Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:3]([NH:5][C@H:6]([B:12]1[O:16][C@@H:15]2[CH2:17][C@@H:18]3[CH2:21][C@H:20]([C@:14]2([CH3:24])[O:13]1)[C:19]3([CH3:23])[CH3:22])[CH2:7][CH:8]1[CH2:11][CH2:10][CH2:9]1)=[O:4].Cl.C(N(CC)C(C)C)(C)C.[O:42]([C:49]1[N:54]=[CH:53][C:52]([S:55](Cl)(=[O:57])=[O:56])=[CH:51][CH:50]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C1COCC1>[CH:8]1([CH2:7][C@H:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][S:55]([C:52]2[CH:53]=[N:54][C:49]([O:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:50][CH:51]=2)(=[O:56])=[O:57])[CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[B:12]2[O:16][C@@H:15]3[CH2:17][C@@H:18]4[CH2:21][C@H:20]([C@:14]3([CH3:24])[O:13]2)[C:19]4([CH3:23])[CH3:22])[CH2:11][CH2:10][CH2:9]1
Reactant: CC1(C)[C@@H]2C[C@H]3OB([C@H](CC4CCC4)NC(=O)[C@@H](N)Cc4ccccc4)O[C@@]3(C)[C@H]1C2
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)nc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)[C@@H]2C[C@H]3OB([C@H](CC4CCC4)NC(=O)[C@H](Cc4ccccc4)NS(=O)(=O)c4ccc(Oc5ccccc5)nc4)O[C@@]3(C)[C@H]1C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 20 mL vial was added (2S)-2-amino-N-{(1R)-2-cyclobutyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}-3-phenylpropanamide.HCl (46.3 mg, 0.109 mmol) (prepared as described in Example, THF (1.47 mL), N,N diisopropylethylamine (47.5 μL), and 6-phenoxy-3-pyridine sulfonyl chloride (32.4 mg.) The mixture was stirred at room temperature overnight. The product was purified by preparative TLC on silica plates using 50% ethyl acetate in hexanes to give 35 mg desired product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][CH2:9][CH:10](O)[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)=[CH:5][CH:4]=1.S(=O)(=O)(O)O>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:23]=[C:22]2[C:6](=[CH:5][CH:4]=1)[CH2:7][NH:8][CH2:9][CH:10]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1
Reactant: COc1ccc(CNCC(O)c2ccc(OC)c(OC)c2)cc1
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)C(c1ccc(OC)c(OC)c1)CNC2
Yield: 88.2 %

Procedure:
α-[[(4-methoxybenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol (950 mg) was dissolved in 7.2 ml of trifluoroacetic acid, and after adding thereto 0.22 ml of conc. sulfuric acid under cie dooling, the reaction was allowed to react for 45 minutes. The reaction solution was concentrated, and subjected to azeotropic distillation with toluene 2 times. After adding chloroform, the mixture was basified by addition of 28% aqueous ammonia under ice cooling. By a separating procedure, the chloroform layer was collected, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue obtained was subjected to silica gel column chromatography (chlroform-methanol-28% aqueous ammonia=15:1:0.1), giving 790 mg of 6-methoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline as oily matter.
Reaction SMILES: [F:1][C:2]([F:24])([CH3:23])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[C:12]2=[O:22])=[CH:7][CH:6]=1)[OH:4].[C:25]([Mg]Br)([CH3:27])=[CH2:26]>>[F:24][C:2]([F:1])([CH3:23])[CH:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:20][CH2:19][C:18]([OH:21])([C:25]([CH3:27])=[CH2:26])[CH2:17][CH2:16]3)[C:12]2=[O:22])=[CH:9][CH:10]=1)[OH:4]
Reactant: CC(F)(F)C(O)c1ccc(N2CCC3(CCC(=O)CC3)C2=O)cc1
Reactant: C=C(C)[Mg]Br
Product: C=C(C)C1(O)CCC2(CCN(c3ccc(C(O)C(C)(F)F)cc3)C2=O)CC1

Procedure:
The title compound was prepared in analogy to example 55 from (2-(4-(2,2-difluoro-1-hydroxypropyl)phenyl)-2-aza-spiro[4.5]decane-1,8-dione by reaction with isopropenylmagnesium bromide (0.5 M in THF) as a white solid. MS (m/e): 379[M+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[CH2:14][CH2:13][S:12][CH2:11][CH:10]=2)=[C:4]([F:15])[CH:3]=1.N1C=CC=CC=1.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>ClCCl>[CH2:26]([O:25][C:23]([NH:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[CH2:14][CH2:13][S:12][CH2:11][CH:10]=2)=[C:4]([F:15])[CH:3]=1)=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1cc(F)c(C2=CCSCC2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cc(F)c(C2=CCSCC2)c(F)c1)OCc1ccccc1
Reaction time: 18 h
Yield: 94.3 %

