Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[NH:13][CH2:12][C:11]2[O:14][C:15]([C:17]([O:19]C)=[O:18])=[N:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+:23]>O1CCCC1>[C:1]([O:5][C:6]([CH:8]1[NH:13][CH2:12][C:11]2[O:14][C:15]([C:17]([O-:19])=[O:18])=[N:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3].[Li+:23]
Reactant: COC(=O)c1nc2c(o1)CNC(C(=O)OC(C)(C)C)C2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C1Cc2nc(C(=O)[O-])oc2CN1
Reaction time: 0.17 h

Procedure:
To a solution of 6-(tert-butoxycarbonyl)-2-methoxycarbonyl-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridine (311 mg) in tetrahydrofuran (8.0 ml) were added water (2.0 ml) and lithium hydroxide (25.0 mg) at room temperature. After stirring for 10 minutes, the reaction mixture was distilled under reduced pressure to remove the solvent, whereby the title compound (280 mg) was obtained as a colorless solid. The residue was provided for the subsequent reaction without purification.
Reaction SMILES: Cl.[CH2:2]([N:20](C)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-])=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH2:31](O)C>>[CH2:2]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][CH3:31])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCCCCCN(C)c1ccccc1[N+](=O)[O-]
Reactant: CCO
Agent: Cl
Product: CCCCCCCCCCCCCCCCCCNc1ccccc1NC

Procedure:
Add 23.6 g (0.22 mol) N-methylaniline into 92 g (0.2 mol) 14% hexane solution of N-butyllithium and stir it for 10-20 minutes. Drop 33.3 g (0.1 mol) octadecylbromide into the above solution, while stirring it. Add 200 ml water into the solution, after heating and refluxing the solution for about 17 hours and cooling it down to room temperature. Add 6N hydrochloric acid to the solution after concentrating the solution extracted by 300 ml diethyl ether and deposit it. 32.3 g (0.09 mol) N, N-methyloctadecylaniline is obtained by refinement through crystalization with ethyl alcohol and water. Dissolve the obtained 32.3 g (0.09 mol) N, N-methyloctadecylaniline into 250 ml concentrated sulfuric acid. Add 30 ml concentrated nitric acid into the solution while stirring it in an ice water bath. Leave it about one hour after adding the nitric acid. Add the solution into ice water filter off the deposit from it, and refine it by crystalization with ethyl alcohol and water. With the above step, 14.5 g (0.036 mol) N, N-octadecylmethyl-o-nitroaniline is obtained. Add 100 ml 2N hydrochloric acid into this 14.5 g (0.036 mol) N, N-octadecylmethyl-o-nitroaniline which is dissolved into 200 ml ethyl alcohol. 11.7 g (0.031 mol) N, N-octadecylmethyl-o-phenylene-diamine is obtained after adding 11.75 (0.18 mol) zinc dust into the above solution to be heated and refluxed for one hour.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][C:5]([F:10])=[C:4]([Cl:11])[N:3]=1.P(Br)(Br)[Br:13].C(Cl)Cl.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Br:13][CH2:8][C:7]1[C:2]([Cl:1])=[N:3][C:4]([Cl:11])=[C:5]([F:10])[CH:6]=1
Reactant: OCc1cc(F)c(Cl)nc1Cl
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Fc1cc(CBr)c(Cl)nc1Cl
Temperature: 25 °C
Yield: 88 %

Procedure:
To a stirred mixture of alcohol 1A (3.52 g, 17.9 mmol) in CHCl3 (100 mL) under argon was added 1M PBr3 in CH2Cl2 (18.0 mL, 18.0 mmol). The reaction mixture was heated to reflux for 15 minutes, cooled to room temperature, then poured into a mixture of ice and saturated NaHCO3 solution (200 mL). The pH was adjusted to basic by addition of solid NaHCO3. The aqueous layer was extracted with EtOAc. The combined EtOAc extracts were washed with brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give 1B (4.11 g, 88%). HPLC Rt=2.78 min. (Column: YMC ODS-A 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH:16]([CH2:19][C:20](O)=[O:21])[NH:15][C:14]3=[O:23])[CH:10]=[N:9]2)=[C:5]([CH3:24])[O:4][N:3]=1.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([NH:32][C:20](=[O:21])[CH2:19][CH:16]1[C:17](=[O:18])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:24])[CH:12]=2)[C:14](=[O:23])[NH:15]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1ccccc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(CC(=O)O)C2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)NC(CC(=O)NCc3ccccc3)C2=O)cn1
Yield: 30 %

