Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][CH:9]=[C:8]([C:11](=O)[CH2:12]Br)[CH:7]=1)=[O:5])C.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[C:21]([NH2:23])=[S:22])[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:21]2[S:22][CH:12]=[C:11]([C:8]3[CH:7]=[C:6]([C:4]([OH:3])=[O:5])[O:10][CH:9]=3)[N:23]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[CH3:16]
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Reactant: CCOC(=O)c1cc(C(=O)CBr)co1
Product: CCOc1ccc(-c2nc(-c3coc(C(=O)O)c3)cs2)cc1OCC

Procedure:
5-Ethoxycarbonyl-3-(α-bromoacetyl)furan and 3,4- diethoxythiobenzamide were subjected to the same reaction as in Example 1 and then to the same hydrolysis as in Example 147 to obtain 2-(3,4-diethoxyphenyl)-4-(5-carboxy-3-furyl)thiazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:25][C:26](Br)=[O:27].[C:29]1([CH2:39][NH2:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:25][C:26]([NH:40][CH2:39][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1)=[O:27]
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OC)c(OC)c1
Reactant: O=C(Br)CBr
Reactant: NCc1cccc2ccccc12
Product: COc1ccc2c(c1)CCN(CC(=O)NCc1cccc3ccccc13)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 1-(3,4-dimethoxy-benzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-napthalenemethylamine
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@H:13]2[CH2:17][C@@H:16]([O:18][CH3:19])[CH2:15][N:14]2[C:20](=[O:29])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[O:12])=[CH:6][CH:5]=1.C[Si](C)(C)[O-].[K+]>C1COCC1>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:20]([N:14]2[CH2:15][C@H:16]([O:18][CH3:19])[CH2:17][C@@H:13]2[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:30])=[O:2])=[CH:5][CH:6]=2)=[O:12])=[O:29])=[CH:27][CH:26]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@H]2C[C@@H](OC)CN2C(=O)Nc2ccc(Cl)cc2)cc1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CO[C@@H]1C[C@H](C(=O)Nc2ccc(C(=O)O)cc2)N(C(=O)Nc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
Into a solution of 9 (3.0 g, 6.94 mmol) in THF (50 mL) was added potassium trimethylsilanolate (3.85 g, 27.3 mmol). The solution was stirred at RT for 48 h before concentrating under reduced pressure and adding EtOAc. The solution was washed sequentially with 1N HCl, and brine, before drying over MgSO4 and concentrating under reduced pressure to give 10 (2.9 g, 100%). MS: APCI (AP+): 418.1 (M)+, (AP−): 416.1 (M)−
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11]([O:13][C@@H:14]2[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)=[O:12])[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:28][CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31]>C(#N)C>[Br-:28].[F:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:11]([O:13][C@@H:14]2[CH:19]3[CH2:20][CH2:21][N+:16]([CH2:29][C:30](=[O:31])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([CH2:17][CH2:18]3)[CH2:15]2)=[O:12])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)cc1F
Reactant: O=C(CBr)c1ccccc1
Solvent: CC#N
Product: Cc1ccc(NC(C(=O)O[C@H]2C[N+]3(CC(=O)c4ccccc4)CCC2CC3)c2ccccc2)cc1F
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.2 %

Procedure:
(R)-Quinuclidin-3-yl 2-(3-fluoro-4-methylphenylamino)-2-phenylacetate (C97) (80 mg, 0.22 mmol) and 2-bromo-1-phenylethanone (45.4 mg, 0.23 mmol) are dissolved in acetonitrile (3 mL) and stirred at RT overnight (Conversion complete by UPLC/MS). Acetonitrile is evaporated and the residue is purified by flash chromatography (DCM/MeOH=97/3) affording the title compound as a white solid (29 mg, 23% yield, bromide salt, mixture of diastereoisomers).
