Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20].Cl[Si:22]([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[F:13][C:14]1[C:15]([F:20])=[C:16]([Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:17]=[CH:18][C:19]=1[Si:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: Fc1ccccc1F
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)c1ccc([Si](C)(C)C)c(F)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
step 1—To a solution of di-iso-propylamine (150 mL, 108.3 g, 1.07 mol) in THF (500 mL) cooled to −78° C. and maintained under a N2 atmosphere was added over 1 15 min period, n-BuLi (100 mL, 1.00 mol, 10M in hexanes). The resulting mixture was stirred for 30 min at −78° C. A mixture of 23a (45 mL, 52.110 g, 0.457 mol) and chlorotrimethylsilane (130.0 mL, 111.28 g, 1.024 mol) was added at a rate which maintained the internal reaction temperature below −50° C. The solution was stirred at −78° C. for 1 h. The reaction was quenched at −78° C. by addition of 1M H2SO4, diluted with MTBE and the mixture was saturated with solid NaCl. The phases were separated and the aqueous phase was extracted with MTBE (300 mL). The combined organic extracts were dried (MgSO4), filtered and the solvents evaporated to afford 118 g (100%) of 23b as a white solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:19]1[CH2:22][CH2:21][C:20]1=[O:23]>CC(C)=O>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH:19]1[CH2:22][CH2:21][C:20]1=[O:23]
Reactant: O=C1CCC1Br
Reactant: Oc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: O=C1CCC1Oc1ccccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 2-(trifluoromethyl)phenol (2.72 g, 16.8 mmol) in acetone (147 mL) at 0° C. was treated with cesium carbonate (5.47 g, 16.8 mmol), followed by drop-wise addition of C3 (2.5 g, 16.8 mmol). The mixture was stirred at 0° C. for 1.5 hours, filtered through Celite, and concentrated in vacuo to afford the title compound as a colorless oil. Yield: 3.5 g, 15 mmol, 89%. 1H NMR (400 MHz, CDCl3) δ 7.56 (br d, J=7.7 Hz, 1H), 7.45-7.50 (m, 1H), 7.14 (d, J=8.3 Hz, 1H), 7.07 (br dd, J=7.6, 7.6 Hz, 1H), 5.31-5.37 (m, 1H), 2.92-3.00 (m, 2H), 2.55-2.66 (m, 1H), 2.19-2.30 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N-:11]=[N+:12]=[N-:13].[Na+].CCOC(C)=O.O>CCO.[Cl-].[Zn+2].[Cl-]>[Br:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]2[NH:13][N:12]=[N:11][N:5]=2)=[C:2]([F:1])[CH:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(Br)cc1F
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Fc1cc(Br)ccc1-c1nnn[nH]1
Yield: 32.9 %

Procedure:
2-Fluoro-4-bromobenzonitrile (300 mg, 1.5 mmol) dissolved in EtOH, added sodium azide (320 mg, 4.9 mmol), Zinc chloride (240 mg, 1.8 mmol). This mixture was stirred refluxed for 38 h. Work up (EtOAc/H2O) afforded the crude. Crude was washed with petether to obtain the titled compound (120 mg) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.89-7.79 (m, 1H), 7.59 (dd, J 1.6, 10.04, 1H), 7.45 (dd, J 1.8, 8.3, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[N:21]2[CH:22]=[C:23]([O:26][C@@H:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[C@@H:30]([NH2:37])[CH2:29][CH2:28]3)[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1.CCN(C(C)C)C(C)C.[C:47]([C:51]1[CH:55]=[C:54]([NH:56][C:57](=O)[O:58]CC(Cl)(Cl)Cl)[N:53]([C:65]2[CH:70]=[CH:69][C:68]([CH3:71])=[CH:67][CH:66]=2)[N:52]=1)([CH3:50])([CH3:49])[CH3:48]>O1CCOCC1>[C:47]([C:51]1[CH:55]=[C:54]([NH:56][C:57]([NH:37][C@@H:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@@H:27]([O:26][C:23]3[CH:24]=[CH:25][C:20]4[N:21]([C:17]([C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=5[S:10][CH2:9][CH2:8][O:7][CH:2]5[CH2:3][CH2:4][CH2:5][CH2:6][O:1]5)=[N:18][N:19]=4)[CH:22]=3)[CH2:28][CH2:29]2)=[O:58])[N:53]([C:65]2[CH:70]=[CH:69][C:68]([CH3:71])=[CH:67][CH:66]=2)[N:52]=1)([CH3:50])([CH3:48])[CH3:49]
Reactant: N[C@H]1CC[C@H](Oc2ccc3nnc(-c4ccccc4SCCOC4CCCCO4)n3c2)c2ccccc21
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@H](Oc3ccc4nnc(-c5ccccc5SCCOC5CCCCO5)n4c3)c3ccccc32)cc1
Temperature: 25 °C
Yield: 44.7 %

