Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3]C1=O.[OH-].[Li+].O.[C:10]([OH:16])([C:12]([F:15])([F:14])[F:13])=[O:11].[CH2:17]1COC[CH2:18]1>CO>[F:13][C:12]([F:15])([F:14])[C:10]([O-:16])=[O:11].[F:13][C:12]1([F:15])[CH2:10][CH2:18][CH2:17][C@H:5]([OH:1])[C@@H:4]1[NH3+:3]
Reactant: O=C1NCCO1
Reactant: O=C(O)C(F)(F)F
Reactant: C1CCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C([O-])C(F)(F)F
Product: [NH3+][C@H]1[C@@H](O)CCCC1(F)F
Temperature: 50 °C

Procedure:
A heterogeneous mixture of compound 77 (80 mg, 0.45 mmol) and lithium hydroxide (97 mg, 2.26 mmol) in THF (1.7 mL), methanol (1744), and water (347 μL) was warmed to 50° C. After cooling to RT, the reaction mixture was filtered though celite and TFA (500 μL, 6.49 mmol) was added to filtrate. The filtrate was dried under reduced pressure to yield (1S,6S)-2,2-difluoro-6-hydroxycyclohexanaminium trifluoroacetate (78, 120 mg, quant. yield). 1H NMR (500 MHz, CD3OD) δ 4.21 (s, 1H), 3.63 (d, J=19.7, 1H), 3.31 (s, 1H), 2.17 (d, J=11.2, 1H), 1.89 (d, J=32.2, 7H), 1.73-1.53 (m, 2H).
Reaction SMILES: [OH:1][C:2]1([CH2:7][CH2:8][C@H:9]2[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[N:10]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3]1.[H-].[Na+].[CH3:25]I>>[CH3:25][O:1][C:2]1([CH2:7][CH2:8][C@H:9]2[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[N:10]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCC2(O)CCCC2)COC1(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: COC1(CC[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)CCCC1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
The (S)-tert-butyl 4-(2-(1-hydroxycyclopentyl)ethyl)-2,2-dimethyloxazolidine-3-carboxylate was added to a suspension of NaH (568 mg, 14.2 mmol, 4.0 equiv) and the mixture stirred for 0.5 h. Methyl iodide (2.106 g, 14.2 mmol, 4.0 equiv) was added and the mixture stirred for 48 h at ambient temperature. The excess NaH was quenched by careful addition of water. The mixture was evaporated, and then taken up in EtOAc. The solution was washed with water, then brine and evaporated. The ether was purified by flash chromatography on silica, eluting with 0-41% EtOAc in hexanes. This afforded 1170 mg (3.4 mmol, 95% yield for two steps) of the desired (S)-tert-butyl 4-(2-(1-methoxycyclopentyl)ethyl)-2,2-dimethyloxazolidine-3-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1)[CH3:2].[N:13]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl>[NH:11]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:12])[NH2:13]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cccc(NN)c1
Reaction time: 1 h

Procedure:
To a solution of m-aminobenzoic acid ethyl ester (200 g, 1.21 mmol) in conc. HCl (200 mL) was added an aqueous solution (250 mL) of NaNO2 (102 g, 1.46 mmol) at 0° C. and the reaction mixture was stirred for 1 h. A solution of SnCl2.2H2O (662 g, 2.92 mmol) in conc. HCl (2 L) was then added at 0° C. The reaction solution was stirred for 2 h at RT. The precipitate was filtered and washed with ethanol and ether to yield ethyl 3-hydrazinobenzoate, which was used for the next reaction without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11](O)=[O:12])=[N:2]1.CO>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][OH:12])=[N:2]1
Reactant: O=C(O)Cc1noc2ccccc12
Solvent: CO
Solvent: C1CCOC1
Product: OCCc1noc2ccccc12
Temperature: 25 °C
Yield: 67.9 %

