Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](S(C3C=CC(C)=CC=3)(=O)=O)[N:11]=[C:10]([CH:23]3[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]3)[C:9]=2[C:32]2[CH:37]=[CH:36][N:35]=[CH:34][N:33]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:29]([N:26]1[CH2:25][CH2:24][CH:23]([C:10]2[C:9]([C:32]3[CH:37]=[CH:36][N:35]=[CH:34][N:33]=3)=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[NH:12][N:11]=2)[CH2:28][CH2:27]1)(=[O:31])[CH3:30]
Reactant: CC(=O)N1CCC(c2nn(S(=O)(=O)c3ccc(C)cc3)c(-c3ccc(Cl)cc3)c2-c2ccncn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)N1CCC(c2n[nH]c(-c3ccc(Cl)cc3)c2-c2ccncn2)CC1

Procedure:
This reaction was carried out in a 50 ml round bottom flask. 4-{3-(1-Acetylpiperidin-4-yl)-5-(4-chlorophenyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrazole-4-yl}pyrimidine (9) (0.5 g) charged to the reactor, followed by ethanol (5 ml), which, in turn, was followed by potassium carbonate (1 g). The mixture was stirred until completion of the reaction, as indicated by liquid chromatography. The ethanol was then removed in vacuo, and the resulting solid was dissolved in ethyl acetate. The organic layer washed with water, and concentrated in vacuo to yield a white solid. The product had the following characteristics: 1H NMR (CDCl3, 300 MHz) δ 9.27 (1H, s), 8.54 (1H, broad-s), 7.36 (4H, s), 7.01 (1H, d, J=5.1 Hz), 4.82–4.72 (1H, m), 4.02–3.90 (1H, m), 3.72–3.59 (1H, m), 3.30–3.18 (1H, m), 2.79–2.62 (1H, m), 2.18 (3H, s), 2.15–1.78 (4H, m).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[NH:12][C:11]2=[O:19])[CH:7]=[CH:8][CH:9]=1.[CH3:20][O:21][C:22](=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br>CN(C=O)C>[CH3:20][O:21][C:22](=[O:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:12]1[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=2)[C:11]1=[O:19]
Reactant: O=c1[nH]c2ccccc2n1-c1cccc(Cl)c1
Reactant: COC(=O)CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(=O)n(-c2cccc(Cl)c2)c2ccccc21

Procedure:
The product is produces as described in example 1 from 1.2 g. of NaH (80% suspension in mineral oil), 9.8 g. of 1-(3-chlorophenyl)-benzimidazolin-2-one, 80 cc. of DMF, 9.5 g. of 8-bromocaprylic acid methyl ester and 1.2 g. of NaJ.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[I:8]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[O:10])[CH:5]=[N:6][C:7]=1[I:8]
Reactant: OCc1cnc(I)c(Cl)c1
Solvent: ClCCl
Product: O=Cc1cnc(I)c(Cl)c1
Temperature: 40 °C
Reaction time: 24 h
Yield: 67.1 %

Procedure:
A mixture of (5-chloro-6-iodo-3-pyridinyl)methanol (392 mg, 1.455 mmol), CrO2 (Magtrieve) (2.444 g, 29.1 mmol), and DCM (20 ml) was stirred at 40° C. for 24 h. Some starting material was still observed by TLC. More CrO2 (0.61 g) was added and the suspension stirred at 40° C. overnight. TLC showed full conversion. Filtration and concentration afforded 5-chloro-6-iodo-3-pyridinecarbaldehyde (261 mg, 67%) as a brown solid pure enough to be used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]([NH2:15])=[C:6]2[C:10]=1[N:9]([CH2:11][CH3:12])[S:8](=[O:14])(=[O:13])[CH2:7]2.[O:17]=[C:18](Cl)OC(Cl)(Cl)Cl.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[C:10]2[N:9]([CH2:11][CH3:12])[S:8](=[O:14])(=[O:13])[CH2:7][C:6]=2[C:5]([N:15]=[C:18]=[O:17])=[C:4]([F:16])[CH:3]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CCN1c2c(Cl)cc(F)c(N)c2CS1(=O)=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCN1c2c(Cl)cc(F)c(N=C=O)c2CS1(=O)=O

