Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].[Cl:9][C:10]([Cl:14])([Cl:13])[C:11]#[N:12]>CCOCC>[Cl:9][C:10]([Cl:14])([Cl:13])[C:11](=[NH:12])[O:6][CH:3]([CH2:4][CH3:5])[CH2:2][CH3:1]
Reactant: CCC(O)CC
Reactant: N#CC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCC(CC)OC(=N)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.8 %

Procedure:
3-Pentyl trichloroacetimidate was prepared as follows. Under an atmosphere of nitrogen, a solution of 3-pentanol (8.815 g, 100 mmol) in anhydrous Et2O (14 mL) was added dropwise to NaH (0.4 g, 10 mmol, 60% oil dispersion prewashed with hexane) suspended in Et2O (10 mL). The mixture was stirred for 10 min at room temperature, and added dropwise over a period of 20 min to a cold (−5° C.) solution of trichloroacetonitrile (15 mL, 150 mmol) in Et2O (20 mL) under an atmosphere of nitrogen. The reaction mixture was warmed to room temperature, and stirred for 2 h. After removal of solvent, the residue was triturated with MeOH/hexane (1:19, 10 mL) with vigorous stirring for 1 min to give precipitates, which were filtered off and washed with cold hexane. The filtrate was evaporated under reduced pressure to dryness, giving 3-pentyl trichloroacetimidate (16 g, 70% yield) as light brown oil. TLC (EtOAc/hexane, 1:4) Rf=0.3; 1H NMR (600 MHz, CDCl3) δ 8.17 (1 H, br s, NH), 4.89 (1 H, m, J=6.0 Hz), 1.69 (4 H, qd, J=7.4, 6.0 Hz), 0.94 (6 H, t, J=7.4 Hz); 13C NMR (150 MHz, CDCl3) δ 162.7, 92.2, 81.9, 25.7 (2×), 9.4 (2×); HRMS calcd for C7H13Cl3NO (M++H): 232.0063, found: m/z 232.0067. Under an atmosphere of nitrogen, the freshly prepared 3-pentyl trichloroacetimidate (350 mg, 1.5 mmol) and CF3SO3H (13 μL, 0.15 mmol) were added to a solution of alcohol 10a (321 mg, 1.2 mmol) in CH2Cl2 (15 mL). The reaction mixture was stirred at room temperature for 24 h, during which more imidate and CF3SO3H (350 mg and 13 μL mmol) were added 5 times every 4 h period. The reaction was quenched with aqueous NaHCO3 solution (5%). The aqueous layer was extracted with CH2Cl2 (2×). The combined organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/hexane, 3:7) to afford the alkylation product 11a (317 mg, 78% yield). Colorless solid, mp 115-117° C.; TLC (EtOAc/hexane, 1:1) Rf=0.4; [α]D20=−48.9 (c=1.1, CHCl3); IR (neat) 2101, 1712, 1655 cm−1; 1H NMR (600 MHz, CDCl3) δ 6.75 (1 H, s), 5.98 (1 H, d, J=7.4 Hz), 4.53 (1 H, d, J=5.0 Hz), 4.51-4.16 (3 H, m), 3.33-3.28 (2 H, m), 2.82 (1 H, dd, J=17.6, 5.6 Hz), 2.22-2.16 (1 H, m), 2.00 (3 H, s), 1.49-1.45 (4 H, m), 1.25 (3 H, t, J=7.1 Hz), 0.95-0.80 (6 H, m); 13C NMR (150 MHz, CDCl3) δ 171.1, 165.8, 137.9, 128.1, 82.0, 73.4, 61.0, 58.0, 57.2, 30.5, 26.2, 25.6, 23.5, 14.1, 9.5, 9.3; HRMS calcd for C16H27N4O4(M++H): 3390.2032, found: m/z 339.2035.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10]CC2C=CC(OC)=CC=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]2[O:34][N:33]=[C:32]([C:35]([CH3:41])([CH3:40])[C:36]([F:39])([F:38])[F:37])[CH:31]=2)=[O:28])=[C:22]([F:42])[CH:21]=1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:5]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]3[O:34][N:33]=[C:32]([C:35]([CH3:41])([CH3:40])[C:36]([F:38])([F:39])[F:37])[CH:31]=3)=[O:28])=[C:22]([F:42])[CH:21]=2)=[CH:6][NH:7][C:8](=[O:10])[CH:9]=1)[CH3:2]
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)Nc2cc(C(C)(C)C(F)(F)F)no2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc(=O)[nH]cc1-c1ccc(CC(=O)Nc2cc(C(C)(C)C(F)(F)F)no2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.8 %

