Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[CH:8]=[CH:7][CH:6]=[CH:5]2.Cl[C:12]([O:14][CH3:15])=[O:13]>>[CH3:1][C:2]1[CH:3]=[C:4]2[N:9]([C:10]=1[C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Cc1cc2ccccn2c1
Reactant: COC(=O)Cl
Product: COC(=O)c1c(C)cc2ccccn12
Yield: 72.9 %

Procedure:
A mixture of 2-methylindolizine 1 (3.8 g, 29.0 mmol) and methyl chloroformate (22 g (18 ml), 231.6 mmol) was heated at reflux for 2 h. A further 12.2 g (10 ml) of methyl chloroformate were added, and the mixture was heated at reflux for 2 h. The reaction mixture was concentrated under vacuum and then purified by chromatography on a silica column (hexane/ethyl acetate 5:1, silica gel 200-425 mesh) to give 4 g of compound 2 (colorless oil). 1H NMR (CDCl3): δ 9.43 (d, J=7.1 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 6.99-6.93 (m, 1H), 6.73-6.68 (m, 1H), 6.29 (s, 1H), 3.91 (s, 3H), 2.53 (s, 3H), 13C NMR (CDCl3): δ 162.7, 137.0, 134.6, 127.6, 121.8, 117.6, 111.8, 103.5, 103.48, 50.6, 15.1.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:19])[C@@H:6]([OH:18])[C@@H:7]([NH:10]C(=O)OC(C)(C)C)[CH2:8][CH3:9])[CH2:3][CH2:2]1.[ClH:20]>O1CCOCC1>[ClH:20].[ClH:20].[NH2:10][C@@H:7]([CH2:8][CH3:9])[C@H:6]([OH:18])[C:5]([NH:4][CH:1]1[CH2:2][CH2:3]1)=[O:19]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)NC1CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under an atmosphere of argon, tert-butyl (2S,3S)-1-(cyclopropylamino)-2-hydroxy-1-oxopentan-3-ylcarbamate (540 mg, 1.98 mmol) and HCl 4N in dioxane (10.4 ml) were combined to give a light brown solution. The reaction was stirred for 4 h at RT. The solvent was evaporated. The residual solvent was removed under vacuum. The title compound was obtained as a brown solid (480 mg, quant., MS (m/e)=173.2 [M+H+].
Reaction SMILES: [C:1]([C:3]1[C:4]([CH2:21][CH2:22][CH3:23])=[CH:5][C:6](OS(C(F)(F)F)(=O)=O)=[N:7][C:8]=1[S:9][CH2:10][C:11]#[N:12])#[N:2].[O:24]1[C:28]2([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[O:27][CH2:26][CH2:25]1.C(N(CC)CC)C.O>O1CCOCC1>[NH2:2][C:1]1[C:3]2[C:8](=[N:7][C:6]([N:31]3[CH2:32][CH2:33][C:28]4([O:27][CH2:26][CH2:25][O:24]4)[CH2:29][CH2:30]3)=[CH:5][C:4]=2[CH2:21][CH2:22][CH3:23])[S:9][C:10]=1[C:11]#[N:12]
Reactant: CCCc1cc(OS(=O)(=O)C(F)(F)F)nc(SCC#N)c1C#N
Reactant: C1CC2(CCN1)OCCO2
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CCCc1cc(N2CCC3(CC2)OCCO3)nc2sc(C#N)c(N)c12
Temperature: 100 °C
Yield: 87.6 %

