Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:16])([CH3:15])[CH2:3][O:4][C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1.[O:17]1[CH2:29][CH:18]1[CH2:19][O:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>O1CCOCC1>[C:10]([C:9]1[CH:13]=[C:5]([CH:6]=[CH:7][C:8]=1[OH:14])[O:4][CH2:3][C:2]([NH:1][CH2:29][CH:18]([OH:17])[CH2:19][O:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24])([CH3:16])[CH3:15])(=[O:11])[NH2:12]
Reactant: CC(C)(N)COc1ccc(O)c(C(N)=O)c1
Reactant: N#Cc1ccccc1OCC1CO1
Solvent: C1COCCO1
Product: CC(C)(COc1ccc(O)c(C(N)=O)c1)NCC(O)COc1ccccc1C#N

Procedure:
The solution of 2.24 g of 5-(2-amino-2-methylpropoxy)salicylamide in 30 ml of dioxan is refluxed for 7 hours after the addition of 2.3 g of 2-(2,3-epoxypropoxy)benzonitrile, and then concentrated by evaporation. The residue is divided between 10 ml of 2N hydrochloric acid and 100 ml of ethyl acetate. The acidic aqueous phase is rendered alkaline with concentrated ammonia solution, the base is extracted with ethyl acetate and the solvent is evaporated off, whereupon an oil is obtained from which, by crystallisation from isopropanol and recrystallisation from ethyl acetate, 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-1,1-dimethylethylamino]-3-(2-cyanophenoxy)propan-2-ol having a melting point of 125°-126° is obtained.
Reaction SMILES: Cl.[NH2:2][OH:3].[Br:4][C:5]1[N:6]=[CH:7][C:8]([NH:11][C:12](=[O:33])[C@@H:13]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[C:24]([Cl:32])[CH:23]=2)[CH2:14][CH:15]2[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)=[N:9][CH:10]=1>CO.N1C(C)=CC=CC=1C>[Br:4][C:5]1[N:6]=[CH:7][C:8]([NH:11][C:12](=[O:33])[C@@H:13]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[C:24]([Cl:32])[CH:23]=2)[CH2:14][CH:15]2[CH2:20][CH2:19][C:18](=[N:2][OH:3])[CH2:17][CH2:16]2)=[N:9][CH:10]=1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=NO)CC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
A solution of hydroxylamine hydrochloride (7.0 mg, 0.099 mmol) in methanol (0.2 mL) and 2,6-lutidine (0.2 mL) was treated with N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionamide (prepared as in Example 60, 34 mg, 0.066 mmol). The reaction mixture was stirred at 25° C. for 30 min and was then concentrated in vacuo to remove methanol. The resulting residue was suspended in ethyl acetate (10 mL), washed with water 1×5 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 65/35 hexanes/ethyl acetate to 2/3 hexanes/ethyl acetate) afforded the N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-hydroxyimino-cyclohexyl)-propionamide (30 mg, 85.8%) was a white foam: [α]23589=−21.43° (c=0.35, chloroform); EI-HRMS m/e calcd for C20H22BrClN4O4S (M+H)+ 529.0307. found 529.0314.
Reaction SMILES: C[O:2][C:3](=[O:46])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:45])[CH2:10][CH2:11][C:12]1([CH3:44])[CH2:17][C:16](=[O:18])[C:15]2[CH:19]=[CH:20][C:21]([O:26][CH2:27][CH2:28][CH2:29][O:30][C:31]3[CH:36]=[CH:35][C:34]([C:37](=[O:39])[CH3:38])=[C:33]([OH:40])[C:32]=3[CH2:41][CH2:42][CH3:43])=[C:22]([CH2:23][CH2:24][CH3:25])[C:14]=2[O:13]1.[OH-].[Na+]>>[C:37]([C:34]1[CH:35]=[CH:36][C:31]([O:30][CH2:29][CH2:28][CH2:27][O:26][C:21]2[CH:20]=[CH:19][C:15]3[C:16](=[O:18])[CH2:17][C:12]([CH2:11][CH2:10][C:9]([N:5]4[CH2:6][CH2:7][CH2:8][C@H:4]4[C:3]([OH:46])=[O:2])=[O:45])([CH3:44])[O:13][C:14]=3[C:22]=2[CH2:23][CH2:24][CH3:25])=[C:32]([CH2:41][CH2:42][CH3:43])[C:33]=1[OH:40])(=[O:39])[CH3:38]
Reactant: CCCc1c(OCCCOc2ccc3c(c2CCC)OC(C)(CCC(=O)N2CCC[C@H]2C(=O)OC)CC3=O)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Product: CCCc1c(OCCCOc2ccc3c(c2CCC)OC(C)(CCC(=O)N2CCC[C@H]2C(=O)O)CC3=O)ccc(C(C)=O)c1O

