Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27]Br)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:5][CH:4]=1.[N:31]1([C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[N:38]=2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27][N:34]3[CH2:35][CH2:36][N:31]([C:37]4[CH:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:38]=4)[CH2:32][CH2:33]3)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:5][CH:4]=1
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: COc1ccc(CNC(=O)C2(CCCCBr)c3ccccc3-c3ccccc32)cc1
Product: COc1ccc(CNC(=O)C2(CCCCN3CCN(c4ccc5ccccc5n4)CC3)c3ccccc3-c3ccccc32)cc1

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-methoxy-benzylamide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: P(OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.P([O:84][CH2:85][C@@H:86]([OH:95])[C@@H:87]([OH:94])[C@H:88]([OH:93])[C@@H:89]([OH:92])[CH:90]=[O:91])(O)(O)=O.[Cl-].[Mg+2].[Cl-]>>[O:84]=[CH:85][C@@H:86]([C@H:87]([C@@H:88]([C@@H:89]([CH2:90][OH:91])[OH:92])[OH:93])[OH:94])[OH:95]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)COP(=O)(O)O
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: [Cl-]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The reagent solution contains albumin, 50 mg/L, adenosine triphosphate 5 mmol/L, NADP (TPN) 500 mg/L, hexokinase 10 units/ml, glucose 6-phosphate dehydrogenase 0.5 units/ml, magnesium chloride 20 mmol/L, all dissolved in 0.1 molar tris buffer pH 8.0.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]=[N:42][CH:43]=[CH:44][CH:45]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]=[N:42][CH:43]=[CH:44][CH:45]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccnn4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cccnn4)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 40.3 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-pyridazinylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.15 g) was dissolved in methylene chloride (6.0 ml), and a solution of m-chloroperbenzoic acid (61 mg) in methylene chloride (4.5 ml) was added to the mixture at −78° C., and the mixture was stirred for 15 minutes. The reaction mixture was added to an aqueous solution of saturated sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-pyridazinylmethyl)sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 259) (62 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:13])[O:11][CH3:12])=O.S([O-])([O-])(=O)=O.[Mg+2].[CH2:20]([NH2:23])[CH:21]=[CH2:22]>C(Cl)(Cl)Cl>[CH2:20]([N:23]=[CH:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:13])[O:11][CH3:12])[CH:21]=[CH2:22]
Reactant: COC(=O)Nc1ccccc1C=O
Reactant: C=CCN
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Product: C=CCN=Cc1ccccc1NC(=O)OC
Reaction time: 8 h
Yield: 98.2 %

Procedure:
Methyl 2-formylphenylcarbamate (7, 1 g, 5.6 mmol) and magnesium sulfate (3 g) were added to a solution of allylamine (1.5 g, 26 mmol) in chloroform (10 mL) and mixture was stirred overnight. Then mixture was filtered and the residue was washed with chloroform (2×10 mL). The combined filtrates were washed with water (3×10 mL) brine (10 mL), dried with sodium sulfate, and concentrated on a rotary evaporator to afford 15 as yellow oil (1.2 g, 99%). IR (film) 1732, 1635 cm−1; 1H NMR (500 MHz, CDCl3) δ 12.25 (s, 1 H), 8.43 (d, J=8.4 Hz, 1 H), 8.28 (s, 1 H), 7.40-7.34 (m, 1 H), 7.27 (dd, J=7.7, 1.4 Hz, 1 H), 7.02 (td, J=7.5, 0.9 Hz, 1 H), 6.05 (ddt, J=17.1, 10.5, 5.3 Hz, 1 H), 5.25 (ddd, J=17.2, 3.3, 1.6 Hz, 1 H), 5.20-5.13 (m, 1 H), 4.26-4.17 (m, 2 H), 3.76 (s, 3 H); 13C NMR (126 MHz, CDCl3) δ 164.94, 154.73, 140.38, 135.38, 133.25, 131.54, 121.49, 120.32, 118.05, 115.99, 62.88, 52.10; ESIMS m/z (rel intensity) 219 (MH+, 100); EIHRMS m/z M+ calcd. for C12H14N2O2, 218.1055; found, 218.1053.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][NH:4][CH2:3]1.[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18](O)=[O:19])([CH3:14])[CH3:13]>>[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18]([N:4]1[CH2:3][CH:2]([CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)=[O:19])([CH3:14])[CH3:13]
Reactant: CC1CNCc2ccccc21
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccccc2C(C)C1