Procedure:
Trifluoro-methanesulfonic acid 5-cyano-6-cyanomethylsulfanyl-4-propyl-pyridin-2-yl ester (1.83 g, 5.00 mmol) (see Example 1, Method B) and 1,4-dioxa-8-aza-spiro[4.5]decane (0.66 mL, 5.00 mmol) were suspended in 3 mL of dioxane. Triethylamine (0.84 mL, 6.0 mmol) was added. The reaction mixture was heated in a SmithSynthesizer™ (Personal Chemistry) at 100° C. for 2 h. The reaction mixture was poured into water and the resulting solid was collected by filtration and recrystallized from acetonitrile to give 3-amino-6-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-4-propyl-thieno[2,3-b]pyridine-2-carbonitrile as a yellow solid (1.57 g, 88%).
Reaction SMILES: [SH:1][C:2]1[N:3]([C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH2:20])[C:18]=2[N:19]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6].[CH3:21][CH2:22][CH2:23][CH:24]([O:33][C:34]([C:36]1([CH:46]=[CH:45][CH:44]=[CH:43][CH2:42]1)OCC1OC1)=[O:35])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>N1C(C)=CC=CC=1C.C(O)C>[OH:6][CH:5]([CH2:4][O:12][C:46]1[CH:45]=[CH:44][CH:43]=[CH:42][C:36]=1[C:34]([O:33][CH:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:23][CH2:22][CH3:21])=[O:35])[CH2:7][S:1][C:2]1[N:3]([C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH2:20])[C:18]=2[N:19]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6]
Reactant: Nc1ncnc2c1nc(S)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CCCCCCCCC(CCC)OC(=O)C1(OCC2CO2)C=CC=CC1
Solvent: CCO
Solvent: Cc1cccc(C)n1
Product: CCCCCCCCC(CCC)OC(=O)c1ccccc1OCC(O)CSc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 114.2 %

Procedure:
A suspension of 8-mercapto-adenosine (4.9 g, 16.4 mmole), 1-(4-dodecyloxycarbonyl)phenoxy-2,3-epoxy-propane (5.4 g, 14,9 mmole), 2,6-lutidine (5 drops) and absolute ethanol (100 ml) is heated at reflux temperature for a couple of hours, then the obtained solution is allowed to cool slowly under stirring. The white crystalline precipitate which forms is recovered by filtration, washed with ethanol (about 25 ml) and dried under vacuum yielding 6.2 g of the compound of the title with m.p. 163°-65° C.; [α]D20 -39.98° (c=1 in dimethylformamide).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[N:18]1[C:22]([CH3:23])=[N:21][N:20]=[C:19]1[CH2:24]Br.[NH3:27]>CO>[N+:15]([C:13]1[CH:12]=[CH:11][C:10]2[N:18]3[C:22]([CH3:23])=[N:21][N:20]=[C:19]3[CH2:24][N:27]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[CH:14]=1)([O-:17])=[O:16]
Reactant: Cc1nnc(CBr)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Reactant: N
Solvent: CO
Product: Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 8, 2'-chloro-5nitro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone is reacted with a saturated solution of ammonia in methanol to give 8-nitro-1-methyl-6-(o-chlorophenyl)-4H-s-triazolo- [4,3-a][1,4]benzodiazepine of melting point 231°-233° C.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]1>>[O:26]=[S:23]1(=[O:27])[CH2:24][CH2:25][N:20]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=4)[N:10]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:21][CH2:22]1
Reactant: COc1ccc(Nc2nc3c(Br)cccn3n2)cc1
Reactant: O=S1(=O)CCNCC1
Product: COc1ccc(Nc2nc3c(N4CCS(=O)(=O)CC4)cccn3n2)cc1

Procedure:
8-(1,1-dioxidothiomorpholin-4-yl)-N-(4-methoxyphenyl)[1,2,4]triazolo[1,5-a]pyri din-2-amine was prepared from (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(4-methoxy-phenyl)-amine (50.0 mg, 0.157 mmol) and thiomorpholine 1,1-dioxide (25.0 mg, 0.185 mmol) in a manner analogous to Example 30. Product isolated as a tan solid (0.052 g, 89%). MP=231-234° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11 (dd, J=6.4, 1.1 Hz, 1H), 7.50-7.45 (m, 2H), 6.94-6.89 (m, 2H), 6.77 (dd, J=7.7, 6.7 Hz, 1H), 6.73 (dd, J=7.6, 0.9 Hz, 1H), 6.57 (s, 1H), 4.12-4.06 (m, 4H), 3.81 (s, 3H), 3.28-3.23 (m, 4H). MS=374 (MH)+.
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1.CO>CN1C(=O)CCC1>[C:3]1([S:9][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[C:14]([C:21]4[NH:29][C:28]5[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=5[CH:22]=4)[CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Sc1ccccc1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CO
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Sc5ccccc5)nc34)cc21
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 44.8 %

