Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCCC1.C1(NC(N2C3C(=CC(OC4C=CN=C(N(C(OC5C=CC=CC=5)=O)C(=O)OC5C=CC=CC=5)C=4)=CC=3)C=C2)=O)CC1.[CH:47]1([NH:50][C:51]([N:53]2[C:61]3[C:56](=[CH:57][C:58]([O:62][C:63]4[CH:68]=[CH:67][N:66]=[C:65]([NH:69][C:70]([N:72]5[CH2:77][CH2:76][CH:75](N6CCCC6)[CH2:74]C5)=[O:71])[CH:64]=4)=[CH:59][CH:60]=3)[CH:55]=[CH:54]2)=[O:52])[CH2:49][CH2:48]1>CN(C)C=O>[CH:47]1([NH:50][C:51]([N:53]2[C:61]3[C:56](=[CH:57][C:58]([O:62][C:63]4[CH:68]=[CH:67][N:66]=[C:65]([NH:69][C:70]([N:72]5[CH2:77][CH2:76][CH2:75][CH2:74]5)=[O:71])[CH:64]=4)=[CH:59][CH:60]=3)[CH:55]=[CH:54]2)=[O:52])[CH2:49][CH2:48]1
Reactant: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1)N1CCC(N2CCCC2)CC1
Agent: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CC3)c2)ccn1)N1CCCC1
Reaction time: 8 h

Procedure:
N,N-Dimethylformamide (5 ml) and pyrrolidine (0.35 ml, 4.2 mmol) were added to a mixture (470 mg) of phenyl N-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate and phenyl N-(4-(1-cyclopropylaminocarbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate obtained in Example 68; the reaction mixture was stirred overnight; the reaction mixture was partitioned between ethyl acetate and water; and the organic layer was concentrated to yield the title compound as white crystals (200 mg, 0.49 mmol).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](/[C:10](/[C:20]3[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=3)=[C:11](/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)\[CH2:12][CH3:13])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H][H]>[Pd].CCO.CCOC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6](/[C:10](/[C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:24][CH:25]=3)=[C:11](/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)\[CH2:12][CH3:13])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccccc2)c2ccc3[nH]ncc3c2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC/C(=C(/c1ccc(CCC(=O)O)cc1)c1ccc2[nH]ncc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 48 %

Procedure:
A 10-mL recovery flask equipped with a magnetic stir bar and a rubber septum was charged with Compound 1 (50 mg, 0.126 mmol) and EtOH-EtOAc (1:1, 2.5 mL). To this solution, palladium on carbon (13 mg, 10% Pd/C) was added in one portion. The flask was equipped with a hydrogen balloon, and the resulting mixture was stirred at room temperature 36 h. This mixture was filtered through Celite, concentrated, and purified on a RP-C18 column using 30-100% acetonitrile in water in the presence of 0.1% TFA to afford the title compound (24 mg). 1H NMR (300 MHz, Acetone-d6): 6; 7.94 (s, 1H), 7.58 (br, 1H), 7.44 (d, 1H), 7.17-6.97 (m, 6H), 6.8-6.73 (m, 4H), 2.64 (t, 2H), 2.39-2.32 (m, 4H), 0.80 (t, 3H), (NH and CO2H protons not observed). LCMS: 397 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>N1C=CC=CC=1.Cl>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)(C)NS(=O)(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
To a solution of 5-bromopyridine-3-sulfonyl chloride (5 g, 17 mmol) in pyridine (10 mL) at 0° C. was added tert-butylamine (3.6 mL, 2 equiv., 34 mmol). The reaction mixture was allowed to warm to room temperature and then heated to 40° C. for 14 h. After this time the crude reaction mixture was again cooled to 0° C. and diluted with dilute HCl (0.05M, 40 mL). The reaction was stirred at 0° C. for 30 min and the resulting precipitate collected by filtration. The solid was washed with water and dried to afford the title compound as a yellow solid (2.12 g, 7.3 mmol, 42%). No further purification was required.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](SC)=[NH:26].ClCCl>C(O)C.C(=O)(O)[O-].[Na+]>[N:1]1([CH2:7][CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([NH:18][C:25]([C:21]4[S:20][CH:24]=[CH:23][CH:22]=4)=[NH:26])=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSC(=N)c1cccs1
Reactant: Nc1ccc2c(ccn2CCN2CCCCC2)c1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: N=C(Nc1ccc2c(ccn2CCN2CCCCC2)c1)c1cccs1
Reaction time: 3 h
Yield: 44.9 %