Procedure:
Prepared as in Example 10-48 from 3-(1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2,5-dioxoimidazolidin-4-yl)acetic acid (example 10-44) and benzyl amine. Yield: 30%. 1H NMR (CDCl3, 400 MHz): δ 2.18 (s, 3H), 2.41 (s, 3H), 2.56-2.52 (m, 1H, J=16 Hz), 2.56-2.52 (m, 1H), 3.00-2.96 (m, 1H), 4.45-4.44 (d, J=5.6 Hz, 2H), 5.04 (s, 2H), 5.96 (bs, 1H), 6.36 (bs, 1H), 7.36-7.25 (m, 5H), 7.90 (s, 1H, 8.05 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 1.3 μM.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.[O:13]1[CH2:16]C(O)[CH2:14]1.C(N(CC)C(C)C)(C)C.[CH3:27][C@H:28]1[CH2:37][NH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:38]3[CH:39]=[N:40][N:41]([CH:43]4[CH2:46][O:45][CH2:44]4)[CH:42]=3)[CH:34]=2)[N:29]1[C:47](=[O:49])[CH3:48]>ClCCCl>[C:47]([N:29]1[C:30]2[C:35](=[CH:34][C:33]([C:38]3[CH:39]=[N:40][N:41]([CH:43]4[CH2:46][O:45][CH2:44]4)[CH:42]=3)=[CH:32][CH:31]=2)[N:36]([C:5]([O:6][CH:7]2[CH2:16][O:13][CH2:14]2)=[O:11])[CH2:37][C@@H:28]1[CH3:27])(=[O:49])[CH3:48]
Reactant: CC(=O)N1c2ccc(-c3cnn(C4COC4)c3)cc2NC[C@@H]1C
Reactant: OC1COC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(-c3cnn(C4COC4)c3)cc2N(C(=O)OC2COC2)C[C@@H]1C
Temperature: 50 °C
Reaction time: 3 h
Yield: 63.1 %

Procedure:
Triphosgene (0.057 g, 0.192 mmol) was added to a solution of oxetan-3-ol (0.034 mL, 0.576 mmol) and N,N-diisopropylethylamine (0.101 mL, 0.576 mmol) in 1,2-dichloroethane (2.0 mL). The mixture stirred at rt for 30 min. (S)-1-(2-methyl-6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.030 g, 0.096 mmol) and N,N-diisopropylethylamine (0.101 mL, 0.576 mmol) were added and the mixture stirred at 50° C. for 3 h. The reaction mixture was concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 50-100% ethyl acetate-hexane then 5-10% methanol-dichloromethane) to afford (S)-oxetan-3-yl 4-acetyl-3-methyl-7-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.025 g, 63%) as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.95 (d, J=6.74 Hz, 3 H), 2.10 (s, 3 H), 3.49 (br s, 1 H), 3.98 (br dd, J=12.90, 5.86 Hz, 1 H), 4.51 (ddd, J=10.55, 7.18, 5.42 Hz, 2 H), 4.66-4.79 (m, 2 H), 4.79-4.94 (m, 5 H), 5.30-5.45 (m, 1 H), 5.53 (dq, J=14.07, 7.23 Hz, 1 H), 7.30 (dd, J=8.35, 1.91 Hz, 1 H), 7.41 (br s, 1 H), 7.86-8.00 (m, 2 H), 8.25 (s, 1 H). MS (ESI, pos. ion) m/z 413.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([CH2:19][C:20]1[CH:21]=[N:22][C:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:24][CH:25]=1)[CH2:6][P:7]([OH:18])([CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])C.[Li+].[OH-].C(OC(=O)C)C>CC#N.O>[C:30]([O:29][C:27]([NH:26][C:23]1[N:22]=[CH:21][C:20]([CH2:19][CH:5]([CH2:6][P:7]([OH:18])([CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])[C:4]([OH:34])=[O:3])=[CH:25][CH:24]=1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)CP(=O)(O)CCCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(CC(CP(=O)(O)CCCc2ccccc2)C(=O)O)cn1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 76.9 %