Procedure:
The title compound was prepared by the method of Example 7 using the title product of Example 63, except that sodium hydroxide was used instead of lithium hydroxide. Structure assignment was supported by elemental analysis.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:24]([F:27])([F:26])[F:25])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:28]1[CH2:31][CH:30]([C:32]([O:34][CH3:35])=[O:33])[CH2:29]1.[BH3-]C#N.[Na+]>C(O)C>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[C:13]([C:24]([F:25])([F:26])[F:27])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:28]2[CH2:31][CH:30]([C:32]([O:34][CH3:35])=[O:33])[CH2:29]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2C(F)(F)F)CC1
Reactant: COC(=O)C1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: COC(=O)C1CN(Cc2ccc3c(C(F)(F)F)c(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)C1

Procedure:
A mixture of 6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)-2-naphthaldehyde (300 mg, 0.8 mmol) and methyl azetidine-3-carboxylate (184 mg, 1.6 mmol, 2.0 equiv) in anhydrous ethanol (20 mL) was refluxed for 2 h. Then the solvent was removed in vacuo, fresh ethanol and NaBH3CN (150 mg, 2.4 mmol, 3.0 equiv) was added, the resulting mixture was refluxed for 1 h. The reaction mixture was concentrated and the residue was purified by chromatography with silica gel (dichloromethane:methanol 20:1) to give product methyl 1-((6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)methyl)azetidine-3-carboxylate as a white solid (150 mg, yield: 40%). ESI-MS: 477.3 (M+H)+. HPLC: 85.67% 1H NMR (400 MHz, CD3OD) δ: 8.09 (dd, 1H), 8.01 (d, 1H), 7.56 (s, 1H), 7.46-7.51 (m, 2H), 4.42 (m, 1H), 3.77 (s, 2H), 3.71 (s, 3H), 3.57 (t, 2H), 3.45 (t, 2H), 3.35-3.39 (m, 1H), 2.18 (d, 2H), 1.88 (d, 2H), 1.43-1.52 (q, 2H), 1.09-1.22 (m, 3H), 0.89 (s, 9H)
Reaction SMILES: [CH2:1]([NH:3][CH:4]=[O:5])[CH3:2].[CH3:6][O:7][CH:8](Cl)[CH3:9]>C(N(CC)CC)C>[CH3:6][O:7][CH:8]([N:3]([CH2:1][CH3:2])[CH:4]=[O:5])[CH3:9]
Reactant: COC(C)Cl
Reactant: CCNC=O
Solvent: CCN(CC)CC
Product: CCN(C=O)C(C)OC

Procedure:
8.0 g of triethylamine and then a mixture of 42.5 g of triethylamine (0.5 mole in total) and 14.6 g (0.2 mole) of N-ethylformamide are added dropwise, at 0° C., to a mixture of 60 ml of light petroleum and 38 g (0.4 mole) of α-chloroethyl methyl ether.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[N:8][C:7]([C:15](=[NH:17])[NH2:16])=[N:6]1.C(O[CH:25]=[CH:26][C:27]#[N:28])C.C1CCN2C(=NCCC2)CC1.CC#N.CO.C(Cl)Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)=[N:8][C:7]([C:15]2[N:16]=[C:27]([NH2:28])[CH:26]=[CH:25][N:17]=2)=[N:6]1
Reactant: CCOC=CC#N
Reactant: N=C(N)c1nc(-c2nccs2)n(Cc2ccccc2F)n1
Solvent: CC#N
Solvent: CO
Solvent: c1ccncc1
Product: Nc1ccnc(-c2nc(-c3nccs3)n(Cc3ccccc3F)n2)n1
Temperature: 110 °C
Reaction time: 46 h