Procedure:
To a solution of benzo[d]isoxazol-3-yl-acetic acid (0.86 g, 4.85 mmol) in anhydrous THF (40 mL) was added dropwise borane dimethylsulfide complex (0.58 mL, 10 M, 5.8 mmol) at 0° C. The mixture was allowed to warm to room temperature and was stirred over night. MeOH (10 mL) was carefully added and when the gas evolution ceased, the mixture was heated under gentle reflux for 4 hours. The reaction mixture was concentrated in vacuo and the remainder was dissolved in dichloromethane (20 mL). An aqueous solution of Na2CO3 (20 mL) was added and the aqueous layer was extracted with dichloromethane (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by chromatography on silica gel which afforded 537 mg (67.8%) of the title compound.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].N1C=CC=CC=1.[Si:20]([O:27][CH2:28][C:29]1[CH:45]=[CH:44][C:32]([C:33]([NH:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:34])=[C:31]([CH2:46][OH:47])[CH:30]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].C(Cl)Cl>C1COCC1>[Si:20]([O:27][CH2:28][C:29]1[CH:45]=[CH:44][C:32]([C:33]([NH:35][NH:36][C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[O:34])=[C:31]([CH2:46][O:47][C:2]([O:4][C:5]2[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=2)=[O:3])[CH:30]=1)([C:23]([CH3:26])([CH3:24])[CH3:25])([CH3:22])[CH3:21]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1CO
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1COC(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 0.25 h
Yield: 97 %

Procedure:
To a solution of 4-nitrophenyl chloroformate (1.10 g, 5.48 mmol) in 40 mL of anhydrous THF was added pyridine (390 μL, 5.48 mmol) at 0° C. After stirring for 15 min, a solution of 5 (1.50 g, 3.65 mmol) in 15 mL of anhydrous THF was added dropwise within 10 min, and the mixture was allowed to warm up. Stirring was continued at room temperature for 16 h after which 50 mL DCM was added. The mixture was washed with 1M HCl (3×60 mL) and brine (1×50 mL), and the aqueous layers were re-extracted with DCM. The combined organic phases were dried over MgSO4 and the volatiles were removed in vacuo. Flash chromatography of the crude product (1:2 EtOAc-hexane) afforded 6 (97%) as a colorless solid: 1H-NMR (400 MHz, CDCl3): δ 0.11 (s, 6H), 0.94 (s, 9H), 1.49 (s, 9H), 4.79 (s, 2H), 5.58 (s, 2H), 6.71 (br s, 1H), 7.37-7.42 (m, 3H), 7.54 (s, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.96 (br s, 1H), 8.23-8.29 (m, 2H); 13C-NMR (100 MHz, CDCl3): δ −5.1, 18.5, 26.0, 28.3, 64.3, 68.5, 82.3, 121.9, 125.4, 126.5, 127.4, 128.3, 131.4, 133.6, 145.5, 145.7, 152.5, 155.5, 155.6, 168.0; MS (TOF) m/z=598.2 (M+Na+, 100).
Reaction SMILES: [OH:1][C@H:2]([CH3:38])[C@H:3]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[N:21]([CH3:29])[N:20]=3)[N:17]=2)[N:12](COCC[Si](C)(C)C)[CH:11]=1)=[O:9])[CH2:4][O:5][CH3:6].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[OH:1][C@H:2]([CH3:38])[C@H:3]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[N:21]([CH3:29])[N:20]=3)[N:17]=2)[NH:12][CH:11]=1)=[O:9])[CH2:4][O:5][CH3:6]
Reactant: COC[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@@H](C)O
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@@H](C)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 48.5 %

Procedure:
In a 10 mL round-bottom flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((1R,2R)-2-hydroxy-1-methoxymethyl-propyl)-amide (30 mg, 0.055 mmol) and TFA (0.3 ml, 3.9 mmol) were combined with dichloromethane (1 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2.5 h then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (1 mL) and ethylenediamine (0.26 ml, 3.9 mmol) was added. The reaction mixture was stirred at room temperature for 18 h then concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (hot dichloromethane/heptane) to afford 11 mg (47%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((1R,2R)-2-hydroxy-1-methoxymethyl-propyl)-amide as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ: 12.85 (br. s., 1H), 9.16 (s, 1H), 8.78 (dd, J=8.9, 5.5 Hz, 1H), 8.43 (s, 1H), 8.15 (d, J=9.4 Hz, 1H), 7.65 (dd, J=9.6, 2.1 Hz, 1H), 7.15 (td, J=9.2, 2.5 Hz, 1H), 5.17 (d, J=4.2 Hz, 1H), 4.20-4.33 (m, 1H), 4.15 (s, 3H), 3.98-4.09 (m, 1H), 3.59 (dd, J=9.8, 6.8 Hz, 1H), 3.50 (dd, J=9.4, 6.4 Hz, 1H), 3.27 (s, 3H), 1.13 (d, J=6.4 Hz, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([CH:12]=[C:13]([C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=1)[C:14]([F:17])([F:16])[F:15])(=[O:11])=[O:10].[CH2:26]([N:33]([CH2:37][Si](C)(C)C)[CH2:34]OC)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>C1(C)C=CC=CC=1>[CH2:26]([N:33]1[CH2:37][CH:12]([S:9]([CH3:8])(=[O:11])=[O:10])[C:13]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)([C:14]([F:17])([F:15])[F:16])[CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CS(=O)(=O)C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)C1CN(Cc2ccccc2)CC1(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reaction time: 2 h
Yield: 42.5 %