Procedure:
A solution of Example 20 step b (60 mg, 0.11 mmol), DIPEA (26 μL, 0.15 mmol) and 2,2,2-trichloroethyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate (56 mg, 0.138 mmol) in dioxane (5 mL) was heated at 80° C. for 20 h. The reaction was allowed to cool to RT, partitioned between H2O-DCM, the organic phase dried (MgSO4) and concentrated in vacuo. The residue was purified by FCC using MeOH in DCM (0 to 5%) to give the title compound as a yellow foam (38 mg, 45%). LCMS (Method 3): Rt 4.09 min, m/z 772 [MH+].
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]2[C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=[C:8]2[CH:7]=1.C(Cl)(=O)C(Cl)=O.[CH2:24]([N:31]1[C:39]2[CH:38]=[CH:37][CH:36]=[C:35]([NH2:40])[C:34]=2[C:33]([CH2:41][CH3:42])=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[CH2:24]([N:31]1[C:39]2[C:34](=[C:35]([NH:40][C:15]([C:12]3[N:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]4=[N:14][CH:13]=3)=[O:17])[CH:36]=[CH:37][CH:38]=2)[C:33]([CH2:41][CH3:42])=[N:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COCCOc1ccn2c(C(=O)O)cnc2c1
Reactant: CCc1nn(Cc2ccccc2)c2cccc(N)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nn(Cc2ccccc2)c2cccc(NC(=O)c3cnc4cc(OCCOC)ccn34)c12
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 18.8 %