Procedure:
To 1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazole-3-carboximidamide (Intermediate-6, 0.33 mmol) was added a stock solution of 3-ethoxyacrylonitrile (3 equiv) and DBU (1 equiv) in pyridine (3 mL). The reaction was warmed to 110° C. and stirred for 46 h. The reaction mixture was conc. and purified using SiO2 chromatography and an appropriate gradient (CH3CN/MeOH/CH2Cl2) to afford 2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyrimidin-4-amine (I-48) as a light tan solid (78% yield).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[O:15][C:14]([C:16](=[N:18][OH:19])[NH2:17])=[CH:13][CH:12]=1)([O-])=O.[H][H]>[Pd].CO>[ClH:1].[ClH:1].[NH2:2][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[O:15][C:14]([C:16](=[N:18][OH:19])[NH2:17])=[CH:13][CH:12]=1
Reactant: NC(=NO)c1ccc(-c2ccccc2[N+](=O)[O-])o1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NC(=NO)c1ccc(-c2ccccc2N)o1
Yield: 148.9 %

Procedure:
A mixture of the compound of Example XV (14.2 g 0.05 mole), 5% Pd/C (50% H2O) (1 teaspoon), and anhydrous methanol (300 ml) was shaken in a Parr apparatus until the theoretical amount of hydrogen was absorbed. The catalyst was removed by filtration and washed with anydrous methanol. Gaseous HCl was introduced into the filtrate with cooling in ice. The solid was collected by filtration and washed with anhydrous ether to give 10.8 g (75%) of product. An analytical sample, m.p. 238°-239°, was obtained by drying in an Abderhalden.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH3:9][C:10]([CH3:12])=O>>[CH2:12]([N:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[N:6][C:5]1=[O:8])[CH:10]=[CH2:9]
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: CC(C)=O
Product: C=CCn1cc(Cl)cnc1=O
Yield: 64 %

Procedure:
1-Allyl-5-chloropyrimid-2-one was prepared from 5-chloropyrimid-2-one as above in 64% yield. m.p. 130°-131° C. (acetone) (Found: C, 49.22; H, 4.13. Calc. for C7H7ClN2O: C, 49.28; H, 4.13).
Reaction SMILES: C(N(CC)CC)C.[N+:8]([CH2:11][C:12]1([CH2:18][CH2:19][NH2:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([O-:10])=[O:9].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>O1CCCC1>[N+:8]([CH2:11][C:12]1([CH2:18][CH2:19][NH:20][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([O-:10])=[O:9]
Reactant: NCCC1(C[N+](=O)[O-])CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCC1(C[N+](=O)[O-])CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.6 %

Procedure:
Triethylamine (0.64 g, 6.3 mmol) was added dropwise to a mixture of the amine hydrochloride salt (compound 4, 0.70 g, 3.1 mmol) and methane sulfonyl chloride (0.36 g, 6.3 mmol) in tetrahydrofuran (35 nL). After stirring at room temperature for 2 hours, the mixture was filtered, diluted with ethyl acetate, and washed with dilute hydrochloric acid, saturated sodium bicarbonate solution, and water, dried over magnesium sulphate, filtered, and evaporated to dryness. The residue was crystallized from ethyl acetate/heptane to give colorless crystals (0.39 g, 47%); mp 86-88° C.
Reaction SMILES: C(OC(=O)[N:7]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[C:32]3[C:27](=[N:28][CH:29]=[C:30]([Cl:33])[CH:31]=3)[NH:26][CH:25]=2)=[O:23])=[CH:18][N:17]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:33][C:30]1[CH:31]=[C:32]2[C:24]([C:22]([C:19]3[CH:18]=[N:17][C:16]([NH:7][CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[F:15])=[CH:21][CH:20]=3)=[O:23])=[CH:25][NH:26][C:27]2=[N:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1F)c1ccc(C(=O)c2c[nH]c3ncc(Cl)cc23)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1ccc(NCc2ccccc2F)nc1)c1c[nH]c2ncc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.9 %