Procedure:
A solution of compound 95 (0.200 mg, 0.822 mmol) in absolute ethanol (3 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (0.350 g, 1.23 mmol) at room temperature and the resulting mixture was stirred for 3 hours. The reaction was diluted with saturated aqueous sodium bicarbonate (5 mL) followed by dichloromethane (30 mL) and transferred to a separatory funnel. The aqueous was extracted twice more with dichloromethane (2×30 mL). The combined organics were washed with brine and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2M ammonia in methanol:dichloromethane, 5:95) to obtain compound 96 (130 mg, 45%) as a yellow oil. 1H NMR (CDCl3) δ 7.43 (d, J=2.7 Hz, 1H), 7.41 (s, 1H), 7.34 (d, J=8.7 Hz, 1H), 7.21 (d, J=1.2 Hz, 1H), 7.14 (d, J=3.0 Hz, 1H), 7.08 (t, J=4.2 Hz, 1H), 6.67 (dd, J=1.8, 8.7 Hz, 1H), 6.42 (d, J=3.0 Hz, 1H), 4.24 (t, J=7.5 Hz, 2H), 2.73 (t, J=7.5 Hz, 2H), 2.47 (m, 4H), 1.61 (m, 4H); ESI-MS (m/z, %): 353 (M+1); ESI-HRMS calculated for C20H25N4S (MH+): 353.1794, Observed: 353.1796.
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[C:3]=1Cl.[CH:16]1[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:23]>ClCCl>[CH3:5][C:4]1[CH:3]=[CH:2][C:14]2[C:5]3([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:12]4[C:4]3=[CH:3][CH:2]=[CH:14][CH:13]=4)[C:20]3[C:21]([O:22][C:13]=2[CH:12]=1)=[CH:16][C:17]([CH3:23])=[CH:18][CH:19]=3
Reactant: Clc1ccc2c(c1Cl)Cc1ccccc1-2
Reactant: Cc1cccc(O)c1
Solvent: ClCCl
Product: Cc1ccc2c(c1)Oc1cc(C)ccc1C21c2ccccc2-c2ccccc21
Temperature: 40 °C