Procedure:
To a magnetically stirred suspension of 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxylic acid (32.1 mg, 0.136 mmol) (prepared as in Example 1, steps A-D) in dry dichloromethane (1.5 mL), in a sealed vial, was added dry N,N-dimethylformamide (5 μL). The stirred mixture was cooled to 5° C. using ice bath. A solution of oxalyl chloride (86.8 μL, 0.174 mmol; 2M in dichloromethane) was added and the mixture was stirred for 10 minutes, occasionally allowing the resulting gases to vent. To the resulting solution was added 1-benzyl-3-ethyl-1H-indazol-4-amine (40 mg, 0.159 mmol) and triethylamine (30.2 μL, 0.217 mmol). The mixture was allowed to warm to ambient temperature and stirred for 16 hours. The mixture was evaporated to dryness under a stream of nitrogen. The resulting residue was purified using preparative thin layer chromatography, eluting with 5% methanol in dichloromethane. The material was further purified with a second preparative thin layer chromatography, eluting with 8% methanol in chloroform containing 0.5% ammonium hydroxide solution to provide N-(1-benzyl-3-ethyl-1H-indazol-4-yl)-7-(2-methoxyethoxy)imidazo[1,2-a]pyridine-3-carboxamide (12 mg). MS (APCI), positive scan, m/z=470.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[CH3:32][C:33]1[CH:42]=[C:41]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:29])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:46]4[CH2:47][CH2:48][N:43]([C:41]5[C:40]6[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=6)[N:34]=[C:33]([CH3:32])[CH:42]=5)[CH2:44][CH2:45]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: Cc1cc(N2CCNCC2)c2ccccc2n1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: Cc1cc(N2CCN(C(=O)c3cccc(-c4cnc5c(c4)N(Cc4cc(Cl)ccc4C(F)(F)F)CCN5)c3)CC2)c2ccccc2n1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-methyl-4-(1-piperazinyl)quinoline as in General Procedure 10 to give the title compound. LCMS: m/z=656.99 (M+H+); retention time=0.61 minutes.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C[O:9][C:10](=[O:24])[C@@H:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][N:12]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:20]([O:19][C:17]([N:12]1[CH2:13][C@@H:14]([OH:16])[CH2:15][C@H:11]1[C:10]([OH:24])=[O:9])=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (10 mL) was added to a solution of N-tert-butoxycarbonyl-cis-4-hydroxy-L-proline methyl ester (Compound D101 (J), 1.10 g) in dichloromethane (10 mL) at 0° C. After stirring at 0° C. for 10 min and at room temperature for 3 hr, the mixture was evaporated in vacuo to give a crude N-tert-butoxycarbonyl-cis-4-hydroxy-L-proline trifluoroacetate. The crude N-tert-butoxycarbonyl-cis-4-hydroxy-L-proline trifluoroacetate was dissolved in dichloromethane (20 mL), and N-tert-butoxycarbonyl-sarcosine (844 mg), triethylamine (1.25 mL), 1-hydroxybenzotriazole (663 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (856 mg) were added at 0° C. After stirring at 0° C. for 30 min and at room temperature for 17 hr, the solvent was removed in vacuo. The residue was diluted with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate, water, and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue as purified by silica gel column chromatography (chloroform then chloroform-methanol=50:1 to 30:1, v/v) to afford the title compound (452 mg) as a colorless oil. The compound appears as a mixture of rotamers: 1H NMR (400 MHz, CDCl3) δ 1.42 and 1.46 (each s, total 9H), 2.04-2.14 (m, 1H), 2.26-2.39 (m, 1H), 2.94 (s, 3H), 3.52-4.17 (m, 4H), 3.75 and 3.77 (each s, total 3H), 4.17-4.28 (m, 1H), and 4.38-4.62 (m, 2H).
Reaction SMILES: [CH3:1][I:2].[CH3:3][C:4]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:5]>C(O)C>[I-:2].[CH2:17]([O:16][C:15]([NH:14][C:4]([CH3:3])([CH3:5])[CH2:6][CH2:7][N+:8]1([CH3:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CI
Reactant: CC(C)(CCN1CCCCC1)NC(=O)OCc1ccccc1
Solvent: CCO
Product: CC(C)(CC[N+]1(C)CCCCC1)NC(=O)OCc1ccccc1
Product: [I-]
Reaction time: 72 h

Procedure:
In a 15 mL pressure tube, methyl iodide (2.0 mL, 5 equiv, 31.3 mmol) was added to a stirred solution of benzyl 2-methyl-4-(piperidin-1-yl)butan-2-ylcarbamate (1.91 g, 6.27 mmol) in ethanol (2.0 mL, 3.1 M). The pressure tube was sealed and the reaction was left to stir for 3 days. The yellow solution was poured into a round bottomed flask and the tube rinsed with ethanol. The reaction mixture was concentrated in vacuo to a syrup. Repeated addition and evaporation of isopropyl alcohol (3×10 mL) from the flask followed by acetonitrile (50 mL) gave a white solid. This solid was recrystallized from isopropyl alcohol. The crystals were filtered and rinsed with a small amount of cold isopropyl alcohol and dried under high vacuum to give white crystals, (2.51 g, 89.6%). 1H NMR (D2O, 400 MHz): δ 1.30 (s, 6H), 1.43-1.82 (m, 6H), 2.04-2.10 (m, 2H), 2.84 (s, 3H), 3.04-3.24 (m, 6H), 5.08 (s, 2H), 7.38-7.50 (m, 5H). LRMS (ESI+) for C19H31N2O2+ (319.2); Found: 319 (M+).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)=[O:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[OH-].[Na+].C(Cl)Cl.Cl>C1COCC1.CCO>[CH2:37]([N:25]([CH2:24][C:15]1[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:14]=1[C:8]1[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:39])=[O:3])[CH:7]=1)[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)=[O:27])[CH3:38]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)NCc2ccc(O)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: C1CCOC1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=O)NCc1ccc(O)cc1
Reaction time: 2.5 h