Procedure:
To a mixture of 7-chloro-1-ethyl-5-fluoro-1,3-dihydro-2,1-benzisothiazol-4-amine-2,2-dioxide (1.30 g, 4.91 mmol), diphosgene (1.17 g, 1.2 eq) in p-dioxane (20 mL), triethylamine (0.6 g, 1.2 eq) was added and the resulting reaction mixture was heated at reflux for overnight. The precipitated triethylamine hydrochloride was filtered off and the solvents were removed in vacuo and dried to give the title compound of Step A as a brown semisolid. 1H NMR (CDCl3, 400 MHz): δ 7.21 (d,1H, J=9.5 Hz), 4.28 (s,2H), 3.94 (q,2H), 1.22 (t,3H, J=7.5 Hz).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[O:6][C:7]1[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([Cl:16])[N:10]=[C:9]([Cl:17])[N:8]=1.[C:22]([O-:25])(=[O:24])[CH3:23].[Na+]>>[Cl:17][C:9]1[N:8]=[C:7]([O:6][C:5]2[CH:4]=[C:3]([CH:20]=[C:19]([CH3:21])[CH:18]=2)[CH2:2][O:25][C:22](=[O:24])[CH3:23])[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([Cl:16])[N:10]=1
Reactant: CC(=O)[O-]
Reactant: Cc1cc(CBr)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Agent: [Na+]
Product: CC(=O)OCc1cc(C)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
To a stirred solution of (66) (14.4 g, 36.9 mmol) in anhydrous DMF-(50 ml), was added sodium acetate (6.05 g, 73.8 mmol) and the mixture was stirred in an oil bath (90˜100° C.) for overnight. After cooling to room temperature, the mixture was partitioned between ether and water. The ether layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ether: hexanes (from 1:9 to 1:4)) to afford 10 g (73%) of a white solid. m.p. 76-77° C.; 1H NMR (200 MHz, CDCl3) δ 1.41 (6H, d, J=7.2 Hz), 2.12 (3H, s), 2.39 (3H, s), 3.58 (1H, m), 5.09 (2H, s), 6.88 (1H, s), 6.93 (1H, s), 7.08 (1H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](O)=[O:15])[CH2:12][C@:11]2([CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(N(C)C)=C(C)C.[F:33][C:34]1[C:40]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:39][CH:38]=[CH:37][C:35]=1[NH2:36].CCN(C(C)C)C(C)C>C(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:15])[NH:36][C:35]2[CH:37]=[CH:38][CH:39]=[C:40]([O:41][C:42]([F:43])([F:44])[F:45])[C:34]=2[F:33])[CH2:12][C@:11]2([CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[C@H:9]1[CH2:10]2)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1[C@H](C(=O)O)C[C@@]2(COC3CCCCO3)C[C@@H]12
Reactant: Nc1cccc(OC(F)(F)F)c1F
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@H](C(=O)Nc2cccc(OC(F)(F)F)c2F)C[C@@]2(COC3CCCCO3)C[C@@H]12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of (1R,3S,5S)-5-(tetrahydro-pyran-2-yloxymethyl)-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (100 mg, 0.29 mmol) in dry CH2Cl2 (1 mL) under argon at 0° C. was added 1-chloro-N,N,2-trimethylpropenylamine (58 μL, 0.44 mmol) and the reaction mixture was stirred at 0° C. for 1.5 h. 2-Fluoro-3-(trifluoromethoxy)aniline (86 mg, 0.44 mmol) was added, followed by DIPEA (100 μL, 0.59 mmol) and the mixture was stirred at RT overnight. Then poured into water and extracted with CH2Cl2 (×2), the organics were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (eluent: c-hexane to c-hexane/EtOAc 85:15). TLC, Rf (c-hexane/EtOAc 2:1)=0.45; MS (UPLC/MS): 519.3 [M+H]+, 536.3 [M+NH4]+, 517.4 [M−H]−, 563.3 [M−HCOO]−; tR (HPLC conditions f): 2.51 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.Br[C:15]1[S:19][C:18]([C:20]2([OH:24])[CH2:23][CH2:22][CH2:21]2)=[N:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[NH2:1][C:2]1[CH:3]=[C:4]([C:15]2[S:19][C:18]([C:20]3([OH:24])[CH2:23][CH2:22][CH2:21]3)=[N:17][CH:16]=2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: OC1(c2ncc(Br)s2)CCC1
Reactant: Nc1cc(B(O)O)cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1cc(-c2cnc(C3(O)CCC3)s2)cc([N+](=O)[O-])c1
Temperature: 85 °C
Yield: 91.9 %