Procedure:
Dichlorofluorene (DCF) (35.27 g, 0.15 mole) is weighed into a powder addition funnel and dissolved in 20 mL of dry dichloromethane. Liquid m-cresol (64.88 g, 0.6 mole) is weighed into a 250 mL three-necked round-bottomed flask which is equipped with a stirrer, heating mantle, nitrogen inlet, condenser, thermometer, and drying tube. Dry dichloromethane (80 mL) is added and the mixture is heated to 40° C. with stirring. DCF solution is added slowly to the mixture as the temperature is maintained at about 40° C. The reaction is rapid as evidenced by copious production of HCl bubbles after each addition. After addition is complete, the reaction is stirred for an additional half hour and then checked by LC. The reaction is complete, and the chromatograph shows peaks for the desired bisphenol (9,9-bis(2-hydroxy-4-methylphenyl)fluorene) along with isomers. The mixture is dissolved in toluene and refluxed with 0.5 mL of methanesulfonic acid collecting water formed during the cyclization reaction in a Dean-Stark trap. The toluene is then removed by rotary evaporation and the residue is slurried with acetonitrile, chilled and filtered to yield the spiro-ether [3',6'-dimethylspiro[fluorene-9,9'-xanthene] as an off-white powder. The isomeric bisphenols formed in the alkylation reaction do not cyclize and remain dissolved in the acetonitrile.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:32]([F:33])=[CH:31][C:11]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[CH2:23][O:22][C:21]4=[O:30])[CH2:16][CH2:15]3)=[O:13])=[C:10]([O:34][CH3:35])[CH:9]=2)[CH2:3][CH2:2]1.[C:36](OC(=O)C)(=[O:38])[CH3:37].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:36]([N:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:32]([F:33])=[CH:31][C:11]([C:12]([N:14]3[CH2:15][CH2:16][CH:17]([N:20]4[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[CH2:23][O:22][C:21]4=[O:30])[CH2:18][CH2:19]3)=[O:13])=[C:10]([O:34][CH3:35])[CH:9]=2)[CH2:3][CH2:2]1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(OC2CCNCC2)c(F)cc1C(=O)N1CCC(N2C(=O)OCc3ccccc32)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(OC2CCN(C(C)=O)CC2)c(F)cc1C(=O)N1CCC(N2C(=O)OCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 1-(1-(4-(4-piperidinyloxy)-5-fluoro-2-methoxybenzoyl)piperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one of Example 16 (200 mg, 0.41 mmol) in DCM (5 mL) at ambient temperature was added acetic anhydride (77 mg, 0.75 mmol) and DIEA (0.17 mL, 1.0 mmol). The solution was stirred at ambient temperature for 24 h, diluted with DCM (20 mL), washed with saturated aqueous NaHCO3 (50 mL), dried (MgSO4), and filtered. The solvent was removed under reduced pressure and the residue was purified by pressurized silica gel column chromatography using a gradient elution of 2-5% MeOH-DCM. 1-(1-(4-(N-acetyl-4-piperidinyloxy)-5-fluoro-2-methoxybenzoyl)piperidin-4-yl) -4H-3,1-benzoxazin-2(1H)-one was obtained as an amorphous solid.
Reaction SMILES: [OH:1][C:2]([CH:4]([C:6]1[CH:15]=[CH:14][C:9]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=1)[CH3:5])=[O:3].O.[OH-].[Na+:18]>C1(C)C=CC=CC=1>[Na+:18].[O-:3][C:2]([CH:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][CH:11]([CH3:12])[CH3:13])=[CH:14][CH:15]=1)[CH3:5])=[O:1]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)Cc1ccc(C(C)C(=O)[O-])cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A solution of (S)-enriched ibuprofen having an enantiomeric purity of 95.5% (211 kg) in toluene (797 kg) was heated to 60° C. with water (300 l) and aqueous sodium hydroxide solution (52 l--specific gravity 1.5) and allowed to settle for four hours. The aqueous layer was separated and the toluene layer washed with water. The aqueous washings and the aqueous layer were combined and residual toluene removed by distillation. Acetone (1684 kg) was added and the mixture cooled to 20° C. The sodium salt of (S)-enriched ibuprofen dihydrate (having an enantiomeric purity of 99.9%) separated, was collected by filtration and dried in vacuo. (Yield 143.5 kg).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][C:3]=1[N:16]1[N+:20]([O-])=[C:19]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:18]2=[N:17]1.C1(C)C=CC=CC=1.N12CCCCC1CNCC=C2.[H][H]>[Ni].CC(O)CC>[OH:1][C:2]1[C:7]([C:8]([CH3:10])([CH3:11])[CH3:9])=[CH:6][C:5]([C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:4][C:3]=1[N:16]1[N:20]=[C:19]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:18]2=[N:17]1
Reactant: CC(C)(C)c1cc(-n2nc3cc(Cl)ccc3[n+]2[O-])c(O)c(C(C)(C)C)c1
Reactant: [H][H]
Agent: [Ni]
Agent: C1=CN2CCCCC2CNC1
Solvent: Cc1ccccc1
Solvent: CCC(C)O
Product: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Yield: 78.8 %