Reaction SMILES: C(OC(=O)[N:7]([C:16]1[N:17]([CH2:21][C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)[CH:18]=[CH:19][N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:29][C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([Cl:28])[CH:25]=1)[CH2:21][N:17]1[CH:18]=[CH:19][N:20]=[C:16]1[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1)c1nccn1Cc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(CNc2nccn2Cc2cc(Cl)cc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of [1-(3,5-dichloro-benzyl)-1H-imidazol-2-yl]-(4-fluoro-benzyl)-carbamic acid tert-butyl ester in CH2Cl2 was added trifluoroacetic acid. The reaction solution was stirred at room temperature for 3 h. When all the starting material was consumed, the mixture was diluted with CH2Cl2 and washed with water. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel preparative TLC using CH2Cl2:MeOH 95:5 as an eluent to afford the title compound (24 mg, 63%); LCMS m/z 350 [C17H14Cl2FN3+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH:9]=O)[CH:2]=1.Cl.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19]N)=[CH:15][CH:14]=1.C(O)(=O)C>C(O)C>[Br:12][C:13]1[CH:14]=[C:15]2[C:16](=[CH:17][CH:18]=1)[NH:19][CH:9]=[C:8]2[CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: NNc1ccc(Br)cc1
Reactant: O=CCCc1cccnc1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: Brc1ccc2[nH]cc(Cc3cccnc3)c2c1

Procedure:
A mixture of 3-pyridin-propionaldehyde (1 g; 0.0074 mol) and of 4-bromophenylhydrazin hydrochloride (1.8 g; 0.0074 mol) with acetic acid (4.44 ml) in absolute ethanol (50 ml) was refluxed for 3 hours. The reaction was then quenched with a saturated solution of aqueous sodium carbonate and the product was extracted with ethyl acetate. The organic extract was dried (MGSO4) and evaporated under vacuum. After purification by Flash Chromatography on silica gel using as eluent methylene chloride/methanol (98/2), the desired compound was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[CH:4][C:5]([C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]2[NH:32][C:31](=[O:33])[N:30]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[CH2:29][CH2:28][C:27]=2[CH:40]=1.C(=O)([O-])[O-].[K+].[K+].CN1C(=O)CCC1>O>[Br:1][C:2]1[C:3]([N:37]2[CH2:36][CH2:35][CH:34]([N:30]3[CH2:29][CH2:28][C:27]4[CH:40]=[C:23]([O:22][CH3:21])[CH:24]=[CH:25][C:26]=4[NH:32][C:31]3=[O:33])[CH2:39][CH2:38]2)=[CH:4][C:5]([C:8]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1
Reactant: O=C(c1cc(Cl)c(Br)cn1)N1CCc2cc(F)ccc21
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5cc(F)ccc54)ncc3Br)CC1)C(=O)N2
Temperature: 130 °C
Reaction time: 10 h

Procedure:
0.38 g (1.1 mmol) (5-bromo-4-chloro-pyridin-2-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone, 0.29 g (1.1 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.22 g (1.6 mmol) potassium carbonate and 3.0 mL NMP were combined and stirred for 10 h at 130° C. Then the reaction mixture was combined with water and the precipitate formed was suction filtered and dried.
