Azzindani/Open_Reaction_Data huggingface dataset:
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][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH2:38][C:39]5[N:43]([CH2:44][CH2:45][CH3:46])[CH:42]=[N:41][N:40]=5)=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[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][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH2:38][C:39]5[N:43]([CH2:44][CH2:45][CH3:46])[CH:42]=[N:41][N:40]=5)=[O:56])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4CCC)cc2)CCN3CCC)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)Cc4nncn4CCC)cc2)CCN3CCC)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-(4-propyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (843.7 mg) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.48 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 1 hour at −78° C. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethanol:ethyl acetate 1:5→1:4), to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-(4-propyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 141) (490.8 mg) as yellow amorphous.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]12[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:7]2=[O:19])(=[O:5])[CH3:4]>CO>[Br:1][CH2:4][C:3]([C:6]12[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:7]2=[O:19])=[O:5]
Reactant: CC(=O)C12CCCCC1c1ccccc1C2=O
Reactant: BrBr
Solvent: CO
Product: O=C(CBr)C12CCCCC1c1ccccc1C2=O
Reaction time: 2 h

Procedure:
Bromine (1.2 ml) was added to a mixture of 9a-acetyl-1,2,3,4,4a,9a-hexahydrofluoren-9-one (5 g) in methanol (20 ml) at 20-30° C. The reaction mixture was stirred for 2 hours and quenched with NaHCO3 solution (0.8 g NaHCO3 and 24 ml water). The mixture was extracted with CH2Cl2 (3×30 ml) and the organic phase was washed with water (30 ml) and dried over Na2SO4. Evaporation gave 6.6 g of the crude product which was used without further purification for the next step.
Reaction SMILES: Cl[C:2]1[N:27]=[CH:26][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[CH3:28][NH:29][CH2:30][CH2:31][OH:32]>>[CH3:28][N:29]([C:2]1[N:27]=[CH:26][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1)[CH2:30][CH2:31][OH:32]
Reactant: CNCCO
Reactant: O=S(=O)(c1ccccc1)c1ccc(Nc2ncnc3cnc(Cl)cc23)cc1
Product: CN(CCO)c1cc2c(Nc3ccc(S(=O)(=O)c4ccccc4)cc3)ncnc2cn1