Procedure:
To NaH (60 wt % in mineral oil; 0.050 g, 1.259 mmol) in 1 mL NMP was added benzenethiol (0.129 ml, 1.259 mmol). After 10 min, a clear/colorless solution resulted. 2-(2-Chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.075 g, 0.252 mmol) was added as a solid and the reaction became orange. After 1 h, the reaction was sealed and heated to 70° C. for 1 h. The reaction was cooled and was partitioned between saturated aq. NaHCO3 and EtOAc. The organic layer was washed with saturated aq. NaHCO3 (3×) and saturated aq. NaCl (1×), and the organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was treated with DCM and purified by silica gel chromatography (25 g column) using 0-50% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford a yellow solid. The material was treated with 1 mL MeOH, sonicated, and filtered, rinsing with MeOH, to give 2-(2-(phenylthio)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.042 g, 0.113 mmol, 45% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.18-11.45 (1H, m), 8.28 (1H, d, J=8.6 Hz), 8.09 (1H, dd, J=7.5, 1.5 Hz), 7.67-7.79 (3H, m), 7.48-7.61 (4H, m), 7.36 (1H, d, J=8.8 Hz), 7.05 (1H, d, J=2.3 Hz), 6.92-6.98 (1H, m), 3.33-3.42 (2H, m), 2.50-2.55 (2H, m). m/z (ESI, +ve) 371.9 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)#[N:2].C(O)(=[O:29])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH:6]=[C:7]2[C:8]=1[NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:17][C:18]2=1)(=[O:29])[NH2:2]
Reactant: CC(=O)O
Reactant: COc1ccccc1-c1ccc(Nc2ccc(C(=O)O)cc2)c(C#N)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: COc1ccccc1-c1cc(C(N)=O)c2[nH]c3ccc(C(=O)O)cc3c2c1
Temperature: 130 °C

Procedure:
A 5 ml microwave vial was loaded with 4-(3-cyano-2′-methoxybiphenyl-4-ylamino)benzoic acid (63 mg, 0.161 mmol), Acetic Acid (4 ml) and Palladium(II) acetate (106 mg, 0.472 mmol), sealed and heated to 130° C. for 12 hours. The reaction mixture was filtered through a 0.45 um Nylon filter, the filter rinsed with acetic acid and the collected liquids evaporated. 31.5 mg of 8-carbamoyl-6-(2-methoxyphenyl)-9H-carbazole-3-carboxylic acid were isolated as a brown film and used without further purification. MS (ESI) m/z 359 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([NH2:17])=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]#[N:17])[N:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)Cc1csc(-c2ccc(Cl)c(Cl)c2)n1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: N#CCc1csc(-c2ccc(Cl)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 2-[2-(3,4-dichlorophenyl)thiazol-4-yl]-acetamide (2.87 g., 0.01 mole) in pyridine (30 ml.) is added gradually p-toluenesulfonyl chloride (1.91 g., 0.01 mole). After stirring for one hour, the mixture is poured into excess ice-water to give the title compound.
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1.O.[F:13][C:14]([F:19])([F:18])[C@H:15]([OH:17])[CH3:16]>CN(C)C=O>[F:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][O:17][C@H:15]([CH3:16])[C:14]([F:19])([F:18])[F:13])[CH:6]=1
Reactant: Fc1cccc(CBr)c1
Reactant: C[C@@H](O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](OCc1cccc(F)c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 69.3 %

Procedure:
Under argon atmosphere, a suspension of sodium hydride (76 mg, 60 wt % oil dispersion) in N,N-dimethylformamide (2.0 ml) was cooled to 0° C., a solution of N,N-dimethylformamide (2.0 ml) in (R)-1,1,1-trifluoropropan-2-ol (219 mg) was added thereto, and the mixture was stirred for 25 minutes. Then, a solution of 1-bromomethyl-3-fluorobenzene (297 mg) in N,N-dimethylformamide (2.0 ml) was added thereto, and then the mixture was stirred for 2 hours. To this reaction mixture was added water, and the mixture was extracted with ethyl acetate. This organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (eluent: n-hexane/ethyl acetate=9/1) to give the titled compound (242 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[NH:4][C:5](=[S:15])[N:6]([CH2:9][CH:10]([O:12][CH2:13][CH3:14])[CH3:11])[C:7]=1[NH2:8].[CH:17](O)=O>>[CH2:13]([O:12][CH:10]([CH3:11])[CH2:9][N:6]1[C:7]2[N:8]=[CH:17][NH:1][C:2]=2[C:3](=[O:16])[NH:4][C:5]1=[S:15])[CH3:14]
Reactant: CCOC(C)Cn1c(N)c(N)c(=O)[nH]c1=S
Reactant: O=CO
Product: CCOC(C)Cn1c(=S)[nH]c(=O)c2[nH]cnc21
Temperature: 70 °C
Yield: 29 %