Reaction SMILES: N#N.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[C:32]([O:35][CH2:36][C:37]1[O:41][N:40]=[C:39]([CH3:42])[C:38]=1Br)(=[O:34])[CH3:33].CCN(CC)CC.[CH3:51][C:52]1([CH3:59])[C:56]([CH3:58])([CH3:57])[O:55][BH:54][O:53]1>O1CCOCC1.CC#N.CC#N.Cl[Pd]Cl>[C:32]([O:35][CH2:36][C:37]1[O:41][N:40]=[C:39]([CH3:42])[C:38]=1[B:54]1[O:55][C:56]([CH3:58])([CH3:57])[C:52]([CH3:59])([CH3:51])[O:53]1)(=[O:34])[CH3:33]
Reactant: CC1(C)OBOC1(C)C
Reactant: CC(=O)OCc1onc(C)c1Br
Agent: Cl[Pd]Cl
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: N#N
Solvent: C1COCCO1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)OCc1onc(C)c1B1OC(C)(C)C(C)(C)O1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To a 500 mL flask (under N2 (g)) was added dichlorobis(acetonitrile)palladium(II) (0.551 g, 2.12 mmol) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (3.50 g, 8.53 mmol). To the solids was sequentially added a solution of (4-bromo-3-methylisoxazol-5-yl)methyl acetate (24.8 g, 106 mmol) in 1,4-dioxane (65 mL), Et3N (44.3 mL, 318 mmol), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (24 mL, 160 mmol). The flask was sequentially evacuated and purged under N2 and this process was repeated three times. The reaction mixture was heated to 110° C. (under a constant stream of N2 (g)) and allowed to stir for ˜4 h. LC-MS analysis at this point showed complete conversion of the starting bromo-isoxazole. The reaction mixture was cooled to room temperature and EtOAc (100 mL) was added. After 15 min of stirring, the suspension was filtered over a pad of Celite. The filter cake was washed with EtOAc (3×100 mL), concentrated in vacuo, and the solvent was switched using 1,4-Dioxane (2×50 mL). The borate ester with used without further purification.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].I[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([C:21]3[CH:25]=[C:24]([CH3:26])[N:23]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)[N:22]=3)[O:18][N:17]=2)=[CH:12][CH:11]=1.O>CN(C=O)C.[Cu]I.C(OCC)(=O)C>[CH3:26][C:24]1[N:23]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)[N:22]=[C:21]([C:19]2[O:18][N:17]=[C:16]([C:13]3[CH:14]=[CH:15][C:10]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[CH:11][CH:12]=3)[N:20]=2)[CH:25]=1
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(I)cc4)no3)cc2C)cc1
Reactant: OCC(F)(F)F
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(OCC(F)(F)F)cc4)no3)cc2C)cc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 17.5 %

Procedure:
A solution of 2,2,2-trifluoroethanol (175 mg, 1.75 mmol) in DMF (2 ml) was added to sodium hydride (117 mg of a 60% suspension in mineral oil, 2.94 mmol). The mixture was stirred at 50° C. for 15 minutes. Then, 3-(4-iodophenyl)-5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazole (Example 13, 200 mg, 0.44 mmol) and copper(I) iodide (167 mg, 0.88 mmol) were added and the reaction mixture was stirred at 110° C. for one hour. The reaction mixture was cooled and water (100 mL) and ethyl acetate (100 mL) was added. The layers were separated and the organic layer was washed with water and brine and then dried with magnesium sulfate. The solvent was evaporated and the residue was purified, first using preparative HPLC and then via flash chromatography (silica, gradient elution from cyclohexane/ethyl acetate 10:1 to 3:1) to afford the title compound as a white solid (33 mg, 18%): 1H NMR (400 MHz, CDCl3) 8.19 (d, 2H), 7.13 (d, 2H), 7.07 (d, 2H), 7.03 (d, 2H), 6.78 (s, 1H), 5.42 (s, 2H), 4.42 (quart, 2H), 2.32 (s, 3H), 2.26 (s, 3H); ES-MS m/z 429 (MH)+, HPLC RT (Method D) 3.19 min.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Si](C)(C)C)(=O)=O.[F-].[Cs+].[P:21]([O:32]CCCC)([O:27][CH2:28][CH2:29][CH2:30][CH3:31])[O:22][CH2:23][CH2:24][CH2:25][CH3:26].C(#N)C>CCOC(C)=O>[C:7]1([P:21](=[O:32])([O:27][CH2:28][CH2:29][CH2:30][CH3:31])[O:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Reactant: CCCCOP(OCCCC)OCCCC