Procedure:
To a suspension of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide (1.5 g, 2.55 mmol) in DCM (20 mL) was added TFA (2 mL, 26.9 mmol) dropwise. The mixture was stirred at 25° C. for 2 h. The mixture was then concentrated. To the residue was added H2O (50 mL) dropwise and then neutralized with saturated Na2CO3 solution to adjust pH=7.5. The precipitate was filtered, washed with H2O (50 mL×3) and dried in vacuo. To the solid was added PE/EA (3:1, v/v, 30 mL) and stirred for 0.5 h. The solid was filtered, washed with PE/EA (3:1, v/v, 30 mL×2). The solid was redissolved in DCM/MeOH (20:1, v/v, 50 mL) and then concentrated in vacuo to a minimal amount of solvent (about 10 mL). The solid was filtered, washed with CH3CN (10 mL×2) and dried in vacuo. The residue was redissolved in DCM/MeOH (10:1, v/v, 50 mL) and concentrated in vacuo to give a white solid of 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide (440 mg, 0.938 mmol, 36.7% yield): 1H NMR (400 MHz, CD3OD): δ 7.39-7.36 (m, 1H), 7.36-7.30 (m, 1H), 7.25-7.18 (m, 2H), 6.37 (s, 1H), 5.99 (s, 1H), 4.11 (q, J=7.2 Hz, 2H), 3.82 (s, 2H), 1.53 (s, 6H), 1.37 (t, J=6.8 Hz, 3H). ES-LCMS m/z: 468 (M+H); CHN analytical report: average (%): N, 8.717; C, 55.32; H, 4.672.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[CH:6](OCC)([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C>[CH2:8]([O:7][CH:6]([O:10][CH2:11][CH3:12])[N:1]1[CH:5]=[CH:4][N:3]=[N:2]1)[CH3:9]
Reactant: c1c[nH]nn1
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(OCC)n1ccnn1
Yield: 56.8 %

Procedure:
After the addition of 2.5 g of p-toluenesulphonic acid hydrate, 34.5 g (0.5 mol) of triazole in 222 g (1.5 mol) of triethyl orthoforrnate are heated until the internal temperature reaches 150° C., while ethanol is distilled off. 2 g of sodium carbonate are added and the mixture is distilled using high vacuum. 48.6 g (56.8% of theory) of N-diethoxymethyltriazole are obtained.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[H-].[Na+].C1(C)C(C([O:21][C@@H:22]2[C@@H:26]([CH2:27][O:28]C(C3C(C)=CC=CC=3)=O)[O:25][C@H:24](Cl)[CH2:23]2)=O)=CC=CC=1.O>CN(C)C=O>[O:10]([C:3]1[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=1)[C@@H:24]1[O:25][C@H:26]([CH2:27][OH:28])[C@@H:22]([OH:21])[CH2:23]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Cc1ccccc1C(=O)OC[C@H]1O[C@H](Cl)C[C@@H]1OC(=O)c1ccccc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(O[C@H]2C[C@H](O)[C@@H](CO)O2)cc1
Reaction time: 3 h
Yield: 69.6 %