Procedure:
Prepared according to Procedure C from 6-chloro4-(4-phenylsulphonylanilino)-pyrido[3,4-d]pyrimidine and 2-(methylamino)ethanol; δH [2H6]-DMSO 9.99 (1H,s), 8.89 (1H,s), 8.48 (1H,s), 8.20 (2H,d), 7.97-8.09 (4H,m), 7.60-7.78 (3H,m), 7.27 (1H,s), 4.27 (1H,t), 3.75-3.85 (2H,m), 3.60-3.71 (2H,m), 3.21 (3H,s); m/z (M+1)+436.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=O)[C:4]=1[CH3:12])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[CH2:38]([N:40]([CH2:44][CH3:45])[CH2:41][CH2:42][NH2:43])[CH3:39]>O1CCCC1>[CH2:38]([N:40]([CH2:44][CH3:45])[CH2:41][CH2:42][NH:43][C:9]([C:5]1[C:4]([CH3:12])=[C:3]([CH:1]=[O:2])[NH:7][C:6]=1[CH3:8])=[O:11])[CH3:39]
Reactant: CCN(CC)CCN
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
Into a 10-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, addition funnel and an air condenser were charged 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (0.25 Kg; 1.5 mole), tetrahydrofuran (3.5 L), dicyclohexyl carbodimide (0.432 Kg), 1-hydroxy benzotriazole (0.306 Kg) and stirred well for 30 minutes. To this solution, a premixed solution of TEA (0.42 L) in tetrahydrofuran (1.25 L) and 2-diethylaminoethyl amine (0.286 L; 2.04 mole) in tetrahydrofuran (1.25 L) were added successively at 25-30° C. After addition, the reaction mixture was stirred for 16 hours at 25-30° C. and the byproduct generated was removed by filtration through filtration funnel. The solvent was removed by distillation under diminished pressure. The resulting product was suspended in DM water and the pH of the slurry adjusted to 12-13 with aqueous NaOH solution. After pH adjustment, the product was extracted with ethyl acetate and washed successively organic layer with aqueous NaHCO3, saturated solution of NaCl and DM water. Organic layer was separated and ¾th of the solvent distilled under diminished pressure. The product was cooled to 0-5° C. and stirred for 2 hours, filtered and washed with chilled ethyl acetate (70 mL). The product was dried at 60° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@H:21]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH2:22][CH3:23])[C:11](=[O:30])[C@:10]([CH2:32][CH:33]([OH:36])CO)([CH3:31])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.I([O-])(=O)(=O)=O.[Na+].CO>O.C1COCC1.[Na+].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@H:21]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[CH2:22][CH3:23])[C:11](=[O:30])[C@:10]([CH2:32][CH:33]=[O:36])([CH3:31])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](C1CCCCO1)N1C(=O)[C@@](C)(CC(O)CO)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC[C@@H](C1CCCCO1)N1C(=O)[C@@](C)(CC=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-3-methyl-1-((1S)-1-(tetrahydro-2H-pyran-2-yl)propyl)piperidin-2-one (3 mg, 5.61 μmol; Example 224, Step D) in water (20.0 μL) and THF (40.0 μL) was treated with sodium periodate (3.60 mg, 0.02 mmol). After a precipitate formed, methanol (40 μL) was added to form an emulsion which was stirred at ambient temperature for 1 hour. The reaction was diluted with sat. aq. NaCl solution and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and the filtrate was concentrated to provide a mixture of two diastereomers which was used in the next step. Mass Spectrum (ESI) m/z=502.1 (M+1)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[C:11]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][OH:18])[CH:10]=[C:9]([C:19]#[C:20][CH2:21][CH2:22][CH2:23][OH:24])[CH:8]=1>CO.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[CH:10]=[C:9]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[CH:8]=1
Reactant: OCCCC#Cc1cc(C#CCCCO)cc(C#CCCCO)c1
Agent: [Pd]
Solvent: CO
Product: OCCCCCc1cc(CCCCCO)cc(CCCCCO)c1
Reaction time: 4 h
Yield: 98.1 %

Procedure:
1,3,5-tris-(5-hydroxy-1-pentynyl)-benzene (2.84 g, 8.6 mmol) was dissolved in methanol (30 mL) and 10% Pd/C (5% w/w) was added. The resulting mixture was hydrogenated on a Parr hydrogenation apparatus (45 psi) for 4 hours. The catalyst was removed by filtration through a celite pad. The filter cake was rinsed with methanol, and the combined organic liquors were concentrated under reduced pressure. The crude product was purified by column chromatography (CHCl3:MeOH 6:1) to afford 2.84 g of 1,3,5-tris-(5-hydroxypentyl)-benzene. Yield 96%. 1H NMR (300 MHz, CDCl3) δ 6.81 (s, 3H), 3.62 (t, J=6.3 Hz, 6H), 2.57 (t, J=7.5 Hz, 6H), 1.53-1.70 (m, 12H), 1.38 (m, 6H) ppm; 13C NMR (75 MHz, CDCl3) δ 142.5, 126.1, 63.1, 36.1, 32.9, 31.5, 25.7 ppm.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[CH2:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([NH:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])=[N:11][C:10]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C1COCC1>[F:1][C:2]1[CH:23]=[CH:22][C:5]2[CH2:6][CH2:7][CH2:8][C:9]3[S:13][C:12]([NH:14][C:15](=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][S:32]([CH3:31])(=[O:34])=[O:33])=[N:11][C:10]=3[C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCCCC(=O)Nc1nc2c(s1)CCCc1ccc(F)cc1-2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCCCC(=O)Nc1nc2c(s1)CCCc1ccc(F)cc1-2
Temperature: 25 °C
Reaction time: 6 h
Yield: 37.9 %