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCOP(=O)(OCCCC)c1ccccc1

Procedure:
2-(trimethylsilyl)phenyl trifluoromethanesulfonate (25 mg, 0.083 mmol), Cesium Fluoride (70 mg, 0.461 mmol), Tributyl phosphite (83 mg, 0.335 mmol), Acetonitrile (1 ml): Reaction Time: 24 h; Rf: 0.4 (1:3 EtOAc:Pet. Ether); Thick oil; 16.3 mg, 72%; 1H NMR (400 MHz, CDCl3, TMS) δ 7.80 (dd, J=6.8, 13.3 Hz, 2H), 7.55 (t, J=7.5 Hz, 1H), 7.50-7.42 (m, 2H), 4.12-3.95 (m, 4H), 1.65 (quint, J=7.3 Hz, 4H), 1.39 (sext, J=7.3 Hz, 4H), 0.9 (t, J=7.3 Hz, 6H); 13C NMR (100 MHz, CDCl3, TMS) δ 132.3 (d, J=3.1 Hz), 131.7 (d, J=9.3 Hz), 128.4 (d, J=15.4 Hz), 128.3 (d, J=187.3 Hz), 65.8 (d, J=5.4 Hz), 32.4 (d, J=6.9 Hz), 18.7, 13.6; 31P NMR (162 MHz, CDCl3) δ 18.8; Mass (M+Na)+ 293; Known compound, Lit. X. Lu, J. Zhu, Synthesis 1987, 8, 726.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH2:14][C:15]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[C:16]=1[C:17]([OH:19])=[O:18].O>CN(C)C=O>[NH2:14][C:15]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[C:16]=1[C:17]([O:19][CH3:5])=[O:18]
Reactant: COc1cc(N)c(C(=O)O)c(OC)c1
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(N)cc(OC)cc1OC
Reaction time: 1 h
Yield: 77.5 %

Procedure:
Dimethyl sulfate (1.04 ml, 11.0 mmol) was added dropwise to a mixture of potassium carbonate (3.34 g, 24.2 mmol) and 2-amino-4,6-dimethoxybenzoic acid (2.56 g, 11.0 mmol) in dimethylformamide (70 ml) at 0° C. The reaction was stirred for 1 hour, then poured into water. The resulting precipitate was filtered, washed with water and dried in vacuo. The filtrate was extracted with ethyl acetate, and the combined organic extracts were dried (magnesium sulphate) and concentrated in vacuo. The combined solids were dried in vacuo to yield methyl 2-amino-4,6-dimethoxybenzoate (1.8 g, 77% yield) as a yellow crystalline solid:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]([CH3:19])[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:10])[CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:22][C@@H:23]([CH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25])[CH3:21].[F-].[Cs+]>COC(O)C(O)OC>[CH2:20]([O:22][C@@H:23]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([N:8]([CH3:19])[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:10])[N:7]=2)=[CH:31][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25])[CH3:21]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(Br)n1
Reactant: CCO[C@@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC
Agent: COC(O)C(O)OC
Agent: [Cs+]
Agent: [F-]
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C[C@H](OCC)C(=O)OC)cc2)n1
Temperature: 80 °C
Reaction time: 18 h
Yield: 45.3 %

Procedure:
3.2 g (9.7 mmol) of 1-(6-bromopyrid-2-yl)-3-heptyl-1-methylurea, 4.2 g (12.6 mmol) of methyl 2(S)-ethoxy-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]propanoate (prepared as in Example 7e) and 4.4 g (29.1 mmol) of caesium fluoride are placed in 200 ml of dimethoxyethylene glycol. The reaction medium is degassed, 0.23 g (0.3 mmol) of dichlorodiphenylphosphinoferrocenepalladium is then added and the reaction medium is stirred at 80° C. for 18 hours. After addition of water, the reaction medium is extracted with ethyl acetate. The organic phase is washed with water, with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by thin-layer chromatography on silica eluted with an 80/20 heptane/ethyl acetate mixture. 2 g (45%) of methyl 2(S)-ethoxy-3-{4-[6-(3-heptyl-1-methylureido)pyrid-2-yl]phenyl}propanoate are obtained.