Procedure:
Trifluoroacetic acid (6 μL, 78 μmol) was added to 2-(3,5-Dichlorophenyl)-3,3,3-trifluoroprop-1-en-1-yl methyl sulfone (500 mg, 1.57 mmol) in toluene (3 mL). N-Benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine (558 mg, 2.35 mmol) in toluene (2 mL) was added at room temperature over 10 minutes. The reaction mixture was stirred for two hours and then additional N-Benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine (74.4 mg, 313 μmol) was added. The reaction mixture was stirred for additional two hours and then left standing over night. Water was added and after stirring for a while the phases were separated and the aqueous phase was extracted with toluene. The combined organic phases were dried over sodium sulfate and evaporated. The crude product is taken up in warm iso-propanol (1 mL) and 10% hydrochloric acid (0.5 mL) and a drop of methanol was added. The formed crystals were filtered off. The hydrochloride was suspended in water and sodium hydroxide and tert-buthyl methylether was added. The organic phase was separated and the aqueous phase was extracted with tert-buthyl methylether. The combined organic phases were dried over sodium sulfate, filtered and evaporated. This procedure yielded 1-benzyl-3-(3,5-dichlorophenyl)-4-(methylsulfonyl)-3-(trifluoromethyl)pyrrolidine (302 mg, 99% purity, 42% yield).
Reaction SMILES: [N:1]#[C:2][NH2:3].[N:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[C:5]=[S:6].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([F:35])[CH:28]=1)=[O:26]>>[NH2:1][C:2]1[N:3]=[C:5]([NH:4][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH2:14][CH2:15][N:16]([CH2:19][CH:20]4[CH2:22][CH2:21]4)[CH2:17][CH2:18]3)=[CH:11][CH:12]=2)[S:6][C:24]=1[C:25]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([F:35])[CH:28]=1)=[O:26]
Reactant: S=C=Nc1ccc(N2CCN(CC3CC3)CC2)cc1
Reactant: COc1ccc(C(=O)CBr)cc1F
Reactant: N#CN
Product: COc1ccc(C(=O)c2sc(Nc3ccc(N4CCN(CC5CC5)CC4)cc3)nc2N)cc1F

Procedure:
This compound was prepared from cyanamide, 1-(4-isothiocyanato-phenyl)-4-cyclopropylmethylpiperazine (of Example 14G) and 2-bromo-1-(3-fluoro-4-methoxyphenyl)ethanone (of Example 13) following the procedure used in Example 24. Mass spectrum (ES) MH+=482.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](Br)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C([N:19]1[CH2:24][CH2:23][C:22](=O)[C:21]([CH3:27])([CH3:26])[CH2:20]1)C1C=CC=CC=1>>[ClH:1].[CH3:26][C:21]1([CH3:27])[C:22]([C:4]2[C:5]3[O:9][CH:8]=[CH:7][C:6]=3[CH:10]=[C:2]([Cl:1])[CH:3]=2)=[CH:23][CH2:24][NH:19][CH2:20]1
Reactant: CC1(C)CN(Cc2ccccc2)CCC1=O
Reactant: Clc1cc(Br)c2occc2c1
Product: CC1(C)CNCC=C1c1cc(Cl)cc2ccoc12
Product: Cl

Procedure:
Beginning with 5-chloro-7-bromobenzofuran and 1-benzyl-3,3-dimethyl-4-oxopiperidine, 0.29 gm of the title compound were prepared essentially as described in EXAMPLE 5.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:8][CH:7]=1)[CH2:2][C:3]#[CH:4].[CH2:20]([O:22][C:23](=[O:42])[C@@H:24]([O:40][CH3:41])[CH2:25][C:26]1[CH:31]=[CH:30][C:29](OS(C(F)(F)F)(=O)=O)=[CH:28][CH:27]=1)[CH3:21]>>[CH2:20]([O:22][C:23](=[O:42])[C@@H:24]([O:40][CH3:41])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:4]#[C:3][CH2:2][CH2:1][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:13])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][CH:7]=2)=[CH:28][CH:27]=1)[CH3:21]
Reactant: C#CCCOc1ccc(C(=O)c2ccccc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)OC
Product: CCOC(=O)[C@H](Cc1ccc(C#CCCOc2ccc(C(=O)c3ccccc3)cc2)cc1)OC