Procedure:
p-Nitrophenol (178 mg, 1.28 mmol) and sodium hydride (64 mg of a 60% dispersion in mineral oil, 1.6 mmol) were stirred together in dry dimethylformamide (4 ml) at room temperature for 30 minutes then the chloride (416 mg, 1.07 mmol) from Example 16 was added. The mixture was stirred for a further 3 hours, then water (100 ml) was added and the mixture was evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with 20% ethyl acetate in hexanes) to give a pale yellow oil which crystallized from a mixture of chloroform and hexanes to give the title compound as a colourless solid (190 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([C:12]([O:14][CH3:15])=[O:13])[CH2:5]2.C([O:20]O)(C)(C)C>C1(C)C=CC=CC=1.C(#N)C.CC(C)[O-].[Zr+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[C:6]([OH:20])([C:12]([O:14][CH3:15])=[O:13])[CH2:5]2
Reactant: COC(=O)C1Cc2cc(Cl)ccc2C1=O
Reactant: CC(C)(C)OO
Agent: [Zr+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: COC(=O)C1(O)Cc2cc(Cl)ccc2C1=O
Temperature: 30 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
To a solution of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate (also known as methyl 5-chloro-1-oxo-2,3-dihydroindene-2-carboxylate) (0.500 g, 2.23 mmol) (Formula IIa wherein R1 is OCH3 and R4 is Cl) and zirconium(1V) isopropoxide (0.0086 g, 0.022 mmol) in toluene (1.34 g, 1.56 mL) at 30° C. was added an aqueous solution of tert-butyl hydroperoxide (70%, 0.316 g, 2.46 mmol). The reaction mixture was stirred for 24 hours at 30° C. and then diluted with acetonitrile (about 6 mL). Quantitative HPLC analysis showed 92% conversion of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate, forming racemic methyl 5-chloro-2,3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylate in 89% yield (97% chemoselectivity).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[C:8]1([Mg]Br)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C(OCC)C>[CH3:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Br[Mg]c1ccccc1
Reactant: Cc1ccsc1Br
Agent: Cl
Solvent: CCOCC
Product: Cc1ccsc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 2-bromo-3-methylthiophene (15.0 g, 0.085 mole) and bis(1,3-diphenylphosphino)propane nickel(II) chloride (0.5 g, 0.009 mole) in diethyl ether (75 mL) was cooled to 0° C. Phenyl magnesium bromide (29.6 mL of a 3M solution in diethyl ether) was added slowly, causing the reaction mixture to reflux. After complete addition, reflux was continued for 15 minutes. The mixture was cooled, and approximately 100 mL of an aqueous 10% hydrochloric acid solution was added. The resultant mixture was extracted with diethyl ether, and the extract was washed with an aqueous saturated sodium bicarbonate solution. The washed extract was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure yielding 17.3 g of 3-methyl-2-phenylthiophene as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][C@H:11]1[CH2:15][N:14]([C:16]([C@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]([F:27])([F:26])[F:25])[CH2:20][CH2:19]2)=[O:17])[C@@H:13]([CH2:28][O:29][C:30]2[C:31]([C:36](O)=[O:37])=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:39]1[CH:43]=[CH:42][C:41]([NH2:44])=[N:40]1.Cl.Cl.N1CCC[C@@H]1COC1C(C(N)=O)=NC=CC=1>>[CH2:1]([O:8][CH2:9][O:10][C@H:11]1[CH2:15][N:14]([C:16]([C@H:18]2[CH2:19][CH2:20][C@H:21]([C:24]([F:25])([F:26])[F:27])[CH2:22][CH2:23]2)=[O:17])[C@@H:13]([CH2:28][O:29][C:30]2[C:31]([C:36]([NH:44][C:41]3[CH:42]=[CH:43][O:39][N:40]=3)=[O:37])=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccon1
Reactant: O=C(O)c1ncccc1OC[C@H]1C[C@@H](OCOCc2ccccc2)CN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: Cl
Agent: NC(=O)c1ncccc1OC[C@H]1CCCN1
Product: O=C(Nc1ccon1)c1ncccc1OC[C@H]1C[C@@H](OCOCc2ccccc2)CN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 4 of EXAMPLE 1 using 3-(((2R,4R)-4-(benzyloxymethoxy)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid (EXAMPLE 79 Step 6) and isoxazol-3-amine instead of cis-4-(trifluoromethyl)cyclohexanecarboxylic acid and (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[S:33]1[CH2:37][CH2:36][NH:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18](=[O:20])[N:35]3[CH2:36][CH2:37][S:33][CH2:34]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: C1CSCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)N1CCSC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 49.3 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole), 1,1'-carbonyldiimidazole (2.82 g, 0.0174 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 3.5 hours while nitrogen was bubbled through it. Solid thiazolidine (2.33 g, 0.0261 mole) was added and the reaction mixture was stirred at 55° C., under nitrogen overnight. The solvent was removed under reduced pressure. The resulting white solid was triturated with water (100 ml), filtered, rinsed with water, twice with 5% potassium hydroxide solution and twice more with water. The resulting solid was heated in boiling isopropyl alcohol and filtered hot. Upon cooling to room temperature, a white solid precipitated. The solid was collected by filtration and dried under high vacuum to give 3.08 g (49.4%) of title compound, mp. 215°-218° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([CH3:11])[N:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[Br:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Br:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:3]=[C:4]3[N:10]([CH3:11])[N:9]=[CH:8][C:5]3=[N:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Cn1ncc2ncc(Br)cc21
Reactant: OB(O)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1ncc2ncc(-c3cccc(Br)c3)cc21
Temperature: 90 °C