Reaction SMILES: [H-].[Na+].C[C:4](P(OC)(O)=O)([C:6]([O-:8])=[O:7])[CH3:5].[CH:14]1([O:19][C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])C=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.O1CCC[CH2:31]1>>[CH:14]1([O:19][C:20]2[CH:21]=[C:22](/[CH:5]=[CH:4]/[C:6]([O:8][CH3:31])=[O:7])[CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: C1CCOC1
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Agent: [H-]
Agent: [Na+]
Product: COC(=O)/C=C/c1ccc(OC)c(OC2CCCC2)c1

Procedure:
To a stirred suspension of 7.5 g (0.16 mol) of a 50% oil suspension of sodium hydride (previously washed with three, 10 mL portions of hexane) in 600 mL of dry tetrahydrofuran under a nitrogen atmosphere was added dropwise at room temperature 16.5 mL (0.10 mol) of trimethylphosphonoacetate in 100 mL of dry tetrahydrofuran over a 20 minute period. The white suspension was stirred for an additional 2 hours after which time 20.4 g (0.09 mol) of 3-cyclopentoxy-4-methoxybenzaldehyde in 150 mL of dry tetrahydrofuran was added dropwise over a 10 minute period. The final reaction mixture was stirred for an additional hour after which time the mixture was quenched with 75 mL of saturated sodium chloride. After separation of the solvent layers, the organic fraction was dried over sodium sulfate and concentrated. Liquid chromatography of the crude product over 250 g of silica gel with 20% ethyl acetate in hexane provided the desired, analytically pure product upon crystallization from hexane.
Reaction SMILES: [C:1]1(=[N:6][NH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([S:18](=[O:21])(=[O:20])[NH2:19])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:25]=1.N12CCCN=C1CCCCC2.Cl>O.C(#N)C>[C:1]1(=[N:6][NH:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([S:18]([NH:19][C:33]([NH:32][C:26]3[N:25]=[C:24]([O:23][CH3:22])[CH:29]=[C:28]([O:30][CH3:31])[N:27]=3)=[O:34])(=[O:20])=[O:21])[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NN=C2CCCC2)cc1S(N)(=O)=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)c1ccc(NN=C2CCCC2)cc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Reaction time: 2 h
Yield: 65.6 %

Procedure:
1.5 g (4.8 mmol) of methyl 4-cyclopentylidenehydrazino-2-sulfamoylbenzoate and 1.6 g (5.8 mmol) of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate are initially introduced into 20 ml of acetonitrile. 1.6 g (10.6 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) are added dropwise at 0° C. and the mixture is stirred at this temperature for 2 hours. It is poured into water and the pH is brought to 2-3 with 2 N hydrochloric acid. The aqueous phase is extracted three times with CH2Cl2. After the methylene chloride phase has been washed with 2 N hydrochloric acid and water, it is dried and evaporated. The residue is triturated with diisopropyl ether. After filtering off with suction and drying, 1.55 g (65% of theory) of methyl 4-cyclopentylidenehydrazino-2-[3-(4,6-dimethoxypyrimidin-2-yl)-ureidosulfonyl]benzoate of melting point 168-170° C. (decomposition) are obtained.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.Cl>CN(C)C=O.CCCCCC>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
A slurry of hexane-washed sodium hydride (3 g, 75 mmol) in dimethyl formamide (80 mL) was stirred as a solution of N-(t-butoxycarbonyl)4-hydroxypiperidine (10 g, 50 mmol) in dimethyl formamide (10 mL) was added dropwise. Slight heating was used to initiate reaction, but the reaction needed to be cooled in an ice bath to control the reaction rate. Approximately 30 min after the addition was complete, solid 4-fluoro-1-nitrobenzene (7.4 g, 52 mmol) was added at once. The reaction was stirred for about 3 hours. The reaction was poured into ice water. The pH of the resulting liquid was adjusted to neutrality with 1 N hydrochloric acid. The resulting solid was isolated by filtration, washed with water, and dried under reduced pressure to give 16 g of 4-(N-(t-butoxycarbonyl)piperidin-4-yl)oxy-1-nitrobenzene, NMR (CDCl3, TMS) δ1.45 (s, 9), 1.72 (m, 2), 1.98 (m, 2), 3.38 (m, 2), 3.68 (m, 2), 4.62 (m, 1), 6.98 (m, 2), 8.19 (m, 2).