Procedure:
To a solution of 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-3-[hydroxy-(3-phenyl-propyl)-phosphinoyl]-propionic acid ethyl ester (0.240 g 0.489 mmol) in MeCN (3 mL) was added a solution of LiOH (0.059 g 2.45 mmol) in H2O (3 mL). The mixture was then stirred at 20° C. for 1.5 hours. Ethylacetate was added and the mixture was washed with 1 M HCL and brine and filtered to give 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-3-[hydroxy-(3-phenyl-propyl)-phosphinoyl]-propionic acid (0.174 g, 77%) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[C:14](#[N:16])C.ClS(N=C=O)(=O)=O.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>CCOC(C)=O.C(OCC)(=O)C.CCCCCC.CN(C)C=O>[C:14]([C:9]1[N:8]([NH:7][C:6](=[O:13])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:12]=[CH:11][CH:10]=1)#[N:16]
Reactant: CC#N
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Agent: O=C1c2ccccc2C(=O)C1(O)O
Agent: O=C=NS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nn1cccc1C#N
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A 2 L, 3-neck RB was fitted w/stir bar, N2 inlet, rubber septum low-temp. thermometer and ice/acetone cooling bath. Pyrrol-1-yl-carbamic acid tert-butyl ester (99.0 g, 0.543 mol) was added to the reactor, dissolved w/anhydrous acetonitrile (700 mL) and the stirred solution was cooled to 0° C. Chlorosulfonyl isocyanate (49.7 mL, 0.57 mol) was added dropwise via syringe (maintaining an internal temp. below 5° C.); after ˜20 minutes a suspension was observed. After 45 minutes N,N-dimethylformamide (anhydrous, 100 mL) was added dropwise via addition funnel (keeping internal temp. below 5° C.) and the reaction mixture became a solution. Stirring @ 0° C. was continued for 45 minutes, then the reaction was allowed to warm to RT; monitoring by TLC (silica gel, 1:3 ethyl acetate/hexane, UV, ninhydrin stain) of a quenched sample indicated that the reaction had progressed to completion. The mixture was poured onto ice (˜2 L) and stirred with addition of EtOAc (2 L). The layers were separated and the organic layer was dried over magnesium sulfate. The dried solution was filtered through a pad of 30/40 Magnesol and the filtrate was concentrated to dryness in vacuo, then the residue was dissolved in a minimum volume of dichloromethane and chromatographed on a plug of silica gel, eluting with ethyl acetate/hexane, 0-50% ethyl acetate. The clean, product-containing fractions were combined and concentrated to dryness in vacuo, to afford the desired product as a white solid, 69.8 g (62%). A somewhat impure fraction provided additional material, 16.8 g (15%), bringing the total recovery to 86.6 g, (77%). 1H-NMR (CD3OD): δ 7.01 (dd, 1H, J=3.0, 1.6 Hz), 6.82 (dd, 1H, J=4.4, 1.7 Hz), 6.19 (dd, 1H, J=4.2, 2.9 Hz), 4.88 (s, 1H, H2O+NH—), 1.50 (br s, 9H, HN—BOC); MS: LC/MS (+esi), m/z=207.9 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[C:14]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[F:27])[C:22]#[N:23])[C:13](=[O:28])[CH:12]=[CH:11]2.[O:29]1CCOCC1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[C:15]([CH:16]=[CH:17][CH:18]=1)=[C:14]([C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[F:27])[C:22]([NH2:23])=[O:29])[C:13](=[O:28])[CH:12]=[CH:11]2
Reactant: N#Cc1ccc(F)c(-c2c(=O)ccn3c(-c4ccc(F)cc4F)cccc23)c1
Reactant: C1COCCO1
Product: NC(=O)c1ccc(F)c(-c2c(=O)ccn3c(-c4ccc(F)cc4F)cccc23)c1