Procedure:
37.4 g (0.1 mol) of 2-(2'-hydroxy-3',5'-di-t-butylphenyl)-5-chlorobenzotriazole-N-oxide, 0.25 g of Raney nickel catalyst, 150 ml of toluene, 100 ml of 2-butanol and 0.5 g of 1,5-diazabicyclo[5.4.0]undecene were charged into a 500-ml stainless autoclave equipped with an agitator. After the air in the autoclave had been replaced by nitrogen, hydrogen was charged to a pressure of 8 kg/cm2. The temperature of the resultant mixture was increased to 60° C. under agitation, and reaction was been effected while agitation being continued until no hydrogen gas was absorbed by the mixture. After the reaction had been completed, after treatment was performed in the same way as that employed in Example 9 to obtain 28.2 g of 2-(2'-hydroxy-3',5'-di-t-butylphenyl)-5-chlorobenzotriazole as a target substance (yield, 79%; melting point, 153° to 155° C.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[NH:10][C:11]([NH:13][CH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[N:19]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[CH2:18]2)=[O:12])#[N:2].Cl.[H][H]>C(O)(C)C.C(O)(=O)C.[Pt]=O>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[NH:10][C:11]([NH:13][CH2:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[N:19]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[CH2:18]2)=[O:12]
Reactant: [H][H]
Reactant: Cc1ccc(C#N)c(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)c1
Agent: O=[Pt]
Agent: Cl
Solvent: CC(=O)O
Solvent: CC(C)O
Product: Cc1ccc(CN)c(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)c1

Procedure:
A mixture of 1-(2-cyano-5-methylphenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea (0.54 g, 1.0 mmol), platinum oxide (0.1 g), and 5-6M HCl in isopropanol (2 mL) in acetic acid (15 mL) is hydrogenated under 50 psi hydrogen for 48 hrs. The mixture is filtered through Celite, the filtrate is evaporated under vacuum, and the residue is purified by preparative HPLC to provide the product.
Reaction SMILES: Cl.C[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1.[CH:12](O)=O.Cl.Br>O>[OH:3][C:4]1[CH:9]=[CH:8][C:7]2[NH:10][CH:12]=[N:11][C:6]=2[CH:5]=1
Reactant: O=CO
Reactant: COc1ccc(N)c(N)c1
Agent: Br
Agent: Cl
Solvent: O
Product: Oc1ccc2[nH]cnc2c1
Yield: 88 %

Procedure:
Twenty grams (0.114 mole) of 4-methoxy-1,2-phenylenediamine hydrochloride was refluxed with 30 ml of 88% formic acid, 15 ml of concentrated HCl and 90 ml of water for eight hours. The solvent was then removed in vacuo and the residue was treated with 100 ml of concentrated NH4OH, extracted with dichloromethane (2×200 ml), dried over MgSO4 and concentrated to leave a thick oil which was converted to its HCl salt, mp 212°-5° C. (12.8 g, 60%). This compound (12.0 g, 65 mmole) was refluxed with 125 ml of concentrated HBr, under argon, for three hours. After evaporation in vacuo, the residue was dissolved in water, neutralized with solid NaHCO3. The product deposited was recrystallized from water, yielding 7.7 g (88%) of 5-hydroxy-1H-benzimidazole, mp 216°-8° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[NH:19][CH:20]=[C:21]([CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[N:30][CH:31]=4)[C:22](=[O:24])[N:23]=3)=[CH:11][C:10]=2[F:32])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].[CH3:37]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[N:19]([CH3:37])[CH:20]=[C:21]([CH2:25][C:26]4[CH:31]=[N:30][CH:29]=[N:28][CH:27]=4)[C:22](=[O:24])[N:23]=3)=[CH:11][C:10]=2[F:32])=[CH:4][C:3]=1[C:33]([F:35])([F:36])[F:34]
Reactant: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)[nH]cc1Cc1cncnc1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CI
Product: Cn1cc(Cc2cncnc2)c(=O)nc1OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.2 %