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([NH:10][C:11]1[CH:27]=[CH:26][C:14]([O:15][CH2:16][CH2:17][NH:18][C:19](=O)OC(C)(C)C)=[CH:13][CH:12]=1)=[O:9].[ClH:28].C([O:32][CH2:33][CH3:34])(=O)C>CO>[ClH:28].[OH:32][C@H:33]([C:34]1[CH:8]=[CH:7][CH:2]=[CH:3][CH:4]=1)[CH2:19][NH:18][CH2:17][CH2:16][O:15][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:8](=[O:9])[CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(NC(=O)Cc2ccccn2)cc1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CO
Product: O=C(Cc1ccccn1)Nc1ccc(OCCNC[C@H](O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3.62 g of tert-butyl N-[2-[4-[[2-(2-pyridyl)acetyl]amino]phenoxy]ethyl]carbamate in 30 ml of methanol was added 50 ml of a 4N hydrochloride-ethyl acetate solution. After the reaction solution was stirred at room temperature for eight hours, the solvent was evaporated in vacuo. To the residue were added an aqueous solution of sodium hydrogen carbonate and potassium carbonate to adjust to pH about 12. The resulting aqueous phase was extracted with a mixed solvent of chloroform and tetrahydrofuran. The organic layer was dried over anhydrous magnesium sulfate and concentrated, the resulting residue was dissolved in 40 ml of methanol, and 1.02 g of (R)-styrene oxide was added thereto. After the reaction solution was heated to reflux for 26 hours, the solvent was evaporated in vacuo. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=30/1→10/1) and dissolved in methanol, 0.59 ml of a 4N hydrogen chloride-ethyl acetate solution was added, and the solvent was evaporated in vacuo. The resulting crude crystals were recrystallized from methanol-ethanol to give 320 mg of (R)-4′-[2-[(2-hydroxy-2-phenylethyl)-amino]ethoxy]-2-(2-pyridyl)acetanilide hydrochloride
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[N:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[N:17]3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:34][NH:35][C@H:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH2:38][CH2:37]1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[CH3:34][N:35]([C@H:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39][CH2:38][CH2:37]1)[C:21]([C:19]1[CH:18]=[N:17][N:16]([CH:13]2[CH2:12][CH2:11][N:10]([C:8](=[O:9])[CH2:7][N:6]3[C:2]([CH3:1])=[CH:3][C:4]([C:24]([F:26])([F:25])[F:27])=[N:5]3)[CH2:15][CH2:14]2)[N:20]=1)=[O:23]
Reactant: CN[C@@H]1CCCc2ccccc21
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(n2ncc(C(=O)O)n2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(n2ncc(C(=O)N(C)[C@@H]3CCCc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
To a slurry of 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-2H-1,2,3-triazole-4-carboxylic acid (0.070 g, 0.18 mmol) (i.e. the product of Example 32, Step C) in dichloromethane (2 mL) was added oxalyl chloride (0.05 mL, 0.35 mmol) and one drop of N,N-dimethylformamide. After 45 minutes the reaction mixture was concentrated in vacuo and the resulting residue was dissolved in dichloromethane (10 mL). The reaction mixture was then added to a solution of (R)—N-methyl-1,2,3,4-tetrahydronaphthalen-1-ylamine (32 mg, 0.20 mmol) and triethylamine (0.033 mL, 0.24 mmol) in dichloromethane (2 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. The organic layer was washed with saturated aqueous sodium bicarbonate, dried (Na2SO4) and the solvent was removed with a rotary evaporator. The residue was purified by medium pressure liquid chromatography (MPLC) using 35-60% ethyl acetate in hexanes as eluant to afford 74 mg of the title product, a compound of the present invention as an oil.