Procedure:
To a solution of commercially available (3-amino-5-nitrophenyl)boronic acid (18 g, 99 mmol) and Intermediate 1 (25.5 g, 109 mmol) in DME (360 mL) were added tetrakis(triphenyl-phosphine)palladium(0) (5.72 g, 4.95 mmol) and 2M Na2CO3(aq) (148 mL, 297 mmol), and the mixture was degassed and then heated to 85° C. for 5 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate (500 mL) and filtered through Celite (ethyl acetate rinse). The filtrate was washed with brine (300 mL), dried (Na2SO4) and concentrated in vacuo. The impure material was split into two batches, and each purified by Chromatography on silica gel (70:30 to 0:100 hexanes:ethyl acetate) then the product fractions from the two purifications were combined and concentrated in vacuo to provide 26.53 g (91 mmol, 92%) of 1-[5-(3-amino-5-nitrophenyl)-1,3-thiazol-2-yl]cyclobutanol as a green solid. MS ESI: [M+H]+ m/z 292.0. 1H NMR (DMSO-d6): δ 8.15 (1H, s), 7.54 (1H, s), 7.33 (1H, s), 7.14 (1H, s), 6.58 (1H, s), 6.00 (2H, s), 2.56-2.47 (2H, m), 2.39-2.29 (2H, m), 1.95-1.83 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:13])([CH3:14])[C:6]=3[CH:15]=2)=[CH:19][CH:18]=1
Reactant: CN1C(=O)OC(C)(C)c2cc(N)ccc21
Reactant: OB(O)c1ccc(Cl)cc1
Product: CN1C(=O)OC(C)(C)c2cc(Nc3ccc(Cl)cc3)ccc21

Procedure:
Prepared from 6-amino-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 4-chlorophenyl boronic acid according to the coupling procedure described in example 1. MS (ESI) m/z [M+H]+ (317/319); MS (ESI) m/z [M−H]−(315/317); Anal. calcd for C17H17ClN2O2: C, 64.46; H, 5.41; N, 8.84. Found: C, 63.40; H, 5.46; N, 7.97.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:15]1([CH2:18][CH:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=2)[CH2:20][NH2:21])[CH2:17][CH2:16]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1)[CH2:18][CH:15]1[CH2:16][CH2:17]1)=[O:6]
Reactant: NCC(CC1CC1)c1ccc(C(F)(F)F)nc1
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(Cl)c(C(=O)NCC(CC2CC2)c2ccc(C(F)(F)F)nc2)c1

Procedure:
From 2-chloro-5-(methylsulfonyl)benzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-1-amine. LCMS (MH+): m/z=461.1, tR (minutes, Method G)=2.88
Reaction SMILES: Cl[C:2]1[C:11]2[CH:12]=[CH:13][N:14]=[CH:15][C:10]=2[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].O>CN1C(=O)CCC1>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:11]3[CH:12]=[CH:13][N:14]=[CH:15][C:10]=3[C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[N:3]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Clc1nc2cnccc2c2cnccc12
Reactant: Nc1cccc(Cl)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: Clc1cccc(Nc2nc3cnccc3c3cnccc23)c1
Temperature: 120 °C