Procedure:
To a solution of 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-3-fluorophenyl) ethyl]oxy}-5-(5-pyrimidinylmethyl)-4(1H)-pyrimidinone (80 mg, 0.154 mmol) and Hunig's base (0.040 mL, 0.230 mmol) in DCM (3.0 mL) was added MeI (0.019 mL, 0.307 mmol) dropwise. The mixture was stirred at room temperature for 2 h. Purification via reverse phase flash chromatography afforded the title compound (15 mg, 18.26% yield). LCMS: rt=3.32 min, [M+H+]=535
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=1)=[O:11].Br[C:26]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][N:27]=1>>[CH3:33][O:32][C:31]1[C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)=[O:11])=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: COc1cccnc1Br
Product: COc1cccnc1NC[C@@H]1[C@H](C)CCCN1C(=O)c1cc(C)ccc1-c1cnn(C)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone and 2-bromo-3-methoxypyridine. ESI-MS (m/z): 434 [M+1]+.
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[N+:12]([CH:15](C(OC)=O)[C:16]([O:18][CH3:19])=[O:17])([O-])=[O:13]>C1(C)C=C(C)C=C(C)C=1>[CH:1]1([C:4]2[C:15]([C:16]([O:18][CH3:19])=[O:17])=[N:12][O:13][C:5]=2[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)C(C(=O)OC)[N+](=O)[O-]
Reactant: C(#CC1CC1)c1ccccc1
Solvent: Cc1cc(C)cc(C)c1
Product: COC(=O)c1noc(-c2ccccc2)c1C1CC1

Procedure:
A solution of (cyclopropylethynyl)benzene (300 mg, 2.110 mmol) and dimethyl nitromalonate (0.854 mL, 6.33 mmol) in mesitylene (4 mL) was heated to 150° C. for 16 h. The reaction mixture was concentrated to yield a crude product which was purified by silica gel chromatography with hexanes/ethyl acetate (10/1) to yield methyl 4-cyclopropyl-5-phenylisoxazole-3-carboxylate. The compound was re-purified by preparative HPLC [Column: PHENOMENEX® S10 30×100 mm; Gradient time: 10 min; Flow rate=40 ml/min; Solvent A=10% MeOH−90% Water−0.1% TFA; Solvent B=90% MeOH−10% water−0.1% TFA; Start % B=20; Final % B=100] to yield methyl 4-cyclopropyl-5-phenylisoxazole-3-carboxylate (170 mg). The compound had an HPLC ret. time=2.77 min.−Column. YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO4; Solvent B=90% MeOH−10% water−0.2% H3PO4; Start % B=0; Final % B=100. LC-MS: M+1=244+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].Br[CH2:15][CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:5]=[CH:4][C:3]=1[O:13][CH2:15][CH2:16][CH2:17][OH:18]
Reactant: Oc1ccc(OC(F)(F)F)cc1Cl
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCCOc1ccc(OC(F)(F)F)cc1Cl
Yield: 96 %

Procedure:
To a solution of 2-chloro-4-trifluoromethoxyphenol (16.4 g, 0.077 mole) in 100 mL of acetonitrile was added 3-bromopropanol (12.87 g, 0.092 mole) and potassium carbonate (21.33 g, 0.154 mole). The resulted solution was refluxed at 75° C.-80° C. overnight. The solvent was then evaporated. The residue was dissolved in 100 mL of ethyl acetate and washed with 100 mL of H2O. The organic layer was separated, dried over MgSO4, filtered and the organic solvent was evaporated to yield 20 g of the product.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[O:59](C1C=CC(C(Cl)=O)=CC=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>>[CH3:32][CH:31]([CH3:33])[C@H:26]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][C:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:1](=[O:8])[C:2]4[CH:3]=[CH:4][C:5]([O:59][C:60]5[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=5)=[CH:6][CH:7]=4)=[CH:15][CH:14]=3)=[CH:17][CH:18]=2)[C:22]1=[O:25])[C:27]([O:29][CH3:30])=[O:28]
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(Oc5ccccc5)cc4)cc3)cc2C1=O
Yield: 76 %

Procedure:
The compound of example 149 was prepared analogous to compound of example 97 by reaction of compound of example 6 with 4-phenoxy benzoyl chloride.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.Cl[C:21]1[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=1.C(N(CC)CC)C>CN(C=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][O:11][C:9]([N:6]2[CH2:5][CH2:4][CH:3]([CH2:2][NH:1][C:21]3[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=3)[CH2:8][CH2:7]2)=[O:10])=[CH:14][CH:15]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: NCC1CCN(C(=O)OCc2ccc(F)cc2)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccc(F)cc1)N1CCC(CNc2ncc(F)cn2)CC1