Procedure:
To a solution of 6-bromo-1-methyl-1H-pyrazolo[4,3-b]pyridine (120 mg, 0.566 mmol) and 3-bromophenylboronic acid (136 mg, 0.679 mmol) in degassed 1,4-dioxane (6 mL) and water (2 mL) was added K2CO3 (391 mg, 2.83 mmol) and tetrakis(triphenylphosphine)palladium(0) (32 mg, 0.028 mmol). The reaction mixture was heated at 90° C. for 1 h, cooled and partitioned between ethyl acetate and brine. The organic layer was separated, dried over Na2SO4 and concentrated to give crude which was purified by chromatographic column to afford the desired product. LCMS-ESI+: calc'd for C13H10BrN3: 288.01 (M+H+); Found: 288.2 (M+H+).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([C:7]([O:9]C)=O)[N:2]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[NH2:18][C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1.F[C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(=O)NC2C=NC=CN=2)C1>>[N:20]1[CH:21]=[CH:22][N:23]=[CH:24][C:19]=1[NH:18][C:7]([C@@H:3]1[CH2:4][C@H:5]2[C@H:1]([CH2:6]2)[N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:9]
Reactant: Nc1cnccn1
Reactant: COC(=O)[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)Nc1cnccn1
Product: CC(C)(C)OC(=O)N1[C@H](C(=O)Nc2cnccn2)C[C@@H]2C[C@@H]21

Procedure:
(1S,3S,5S)-tert-Butyl 3-(pyrazin-2-ylcarbamoyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate 121B was prepared from 121A and 2-amino pyrazine using the procedure as reported in 65A. LC/MS [M+H]+: 305; Ret time (Method A): 1.63 min.
Reaction SMILES: CC1NC(C)=CC=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:8]=1.C(O)C.Cl.[NH2:30]O.Cl>O>[NH:22]1[CH2:23][CH2:24][CH:19]([C:16]2[CH:17]=[CH:18][C:13]([C:9]3[N:8]=[C:7]([NH2:30])[CH:12]=[CH:11][CH:10]=3)=[CH:14][CH:15]=2)[CH2:20][CH2:21]1
Reactant: NO
Reactant: Cc1cc(-c2cccc(-c3ccc(C4CCNCC4)cc3)n2)c(C)[nH]1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cccc(-c2ccc(C3CCNCC3)cc2)n1