Procedure:
5-chloropyrido[4,3-c][1,7]naphthyridine (10 mg) was mixed in NMP (0.3 ml) with 3-chloroaniline (60 ul) and the mixture was heated at 120° C. for 10 min. Water was added and the resulting solid was filtered and dried. N-(3-chlorophenyl)pyrido[4,3-c][1,7]naphthyridin-5-amine was isolated as a solid (5 mg). LCMS (ES)>95% pure, m/z 307 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5](=[C:9]([Cl:11])[CH:10]=1)[C:6]([OH:8])=O.[NH:13]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)C(=O)C1=O.OO.ClC1C=CC=C(C(O)=O)C=1N.NOC1CCCCCC=1>C1(C)C=CC=CC=1>[Cl:11][C:9]1[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]2[C:5]=1[C:6](=[O:8])[N:13]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:23]1=[N:12]2
Reactant: Nc1cc(Cl)cc(Cl)c1C(=O)O
Reactant: O=C1Nc2ccccc2C1=O
Agent: NOC1=CCCCCC1
Agent: Nc1c(Cl)cccc1C(=O)O
Agent: OO
Solvent: Cc1ccccc1
Product: O=c1c2c(Cl)cc(Cl)cc2nc2n1CCCCC2
Temperature: 25 °C

Procedure:
To a stirred suspension of 15 g of 4,6-dichloroanthranilic acid (prepared from the corresponding isatine: T. Sandmeyer Helv. Chim. Acta, 2:234 (1919), by oxidation with alkaline hydrogen peroxide, following the procedure described by Baker et al., J. Org. Chem., 17:141 (1952) for the synthesis of 3-chloroanthranilic acid) in 100 mL of toluene was added 20 g of 1-aza-2-methoxy-1-cycloheptene. The mixture was stirred for an hour at room temperature, followed by heating under reflux for 18 hours. Then the mixture was concentrated in vacuo and volatile material was removed at 130° C. at 1 torr. The dark brown residue was chromatographed using 8:1 chloroform-ethyl acetate to give 9 g of the desired material as a crystalline solid, m.p. 110° C.-112° C.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])([O-])=O.[Na+].[Na+].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O.O1CCCC1>[C:19]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture containing 8.21 g of L-Phenylalanine, 5.565 g of Na2CO3 in 40 ml of water and 20 ml of tetrahydrofuran (THF) was stirred at room temperature. Benzoyl chloride, 7.73 g, dissolved in 20 ml of anhydrous THF, was added gradually over a period of 45 minutes with continued stirring at room temperature. Stirring was allowed to continue for an additional hour, at which time the reaction mixture was transferred to a rotary evaporator at 30° C. to remove the THF. An excess of water was then added and the reaction mixture extracted four times with ethyl acetate. The aqueous phase was then titrated to pH 2 with 3N HCl. A white crystalline precipitate formed which was recovered by filtration, washed three times with cold dilute HCl and three times with cold water, and dried in a vacuum oven over P2O5 at about 50° C. The product was recrystallized from aqueous ethanol, yielding 8.37 g, m.p. 183° C.-184° C., which migrated at a single compound on thin layer chromatography in five separate solvent systems.
Reaction SMILES: [ClH:1].[OH:2][C@H:3]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:4][NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[C:16]([S:23][CH:24]([CH3:26])[CH3:25])[CH:15]=2)=[CH:10][CH:9]=1.[CH2:33](O)[CH3:34].Cl>>[ClH:1].[OH:2][C@H:3]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:4][NH:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH2:33][CH3:34])=[O:21])=[C:16]([S:23][CH:24]([CH3:26])[CH3:25])[CH:15]=2)=[CH:12][CH:13]=1
Reactant: CCO
Reactant: CC(C)Sc1cc(-c2ccc(CCNC[C@H](O)c3ccccc3)cc2)ccc1C(=O)O
Agent: Cl
Product: CCOC(=O)c1ccc(-c2ccc(CCNC[C@H](O)c3ccccc3)cc2)cc1SC(C)C