Procedure:
To [5-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-(2-fluoro-benzyl)-carbamic acid tert-butyl ester (584, 0.030 g, 0.062 mmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (1.0 mL, 0.013 mol). The reaction was stirred at room temperature overnight, then poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 2% to 15% methanol in dichloromethane to give the desired compound (P-0404, 2.8 mg, 12%). MS (ESI) [M+H+]+=381.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10](=[O:18])[N:11]([CH:13]3[CH2:17][CH2:16][NH:15][CH2:14]3)[N:12]=2)[C:5]([O:19][CH3:20])=[CH:4][C:3]=1[NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C.Br[CH2:40][CH2:41][CH2:42][CH3:43]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10](=[O:18])[N:11]([CH:13]3[CH2:17][CH2:16][N:15]([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:14]3)[N:12]=2)[C:5]([O:19][CH3:20])=[CH:4][C:3]=1[NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1cc(NC(=O)OCc2ccccc2)c(Cl)cc1-c1nn(C2CCNC2)c(=O)o1
Reactant: CCCCBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCN1CCC(n2nc(-c3cc(Cl)c(NC(=O)OCc4ccccc4)cc3OC)oc2=O)C1
Temperature: 60 °C

Procedure:
1.5 g (3.37 mmol) of phenylmethyl [2-chloro-4-(5-oxo-4-(pyrrolidin-3-yl)-4,5-dihydro-1,3,4-oxadiazol-2-yl)-5-methoxyphenyl]carbamate dissolved in 26 ml of acetonitrile, and 1.41 ml (10.1 mmol) of triethylamine are placed in a 100 ml three-necked round-bottomed flask. A solution of 0.6 g (4.38 mmol) of 1-bromobutane in 4 ml of acetonitrile is added and the mixture is heated at 60° C. for 15 h.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].[C:11]([O:15][CH3:16])(=[O:14])[NH:12][NH2:13]>C(O)C>[N:8]1[CH:9]=[CH:10][C:5]([C:1](=[N:13][NH:12][C:11]([O:15][CH3:16])=[O:14])[CH2:2][CH3:3])=[CH:6][CH:7]=1
Reactant: CCC(=O)c1ccncc1
Reactant: COC(=O)NN
Solvent: CCO
Product: CCC(=NNC(=O)OC)c1ccncc1
Yield: 62.7 %

Procedure:
A solution of 4.05 gm (0.03 mole) of 4-propionylpyridine, 2.70 gm (0.03 mole) of methyl carbazate and 100 ml of absolute ethanol is refluxed 6 hr. The solution is evaporated in vacuo to give a solid. The crude product is crystallized from ethyl acetate/Skellysolve B to yield 3.90 gm (63%) of the title compound having a melting point of 216.2° C. (decomp.).
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1(C)C=CC=CC=1>[CH2:3]([C:2]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[C:13]([OH:23])[C:8]2[C:7]([CH:1]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCC#Cc1ccccc1C(=O)Cc1ccc(OC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCc1cc2ccccc2c(O)c1-c1ccc(OC)cc1
Yield: 58.3 %