Procedure:
5,6-Diamino-1-(2-ethoxy-propyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.60 g, 2.45 mmol) obtained from Example 5(d) was suspended in formic acid (6 mL) and the obtained solution was heated at 70° C. for 2 h. Excess formic acid was evaporated off under reduced pressure. 10% sodium hydroxide (6 mL) was added to the solid and the obtained solution was heated at 70° C. for 2 h. The pH of the solution was adjusted to neutral pH with 2M sulphuric acid. The obtained precipitate was collected by filtration and washed with water. Purified by preparative HPLC, the title compound (0.18 g, 29% yield) was obtained as a solid.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[CH:29]=[C:28]([F:30])[C:27]([N:31]2[C:36](=[O:37])[CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[N:33]([CH3:42])[C:32]2=[O:43])=[CH:26][C:11]=1[O:12][C:13]1[C:14]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[N:15][C:16]([CH3:19])=[N:17][CH:18]=1.[ClH:44]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:44][C:10]1[CH:29]=[C:28]([F:30])[C:27]([N:31]2[C:36](=[O:37])[CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[N:33]([CH3:42])[C:32]2=[O:43])=[CH:26][C:11]=1[O:12][C:13]1[C:14]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[N:15][C:16]([CH3:19])=[N:17][CH:18]=1
Reactant: Cl
Reactant: COC(=O)COc1nc(C)ncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COC(=O)COc1nc(C)ncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
60 mg of isoamyl nitrite was added to a mixture of 0.17 g of 5-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-(methoxycarbonyl)methoxy-2-methylpyrimidine, 67 mg of copper(I) chloride, 137 mg of copper(II) chloride and 2 ml of acetonitrile dropwise at room temperature, and the mixture was stirred for 1 hour. This reaction solution was poured into 2% hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 20 mg of 5-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-(methoxycarbonyl)methoxy-2-methylpyrimidine [present compound 4-85].
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([N:27]=[C:28]=[O:29])=[CH:26][C:21]=2[CH2:20][CH2:19]1>>[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([NH:27][C:28](=[O:29])[O:17][C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]4)=[CH:26][C:21]=2[CH2:20][CH2:19]1
Reactant: Oc1ccc2c(c1)CCN2Cc1ccccc1
Reactant: O=C=Nc1ccc2c(c1)CCO2
Product: O=C(Nc1ccc2c(c1)CCO2)Oc1ccc2c(c1)CCN2Cc1ccccc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-ol (35.0 mg, 0.155 mmol) using the same procedure employed for Example 2 (2), but with 2,3-dihydro-1-benzofuran-5-ylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (9.0 mg, 13%) having the following characteristics.
Reaction SMILES: CC(O[C:6](=[O:22])[NH:7][C@@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]1=[O:21])(C)C.C(O)(C(F)(F)F)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+].[Cl:47][C:48]1[CH:57]=[C:56]2[C:51]([C:52]([N:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)=[CH:53][C:54]([NH2:58])=[N:55]2)=[CH:50][CH:49]=1>>[NH2:58][C:54]1[CH:53]=[C:52]([N:59]2[CH2:60][CH2:61][N:62]([C:6]([NH:7][C@H:8]3[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15](=[O:20])[C:16]([CH3:17])([CH3:18])[CH3:19])[C:9]3=[O:21])=[O:22])[CH2:63][CH2:64]2)[C:51]2[C:56](=[CH:57][C:48]([Cl:47])=[CH:49][CH:50]=2)[N:55]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCCN(C(=O)C(C)(C)C)C1=O
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)N1CCCC[C@H](NC(=O)N2CCN(c3cc(N)nc4cc(Cl)ccc34)CC2)C1=O