Procedure:
The suspension of 4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-(isopropylthio)-4-biphenylcarboxylic acid hydrochloride in hydrogen chloride ethanol solution (5.5M, 1 ml) was stirred under reflux for 1.5 hours. The mixture solution was evaporated under reduced pressure and the resultant solid was washed with isopropyl ether to give ethyl 4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-(isopropylthio)-4-biphenylcarboxylate hydrochloride (37 mg).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[N:11]=[CH:10][C:9]([O:12][C@H:13]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:14]2=[O:24])=[CH:8][CH:7]=1)(=[O:5])=[O:4].CCN(C(C)C)C(C)C.Cl[C:35]1[N:40]=[CH:39][C:38]([CH2:41][CH3:42])=[CH:37][N:36]=1.O>CN(C=O)C.CCOC(C)=O>[CH2:41]([C:38]1[CH:37]=[N:36][C:35]([N:21]2[CH2:22][CH2:23][CH:18]([N:15]3[CH2:16][CH2:17][C@H:13]([O:12][C:9]4[CH:10]=[N:11][C:6]([S:3]([CH3:2])(=[O:4])=[O:5])=[CH:7][CH:8]=4)[C:14]3=[O:24])[CH2:19][CH2:20]2)=[N:40][CH:39]=1)[CH3:42]
Reactant: CS(=O)(=O)c1ccc(O[C@H]2CCN(C3CCNCC3)C2=O)cn1
Reactant: CCc1cnc(Cl)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1cnc(N2CCC(N3CC[C@H](Oc4ccc(S(C)(=O)=O)nc4)C3=O)CC2)nc1
Temperature: 100 °C
Yield: 30.2 %

Procedure:
To a solution of (S)-3-(6-(methylsulfonyl)pyridin-3-yloxy)-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride salt (100 mg, 0.26 mmol) and DIEA (0.324 mL, 1.86 mmol) in DMF (3 mL) was added 2-chloro-5-ethylpyrimidine (76 mg, 0.532 mmol). The reaction was heated to 100° C. for 4 hours at which point the reaction was poured into water (10 mL) and EtOAc (10 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2×5 mL). The combined organic layers were dried with MgSO4 and concentrated in vacuo. The resulting material was purified by silica gel chromatography eluting with 1:1 hexanes/EtOAc to EtOAc to yield (S)-1-(1-(5-ethylpyrimidin-2-yl)piperidine-4-yl)-3-(6-(methylsulfonyl)pyridine-3-yloxy)pyrrolidin-2-one (35 mg, 30%) as an off white solid. Mass spectrum (apci) m/z=452.2 (M+H).
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:14])=[C:6]([O:12][CH3:13])[CH:7]=[C:8]([CH:11]=1)[CH:9]=[O:10])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:21](I)[CH2:22][CH3:23]>CN(C)C=O>[CH3:13][O:12][C:6]1[CH:7]=[C:8]([CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[O:14][CH2:21][CH2:22][CH3:23])[CH:9]=[O:10]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1c(OC)cc(C=O)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 12 h
Yield: 56.6 %

Procedure:
A mixture of 5-nitrovanillin (19.72 g, 100 mmol), potassium carbonate (35 g, 253.23 mmol) and propyl iodide (32.86 mL, 335.83 mmol) in 160 mL of N,N-dimethylformamide was stirred at 60° C. for 12 hours. The mixture was then cooled, quenched with water and extracted with methylene chloride. The organic layer was washed several times with water, dried over magnesium sulfate, filtered and evaporated in vacuo to an oil which was purified by flash chromatography on silica gel (230-400 mesh) using 2:1 hexane/ethyl acetate as eluent, to provide 3-methoxy-4-propoxy-5-nitrobenzaldehyde (13.54 g, 57%). 1H NMR (CDCl3): 1.00 (t, 3H), 18.5 (m, 2H), 4.00 (s, 3H), 4.25 (t, 2H), 7.65 (s, 1H), 7.85 (s, 1H), 9.95 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[C:9]1([C:2]2[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Nc1ccnc(-c2ccccc2)c1
Temperature: 100 °C
Yield: 87.7 %