Procedure:
Prepared in analogy to example 1.1 from 4-methyl-1,2,3,4-tetrahydro-isoquinoline (CA [110841-71-9]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6].C([O-])(=O)C.[K+].Cl[C:17]1[N:22]=[C:21]2[N:23]([CH3:32])[C:24](=[O:31])[N:25]([CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:20]2=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.CO.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O>[CH3:28][C:27]([CH3:30])([CH3:29])[CH2:26][N:25]1[C:20]2[C:21](=[N:22][C:17]([C:2]3[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=3[CH3:10])[C:5]#[N:6])=[CH:18][CH:19]=2)[N:23]([CH3:32])[C:24]1=[O:31]
Reactant: Cc1ccc(C#N)cc1Br
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(Cl)nc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: Cc1ccc(C#N)cc1-c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: 90 °C

Procedure:
To a microwave vial, 3-bromo-4-methylbenzonitrile (250 mg, 1.28 mmol), Bispinnacoloto(diboron) (356 mg, 1.4 mmol), Potassium Acetate (560 mg, 5.74 mmol), and Bis(diphenylphosphino)ferrocene dicholoropalladium (180 mg, 0.25 mmol) was added under nitrogen and suspended in dioxane (2.5 ml). The mixture was refluxed at 90° C. overnight, and showed the intermediate boronic ester. The reaction was cooled to room temperature and to the reaction mixture was added 14-1 (191 mg, 0.76 mmol), cesium carbonate (830 mg, 2.6 mmol), bis(tri-t-butylphosphine)palladium(0) (65 mg, 0.13 mmol) and water (0.7 mL). The mixture was refluxed at 90° C. overnight, at the desired coupled product was observed by LC/MS. The mixture was diluted with methanol and purified using reverse phase chromatography (10-100%, 0.1% TFA in H2O/Acetonitrile); the desired fractions were collected and concentrated to produce 3-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]-4-methylbenzonitrile (15-1). HRMS (M+H)+: observed=335.1865, calculated=335.1866.
Reaction SMILES: C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(=O)[NH:22][CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34]([CH3:45])([CH3:44])[C:35]([N:37]3[CH:41]4[CH2:42][CH2:43][CH:38]3[CH2:39][CH2:40]4)=[O:36])[CH:32]=2)[NH:27][C:26]=1[C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[C:48]([CH3:53])[CH:47]=1)(C)(C)C>>[NH2:22][CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34]([CH3:45])([CH3:44])[C:35]([N:37]3[CH:38]4[CH2:39][CH2:40][CH:41]3[CH2:42][CH2:43]4)=[O:36])[CH:32]=2)[NH:27][C:26]=1[C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[C:48]([CH3:53])[CH:47]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCNC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCN)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95.9 %

Procedure:
To a solution of {2-[5-[2-(7-aza-bicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-2-oxo-ethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]-ethyl} carbamic acid tert-butyl ester (252 mg in 10 mL methylene chloride) at 0° C. was added 0.60 mL anisole followed by 3.7 mL trifluoroacetic acid and the mixture stirred at 0° C. After 1.5 hours, the mixture was concentrated in vacuo and the residual acid removed by azeotrope with toluene. Purifiaction by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 90:7:1) gave the title compound (196 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([NH2:10])=[O:9])[C:3]1=[O:11].O[CH:13]1CCN(C(C)C(OCC)=O)C1=O>>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]([CH3:13])[C:8]([NH2:10])=[O:9])[C:3]1=[O:11]
Reactant: NC(=O)CN1CCC(O)C1=O
Reactant: CCOC(=O)C(C)N1CCC(O)C1=O
Product: CC(C(N)=O)N1CCC(O)C1=O