Procedure:
N1-(9-fluoro-5,6-dihydro-4H-benzo[6,7]cyclohepta-[d][1,3]thiazol-2-yl)-5-aminopentanamide (115 mg, 0.34 mmole) was dissolved in 2 ml of dry THF, cooled with an ice bath, triethylamine was added (96 μl, 0.69 mmole) followed by addition of 27 μl of methane sulfonyl chloride (0.35 mmole). The reaction mixture was stirred at room temperature for 6 hours, quenched with saturated sodium carbonate solution and extracted with 3×3 ml of ethyl acetate. The combined ethyl acetate extracts were washed with saturated sodium chloride solution, concentrated and chromatographed (12 g of silica gel, EtOAc/hexanes/7N NH3 in MeOH, 50:50:2) to give 53 mg of the desired product as a white solid (38%): m.p. 145-147° C.; 412 (ESMS, MH+).
Reaction SMILES: C[Si](C)(C)CC[O:5][C:6](=[O:46])[CH:7]([CH2:33][CH:34]=[CH:35][CH2:36][P:37]([O:40][CH:41]([C:43]([OH:45])=[O:44])[CH3:42])([OH:39])=[O:38])[CH2:8][C:9]([CH3:32])=[CH:10][CH2:11][C:12]1[C:13]([O:25]CC[Si](C)(C)C)=[C:14]2[C:18](=[C:19]([CH3:23])[C:20]=1[O:21][CH3:22])[CH2:17][O:16][C:15]2=[O:24].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:43]([CH:41]([O:40][P:37]([CH2:36][CH:35]=[CH:34][CH2:33][CH:7]([CH2:8][C:9]([CH3:32])=[CH:10][CH2:11][C:12]1[C:13]([OH:25])=[C:14]2[C:18](=[C:19]([CH3:23])[C:20]=1[O:21][CH3:22])[CH2:17][O:16][C:15]2=[O:24])[C:6]([OH:46])=[O:5])([OH:39])=[O:38])[CH3:42])([OH:45])=[O:44]
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CC(CC=CCP(=O)(O)OC(C)C(=O)O)C(=O)OCC[Si](C)(C)C)C(=O)OC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1c(C)c2c(c(O)c1CC=C(C)CC(CC=CCP(=O)(O)OC(C)C(=O)O)C(=O)O)C(=O)OC2
Reaction time: 16 h

Procedure:
A solution of crude 2-{4-[(1-carboxy-ethoxy)-hydroxy-phosphoryl]-but-2-enyl}-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid 2-trimethylsilanyl-ethyl ester (AC-2101-59) and tetrabutylammonium fluoride in THF (1 M, 54 μL, 0.054 mmol) was stirred with THF (1 mL) for 2 hours at ambient temperature, when more tetrabutylammonium fluoride in THF (54 μL, 0.054 mmol) was added. The reaction was stirred for an additional 16 hours, by which time the reaction was complete. The reaction mixture was concentrated in vacuo and the product was purified by RP HPLC using a Phenomenex Synergi 5μ Hydro RP 80A column (50×21.2 mm) with eluents of H2O, 0.1% TFA-CH3CN, 0.1% TFA to provide the product (8.0 mg) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.51 (d, 3H, J=7 Hz), 1.79 (s, 3H), 2.05-2.40 (m, 4H), 2.11 (s, 3H), 2.49-2.71 (m, 3H), 3.38 (d, 2H, J=6 Hz), 3.76 (s, 3H), 4.85 (br s, 1H), 5.20 (s, 2H), 5.21-5.30 (m, 1H), 5.33-5.63 (m, 2H) ppm; 31P (121.4 MHz, CDCl3) δ 27.7 ppm; MS (m/z) 525.2 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[CH:9]3[CH2:11][CH2:12][CH2:13][CH2:14][CH:8]3[O:7][C:6]=2[C:5](C(O)=O)=[CH:4][C:3]=1[Cl:18].C(N(CC)CC)C.C(OC(Cl)=O)C.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:10]2[CH:9]3[CH2:11][CH2:12][CH2:13][CH2:14][CH:8]3[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:18]
Reactant: Nc1c(Cl)cc(C(=O)O)c2c1C1CCCCC1O2
Agent: CCOC(=O)Cl
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Nc1c(Cl)ccc2c1C1CCCCC1O2
Reaction time: 2 h