Procedure:
4-(4-Amino-2,6-difluorophenyl)-5,6-dihydro-2H-thiopyran (15.0 g, 66 mM) was dissolved in dry dichloromethane (250 ml), pyridine (9.45 g, 113 mM) added, and the whole stirred under nitrogen at −20°. Benzyl chloroformate (17.1 g, 100 mM) in dry dichloromethane (25 ml) was added dropwise, and the mixture allowed to warm to ambient over 18 hours. The mixture was washed with hydrochloric acid (1M, 2×200 ml), then brine (200 ml) and dried (magnesium sulfate). Evaporation to a small volume and dilution with isohexane gave the desired product as a white solid (22.5 g).
Reaction SMILES: [C:1]([N:5]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:7]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:22][CH2:23][C:24]([CH3:27])([CH3:26])[N:25]=3)=[CH:17][CH:16]=2)=C)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.ClCCl.C(OCC)(=[O:36])C>C(O)C>[C:1]([N:5]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:7]([CH:13]([OH:36])[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:22][CH2:23][C:24]([CH3:27])([CH3:26])[N:25]=3)=[CH:17][CH:16]=2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(c1ccc(C2=NC(C)(C)CO2)cc1)c1cc(C(C)C)n(C(C)(C)C)n1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CC(C)c1cc(C(O)c2ccc(C3=NC(C)(C)CO3)cc2)nn1C(C)(C)C
Temperature: 100 °C

Procedure:
To 5 ml of 130 mg of α-(1-tert-butyl-5-isopropylpyrazol-3-yl)-4-(4,4-dimethyl-1,3-oxazolin-2-yl)styrene in ethanol was added 0.4 ml of a 3N aqueous solution of an acid at room temperature. The resulting mixture was heated under reflux for 30 minutes. To the reaction mixture was added a 5N aqueous solution of sodium hydroxide to adjust its pH to 11, followed by extraction with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a solution of the residue in 3 ml of 1,4-dioxane were added 100 mg of lithium hydroxide and the resulting mixture was heated at 100° C. for 2 hours. After the completion of the reaction, a 3N aqueous solution of hydrochloric acid was added to adjust the pH to 5, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue so obtained was subjected to chromatography on a silica gel column (developing solvent: 50% dichloromethane/ethyl acetate), whereby 4 mg of the title compound were obtained as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2.[CH:23]([N:26]=[C:27]=[O:28])([CH3:25])[CH3:24]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:27]([NH:26][CH:23]([CH3:25])[CH3:24])=[O:28])[CH:18]=3)[N:13]=1)[CH2:6][CH2:5]2
Reactant: CC(C)N=C=O
Reactant: Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1
Product: CC(C)NC(=O)Nc1ccc2nc(NC3CCc4cc(F)ccc43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method described in example 3 from rac-N2-(5-fluoro-indan-1-yl)-quinoline-2,6-diamine and isopropyl isocyanate; MS: m/e=379.4 (M+H+).
Reaction SMILES: [CH2:1]([C@H:3]1[C@H:6]([CH2:7][C@H:8]([OH:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[O:5][C:4]1=[O:21])[CH3:2].[CH:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C(C)=CC=CC=1>[CH:22]([NH:24][CH2:25][C:26]([O:20][C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:7][C@H:6]1[C@H:3]([CH2:1][CH3:2])[C:4](=[O:21])[O:5]1)=[O:27])=[O:23]
Reactant: CCCCCCCCCCC[C@@H](O)C[C@@H]1OC(=O)[C@H]1CC
Reactant: O=CNCC(=O)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCC[C@H](C[C@@H]1OC(=O)[C@H]1CC)OC(=O)CNC=O
Yield: 43.5 %