Procedure:
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 100 mg (0.302 mmol) 4-(4-(2-(2,5-dimethylpyrrolyl)pyrid-6-yl)phenyl)piperidine, 10 mL ethanol, 1 mL water, and 417 mg (6.04 mmol) hydroxylamine hydrochloride. The reaction was refluxed 20 hours cooled, and poured into dilute aqueous hydrochloric acid, then washed with ethyl acetate. The aqueous layer was adjusted to pH 10 with 6 N sodium hydroxide solution and extracted twice with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, and evaporated. The resulting oil (77 mg, 100%) was converted to the hydrochloride salt using HCl in, ether to afford a tan solid, 32 mg (32%), mp dec. above 150° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[N:7]=3)[CH2:13][CH2:12]2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1nccc(N2CCC(C=O)CC2)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nccc(N2CCC(CN3CCN(C(=O)OC(C)(C)C)CC3)CC2)n1
Yield: 36.7 %

Procedure:
To a solution of 1-(2-methylpyrimidin-4-yl)-4-(formyl)piperidine (4.25 g) and N-t-butoxycarbonyl piperazine (5.34 g) in methanol/acetic acid (99:1) (100 ml) was added sodium cyanoborohydride (5.41 g) portionwise over 30 minutes and the resultant suspension stirred at ambient temperature for 3 hours. The suspension was quenched by addition of saturated aqueous sodium bicarbonate solution and the resulting mixture extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 10% methanol in ethylacetate to give 1-(tert-butoxycarbonyl)-4-[1-(2-methylpyrimidin-4-yl)-4-piperidylmethyl]piperazine (2.85 g) as a solid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1>C1C=CC=CC=1>[N:8]1([CH:3]=[CH:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C1CCNC1
Reactant: C#CC(=O)OCC
Solvent: c1ccccc1
Product: CCOC(=O)C=CN1CCCC1
Reaction time: 8 h
Yield: 69 %

Procedure:
A solution of 29.43 g of ethyl propiolate (0.30 mol) in 200 ml of benzene was held at 25° in a water bath with magnetic stirring. A solution of 21.34 g of pyrrolidine in 50 ml of benzene was added dropwise over a period of 45 minutes, during which time the temperature rose to 35°. The clear brown solution was stirred overnight and the solvent removed under reduced pressure at 55°. The residue was distilled under reduced pressure to give 35.05 g of yellow oil, boiling point 110° (0.4 torr), which crystallized upon standing. The yellow solid was recrystallized from petroleum ether to give 31.36 (62%) of yellowish platelets, m.p. 37.5°-39.5°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14](=[O:22])[CH2:13][CH:12]2O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O>N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:14](=[O:22])[CH:13]=[CH:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(O)C2(CCN(Cc3ccccc3)CC2)N1c1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C1C=CC2(CCN(Cc3ccccc3)CC2)N1c1ccccc1
Temperature: 50 °C

Procedure:
To 8-benzyl-4-hydroxy-1-phenyl-1,8-diazaspiro[4.5]decan-2-one (400 mg, 1.19 mmol) in pyridine (10 mL) was added thionyl chloride (0.26 g, 3.57 mmol) at 0° C. under N2. The mixture was heated to 50° C. for 5 hours. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with sat aqueous NaHCO3. The organic layer was separated, dried over Na2SO4 and evaporated to give crude 8-benzyl-1-phenyl-1,8-diaza-spiro[4.5]dec-3-en-2-one, which was purified by column (Petroleum ether/EtOAc 4:1) to give 8-benzyl-1-phenyl-1,8-diaza-spiro[4.5]dec-3-en-2-one. 1H NMR (300 MHz, MeOD) δ 7.89 (d, J=6.0 Hz, 1H), 7.44-7.52 (m, 3H), 7.17-7.27 (m, 5H), 7.14-7.17 (m, 2H), 6.26 (d, J=6.3 Hz, 1H) 3.54 (s, 2H), 2.87-2.91 (m, 2H), 2.35-2.44 (m, 2H), 1.99-2.09 (m, 2H), 1.59-1.64 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([Cl:27])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][CH:18]=1)[O:8][CH:9]([CH3:15])[C:10]([O:12]CC)=[O:11].[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([Cl:27])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][CH:18]=1)[O:8][CH:9]([CH3:15])[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)C(C)Oc1cccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(Oc1cccc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)c1)C(=O)O
Reaction time: 16 h