Procedure:
To a solution of 3-[6-(2,4-difluorophenyl)-2-oxo-2H-quinolizin-1-yl]-4-fluorobenzonitrile (Example 30) in dioxane/2N KOH was heated to 60° C. for 1 h. The solution was concentrated and purified via reverse phase HPLC (10-100% acetonitrile in H2O, Kromisil, C8, 30×100 mm) to give a title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[S:16][CH:17]=[C:18]([CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([S:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=4)[N:19]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].ClC1C=C(C(OO)=[O:41])C=CC=1>C(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[S:16][CH:17]=[C:18]([CH2:20][O:21][C:22]4[CH:23]=[CH:24][C:25]([S:28]([C:29]([F:31])([F:32])[F:30])=[O:41])=[CH:26][CH:27]=4)[N:19]=3)[CH2:11][CH2:10]2)=[N:5][CH:4]=1)[CH3:2]
Reactant: CCc1cnc(N2CCC(c3nc(COc4ccc(SC(F)(F)F)cc4)cs3)CC2)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCc1cnc(N2CCC(c3nc(COc4ccc(S(=O)C(F)(F)F)cc4)cs3)CC2)nc1
Reaction time: 1.5 h

Procedure:
To a solution of 5-Ethyl-2-{4-[4-(4-trifluoromethylsulfanyl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine (Example 16) in DCM at room temperature was added 3-chloro-benzenecarboperoxoic acid (2 eq.). The reaction was allowed to stir for 1.5 hours and an additional portion of 3-chloro-benzenecarboperoxoic acid (1 eq.) was added to the reaction mixture. The reaction was stirred at room temperature for an additional 4 hours. The organic solution was washed with sodium bicarbonate; the organic layer was isolated, dried over sodium sulfate and filtered. The filtrate was concentrated and the crude product was purified by column chromatography to afford the desired product. 1H NMR (DMSO-d6): δ 8.40 (2H, s), 7.58 (2H, d), 7.22 (1H, s), 7.02 (2H, d,), 5.17 (2H, s), 3.74 (2H, m), 3.16 (1H, m), 2.96 (2H, m), 2.57 (2H, m), 2.22 (4H, m), 1.24 (3H, m).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C1C(=O)N([I:18])C(=O)C1.O>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:10]([I:18])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncnc2[nH]cc(I)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (8.0 g, 52.32 mmol, 1.0 eq) in DMF (40 mL), NIS (15.7 g, 57.55 mmol, 1.1 eq) was added at 0° C. The reaction mixture was stirred overnight at room temperature. Water (40 mL) was added to the reaction mixture, extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under vacuum to give 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (14.6 g, 100% in yield).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[O:5]=[C:6]([CH:8]=[C:9]([CH3:11])[CH3:10])[CH3:7].C=CC=CC.[C:17]1([CH3:23])[CH:22]=CC=[CH:19][CH:18]=1>>[CH3:7][C:6]([CH:8]1[C:17]([CH3:23])([CH3:22])[CH2:18][CH:19]=[CH:10][CH:9]1[CH3:11])=[O:5]
Reactant: CC(=O)C=C(C)C
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C=CC=CC
Product: CC(=O)C1C(C)C=CCC1(C)C
Reaction time: 3 h

Procedure:
In a 3-liter four-necked flask equipped with a dropping funnel, thermometer, condenser and a stirrer, placed were aluminum chloride (70 g) and toluene (300 ml) under ice cooling in a nitrogen gas stream. Under stirring, a solution of mesityl oxide (120 g) in toluene (300 ml) was added drop by drop during 1 hour at 2 to 5° C. After the addition, a solution of 1,3-pentadiene (450 g) in toluene (1,200 ml) was added drop by drop at 0 to −5° C. during 4 hours. After the addition, the mixture was stirred at the same temperature for 3 hours. After 3 hours at 30 to 40° C., the reaction was completed. The reaction mixture was cooled, followed by decomposition, washing with water (1,200 ml). After further washing with water (1,200 ml), the reaction mixture was washed with a 5% aqueous solution (500 ml) of sodium carbonate. Final washing with saturated salt solution (500 ml) gave a toluene solution of the product.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].Cl[C:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7].N1C=CC=CC=1.NN.C(=O)([O-])[O-].C(OCC=C)(=O)NN.C1(O)C=CC=CC=1>C(Cl)Cl>[C:6](=[O:7])([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[O:4][CH2:1][CH:2]=[CH2:3]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C=CCO
Agent: C=CCOC(=O)NN
Agent: NN
Agent: O=C([O-])[O-]
Solvent: Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)Oc1ccccc1
Reaction time: 2 h
Yield: 97 %