Procedure:
Prepared according to the procedure described in Example 36, above. Hydroxy β-lactone 13f (10 mg, 0.033 mmol), N-formylglycine (12.0 mg, 0.120 mmol), triphenylphosphine (26.6 mg, 0.099 mmol), and 0.5 mL of xylene were combined and the mixture was azeotroped in vacuo for 1.0 h. THF (1.4 mL) was then added followed by DIAD (21.0 μL, 0.108 mmol). After 12 hours the mixture was concentrated in vacuo, and purified by chromatography (SiO2, 10 to 30% EtOAc:hexanes) to afford β-lactone 15i (5.5 mg, 43%).
Reaction SMILES: C(C1C=C[C:8]([C:11]([CH3:40])([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:39])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:29]2C=CC(CC(C)C)=CC=2)([CH3:28])[C:25]([OH:27])=[O:26])[C:12]([OH:14])=[O:13])=CC=1)C(C)C.[OH-].[K+]>C(O)C.O>[O:39]=[C:19]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])[CH2:18][CH2:17][CH2:16][CH2:15][C:11]([CH3:8])([CH3:40])[C:12]([OH:14])=[O:13]
Reactant: CC(C)Cc1ccc(C(C)(CCCCC(=O)CCCCC(C)(C(=O)O)c2ccc(CC(C)C)cc2)C(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CCCCC(=O)CCCCC(C)(C)C(=O)O)C(=O)O
Yield: 86 %

Procedure:
According to the procedure given for 210f, 209c (30.0 g, 81.0 mmol) was saponified with KOH (85%, 18.9 g, 286 mmol) in ethanol (143 mL) and water (48 mL) at reflux for 5 h. The solid product obtained after extraction and drying was purified by flash chromatography (silica; hexanes/ethyl acetate=90/10) to afford 210c (22.0 g, 86%) as a white solid. Mp 60-61.5° C. 1H NMR (CDCl3): δ 11.40 (br., 2 H), 2.41 (t, 4H, J=7.3), 1.62-1.48 (m, 8 μl), 1.32-1.18 (m, 4 H), 1.18 (s, 12 H). 13C NMR (CDCl3=77.0 ppm): δ 211.11, 184.74, 42.49, 42.14, 40.42, 24.92, 24.62, 23.99. HRMS (LSIMS, gly): Calcd for C17H31O5 (MH+): 315.2171, found: 315.2183. HPLC: 94.5% pure. Anal. (C17H30O5) C, H.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[S:10][C:11]=2[CH:12]=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][Mg]Br>C1COCC1.C(OCC)C>[C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[S:10][C:11]=2[CH:12]([OH:13])[CH3:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1sc2ccccc2c1-c1ccccc1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1sc2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-phenylbenzo[b]thiophene-2-carbaldehyde (430 mg, 1.87 mmol) in THF (10 mL) at −78° C. and under a nitrogen atmosphere was added 3.0M methylmagnesium bromide in diethyl ether (1.24 mL) and stirring continued for 30 min. The reaction mixture was quenched with a saturated solution of NH4Cl (20 mL) and slowly warmed to RT. The mixture was extracted with EtOAc (×2) and the combined organic fractions washed with water, dried (Na2SO4) and concentrated in vacuo affording the title compound as a white solid (472 mg, quantitative). 1H NMR (CDCl3, 400 MHz): δ 7.88-7.84 (1H, m), 7.52-7.28 (8H, m), 5.21 (1H, q, J=6.35 Hz), 2.03 (1H, s), 1.59 (3H, d, J=6.63 Hz)
Reaction SMILES: [CH3:1][CH:2]([C:4](=[CH:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[C:5](OCC)=[O:6])[CH3:3].[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.O>C1(C)C=CC=CC=1>[CH3:3][CH:2]([C:4](=[CH:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:17])[CH3:18])[CH2:5][OH:6])[CH3:1]
Reactant: CCOC(=O)C(=CC=C(C)CCC=C(C)C)C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: O
Product: CC(C)=CCCC(C)=CC=C(CO)C(C)C
Temperature: -72 °C
Reaction time: 0.17 h
Yield: 84.4 %

Procedure:
To a solution of ethyl 2-(1-methylethyl)-5,9-dimethyl-2,4,8-decatrienate (280 mg, 1.14 mmol) in toluene (5 ml) chilled at -72° C. under argon atmosphere was dropwise added 0.92M solution of diisobutylaluminum hydride in hexane (3.72 ml, 3.42 mmol). After stirring at -72° C. for 10 minutes, the reaction mixture was mixed with water (1.5 ml) for stopping the reaction. The reaction mixture was vigorously stirred at room temperature for 1 hour, and precipitates were filtered off. The filtrate was concentrated and the residue was chromatographed on a silica gel column to give 2-(1-methylethyl)-5,9-dimethyl-2,4,8-decatrien-1-ol (214 mg, 84%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:9][N:8]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>CN(C=O)C.C(Cl)Cl>[NH2:1][C:2]1[C:3]2[C:10]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:9][N:8]([CH:31]3[CH2:32][CH2:33][N:34]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:35][CH2:36]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncnc2c1c(C(=O)c1cccc(NC(=O)Nc3cc(Cl)cc(Cl)c3)c1)cn2C1CCNCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCC(n2cc(C(=O)c3cccc(NC(=O)Nc4cc(Cl)cc(Cl)c4)c3)c3c(N)ncnc32)CC1
Yield: 19 %