Procedure:
To a cold solution of 0.3 g 1-amino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylic acid in 40 ml chloroform is added 0.3 g of triethylamine and then 0.2 g ethylchloroformate in 10 ml chloroform. Stirring is continued for 2 hours. This is then added to a cold mixture of 3 g 3-aminoguinuclidine dihydrochloride in 20 ml water containing 7.5 g K2CO3. Stirring is continued overnight. The reaction mxiture is then diluted with chloroform, the two layers separated and the chloroform layer washed twice with water, dried over magnesium sulfate and evaporated to dryness to give 1-amino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-(N-1-azabicylo[2.2.2.]oct-3-yl]carboxamide as an oily product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C@@H:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])=[CH:6][CH:5]=1)[CH3:2].Br[C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][CH2:23][C:24]2=[O:27])=[C:20]([F:28])[CH:19]=1.CNCCNC>O1CCOCC1>[CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C@@H:11]2[CH2:15][CH2:14][N:13]([C:18]3[CH:26]=[C:25]4[C:21](=[C:20]([F:28])[CH:19]=3)[CH2:22][CH2:23][C:24]4=[O:27])[C:12]2=[O:16])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(O[C@@H]2CCNC2=O)cn1
Reactant: O=C1CCc2c(F)cc(Br)cc21
Agent: CNCCNC
Solvent: C1COCCO1
Product: CCOc1ccc(O[C@@H]2CCN(c3cc(F)c4c(c3)C(=O)CC4)C2=O)cn1
Temperature: 100 °C

Procedure:
In a further alternative preparation a mixture of (R)-3-((6-ethoxypyridin-3-yl)oxy)pyrrolidin-2-one (2.00 g), 6-bromo-4-fluoro-2,3-dihydro-1H-inden-1-one (2.30 g), N,N′-dimethyl-ethylene-diamine (10 mL) and 1,4-dioxane (20 mL) was purged with argon and cesium carbonate (3.8 g) and copper(I) iodide (100 mg) were added. The mixture was heated to 100° C. for 1.5 hours. After cooling to r.t. the mixture was diluted with EA and washed with water (5 times) and brine. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by SGC (eluent: heptane with 0 to 70% EA) to provide Example 2-08. 1H-NMR (400 MHz, DMSO) δ 7.99 (1H, dd, J=11.3, 1.8 Hz), 7.97 (1H, d, J=3.1 Hz), 7.77 (1H, d, J=1.8 Hz), 7.53 (1H, dd, J=8.9, 3.1 Hz), 6.76 (1H, d, J=8.9 Hz), 5.22 (1H, dd, J=8.3, 8.3 Hz), 4.24 (2H, q, J=7.0 Hz), 3.96 (1H, m), 3.86 (1H, m), 3.11 (2H, m), 2.72 (2H, m), 2.69 (1H, m), 2.13 (1H, m), 1.30 (3H, t, J=7.0 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=3)[N:17]=2)[CH:9]=[N:8]1.C(O)(=O)C.[NH:33]1[CH2:36][CH:35]([C:37]([OH:39])=[O:38])[CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]([C:12]([F:15])([F:13])[F:14])=[C:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:22]=[CH:23][C:24]([CH2:25][N:33]4[CH2:36][CH:35]([C:37]([OH:39])=[O:38])[CH2:34]4)=[CH:27][CH:28]=3)[N:17]=2)[CH:9]=[N:8]1
Reactant: O=C(O)C1CNC1
Reactant: O=Cc1ccc(-c2noc(-c3cnn(-c4ccccn4)c3C(F)(F)F)n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(O)C1CN(Cc2ccc(-c3noc(-c4cnn(-c5ccccn5)c4C(F)(F)F)n3)cc2)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 63.5 %