Procedure:
According to the process described in paragraph (b) of Example 1, from ethyl (R/S)-2-(3-hydroxy-2-oxo-1-pyrroldinyl)propionate there is obtained, after chromatographic filtration of silica gel (granular size 0.2-0.5 mm), elution with acetonitrile/ethanol (1:1) and crystallization from acetonitrile, (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)propionamide of melting point 139°-141°.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]2[CH2:25][CH2:24]2)[C:5]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.C([Sn](CCCC)(CCCC)[CH:31]=[CH:32][O:33]CC)CCC.O.CCOC(C)=O>O1CCOCC1.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>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]2[CH2:25][CH2:24]2)[C:5]2[C:10]([C:32](=[O:33])[CH3:31])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(NC4CC4)nc(Cl)nc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)c1cn(S(=O)(=O)c2ccc(C)cc2)c2nc(Cl)nc(NC3CC3)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 45.7 %

Procedure:
A solution of 2-chloro-N-cyclopropyl-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (489 mg, 1.00 mmol) in dioxane (6 mL) was degassed with Ar before being charged with tributyl(ethoxyvinyl)tin (0.371 mL, 1.10 mmol) and Pd(Ph3P)4 (90 mg, 0.078 mmol). The mixture was stirred at 100° C. for 18 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by HPLC to give 1-(2-chloro-4-(cyclopropylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethanone (185 mg).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][N:9]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:10][C@@H:11]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH3:12])(=O)=O.[H-].[Na+].O>CS(C)=O>[CH3:12][C@H:11]1[CH2:10][N:9]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:8][CH2:7][CH2:6][N:13]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: C[C@@H](CN(CCCOS(C)(=O)=O)C(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
To a solution of (S)-6-Benzyloxycarbonylamino-4-(tert-butoxycarbonyl)-4-azaheptyl methanesulfonate (425 g, 0.956 mol) in dimethyl sulfoxide (1.6 L) was added 60% sodium hydride (76.5 g, 1.91 mol) at an internal temperature of 25° C. or below, followed by stirring at room temperature for 2 hours. After confirming the disappearance of the starting materials by TLC, the reaction mixture was poured into water, followed by extracting with ethyl acetate. The resulting organic layer was washed with saturated brine, 0.5 N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine in this order, and then dried over anhydrous sodium sulfate. The resulting solution was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (14% ethyl acetate-petroleum ether) to give the target product as a pale yellow oil (199 g, containing about 30 g of mineral oil, yield 50.4%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:25]([C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1)[CH3:26]>>[CH2:25]([C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[N:28]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1)[CH3:26]
Reactant: CC[C@@H]1COC(=O)N1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(I)cc3)CC2)nc1C
Product: CC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3nc(C)c(C)cc3C)CC2)cc1
Yield: 77.2 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using (4-iodophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (435 mg) described in Preparation Example 176 and (R)-4-ethyloxazolidin-2-one (138 mg) described in Preparation Example 26, the title compound (326 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:5])[O:4][CH2:3]1.[F:6][C:7]1[CH:12]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=[CH:9][C:8]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[C:24]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[O:23][C:20]2=[CH:21][N:22]=1>CO.ClCCl>[F:6][C:7]1[CH:12]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:10]=[CH:9][C:8]=1[C:17]1[CH:18]=[C:19]2[CH:25]=[C:24]([CH:26]3[CH2:31][CH2:30][N:29]([CH2:3][C:2]([CH3:5])([OH:4])[CH3:1])[CH2:28][CH2:27]3)[O:23][C:20]2=[CH:21][N:22]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc3cc(C4CCNCC4)oc3cn2)c(F)c1
Reactant: CC1(C)CO1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(O)CN1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4F)ncc3o2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
1,1-Dimethyloxirane (55 μL) is added to a solution of 5-(2-fluoro-4-methanesulfonyl-phenyl)-2-piperidin-4-yl-furo[2,3-c]pyridine (0.15 g) in methanol (2 mL) and dichloromethane (3 mL) at room temperature. The solution is stirred at 50° C. overnight. The solution is concentrated to give the crude title compound that is used without further purification. LC (method 4): tR=0.98 min; Mass spectrum (ESI+): m/z=447 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[CH:7][N:6]=1)(=[O:4])=[O:3]>C(O)C.O1CCCC1.[C].[Pd]>[CH3:1][S:2]([C:5]1[N:6]=[CH:7][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Oc2ccc(N)cc2)cn1
Reaction time: 15 h
Yield: 100.3 %