Procedure:
This compound was prepared from (4-but-3-ynyloxy-phenyl)-phenylmethanone and (2S)-2-Methoxy-3-(4-trifluoromethane-sulfonyloxy-phenyl)-propionic acid ethyl ester (Example 1, Step A) following the procedure described in Example 38, Step C (66%). 1H-NMR (200.15 MHz, CDCl3): δ 37.85–7.73 (m, 4H), 7.57–7.43 (m; 3H), 7.34 (d, 2H, J=8.1), 7.16 (d, 2H, J=8.3), 7.00 (d, 2H, J=8.6), 4.25 (t, 2H, J=7.0), 4.18 (q, 2H, J=7.0), 3.92 (dd, 1H, J=7.3, 5.6), 3.34 (s, 3H), 3.01 (s, 1H), 2.98 (d, 1H, J=3.5), 2.93 (t, 2H, J=7.0), 1.23 (t, 3H, J=7.3).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[CH:18][N:17]=[CH:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[N:23]1[CH:24]=[CH:25][C:20]([C:19]2[N:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[CH:16]=[N:17][CH:18]=2)=[CH:21][CH:22]=1
Reactant: c1ccc(COc2ccc(-n3cncc3-c3ccncc3)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Oc1ccc(-n2cncc2-c2ccncc2)cc1
Temperature: 75 °C
Yield: 88 %

Procedure:
A solution of Preparation 81 (4-(1-(4-(benzyloxy)phenyl)-1H-imidazol-5-yl)pyridine, 2 g, 6.1 mmol) and anisole (13 mL, 122 mmol) in trifluoracetic acid (50 mL) was heated at 75° C. for 24 h. The solvent was removed in vacuo and the residue was purified via silica gel chromatography with chloroform-methanol-ammonium hydroxide (94:5:1) to afford 1.27 g (88%) of the title compound; diagnostic 13C NMR signals (100 MHz, CDCl3) δ 158.402, 149.145, 141.061, 138.018, 120.600, 129.822, 127.482, 127.370, 121.933, 116.497; MS (AP/CI) 238.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[C:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)#[N:17]>>[CH3:1][C:2]1[C:3]([C:11]2[S:12][C:13]([C:22]([C:21]3[CH:25]=[CH:26][C:18]([C:16]#[N:17])=[CH:19][CH:20]=3)=[O:23])=[CH:14][CH:15]=2)=[N:4][O:5][C:6]=1[C:7]([F:8])([F:10])[F:9]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1c(-c2cccs2)noc1C(F)(F)F
Product: Cc1c(-c2ccc(C(=O)c3ccc(C#N)cc3)s2)noc1C(F)(F)F
Yield: 36 %

Procedure:
Prepared from 4-Methyl-3-thiophen-2-yl-5-trifluoromethyl-isoxazole and 4-cyanobenzoyl chloride by the method described in Example 3. Crude product was chromatographed on silica gel with EtOAc/hexanes (10 then 20%) as eluant to afford product as a colorless solid (130 mg, 36%). 1H NMR (CDCl3) 2.42 (d, J=1.3, 3 H), 7.62 (d, J=4.0, 1 H), 7.67 (d, J=4.0, 1 H), 7.85 (d, J=8.3, 1 H), 7.98 (d, J=7.9, 1 H). 13C NMR 8.0, 114.9, 116.3, 118.7 (q, J=271), 118.0, 129.1, 129.8, 132.7, 135.3, 137.6, 141.1, 144.6, ˜155 (q, obscured due to baseline noise), 157.7, 186.4. 19F NMR −63.1. LC/MS 7.08 min, [M+1]+ 363.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([Cl:10])=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.Cl[C:19]([C:21]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22]1)=[O:20]>O1CCCC1.CCOCC>[CH3:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([Cl:10])=[CH:5][C:3]=1[NH:4][C:19]([C:21]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22]1)=[O:20]
Reactant: CCOC(=O)C1(C(=O)Cl)CC1
Reactant: Cc1cc(Cl)c(Cl)cc1N
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C(=O)Nc2cc(Cl)c(Cl)cc2C)CC1
Temperature: 25 °C