Procedure:
{2′-[1-Ethyl-3-(4-hydroxy-benzyl)-ureidomethyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid ethyl ester (0.535 g, 0.98 mmol) in THF (5 mL) and EtOH (4 mL) was treated with 1N aqueous NaOH (3 mL), and the reaction was stirred for 2.5 hours. Analytical LCMS indicated that starting material was still present, so additional 1N aqueous NaOH was added, and the reaction was heated with a heat gun. Once no starting material was seen by analytical LCMS, the mixture was worked-up with CH2Cl2 and 1N aqueous HCl, and the organic layer was dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=S.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[NH2:20][C:21](N)=[S:22].Br[CH2:25][C:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1)=O>C1COCC1.CCO>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:21]2[S:22][CH:25]=[C:26]([C:28]3[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=3)[N:20]=2)[CH2:16][CH2:15]1
Reactant: NC(N)=S
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Reactant: CN1CCNCC1
Agent: S=C(n1ccnc1)n1ccnc1
Solvent: CCO
Solvent: C1CCOC1
Product: CN1CCN(c2nc(-c3ccc(C(=O)O)cc3)cs2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To thiocarbonyldiimidazole (2 g, 11.5 mmol) in THF (30 mL) at RT was added N-methylpiperazine (1.00 g, 10 mmol) drop wise. The reaction was stirred at RT for 2 h and then at 55° C. for 1 h. The reaction was cooled to RT and 20 mL of THF was removed in vacuo. 2M NH3 (10 mL) in MeOH was added and the reaction stirred for 15 h. A further 2M NH3 (10 mL) in MeOH was added and the reaction maintained at 55° C. for 8 h. A pale yellow precipitate (1.00 g) was observed and filtered off, dried and used directly in the next step. The thiourea (0.84 g, 5.2 mmol) was dissolved in EtOH (30 mL) and 4-(2-bromo-acetyl)-benzoic acid (1.28 g, 5.2 mmol) was added. The reaction was heated at reflux for 3 h. The reaction was cooled to RT and the solid filtered off. The solid was washed with Et2O and dried thoroughly. This procedure provided the title compound as a pale yellow solid (1.23 g, 77%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4]1.Cl[CH2:16][CH2:17][CH:18]([C:22]1[CH:27]=[CH:26][C:25]2[O:28][CH2:29][O:30][C:24]=2[CH:23]=1)[CH2:19][CH2:20]Cl>CC(C)=O.O>[C:9]1([N:5]2[CH2:4][CH:3]([CH2:2][N:1]3[CH2:16][CH2:17][CH:18]([C:22]4[CH:27]=[CH:26][C:25]5[O:28][CH2:29][O:30][C:24]=5[CH:23]=4)[CH2:19][CH2:20]3)[O:7][C:6]2=[O:8])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: ClCCC(CCCl)c1ccc2c(c1)OCO2
Reactant: NCC1CN(c2ccccc2)C(=O)O1
Solvent: O
Solvent: CC(C)=O
Product: O=C1OC(CN2CCC(c3ccc4c(c3)OCO4)CC2)CN1c1ccccc1
Reaction time: 24 h