Procedure:
A solution of (4-fluoro-benzyl)-4-(aminomethyl)piperidine-1-carboxylate (INTERMEDIATE 2C) (0.10 g, 0.38 mmol), 2-chloro-5-fluoro-pyrimidine (0.05 g, 0.38 mmol) and triethylamine (0.11 mL, 0.75 mmol) in DMF (1 mL) was heated at 100° C. for 6 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2/IPA/hexanes) to give 4-[(5-fluoro-pyrimidin-2-ylamino)-methyl]-piperidine-1-carboxylic acid-4-fluoro-benzyl ester. M.S. (M+1): 363.31
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([CH2:22][O:23][CH2:24][C:25]([OH:27])=O)=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([NH:55][C:56]([CH:58]2[CH2:63][CH2:62][C:61]([F:65])([F:64])[CH2:60][CH2:59]2)=[O:57])[CH2:36][CH2:37][N:38]2[CH:43]3[CH2:44][CH2:45][CH:39]2[CH2:40][CH:41]([N:46]2[C:50]([CH3:51])=[N:49][N:48]=[C:47]2[CH:52]([CH3:54])[CH3:53])[CH2:42]3)=[CH:31][CH:30]=1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:21])[CH2:22][O:23][CH2:24][C:25](=[O:27])[NH:28][C:29]1[CH:30]=[CH:31][C:32]([CH:35]([NH:55][C:56]([CH:58]2[CH2:63][CH2:62][C:61]([F:64])([F:65])[CH2:60][CH2:59]2)=[O:57])[CH2:36][CH2:37][N:38]2[CH:43]3[CH2:44][CH2:45][CH:39]2[CH2:40][CH:41]([N:46]2[C:50]([CH3:51])=[N:49][N:48]=[C:47]2[CH:52]([CH3:54])[CH3:53])[CH2:42]3)=[CH:33][CH:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)COCC(=O)NCCCCCCCNC(=O)OCc1ccccc1
Reactant: Cc1nnc(C(C)C)n1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)c1ccc(N)cc1
Solvent: CN(C)C=O
Product: Cc1nnc(C(C)C)n1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)c1ccc(NC(=O)COCC(=O)NCCCCCCCNC(=O)OCc2ccccc2)cc1
Yield: 72 %

Procedure:
The title compound was prepared according to the general amide coupling procedure by reacting acid 22 with amine 6 in DMF overnight. The crude product was purified with chromatography using CH2Cl2/MeOH (13/1) as eluent to give 260 mg white foaming, in 72% yield. 1H NMR (400 MHz, CDCl3): δ8.96 (s, 1H), 7.57 (d, J=8.48 Hz, 2H), 7.35-7.27 (m, 5H), 7.24 (d, J=8.48 Hz, 2H), 6.75 (m, 1H), 6.70 (m, 1H), 5.12-5.08 (m, 3H), 4.91 (m, 1H), 4.29 (m, 1H), 4.14 (s, 2H), 4.09 (s, 2H), 3.40 (m, 1H), 3.37 (m, 1H), 3.30 (q, J=6.68 Hz, 2H), 3.15 (q, J=6.71 Hz, 2H), 2.99 (m, 1H), 2.48 (s, 3H), 2.43 (t, J=6.48 Hz, 2H), 2.30-4 (m, 6H), 2.01-1 (m, 8H), 1.70-1.46 (m, 9H), 1.376 (d, J=6.80 Hz, 3H), 1.373 (d, J=6.84 Hz, 3H), 1.35-1.31 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 173.50, 168.64, 167.15, 159.17, 156.55, 150.59, 138.31, 136.66, 136.51, 128.54, 128.12, 128.00, 127.12, 120.51, 77.24, 71.66, 71.50, 66.60, 58.90, 58.30, 51.68, 47.77, 47.24, 42.83, 40.98, 39.14, 35.33, 34.59, 32.82 (J13C-19F 25.7 Hz), 29.82, 29.36, 28.71, 26.75 (J13C-19F 10 Hz), 26.48, 25.87, 21.65, 13.15. mp 65-67° C. IR v (Diamond, cm−1): 3273, 1656, 1529, 1515, 1251, 1106, 697. MS (ESI) m/z found 891.9 (M+H)+.