Procedure:
As described for example 213, [(3R)-1-(2,2-dimethyl-1-oxopropyl)hexahydro-2-oxo-1H-azepin-3-yl]-carbamic acid-1,1-dimethylethyl ester, TFA, triphosgene, NaHCO3 (sat.), and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product as a light yellow solid. LC-MS: 501 (M++1). 1H NMR (CDCl3) δ 1.30 (s, 9H), 1.50˜1.70 (m, 1H), 1.80˜2.08 (m, 3H), 2.10–2.20 (m, 1H), 3.05˜3.20 (m, 4H), 3.45 (dd, 1H), 3.60–3.74 (m, 4H), 3.80 (br.dd, 1H), 4.66 (m, 1H), 4.94 (br.s, 2H), 5.96 (d, 1H), 6.15 (s, 1H), 7.16 (dd, 1H), 7.60 (d, 1H), 7.71 (d, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:24][C:21]1[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[C:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]3[N:11]=[C:12]([CH3:15])[S:13][CH:14]=3)=[CH:4][N:3]=2)[CH:22]=1
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Reactant: COc1ccc(F)cc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(F)cc1-c1ccc(C#Cc2csc(C)n2)cn1
Temperature: 80 °C

Procedure:
2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (1.0 mmol, 234 mg), 2-methoxy-5-fluorophenylboronic acid (2.0 mmol, 340 mg), dichlorobis(triphenylphosphine)palladium(II) (0.05 mmol, 35 mg), and potassium carbonate (3.5 mmol, 500 mg) were added to deoxygenated DME:water (1:1, 5 mL) at room temperature. The reaction was heated for 18 h at 80° C., then partitioned in a separatory funnel with EtOAc (100 mL) and water (30 mL). The organic layer was washed with one additional portion of water (20 mL) and the combined aqueous layers back extracted with EtOAc (50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2, eluting with a 0% to 60% EtOAc gradient in hexanes, to afford the title compound as a tan solid, which was dissolved in ether and precipitated as the hydrochloride salt with 1M HCl in ether. 1H-NMR (CD3OD, 500 MHz) δ 9.08 (s, 1H), 8.73 (d, 1H), 8.34 (d, 1H), 8.03 (s, 1H), 7.58 (dd, 1H), 7.45 (m, 1H), 7.33 (m, 1H), 3.97 (s, 3H), 2.77 (s, 3H). MS (ESI) 325.4 (M+H+).
Reaction SMILES: [C:1]([O:6][C@H:7]([CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]([O:16][C:17](=[O:21])[CH2:18][CH2:19][CH3:20])[CH2:14][CH3:15])[CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4].C1O[C@@H]1C.BrCCCC=C>>[C:1]([O:6][CH:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([O:16][C:17](=[O:21])[CH2:18][CH2:19][CH3:20])[CH2:14][CH3:15])[CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O[C@@H](CC)CCCC[C@H](C)OC(=O)CCC
Agent: C=CCCCBr
Agent: C[C@@H]1CO1
Product: CCCC(=O)OC(C)CCCCC(CC)OC(=O)CCC