Procedure:
A mixture of 1.92 g of 5-aminomethyl-3-phenyloxazolidin-2-one [obtainable by reaction of 5-chloromethyl-3-phenyloxazolidin-2-one with potassium phthalimide and subsequent hydrolysis] and 2.63 g of 1,5-dichloro-3-(3,4-methylenedioxyphenyl)pentane in 40 ml of acetone and 40 ml of water is boiled for 24 hours and worked up as usual, giving 3-phenyl-5-[4-(3,4-methylenedioxyphenyl)piperidinomethyl]oxazolidin-2-one.
Reaction SMILES: O=CC[CH:4]1[CH2:13][C:12](=O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5]1.O.[NH2:16][CH2:17][CH:18]([OH:20])[CH3:19].[C:21]1(C)C=CC=C[CH:22]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:16]1([CH2:17][CH:18]([OH:20])[CH3:19])[CH:22]=[CH:21][C:13]2[CH2:4][O:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]1=2
Reactant: CC(O)CN
Reactant: O=CCC1CC(=O)c2ccccc2O1
Reactant: Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC(O)Cn1ccc2c1-c1ccccc1OC2
Reaction time: 0.58 h
Yield: 79 %

Procedure:
A solution of 1.9 g of (RS)-2-(2-oxoethyl)-4-chromanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 35 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 2:3). 1.82 g (79%) of (RS)-1-(1,4-dihydro-[1]benzopyrano[4,3-b]pyrrol-1-yl)-propan-2-ol were obtained as a yellow oil.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].S(OC)(O[CH3:24])(=O)=O.O>C(C(C)=O)C(C)C>[CH3:24][N:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:9]1
Reactant: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: Cn1nc(-c2ccccc2)cc1-c1ccccc1
Temperature: 90 °C

Procedure:
Five parts of 3,5-diphenylpyrazole are dissolved in 25 parts (by volume) of methyl isobutyl ketone. Solid anhydrous sodium hydroxide (1.1 parts) is added and the mixture is heated to 90°C. Dimethyl sulfate (3.43 parts) is added and the mixture is next heated to 112°C. to 115°C. The reaction mixture is sampled after 1.5 hours, and no unreacted 3,5-diphenylpyrazole is found to be present. The reaction mixture is cooled to 50°C., and 30 parts of water are added. The pH is next adjusted to between 11 and 12 by the addition of aqueous sodium hydroxide. The organic layer is washed twice with 30 parts water. For yield determination the methyl isobutyl ketone is removed in vacuo, producing 4.95 parts (93% crude yield) of an oil which crystallizes on cooling (melting point 52°C. to 53°C). Analysis of the product shows it to be 85.5% pure as 1-methyl-3,5-diphenylpyrazole.
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[CH:20]([N:23]=[C:24]=[O:25])([CH3:22])[CH3:21]>>[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:24]([NH:23][CH:20]([CH3:22])[CH3:21])=[O:25])#[N:3]
Reactant: CC(C)N=C=O
Reactant: N#Cc1c(OC[C@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Agent: [Cl-]
Product: CC(C)NC(=O)N1CCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N
Yield: 100 %

Procedure:
Prepared as in Example 176b from (R)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example 176c) and isopropyl isocyanate in 100% yield as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 1.07 (d, J=6.5 Hz, 6H), 1.91 (m, 3H), 2.13 (m, 1H), 3.17 (m, 1H), 3.79 (m, 1H), 4.19 (m, 2H), 4.32 (d, J=8.8 Hz, 1H), 5.91 (d, J=8.1 Hz, 1H), 7.89 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[N:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][C:20]=2[CH3:28])[C:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)[CH3:2].C(N(CC)CC)C.S([NH:47][N:48]=[CH:49][CH:50](Cl)Cl)(C1C=CC(C)=CC=1)(=O)=O>CO.O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[N:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][C:20]=2[CH3:28])[C:9]([C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH:50]=[CH:49][N:48]=[N:47]3)=[CH:16][CH:17]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(-c2ccc(N)cc2)n1-c1ccc(C(N)=O)cc1C
Reactant: Cc1ccc(S(=O)(=O)NN=CC(Cl)Cl)cc1
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCc1ccc(-c2ccc(-n3ccnn3)cc2)n1-c1ccc(C(N)=O)cc1C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 51.2 %