Procedure:
A solution of 1-[3-(4-Amino-7-piperidin-4-yl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-3-(3,5-dichloro-phenyl)-urea (100 mg, 0.19 mmol) and methanesulfonylchloride (22 mg, 0.19 mmol) in DMF/CH2Cl2 (2/3, 5 mL) was stirred in a sealed tube for 1.5 hours at room temperature. The reaction mixture concentrated in vacuo. Purification by reverse phase preparative HPLC (HPLC method 2) provided the title compound as a white solid (21.8 mg, 19%). MS: 603.5 (MH+); HPLC Rf: 2.3 min. (HPLC method 2); HPLC purity: 100%.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11]C=[C:13](C(O)=O)[CH:14]=2)[C:9]1=[O:21].CN(C)C=O>O1CCCC1>[CH3:7][N:8]1[C:9](=[O:21])[C:10]2[C:15](=[CH:14][CH:13]=[C:1]([C:2]([Cl:4])=[O:3])[CH:11]=2)[C:16]1=[O:17]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN1C(=O)c2ccc(C(=O)O)cc2C1=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN1C(=O)c2ccc(C(=O)Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (5.86 ml) was added by portions to a solution of 2-methyl-1,3-dioxo-5-isoindolinecarboxylic acid (9.2 g) obtained in Reference Example 229 and dimethylformamide (catalytic amount) in tetrahydrofuran (100 ml) at room temperature. After stirred at room temperature for 1 hour, the solvent was evaporated under reduced pressure. The resulting residue was filtered, washed with diethyl ether and dried under reduced pressure to give the title compound as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C:12]([O:15][C:16]([NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:17])([CH3:14])[CH3:13]>CCO>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:22]1[CH2:21][CH2:20][CH:19]([NH:18][C:16](=[O:17])[O:15][C:12]([CH3:13])([CH3:11])[CH3:14])[CH2:24][CH2:23]1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(c2ccccc2[N+](=O)[O-])CC1
Yield: 100 %

Procedure:
The method of Example 1 was followed using 1-fluoro-2-nitrobenzene (1.0 eq), 4-N-Boc-aminopiperidine (1.2 eq), and TEA (2.0 eq) in EtOH at 55° C. for 48 hours yielding tert-butyl 1-(2-nitro phenyl)piperidin-4-ylcarbamate (100%). LCMS (m/z): 322.2 (MH+); LC Rt=3.15 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9]([N:16]1[CH2:21][CH2:20][CH2:19][CH:18](O)[CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOCC.O>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][CH2:19][CH:18]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[CH2:17]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Reactant: Oc1ccccc1Br
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC(Oc2ccccc2Br)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
Ortho-bromophenol (1.72 g, 9.92 mmol) and racemic Boc-3-hydroxypiperidine (2 g, 9.92 mmol) were placed in THF (60 mL) with triphenylphosphine (3.9 g, 14.9 mmol), and the mixture was cooled to 0° C. DIAD (2.94 mL, 14.9 mmol) was added portion wise over 30 minutes, and the mixture was warmed to r.t. and stirred for about 16 hours. The mixture was diluted with ether (200 mL) and water was added (100 mL). The mixture was washed with 5N NaOH (100 mL), extracted with ether and concentrated. Ethyl acetate/hexanes was added, and the triphenylphosphine oxide was crystallized and filtered away. The residue was chromatographed on silica gel (ethyl acetate/hexanes) to afford the product (1.2 g, 34%) as a clear oil. MS found: 256.0 (M-Boc)
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH3:18][NH:19][NH2:20]>CO>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:19]([CH3:18])[NH2:20])[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Reactant: CNN
Solvent: CO
Product: CCOC(=O)c1c(C)nc(N(C)N)c([N+](=O)[O-])c1Cl
Reaction time: 0.5 h

Procedure:
27.9 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester (0.1 Mol.) are dissolved in about 100 ml. of methanol. At 50°, 9.2 g. of methylhydrazine are dropped in and the mixture is stirred for 30 minutes. On cooling, 4-chloro-6-(1-methyl)hydrazino-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester precipitates, yield: 18 g. (62.2%), m.p. 159°-161° (methanol).
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][C:4]2([O:11][C:10]3[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:15][C:9]=3[N:8]3[CH:20]=[CH:21][CH:22]=[C:7]23)[CH2:3][CH2:2]1.[ClH:30]>>[ClH:30].[NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:15][C:9]=3[N:8]3[CH:20]=[CH:21][CH:22]=[C:7]23)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)OC1(CCN(C(=O)OC(C)(C)C)CC1)c1cccn1-2
Agent: Cl
Product: COC(=O)c1ccc2c(c1)OC1(CCNCC1)c1cccn1-2
Yield: 99.6 %