Procedure:
A solution of 1-[2-(1-hexyn-1-yl)phenyl]-2-[4-(methyloxy)phenyl]ethanone (159) (0.43 g, 1.40 mmol) in toluene was treated with a KHMDS solution in toluene to give 0.25 g (58%) of the title compound (160) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 0.78 (t, J=7.3 Hz, 3H), 1.15-1.30 (m, 2H), 1.40-1.50 (m, 2H), 2.49 (t, J=7.8 Hz, 2H), 3.89 (s, 3H), 5.24 (s, 1H), 7.07 (d, J=8.6 Hz, 2H), 7.26-7.32 (m, 3H), 7.38-7.48 (m, 2H), 7.74 (d, J=8.8 Hz, 1H), 8.17 (d, J=8.1 Hz, 1H). LCMS (ESI): m/z 307 (M+H)+, m/z 305 (M−H)−.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[C:19]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:18]=[C:17]([F:28])[CH:16]=2)=[O:13])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:36][C:37]([Cl:42])([Cl:41])[C:38](Cl)=[O:39]>ClCCl>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[C:19]([O:21][CH:22]3[CH2:23][CH2:24][N:25]([C:38](=[O:39])[C:37]([Cl:42])([Cl:41])[Cl:36])[CH2:26][CH2:27]3)[CH:18]=[C:17]([F:28])[CH:16]=2)=[O:13])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1cc(F)cc(OC2CCNCC2)c1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1cc(F)cc(OC2CCN(C(=O)C(Cl)(Cl)Cl)CC2)c1
Temperature: 22 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To an ice-water cooled solution of 1-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3-{3-fluoro-5-(piperidin-4-yloxy)-phenyl}-urea (390.6 mg, 1.0 mmol) and triethylamine (280 μL, mmol) in dichloromethane (5 mL) is added trichloroacetyl chloride (115 μL, 1.0 mmol). The reaction mixture is allowed to warm up to 22° C. and stirred for 1 hour. After removal of solvent, the residue is purified on a silica gel chromatography with hexanes and ethyl acetate to provide a white solid (520.0 mg, 97% yield, ES+(m/z) 535.9 [M+H]).
Reaction SMILES: [C:1]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:6]=[CH:5][C:4]([C@@:7]23[CH2:26][N:19]([C@H:20]([C:22]([O:24]C)=[O:23])[CH2:21]2)[C:18](=[O:27])[C@@H:17]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][S:8]3)=[CH:3][CH:2]=1.O.[OH-].[Li+]>C1COCC1.CO.O>[C:1]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:6]=[CH:5][C:4]([C@@:7]23[CH2:26][N:19]([C@H:20]([C:22]([OH:24])=[O:23])[CH2:21]2)[C:18](=[O:27])[C@@H:17]([NH:28][C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][S:8]3)=[CH:3][CH:2]=1
Reactant: COC(=O)[C@@H]1C[C@@]2(c3ccc(-c4ccccc4)cc3)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CCCCCC=CCS2
Agent: CC(C)(C)OC(=O)N[C@H]1CCCCC/C=C/CS[C@@]2(c3ccc(-c4ccccc4)cc3)C[C@@H](C(=O)O)N(C2)C1=O
Agent: COC(=O)[C@@H]1C[C@@]2(c3ccc(-c4ccccc4)cc3)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CCCCC/C=C/CS2
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCCCC=CCS[C@@]2(c3ccc(-c4ccccc4)cc3)C[C@@H](C(=O)O)N(C2)C1=O
Reaction time: 5 h