Procedure:
To a stirred solution of 16.0 g (124 mmol) 2-chloro-4-aminopyridine in 200 ml toluene were added 18.2 g (149 mmol) phenylboronic acid, 7.19 g (6.22 mmol) tetrakis(triphenylphosphine)palladium(0) and 130 ml (260 mmol) 2 M aq. sodium carbonate solution. The mixture was heated at 100° C. for 16 h and then cooled to room temperature and extracted three times with ethyl acetate. The combined organic phases were extracted three times with 200 ml 1 M aq. hydrochloric acid. The combined acid extracts were then made alkaline by addition of 5 M aq. sodium hydroxide solution and extracted three times with dichloromethane. The combined organic extracts were dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (acetone) followed by trituration in hexane containing a little ether afforded 18.5 g (87%) 2-phenyl-pyridin-4-ylamine as a white solid. ES-MS m/e (%): 171 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[CH3:18][CH:19]([CH3:36])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:24]=1)=[O:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][N:33]2[CH2:34][CH2:35][CH:30]([C:25]3[CH:24]=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:36])[CH:28]=[CH:27][C:26]=3[CH3:29])[CH2:31][CH2:32]2)=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(Oc2ccc(F)c(F)c2)cc1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(Cc2ccc(Oc3ccc(F)c(F)c3)cc2)CC1
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of 4-(3,4-Difluorophenoxy)benzaldehyde (41.0 mg, 0.170 mmol) and 2-methyl-N-[4-methyl-3-(4-piperidinyl)phenyl]propanamide (45.0 mg, 0.170 mmol) in 1,2-dichloroethane (5.00 mL) was added sodium triacetoxyborohydride (110 mg, 0.520 mmol) and ACOH (10.0 μL, 0.170 mmol) at room temperature. The mixture was stirred overnight. The reaction mixture was quenched by saturated NaHCO3 solution (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, concentrated in vacuo. The crude product was purified by preparative TLC using 5% NH3 (2.0 M in MeOH) in CH2Cl2 to give the desired product N-(3-{1-[4-(3,4-difluorophenoxy)benzyl]-4-piperidinyl}-4-methylphenyl)-2-methylpropanamide (44.0 mg, 54.0%)
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9][Si:10]([CH3:19])([CH3:18])[C:11]1[O:15][CH:14]=[C:13]([CH:16]=[O:17])[CH:12]=1.S(=O)(=O)(O)O>O1CCCC1>[CH:1]1([CH:16]([C:13]2[CH:12]=[C:11]([Si:10]([CH3:19])([CH3:18])[CH3:9])[O:15][CH:14]=2)[OH:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)c1cc(C=O)co1
Reactant: Cl[Mg]C1CCCCC1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc(C(O)C2CCCCC2)co1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of cyclohexylmagnesium chloride (0.24 ml, 0.484 mmol, 2.0M solution in ethyl ether) under argon at 0°, was added dropwise 5-trimethylsilyl-3-furaldehyde (0.072 g., 0.44 mmol) in 5 ml of dry tetrahydrofuran. This solution was allowed to warm to room temperature, stirred for 30 minutes and poured over crushed ice containing several drops of concentrated sulfuric acid. The resulting mixture was partitioned between ethyl ether and 5% sodium bicarbonate. The organic portion was washed with water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a colorless oil. This material was purified by flash chromatography (silica, 10% ethyl ether/pentane) to yield the desired alcohol.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([O:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:16][CH2:15]1)[CH:7]=[CH:6]2)=O.[NH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28].C([BH3-])#N.[Na+]>>[C:20]([C@H:17]1[CH2:18][CH2:19][C@H:14]([O:13][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([CH2:1][NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:4]=3)[N:9]=2)[CH2:15][CH2:16]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3n2)CC1
Reactant: NCCC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCCC(=O)O)ccc3n2)CC1

Procedure:
6-bromo-2-hydroxyquinoline was treated with cis-4-tert-butylcyclohexanol under Mitsunobu conditions, affording 6-bromo-2-((trans)-4-tert-butylcyclohexyloxy)quinoline. 6-bromo-2-((trans)-4-tert-butylcyclohexyloxy)quinoline was then exposed to n-butyllithium and DMF, providing 6-formyl-2-((trans)-4-tert-butylcyclohexyloxy)quinoline. This aldehyde was then treated with 3-aminopropionic acid and sodium cyanoborohydride to afford the title compound, 3-((2-((trans)-4-tert-butylcyclohexyloxy)quinolin-6-yl)methylamino)propanoic acid.