Procedure:
FIG. 5 illustrates the scheme for the synthesis of field-active (2S,7S)2,7-nonanediyl dibutyrate (14): S-propylene oxide (6) (Fluka Chemika-Biochemika, Buchs, Switzerland) was coupled at −20° C. with Grignard reagent 7 in the presence of 0.1 equivalents of a CuI catalyst. Resulting (2S)-8-octen-2-ol (8) was oxidized by m-chloroperoxybenzoic acid (Aldrich Chemical Co.) to the terminal epoxide 9. Hydrolytic kinetic resolution of 9 with Co(II) salen (Jacobsen's) catalyst (R,R)N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminoc (10) (Aldrich Chemical Co.) (24, 25) afforded 2(R),7(S)-1,2-epoxy-7-hydroxyoctane (11), which was separated from unwanted 1,2(S),7(S)-octanetriol (12) by silica flash chromatography [hexane: ether (1:1), then ether as eluents]. Ring opening of 11 with excess of methylmagnesium bromide (Aldrich Chemical Co.) and catalytic amounts of Cul yielded (2S,7S)-2,7-nonanediol (13) which was esterified to (2S,7S)-2,7-nonanediol dibutyrate [14; 77% enantiomeric excess (ee) as determined by chiral GC; 37% overall yield]. GC-MS and NMR data of 14 were consistent with those of 5 (FIG. 4). The remaining 3 stereoisomers of diester 5 were synthesized from (S)- or (R)-propylene oxide (Fluka Chemika-Biochemika) and 5-bromo-pentene (Aldrich Chemical Co.), again by hydrolytic kinetic resolution of terminal epoxide intermediates, with ee of end products ranging between 73-85%.
Reaction SMILES: [BH4-].[Li+].[CH3:3][C:4]1[C:8]([C:9]2[C:18]3[O:17][CH:16]([C:19](OCC)=[O:20])[CH:15]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[N:14]4[C:30](=[O:32])[NH:31][C:12]([C:13]=34)=[CH:11][CH:10]=2)=[C:7]([CH3:33])[O:6][N:5]=1>O1CCCC1>[CH3:3][C:4]1[C:8]([C:9]2[C:18]3[O:17][CH:16]([CH2:19][OH:20])[CH:15]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[N:14]4[C:30](=[O:32])[NH:31][C:12]([C:13]=34)=[CH:11][CH:10]=2)=[C:7]([CH3:33])[O:6][N:5]=1
Reactant: CCOC(=O)C1Oc2c(-c3c(C)noc3C)ccc3[nH]c(=O)n(c23)C1c1ccccn1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OC(CO)C3c1ccccn1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Lithium tetrahydroborate (1.6 mg, 0.071 mmol) was added to ethyl 7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-5-carboxylate (20 mg, 0.05 mmol), from Example 20, in tetrahydrofuran (3 mL). The reaction was stirred at 70° C. for 3 h, then partitioned between water and ethyl acetate. The organic layer was concentrated and the crude product was purified by FCC on silica gel eluting a hexane:ethyl acetate gradient to obtain the product as a mixture of diastereomers. The isomers were separated by prep chiral column chromatography using the following conditions: Column: phenomenex Lux Cellulose C-2 5 μm, 21, 2×250 mm, Mobile phase: 45% EtOH/Hexanes, Gradient condition: isocratic at 18 mL/min, Loading: 13.5 mg in 900 μL, run time: 18 min, peak time: 9.0, 12.1, 24.2 and 15.0 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH:6]=1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>CC(C)=O.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)COc1ccc2cc(C(=O)OC)ccc2c1
Yield: 84.6 %

Procedure:
To a stirred solution of 6-hydroxy-2-naphthoic acid methyl ester (0.500 g, 2.47 mmol) in acetone (25 mL) at rt was added Cs2CO3 (0.886 g, 2.72 mmol) followed by methyl bromoacetate (0.257 mL, 2.72 mmol) dropwise. After 18 h at this temperature, it was diluted with EtOAc (200 mL). This layer was washed with 1 N HCl (20 mL), sat. aq. NaHCO3 (20 mL), and brine (20 mL) and then dried (MgSO4). After concentration, the residue was recrystallized from MeOH:H2O to afford the product (0.573 g, 85%) as a solid; 1H NMR (DMSO-d6) δ3.71 (s, 3H), 3.87 (s, 3H), 4.95 (s, 2H), 7.30 (dd, J=2.6, 8.9 Hz, 1H), 7.38 (d, J=2.4 Hz, 1H), 7.87 (d, J=8.7 Hz, 1H), 7.92 (dd, J=1.6, 8.6 Hz, 1H), 8.06 (d, J=9.1 Hz, 1H), 8.55 (s, 1H); mass spectrum [(+) ESI], m/z 275 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][CH:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]3([CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:11]=2)[OH:9])[CH2:6]CCC[CH2:2]1.C(O)(=O)C([O-])=O>>[CH3:2][N:1]([CH3:6])[CH2:7][CH:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2([CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:11]=1)[OH:9]
Reactant: OC(CN1CCCCC1)C1=CC2(CCCC2)c2ccccc21
Agent: O=C([O-])C(=O)O
Product: CN(C)CC(O)C1=CC2(CCCC2)c2ccccc21

Procedure:
2-Piperidino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol, hydrogen oxalate, m.p. 179.5° C.