5.96 mmol) followed by cyclopropanamine (567 mg, 9.93 mmol) was added and the mixture was stirred at room temperature for 12 h. The reaction mixture was treated with ice and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (1×10 mL), dried (Na2SO4) and concentrated under reduced pressure to afford 4-(4-chloro-2-fluorophenyl)-N-cyclopropylnicotinamide (480 mg, 1.65 mmol, 83% yield). LC/MS (ESI) m/e 291.0 [(M+H)+, calcd for C15H13ClFN2O 291.1]; LC/MS retention time (method C): tR=1.79 min.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)[CH:17]=1)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@@H:8]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[NH:24][CH:23]=2)[CH:17]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ccnc(-c2c[nH]c3ccccc23)c1)C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](C(=O)N1CCC[C@H]1c1ccnc(-c2c[nH]c3ccccc23)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of ((S)-1-Cyclohexyl-2-{(S)-2-[2-(1H-indol-3-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-carbamic acid tert-butyl ester (120 mg, 0.24 mmol) in DCM (2 mL) is added TFA (2 mL). After stirring at room temperature for 1 h, the reaction mixture is concentrated down to give crude (S)-2-Amino-2-cyclohexyl-1-{(S)-2-[2-(1H-indole-3-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-ethanone, which is used in next step without purification.