Procedure:
Allyl phenyl carbonate was prepared in 97% yield by reacting 17.6 grams (0.3 mole) of allyl alcohol with 48.4 grams (0.3 mole) of phenyl chloroformate in the presence of 26.4 grams (0.33 mole) of pyridine and 300 ml of methylene chloride. The allyl phenyl carbonate soluation was washed with 5% HC1, water, dried over anhydrous sodium sulfate, filtered and the methylene chloride evaporated on a rotating evaporator under reduced pressure. The residual allyl phenyl carbonate (52.7 grams--0.29 mole) was dissolved in 200 ml of methanol and treated with 16.0 grams (0.32 mole) of 64% aqueous hydrazine at room temperature. After two hours, gase chromatography indicated that the carbonate had been completely converted to allyl carbazate and phenol. The reaction mixture was stripped of volatiles on the rotating evaporator. The residue was taken up in 200 ml of methylene chloride and washed with 50 grams of 25% sodium hydroxide to remove the phenol. The methylene chloride layer was washed with saturated salt solution, dried over sodium sulfate, filtered and the methylene chloride stripped off on the rotating evaporator. The residue weighed 9.2 grams and assayed 98.0% by gas chromatography. An additional 3.9 grams was recovered by reextracting the aqueous wash.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11](=[O:15])[C:12]([OH:14])=[O:13])=[CH:2]1.[CH2:16]1CCN2C(=NCCC2)C[CH2:17]1.C(Br)C>C1C=CC=CC=1>[CH2:16]([O:13][C:12](=[O:14])[C:11]([CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:15])[CH3:17]
Reactant: O=C(O)C(=O)Cc1c[nH]c2ccccc12
Reactant: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Solvent: CCBr
Product: CCOC(=O)C(=O)Cc1c[nH]c2ccccc12
Yield: 70 %

Procedure:
Following the same method as previously described, 1,0 g 3-indole-pyruvic acid were reacted with 1,5 ml DBU and 790 microliters ethylbromide. In this case the benzene solution appeared red orange. After flash chromatography purification the ethyl ester was obtained with a yield of about 70%.
Reaction SMILES: C(O[C:4]([C:8]1[C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[O:11][C:10]([CH3:22])([CH3:21])[CH:9]=1)=[N:5][C:6]#[N:7])C.[CH:23]1([NH2:26])[CH2:25][CH2:24]1.ClCCl.CCOC(C)=O>CCCCCC>[C:6]([NH:5][C:4]([C:8]1[C:13]2[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=2[O:11][C:10]([CH3:21])([CH3:22])[CH:9]=1)=[N:26][CH:23]1[CH2:25][CH2:24]1)#[N:7]
Reactant: NC1CC1
Reactant: CCOC(=NC#N)C1=CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(C)C=C(C(=NC2CC2)NC#N)c2cc([N+](=O)[O-])ccc2O1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29.5 %

Procedure:
A mixture of 98 mg of N-cyano -6-nitro-2,2-dimethyl-2H-1-benzopyran-4-carboximidic acid ethyl ester, 30 mg of cyclopropylamine, and 1 ml of dichloromethane was stirred at room temperature for 1.5 hours. The reaction mixture was subjected to silica gel column chromatography (AcOEt:n-hexane=l:l) and then recrystallization from a mixture of acetone and n-hexane to obtain 30 mg of N-cyano-N'-cyclopropyl-6-nitro-2,2-dimethyl-2H-1-benzopyran -4-carboxamidine represented by formula shown below.
Reaction SMILES: ClCCl.C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:14]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([S:24]([N:27]3[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]3)(=[O:26])=[O:25])[C:18]=2[CH:17]=[CH:16][N:15]=1>C(N(CC)CC)C>[CH:14]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([S:24]([N:27]3[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]3)(=[O:25])=[O:26])[C:18]=2[CH:17]=[CH:16][N:15]=1
Reactant: O=S(=O)(c1cccc2cnccc12)N1CCC(O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1CCN(S(=O)(=O)c2cccc3cnccc23)CC1
Temperature: -55 °C
Reaction time: 0.08 h
Yield: 89 %