Procedure:
A solution of 1′-tert-butyl 7-methyl spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′,7-dicarboxylate (1.8 g, 4.5 mmol) in HCl (4.5 mL, 4.0M in dioxanes, 18 mmol) was stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness to give methyl spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-7-carboxylate hydrochloride (1.5 g, quant). ESI-MS m/z calc. 298.3. found 299.5 (M+1)+. Retention time: 1.06 minutes (3 min run).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26](O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:26]([O:11][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:18][CH:19]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-2-(t-Butoxycarbonylamino)-3-(biphenyl-4-yl)propionic acid (5 g, 14.6 mmol) is dissolved in methylene chloride (25 mL) under nitrogen and the solution is cooled to 0°. Benzyl alcohol (2 mL, 19 mmol) and 4-dimethylaminopyridine (0.1 g) are added, followed by a solution of dicyclohexylocarbodiimide (3.3 g, 16.1 mmol) in methylene chloride (15 mL). After stirring for 1 hour at 0° and 1 hour at room temperature, the reaction mixture is filtered and the filtrate concentrated in vacuo. The residue is redissolved in ether (100 mL), washed successively with water, 0.5M sodium dihydrogenophosphate, water, saturated sodium bicarbonate and water. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. (S)-2(-t-butoxycarbonylamino)-3-(biphenyl-4-yl)-propionic acid benzyl ester is obtained as a white solid, [α]D =-3.33 (c 0.91, CHCl3).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:20]=[CH:19][C:10]([CH2:11][CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:9][CH:8]=1)(OC)=O.[CH3:21][NH:22][C:23](=[O:31])[C:24]1[C:25](=[CH:27][CH:28]=[CH:29][CH:30]=1)[NH2:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:21][N:22]1[C:23](=[O:31])[C:24]2[C:25](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:26]=[C:1]1[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:19][CH:20]=1
Reactant: COC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CNC(=O)c1ccccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccccc2c1=O
Temperature: 175 °C

Procedure:
A suspension of 5-[4-[(carbomethoxy)methoxy]benzyl]thiazolidine-2,4-dione obtained by following a procedure described in Examples 23 or 24 (100 g, 0.34 M), N-methyl anthranilamide (58.7 g, 0.39 M) and p-toluenesulfonic acid (˜200 mg) was taken in a round bottom flask fitted with a mechanical stirrer, oil bath and Dean-Stark condenser. The reaction mixture was heated to reflux (Internal temperature 150-155° C. oil bath temperature 170-180° C.) for a period of 10-15 h while monitoring the reaction by TLC. After completion of the reaction, reaction mass was cooled to 80° C. and methanol (700 ml) was added slowly through a dropping funnel. The reaction mass was allowed to attain room temperature while stirring and the solid thus obtained was filtered and washed with methanol (150 ml) and dried at 100-120° C. for 1 h to afford 5-[4-[[-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione as a white solid (28 g, Y=23%, P=98%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14]CC=C)=[CH:9][C:10]=2[O:12][CH3:13])[O:5][C:4](=[O:18])[CH:3]=1.[CH3:19][CH2:20][CH2:21]CCC>CCN(C1C=CC=CC=1)CC>[CH3:1][C:2]1[C:11]2[C:6](=[C:7]([CH2:21][CH:20]=[CH2:19])[C:8]([OH:14])=[CH:9][C:10]=2[O:12][CH3:13])[O:5][C:4](=[O:18])[CH:3]=1
Reactant: C=CCOc1cc(OC)c2c(C)cc(=O)oc2c1
Reactant: CCCCCC
Solvent: CCN(CC)c1ccccc1
Product: C=CCc1c(O)cc(OC)c2c(C)cc(=O)oc12

Procedure:
A solution of 4-methyl-5-methoxy-7-allyloxycoumarin (XXXVI; 4.0 g) in diethylaniline (80 ml) was refluxed for 3 h. After cooling, n-hexane (400 ml) was added and the precipitate was collected, washed several times with n-hexane and crystallized twice from EtOAc to give 4-methyl-5-methoxy-7-hydroxy-8-allylcoumarin (XXXVII: 2.8 g; m.p. 198° C.) free from its isomer, the 4-methyl-5-methoxy-6-allyl-7-hydroxycoumarin (which during the successive steps can lead to the formation of a linear furocoumarin). ##STR40##