Procedure:
Into a nitrogen-purged round bottom flask was charged 5.53 grams (0.03 mole) of 2-methyl-4,5-dichloroaniline, 3.18 grams (0.03 mole) of triethylamine and 190 milliliters of tetrahydrofuran solvent. With vigorous stirring, a 5.55 gram (0.03 mole) portion of ethyl 1-chlorocarbonylcyclopropanecarboxylate prepared in Example XVIII was added in one portion, after which the mixture was stirred at ambient temperature for a six-hour period. A precipitate of triethylamine hydrochloride was then filtered off and the filtrate vacuum stripped to give a light yellow solid. The solid was taken up in ether and the solution water-washed, dried over magnesium sulfate, and solvent evaporated to give a yellow powder. Recrystallization from ethyl acetate-hexane gave 4.51 grams (0.01 mole) of ethyl 1-(2-methyl-4,5-dichlorophenylaminocarbonyl)cyclopropanecarboxylate having a melting point of 105° C.-107° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]([C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[CH:9][C:8]=1[Cl:15])O)=[O:4].[OH-].[Na+].Cl[C:19]([O:21]CC)=[O:20]>O1CCOCC1>[Cl:15][C:8]1[CH:9]=[C:10]([Cl:14])[C:11]([Cl:13])=[CH:12][C:7]=1[N:5]1[C:3](=[O:4])[N:2]([CH3:1])[C:19](=[O:20])[O:21]1
Reactant: CCOC(=O)Cl
Reactant: CNC(=O)N(O)c1cc(Cl)c(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cn1c(=O)on(-c2cc(Cl)c(Cl)cc2Cl)c1=O
Reaction time: 0.5 h

Procedure:
1-Methyl-3-(2',4',5'-trichlorophenyl)-3-hydroxyurea (8 g; 0.03 mole) was dissolved in cooled (10° C.) 2 N aqueous sodium hydroxide solution (18 ml.) and mixed with dioxane (80 ml.). Ethyl chloroformate (3.3 ml; 0.034 mole) was added dropwise to the reaction mixture at 10°-15° C. with stirring. The stirring was continued for about 1/2 hour after the addition was completed. The dark, oily product was separated and recrystallized from methanol and boiled with powdered charcoal to yield 2-(2',4',5'-trichlorophenyl)-4-methyl-1,2,4-oxadiazolidine-3,5-dione as tan needle-like crystals melting 112°-114° C. and having the following elemental analysis as calculated for C9H5Cl3N2O3 :
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].CI.[C:13](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOCC>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH3:13])=[CH:4][C:3]=1[CH3:10]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(O)cc(C)c1Br
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cc(C)c(Br)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of commercially available 4-bromo-3,5-dimethylphenol (a compound of Formula 4) (25.0 g, 124.3 mmol), methyl iodide (35.3 g, 248.6 mmol), and potassium carbonate (34.4 g, 248.6 mmol) in 62.5 mL of DMF was stirred for 2 hours at room temperature. The reaction mixture was diluted with 300 mL of ether and washed with 250 mL of water and 5×100 mL of brine. The organic portion was dried (MgSO4), filtered, and evaporated to give an oil, which was purified by flash column chromatography (silica gel, 90:10 hexane/ethylacetate) to give 4-bromo-3,5-dimethylanisole (a compound of Formula 5) (26 g, 120.8 mmol, 97%); 1HNMR (CDCl3) δ2.39 (s, 6H), 3.76 (s, 3H), 6.67 (s, 2H).
Reaction SMILES: ClC(OCC)=O.C([N:14]1[CH2:19][CH2:18][C:17]2([CH2:23][C:22]3[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:21]=3[O:20]2)[CH2:16][CH2:15]1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[F:28][C:25]1[CH:26]=[CH:27][C:21]2[O:20][C:17]3([CH2:16][CH2:15][NH:14][CH2:19][CH2:18]3)[CH2:23][C:22]=2[CH:24]=1
Reactant: Fc1ccc2c(c1)CC1(CCN(Cc3ccccc3)CC1)O2
Agent: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: Fc1ccc2c(c1)CC1(CCNCC1)O2
Temperature: 25 °C
Yield: 46.9 %