Procedure:
A solution of 51.4 g (0.124 mol) of the R enantiomer of ethyl 2-[3-(2,6-dichloro-4-trifluoromethyl-phenoxy)phenoxy]-propionate in 95 ml of ethanol was added dropwise to a stirred solution of 5.9 g (0.148 mol) of sodium hydroxide in 145 ml of water at 0° C. During this procedure, the reaction mixture foamed to such an extent that, after 2/3 of the ester solution had been added, a further 10 ml of ethanol had first to be introduced into the reaction mixture before the remainder of the ester solution could be added. Stirring was continued for a further 16 hours, while cooling with ice, and working-up was then carried out by acidifying the mixture with hydrochloric acid, extracting the resulting mixture three times with methylene chloride, drying the extracts and evaporating them down. The remaining residue was boiled with petroleum ether, and the hot mixture was filtered under suction. In this manner, 47.6 g (97.1% of theory) of the R enantiomer of 2-[3-(2,6-dichloro-4-trifluoromethyl-phenoxy)-phenoxy]-propionic acid were obtained in the form of a solid substance of melting point 120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[Cl:11][C:12]1[CH:35]=[CH:34][CH:33]=[CH:32][C:13]=1[CH:14]=[CH:15][CH2:16][C:17]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:23](=[O:25])[CH3:24])[CH2:18][CH2:19][C:20]([OH:22])=[O:21].[OH-].[Na+]>C(O)C.O>[Cl:11][C:12]1[CH:35]=[CH:34][CH:33]=[CH:32][C:13]=1[CH:14]=[CH:15][CH2:16][C:17]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([C:23](=[O:25])[CH:24]=[CH:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[O:2][CH3:1])[CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: CC(=O)C(CC=Cc1ccccc1Cl)(CCC(=O)O)c1ccccc1
Reactant: COc1ccccc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccccc1C=CC(=O)C(CC=Cc1ccccc1Cl)(CCC(=O)O)c1ccccc1
Temperature: 25 °C

Procedure:
o-Methoxybenzaldehyde (2.72 g., 0.02 mole) in ethanol (10 ml.) is added to a solution of 4-(o-chlorocinnamyl)-4-phenyl-5-oxohexanoic acid (3.57 g., 0.01 mole) and sodium hydroxide (0.56 g., 0.014 mole) in water (50 ml.). The resulting mixture is heated on a steam bath for 24 hours. The reaction solution is cooled to room temperature, diluted with water (200 ml.), and extracted with ether to remove the excess o-methyoxybenzaldehyde. Ether is expelled from the aqueous phase by warming. The solution is cooled in an ice bath, acidified with dilute hydrochloric acid (10 ml.), and the yellow solid which precipitates is collected and air-dried. Several recrystallizations from ethanol yields a pale yellow material with m.p. 206.5°-209.5°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23].[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][C:27]2([C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][CH2:30]2)[CH2:28][CH2:29]1)=[O:23]
Reactant: Cc1ccc(F)c(Nc2c(C(=O)N3CCC4(CCc5ccccc54)CC3)cnc3c(C(=O)O)cnn23)c1
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC4(CCc5ccccc54)CC3)cnc12
Yield: 81.7 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-fluoro-5-methylphenylamino)-6-(spiro[indane-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.042 g, 0.085 mmol) obtained in step 2 and ethanesulfonamide (0.045 g, 0.42 mmol), the title compound (0.041 g, 82%) was obtained.