Procedure:
Under a nitrogen atmosphere, 3-[5-(4-aminophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]-propionic acid ethyl ester (11A, see Scheme 11) (103 mg, 0.26 mmol) was dissolved in methanol (5 mL). Triethylamine (0.07 mL, 0.48 mmol) was added. The mixture was cooled to 0° C. 2,2-dichloroacetaldehyde tosylhydrazone (15A) (62 mg, 0.22 mmol), dissolved in methanol (1.5 mL) was added slowly. The reaction was stirred at 0° C. for 5 min, and then heated to 40° C. for 3 hrs, then cooled to room temperature for 16 hrs. 2,2-dichloroacetaldehyde tosylhydrazone (15A) (62 mg) was added and stirred an additional 4 hr. The reaction was diluted with water (5 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by preparative TLC plate (1500 microns, 10% IPA/CH2Cl2). The desired band (RF=0.3) was isolated and dried under high vacuum to yield 3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-[1,2,3]triazol-1-yl-phenyl)-1H-pyrrol-2-yl]-propionic acid ethyl ester (15B) (50 mg, 43%, light tan powder).
Reaction SMILES: C(O)C=C.[CH2:5]([OH:9])[CH:6]([CH3:8])[CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:29]([OH:40])(=O)[C:30]1[C:31](=CC=CC=1)[C:32](O)=O>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Rh].[Rh].[Rh].[Rh].[Rh].[Rh]>[CH2:5]([O:9][CH:29]1[CH2:30][CH2:31][CH2:32][O:40]1)[CH:6]([CH3:8])[CH3:7]
Reactant: O=C(O)c1ccccc1C(=O)O
Reactant: CC(C)CO
Agent: [Rh]
Agent: [C-]#[O+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C=CCO
Product: CC(C)COC1CCCO1
Yield: 49 %

Procedure:
The autoclave is charged with 50.0 g. of allyl alcohol (861 mmol.), 111.7 g. of isobutanol (1.50 mol.). 0.202 g. of hexarhodium hexadecacarbonyl (0.189 mmol.. 1.14 meq. Rh), 9.6 of triphenylphosphine (36.6 mmol.) and 2.86 g. of phthalic acid (17.2 mmol.), then heated at 125° C. under replenished 800-1200 psi 1:1 H2 /CO for one hour. Quantitative glpc analysis of the product mixture shows the presence of 61.0 g. 2-isobutoxytetrahydrofuran (49% yield) identified based on ir, nmr. and mass spectra which are in complete accord with the assignment. Another product present in relatively minor amount is isolated and identified as 3-(α-tetrahydrofuranyloxy)-2-methyl-propionaldehyde on the basis of its i r spectrum.
Reaction SMILES: [CH2:1]([NH:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=O)=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)[CH2:2][CH3:3].[OH-:27].[Na+].O1C[CH2:32][CH2:31][CH2:30]1>C(O)C>[CH2:1]([N:4]([CH2:30][CH2:31][CH3:32])[C:5]1([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([OH:22])=[O:27])=[CH:18][CH:17]=3)=[CH:12][CH:13]=2)[CH2:7][CH2:6]1)[CH2:2][CH3:3]
Reactant: C1CCOC1
Reactant: CCCNC1(c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc2)CC1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCCN(CCC)C1(c2ccc(C#Cc3ccc(C(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-propylamino-cyclopropyl)-phenylethynyl]-benzoate (Compound 107, 40.0 mg, 0.12 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (160.0 mg, 4.0 mmols, 2.0 mL of a 2N aqueous solution) and stirred overnight at room temperature. Work-up afforded 25.0 mg (69%) of the title compound as a solid.