Procedure:
To a solution of 2-(methylsulfonyl)-5-(4-nitrophenoxy)pyridine (9.88 g) in ethanol (150 mL) and tetrahydrofuran (150 mL) was added 10% palladium carbon (1 g), and the mixture was stirred under a hydrogen atmosphere for 15 hr. Palladium carbon was removed, and the residue was concentrated under reduced pressure to give the title compound (8.9 g, yield 100%) as a pale-yellow oil.
Reaction SMILES: C(O[C:4](=[O:17])[CH:5]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[NH2:18][C:19]([NH2:21])=[O:20].C[O-].[Mg+2].C[O-].CO>>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([CH:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[C:4]([NH:18][C:19]([NH2:21])=[O:20])=[O:17])=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(CC(C)C)c1ccc(Cl)cc1
Reactant: NC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CC(C)CC(C(=O)NC(N)=O)c1ccc(Cl)cc1
Yield: 5.3 %

Procedure:
A mixture of 2-(4-chloro-phenyl)-4-methyl-pentanoic acid ethyl ester (508 mg, 1.99 mmol) and urea (239 mg, 3.99 mmol) in a solution of magnesium methoxide in methanol (7.4 wt %, 4.28 mL, 2.99 mmol) was heated to reflux for 24 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded [2-(4-chloro-phenyl)-4-methyl-pentanoyl]-urea (28.1 mg, 5.2%) as a white solid: mp 164-165° C.; EI-HRMS m/e calcd for C13H17ClN2O2 (M+) 268.0979, found 268.0972.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[CH3:29][N:30]1[CH2:35][CH2:34][CH:33]([O:36][C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)[CH2:32][CH2:31]1>>[CH2:1]([N:3]([CH2:41][C:40]1[CH:39]=[CH:38][C:37]([O:36][CH:33]2[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]2)=[CH:44][CH:43]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:15]2[CH:16]=[C:17]([OH:22])[CH:18]=[CH:19][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CN1CCC(Oc2ccc(C=O)cc2)CC1
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OC2CCN(C)CC2)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 71.6 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (33 mg) and 4-(1-methylpiperidin-4-yloxy)benzaldehyde (94 mg) according to an analogous synthetic method to Example 264 described below and purified by LC-MS, the title compound (31 mg) was obtained.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]23[CH2:15][CH:10]4[CH2:11][CH:12]([CH2:14][CH:8]([N:9]4C(OC(C)(C)C)=O)[CH2:7]2)[CH2:13]3)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([CH2:4][O:5][C:6]23[CH2:15][CH:10]4[CH2:11][CH:12]([CH2:14][CH:8]([NH:9]4)[CH2:7]2)[CH2:13]3)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1C2CC3CC1CC(OCC1CC1)(C3)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1CC1COC12CC3CC(C1)NC(C3)C2