Procedure:
Ethyl chloroformate (65.6 mg, 0.604 mmol) was added to a solution of 1′-benzyl-5-fluoro-3H-spiro[1-benzofuran-2,4′-piperidin](150 mg, 0.504 mmol) in toluene (2 mL) and the reaction mixture was refluxed overnight. The reaction mixture was cooled to room temperature, diluted by addition of toluene, washed successively with aqueous NaHCO3 and H2O. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in ethanol (3.5 mL), aqueous KOH (800 mg, KOH in 0.8 mL H2O) was added and the reaction mixture was stirred at reflux temperature overnight, cooled to room temperature, ethanol was removed in vacuo. Aqueous layer was extracted with Et2O, combined ether layer was washed with 3N aqueous HCl. Combined aqueous layer was made pH 10 by addition of aqueous NaOH. The basic solution was extracted with ethyl acetate. The combined organic layer was washed with H2O, dried over Na2SO4, filtered and concentrated. The residue was purified by HPLC (10-55% CH3CN in H2O, 0.1% NH4OH) to give the titled compound (49 mg).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(N(C(C)C)C(C)C)C.[CH3:25][S:26]([O:29]S(C)(=O)=O)(=O)=[O:27].[C:34]([O-])(O)=[O:35].[Na+]>ClCCl>[CH3:25][S:26]([O:1][CH2:2][C:3]1([CH2:34][OH:35])[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)(=[O:29])=[O:27]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOC(CO)(COS(C)(=O)=O)C1
Reaction time: 16 h

Procedure:
To a solution of (2S) 1,1-dimethylethyl 2-(hydroxymethyl)-4-morpholinecarboxylate (5.63 g) (Heterocycles, 1993, 35, 105) and N-ethyl-N,N-diisopropylamine (9 ml) in dichloromethane (200 ml) at room temperature was added methanesulfonic anhydride (5.42 g). The reaction was stirred for 16 hours. The reaction mixture was poured onto saturated aqueous NaHCO3 solution and the organics were extracted with dichloromethane. The combined organic extracts were dried with MgSO4 and concentrated to give an oil (8.33 g). This was used without further purification.
Reaction SMILES: O=[C:2]([CH3:8])[CH2:3][CH2:4][CH2:5][C:6]#[N:7].[NH2:9][C:10]1[C:15]([CH:16]=O)=[CH:14][CH:13]=[CH:12][N:11]=1>C(O)C>[CH3:8][C:2]1[C:3]([CH2:4][CH2:5][C:6]#[N:7])=[CH:16][C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: CC(=O)CCCC#N
Reactant: Nc1ncccc1C=O
Solvent: CCO
Product: Cc1nc2ncccc2cc1CCC#N

Procedure:
A mixture of 5-oxo-hexanenitrile (5 mL, TCI-US), 2-amino-3-formylpyridine (7 g, J. Org. Chem. 1983, vol.48, p3401) and ethanol (100 mL) was heated to reflux for 12 hours. Following evaporation of the solvent, the residue was chromatographed (silica gel, ethyl acetate) to give 4-[1,8]naphthyridin-2-yl-butyronitirile and the title product as colorless solids. 1H (CDCl3) δ 2.29 (3H, s); 2.83 (2H, t); 3.18 (2H, t); 7.48 (1H, dd); 8.04 (1H, s); 8.20 (1H, dd); 9.03 (1H, dd). Step 2
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[F:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12](/[CH:17]=[CH:18]/[N+:19]([O-])=O)=[CH:13][NH:14]2)=[CH:10][CH:9]=1.C(OCC)(=O)C>O1CCCC1>[F:7][C:8]1[CH:16]=[C:15]2[C:11](=[CH:10][CH:9]=1)[C:12]([CH2:17][CH2:18][NH2:19])=[CH:13][NH:14]2
Reactant: O=[N+]([O-])/C=C/c1c[nH]c2cc(F)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NCCc1c[nH]c2cc(F)ccc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
Aluminum lithium hydride (1.36 g) was suspended in tetrahydrofuran (72 ml), 6-fluoro-3-[(E)-2-nitrovinyl]-1H-indole (1.48 g) was dissolved in tetrahydrofuran (20 ml) and added dropwise under ice-cooling, and the mixture was stirred at 60° C. for 1 hr. Under ice-cooling, excess aluminum lithium hydride was decomposed with ice water, ethyl acetate was added, and the mixture was filtered through a celite (trademark) filter. A 1N aqueous sodium hydroxide solution was added to the filtrate, pH was adjusted to not less than 11, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a brown oil. The oil was purified by amine coating silica gel column chromatography (elution solvent:ethyl acetate-ethyl acetate-methanol (10:1)) to give 6-fluorotryptamine (1.24 g, yield 97%).