Procedure:
To a solution of 4-(5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (1.0 g, 2.60 mmol) in DCM (10 mL) was added acetic acid (15 mL) and azetidine-3-carboxylic acid (1.5 eq, 3.90 mmol). The mixture was stirred at RT for 40 min., then a suspension of sodium triacetoxyborohydride (1 eq, 2.60 mmol) in DCM (30 mL) was added dropwise over 1.5 h. The volatiles were removed in vacuo, water (200 mL) was added and the resulting solid was collected by filtration. Ethyl acetate (40 mL) was added to the crude product and after sonication for 30 min, the solids were collected by filtration and washed additional ethyl acetate to afford 1-(4-(5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzyl) azetidine-3-carboxylic acid (777 mg, 1.65 mmol) as a white solid. The compound had an HPLC retention time=2.55 min. Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.2% H3PO4; Solvent B=90% MeOH, 10% H2O, 0.2% H3PO4. LC/MS M+1=471.05. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.21-3.25 (m, 3H), 3.40-3.44 (m, 2H), 3.64 (s, 2H), 7.51 (d, J=8.3 Hz, 2H), 7.69 (ddd, J=0.8 Hz, 4.7 Hz, 8.3 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 8.03 (d, J=8.3 Hz, 2H), 8.20 (dt, J=1.9 Hz, 7.7 Hz, 1H), 8.66 (dd, J=1.1 Hz, 4.1 Hz, 1 H) 8.73 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[CH3:11][C:12]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([CH3:15])[CH2:13][CH3:14].Cl>ClCCl.C(OCC)(=O)C.N1C=CC=CC=1.ClCCCl>[CH3:15][C:12]([C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([O:9][CH3:10])=[O:8])(=[O:23])=[O:24])=[CH:20][CH:21]=1)([CH3:11])[CH2:13][CH3:14]
Reactant: COC(=O)c1sccc1N
Reactant: CCC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCC(C)(C)c1ccc(S(=O)(=O)Nc2ccsc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.8 %

Procedure:
To a solution of methyl 3-aminothiophene-2-carboxylate (0.184 g; 1.17 mmol) in dichloromethane (2 mL) were added pyridine (0.199 mL; 2.34 mmol) and 4-(1,1-dimethylpropyl)benzenesulfonyl chloride (0.289 g; 1.17 mmol) sequentially. The reaction mixture was stirred for 24 hours at room temperature and then 1,2-dichloroethane (2 mL) and pyridine (1 mL) were added. The reaction mixture was heated at 70° C. for 24 hours, cooled to room temperature, diluted with ethyl acetate and acidified with aqueous hydrochloric acid (2N). The organic layer was separated, concentrated under reduced pressure, and the resulting crude product was purified by chromatography on silica gel eluting with ethyl acetate/hexanes (1:6 v/v) to give the desired product as a white solid (0.21 g).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[O:3].[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)(=[O:10])[CH3:9]>C1(C)C=CC=CC=1>[CH2:6]([O:5][C:1](=[O:4])[CH:2]([OH:3])[CH2:9][C:8](=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH3:7]
Reactant: CCOC(=O)C=O
Reactant: CC(=O)c1ccccn1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)CC(=O)c1ccccn1
Temperature: 135 °C
Yield: 44 %