Temperature: 0 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer was charged tert-butyl 5-(cyclopropylmethoxy)-2-azatricyclo[3.3.1.13,7]decane-2-carboxylate, Intermediate-19 (50 mg, 0.016 mmol) in DCM (5 mL). Then reaction mixture was cooled to 0° C. and trifluoroacetic acid (0.099 g, 0.084 mmol) was added and stirred for 4 hours. After completion of the reaction (reaction was monitored by LCMS) the reaction mixture was concentrated followed by trituration with mixture of hexane:ether (1:1) to give Intermediate-20 (50 mg, yield=95%) as an oily mass.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:10][CH3:11])[CH2:8][CH2:7][O:6][CH2:5][CH:4]1[OH:9].[H-].[Na+].I[CH2:15][CH3:16]>C1COCC1>[CH2:15]([O:9][CH:4]1[C:3]([O:10][CH3:11])([O:2][CH3:1])[CH2:8][CH2:7][O:6][CH2:5]1)[CH3:16]
Reactant: CCI
Reactant: COC1(OC)CCOCC1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC1COCCC1(OC)OC
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 4,4-dimethoxytetrahydro-2H-pyran-3-ol (2.0 g, 12 mmol) in THF (20 mL) cooled in an ice bath was slowly added sodium hydride (0.60 g, 15 mmol) and the resulting slurry was stirred for 1 h. Iodoethane (1.5 mL, 19 mmol) was added and the mixture was stirred at room temperature overnight. More sodium hydride (0.6 g) and iodoethane (3 mL) were added and stirring was continued another overnight. The reaction was quenched with water. The resulting solution was extracted with EtOAc twice and ether twice. The combined extracts were dried, concentrated and purified on silica gel (20% EtOAc/hexanes) to give 2.1 g (90%) of desired product. 1H NMR (CDCl3) δ 3.32-4.00 (7H, m), 3.30 (3H, s), 3.20 (3H, s), 2.05-1.70 (2H, m), 1.25-1.22 (3H, m).
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][C:16]([C:23]#[C:24][C:25]([OH:28])([CH3:27])[CH3:26])=[CH:17][CH:18]=2)[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].BrC1C=C2C(C=C(C)C(C(OC(C)(C)C)C(OCC)=O)=C2C2C=CC(Cl)=CC=2)=CC=1.CC(O)(C#C)C.CCN(CC)CC.[NH4+].[Cl-]>C1COCC1.[Cu]I.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:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][C:16]([C:23]#[C:24][C:25]([OH:28])([CH3:27])[CH3:26])=[CH:17][CH:18]=2)[C:13]=1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(C#CC(C)(C)O)cc2c1-c1ccc(Cl)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#CC(C)(C)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc2ccc(C#CC(C)(C)O)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O
Temperature: 65 °C
Reaction time: 1 h

Procedure:
Preparation of ethyl 2-tert-butoxy-2-(1-(4-chlorophenyl)-7-(3-hydroxy-3-methylbut-1-ynyl)-3-methylnaphthalen-2-yl)acetate: To a solution of ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (30 mg, 0.061 mmol) in THF (1 mL) was added 2-methylbut-3-yn-2-ol (15 mg, 0.18 mmol), CuI (1 mg, 0.006 mmol), Pd(PPh3)4 (3 mg, 0.003 mmol), and Et3N (50 μL, 0.36 mmol). The reaction mixture was stirred at 65° C. for 1 h. A saturated solution of NH4Cl was added. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give 22 mg of the titled compound. 1H-NMR: 400 MHz, (CD3OD) δ: 7.73 (d, J=9 Hz, 1H), 7.67 (s, 1H), 7.57 (m, 2H), 7.48 (m, 1H), 7.40 (d, J=9 Hz, 1H), 7.29 (d, J=9 Hz, 1H), 7.24 (s, 1H), 5.15 (s, 1H), 4.16 (m, 2H), 2.57 (s, 3H), 1.51 (s, 6H), 1.20 (t, J=7 Hz, 3H), 0.99 (s, 9H).