Procedure:
To 100 ml of a dried dichloromethane solution containing 2.67 g of oxalyl chloride was added dropwise at -50° C. 20 ml of a dichloromethane solution containing 1.64 g of dimethylsulfoxide. The mixture was allowed to stand for 5 minutes. To the mixture was added dropwise over a period of 10 minutes, while maintaining the temperature at -55° C., 40 ml of a dried dichloromethane solution containing 5.84 g of 1-(5-isoquinolinesulfonyl)-4-hydroxypiperidine as obtained in Example 7, followed by stirring at that temperature for 20 minutes. To the resulting mixture was added 1.4 ml of triethylamine, and the mixture was stirred for 5 minutes. Then, the temperature of the mixture was raised to 15° C. The mixture was washed twice with 100 ml each of water and dried with anhydrous sodium sulfate. Then, the dichloromethane was removed under reduced pressure to obtain a residue. The residue thus obtained was subjected to purification by silica gel column chromatography (Wacogel C-200, 150 g; solvent: chloroform) to obtain 5.16 g of 1-(5-isoquinolinesulfonyl)-4-piperidone.
Reaction SMILES: [C:1]([O-])(C)(C)C.[K+].[Br-].BrC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:29]([C:33]1[CH:34]=[C:35]([CH:38]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:40]=1)[CH:36]=O)([CH3:32])([CH3:31])[CH3:30].O>O1CCCC1>[C:29]([C:33]1[CH:34]=[C:35]([C:36]#[CH:1])[CH:38]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:40]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1
Reactant: CC(C)(C)[O-]
Agent: BrC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Temperature: -70 °C

Procedure:
73.7 g (0.655 mol) of potassium tert-butanolate were added a little at a time to 117.6 g (0.269 mol) of bromomethyltriphenylphosphonium bromide in 420 ml of dry tetrahydrofuran at 25° C. while cooling. The reaction mixture was then stirred for half an hour and, at -70° C., a solution of 50 g (0.218 mol) of 3,5-di-tertbutylbenzaldehyde in 120 ml of dry tetrahydrofuran was added dropwise. After half an hour, the mixture was allowed to warm to room temperature, and was then stirred overnight and poured into water. Extraction with ether, washing of the organic phase with water, drying over sodium sulfate and evaporation of the solvent produced a viscous residue.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][CH:4]=1)#[CH:2].C([Mg]Br)C.[CH3:14][C:15]([O:18][C:19]([N:21]1[C@H:25]([C:26](N(OC)C)=[O:27])[CH2:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])[CH3:16]>C1COCC1>[I:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:26]([C@@H:25]2[CH2:24][CH2:23][CH2:22][N:21]2[C:19]([O:18][C:15]([CH3:17])([CH3:16])[CH3:14])=[O:20])=[O:27])=[CH:4][CH:5]=1
Reactant: C#Cc1ccc(I)cc1
Reactant: CON(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)C#Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
To a solution of 1-ethynyl-4-iodobenzene 6 (0.908 g, 3.98 mmol) in THF (20 mL) at −78° C. was added ethylmagnesium bromide (3M in ether, 1.39 mL, 4.18 mmol). After 10 minutes the cooling bath was removed and the solution was allowed to stir at room temperature for 1 hour. The reaction mixture was then re-cooled to 0° C. and added to a solution of N-(tert-butoxycarbonyl)-L-proline N′-methoxy-N′-methylamide 2 (0.970 g, 3.76 mmol) in THF (10 mL). The reaction mixture was warmed to room temperature and stirring was continued for 12 hours before the mixture was quenched with saturated NH4Cl. The mixture was diluted with ethyl acetate/H2O, the layers separated and the aqueous phase was re-extracted with ethyl acetate (2×). The combined organic layers were washed (H2O, brine), dried (Na2SO4), and filtered, and the solvent was removed in vacuo. The resulting residue was purified by flash chromatography (hexane:ethyl acetate, 4:1) to give (S)-tert-butyl 2-(3-(4-iodophenyl)propioloyl)pyrrolidine-1-carboxylate 7 (0.908 g, 71%) as a yellow oil which solidified on standing. 1H NMR (400 MHz, CDCl3) δ 7.72-7.76 (m, 2H), 7.26-7.30 (m, 2H), 4.49 (dd, J=8.8, 4.3 Hz, 0.3H), 4.29 (dd, J=8.5, 5.5 Hz, 0.7H), 3.59 (app t, J=6.7 Hz, 2H), 2.20-2.33 (m, 1H), 1.85-2.10 (m, 3H), 1.45, 1.40 (s, 9H, rotamers in 2:3 ratio). LCMS: Anal. Calcd. for C18H20INO3: 425. found: 326 (M+H-Boc)+.