Procedure:
To a solution of (3S,13R,15S,E)-methyl 13-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)-2-oxo-12-thia-1-azabicyclo[11.2.1]hexadec-9-ene-15-carboxylate (90 mg, 0.156 mmol) in THF (1 mL) and MeOH (1.000 mL) was added pre-made solution of lithium hydroxide hydrate (19.58 mg, 0.467 mmol) in Water (1 mL). The resulting cloudy solution was stirred at room for 5 h. Quenched with 5% citric acid, extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, evaporated, to afford the desired product (3S,13R,15S,E)-13-(biphenyl-4-yl)-3-(tert-butoxycarbonylamino)-2-oxo-12-thia-1-azabicyclo[11.2.1]hexadec-9-ene-15-carboxylic acid (84 mg, 0.134 mmol, 86% yield) as an off-white foam. LC-MS (retention time: 3.32 min, method C), MS m/z 565 (M+H).
Reaction SMILES: [Si:1]([O:8][CH2:9]/[C:10](/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[C:11](/[C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)\[CH2:12][OH:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:30](OC(=O)C)(=[O:32])[CH3:31]>CN(C1C=CN=CC=1)C.ClCCl>[C:30]([O:13][CH2:12]/[C:11](/[C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][CH:19]=1)=[C:10](/[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)\[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)[Si](C)(C)OC/C(=C(\CO)c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC/C(=C(\CO[Si](C)(C)C(C)(C)C)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a solution of 46 g of (2Z)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-(methylsulfonyl)phenyl]-3-phenylbut-2-en-1-ol with 120 mmol of DMAP in 1 L of dichloromethane, 120 mmol of acetic anhydride was added dropwise. The resulting mixture was stirred at rt for 1 hr. The reaction mixture was loaded on a silica gel column and eluted with EtOAc to afford 50.5 g of the titled compound as a white solid. 1H NMR (acetone-d6, 500 M Hz): δ 7.68 (d, 2H), 7.33 (d, 2H), 7.15–7.04 (m, 5H), 5.16 (s, 2H), 4.75 (s, 2H), 3.02 (s, 3H), 1.92 (s, 3H), 0.81 (s, 9 H), -0.03 (s, 6H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8]C(=O)OC(C)(C)C)[CH2:4][CH2:3]1.[H-].[Na+].F[C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][C:20]=1[N+:29]([O-:31])=[O:30].Cl>O1CCCC1.O.ClCCl>[NH2:8][C@H:5]1[CH2:4][CH2:3][C@H:2]([O:1][C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][C:20]=2[N+:29]([O-:31])=[O:30])[CH2:7][CH2:6]1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)NC1CCC(O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(O[C@H]2CC[C@H](N)CC2)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl 4-hydroxycyclohexylcarbamate (0.250 g) in tetrahydrofuran (5 mL) was added sodium hydride (0.186 g). After stirring for 15 minutes, 4-fluoro-3-nitrobenzenesulfonamide (0.256 g) was added as a solution in tetrahydrofuran (1 mL). The reaction was heated to 60° C. for 1.5 hours, cooled, and poured into a mixture of dichloromethane (100 mL) and water (25 ml). The aqueous layer was adjusted to pH ˜4 with 1N aqueous HCl and the organic layer was separated, washed with brine (50 ml), dried over magnesium sulfate, filtered, and concentrated. The residue was loaded onto silica gel (GraceResolv 40 g) and eluted using a gradient of 0.5% to 7.5% methanol/dichloromethane over 30 minutes. This solid was treated with HCl (4.0M in dioxane, 5 ml) at room temperature for 1 hour and concentrated to give the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13](C3C=CC(CC(NCC4C=CC=CC=4)=O)=NC=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.ClCCN1CCOCC1.[Br:42]C1C=CC(O)=CC=1>>[Br:42][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:11][CH:12]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=C(Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1)NCc1ccccc1
Agent: ClCCN1CCOCC1
Product: Brc1ccc(OCCN2CCOCC2)cc1

Procedure:
In one aspect, the invention relates to a process for preparing 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide comprising the steps of: reacting 4-(2-chloroethyl)morpholine with 4-bromophenol to yield 4-(2-(4-bromophenoxy)ethyl)morpholine; (2) coupling 4-(2-(4-bromophenoxy)ethyl)morpholine with 6-fluoropyridin-3-yl-3-boronic acid to yield 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine; reacting 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine with acetonitrile to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile; (4) converting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile to methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate; and (5) reacting methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate with benzylamine to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide.
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH:10]2[CH2:13][N:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[CH2:11]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].CC1(C)C(C)(C)OB([C:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH:39]=2)O1>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:8][C:5]1[N:4]=[C:3]([O:9][CH:10]2[CH2:13][N:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[CH2:11]2)[C:2]([C:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH:39]=2)=[CH:7][N:6]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Clc1ncc(Br)c(OC2CN(c3ccc4ccccc4n3)C2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2cnc(Cl)nc2OC2CN(c3ccc4ccccc4n3)C2)CC1
Yield: 63.3 %

Procedure:
To a solution of 2-(3-((5-bromo-2-chloropyrimidin-4-yl)oxy)azetidin-1-yl)quinoline (see PREPARATION P2.11; 600 mg, 1.5 mmol) in 1,4-dioxane (15 mL) was treated with Na2CO3 (318 mg, 3 mmol) in 3 mL of water as a solution, followed by additional of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (556 mg 1.8 mmol) and Pd(dppf)Cl2 (110 mg, 0.15 mmol). The resulting mixture was heated at refluxing overnight under N2 atmosphere. The solution was filtered through CELITE®, and the filter was concentrated. The residue was purified by flash column chromatography on silica gel (20% to 70% EtOAc in petroleum ether) to give the title product (472 mg, 0.95 mmol, yield: 63%). ESI-MS (M+1): 494 calc. for C26H28ClN5O3 493.