Procedure:
A mixture of ethyl glyoxalate (3.060 g, 30.000 mmol) (6.2 mL of a 50% solution in toluene) and 2-acetylpyridine (3.630 g, 30.000 mmol) was heated in an oil bath at 135° C. for 16 hours. The crude residue after removal of toluene was purified by column chromatography. The pure 2-hydroxy-4-oxo-4-pyridin-2-ylbutyric acid ethyl ester was isolated in 44% yield (2.910 g, 13.000 mmol).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:10]=1)[CH2:2]2.C(O)(C(F)(F)F)=O.[CH3:45][NH2:46].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.CO>[CH3:45][NH:46][CH:18]1[CH2:19][CH2:20][N:15]([C:13]2[N:14]=[C:9]([N:3]3[CH2:4][CH:5]4[O:8][CH:1]([CH2:7][CH2:6]4)[CH2:2]3)[N:10]=[C:11]([C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=4)=[O:30])=[CH:26][CH:27]=3)[N:12]=2)[CH2:16][CH2:17]1
Reactant: O=C1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CNC1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1

Procedure:
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-TFA (50 mg) in tetrahydrofuran (5 mL) was treated with methylamine (2.0 M solution in tetrahydrofuran, 0.16 mL), followed by glacial acetic acid (0.009 mL) and sodium triacetoxyborohydride (51 mg). After completion of the reaction, methanol was added and mixture was concentrated to dryness. The residue was purified by HPLC to give the title compound as its di-TFA salt; MS (ES+) 516.3 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.C([Li])CCC.[CH2:14]1[O:24][C:17]2([CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[O:16][CH2:15]1.C(=O)(O)[O-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:20]1([OH:23])[CH2:21][CH2:22][C:17]2([O:24][CH2:14][CH2:15][O:16]2)[CH2:18][CH2:19]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Fc1ccccc1I
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: OC1(c2ccccc2F)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 30.1 %

Procedure:
To a solution of 2-fluoro-1-Iodobenzene (11.1 g, 50.0 mmol) in 50 mL THF, cooled to −78° C. under argon, was added n-butyllithium (20.0 mL 2.5M in hexane, 50.0 mmol). The solution was stirred 10 min. at −78° C., and a solution of 1,4-cyclohexanedione mono-ethylene ketal (7.81 g, 50.0 mmol) in 50 mL THF was added slowly. The solution was warmed to r.t. and stirred for 60 min., then poured onto saturated sodium bicarbonate and extracted with ethylacetate. The combined organic layers were washed with saturated sodium chloride, dried with magnesium sulfate, and concentrated in vacuo. The crude solid was crystallized from dichloromethane/hexane to give 8-(2-Fluoro-phenyl)-1,4-dioxa-spiro-[4.5]decan-8-ol (3.8 g, 30%).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13](=[O:17])[CH:14]([CH3:16])[CH3:15]>>[CH2:7]([N:8]1[C:12]([CH:13]([OH:17])[CH:14]([CH3:16])[CH3:15])=[N:11][CH:10]=[N:9]1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)C=O
Reactant: c1ccc(Cn2cncn2)cc1
Product: CC(C)C(O)c1ncnn1Cc1ccccc1
Yield: 71 %

Procedure:
1-(1-Benzyl-1H-1,2,4-triazol-5-yl)-2-methylpropan-1-ol was synthesized in a manner similar to that of procedure 21 B but using 1-(phenylmethyl)-1H-1,2,4-triazole and isobutyraldehyde as the starting materials. The product was isolated as a white solid in 71% yield.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[Cl:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1>>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[CH:27]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)C(Br)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Reactant: Oc1cccc(Cl)c1
Product: COC(=O)C(Oc1cccc(Cl)c1)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Yield: 95.3 %

Procedure:
As described in Example 44, 8.28 g of methyl bromo{p-[3-(p-chlorophenoxy)propoxy]phenyl}acetate is reacted with 2.96 g of m-chlorophenol to give 8.8 g of the product as a viscous oil.