Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:14]4[CH2:20][CH2:19][CH:17]([CH:18]=3)[N:16](C3C=CC(OC)=CC=3)[CH2:15]4)=[CH:10][CH:11]=2)[N:6]([CH3:29])[C:5]1=[O:30].CC#N.OS(O)(=O)=O.I(O)(=O)(=O)=O>O>[CH:17]12[CH2:19][CH2:20][CH:14]([C:13]([C:9]3[N:8]=[C:7]4[N:6]([CH3:29])[C:5](=[O:30])[N:4]([CH2:3][C:2]([CH3:31])([CH3:32])[CH3:1])[C:12]4=[CH:11][CH:10]=3)=[CH:18]1)[CH2:15][NH:16]2
Reactant: COc1ccc(N2CC3CCC2C=C3c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)cc1
Agent: O=S(=O)(O)O
Agent: [O-][I+3]([O-])([O-])O
Solvent: CC#N
Solvent: O
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CCC3CN4)nc21
Temperature: 50 °C

Procedure:
1-(2,2-Dimethylpropyl)-5-[2-(4-methoxyphenyl)-2-azabicyclo[2.2.2]oct-5-en-5-yl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2-4, 339 mg, 0.78 mmol, 1.0 equiv) was added to CH3CN (7 mL) and water (7 mL) To this suspension was added aqueous H2SO4 (0.78 mL, 0.78 mmol, 1.0 equiv, 1.0 M) followed by periodic acid in one portion (179 mg, 0.78 mmol, 1.0 equiv). The reaction contents were heated to 50° C. for 18 h. Following this duration,
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:24])[C@H:9]([CH:21]([CH3:23])[CH3:22])[NH:10][C:11](OCC2C=CC=CC=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:25]1([C:31]2[CH:38]=[CH:37][CH:36]=[C:33](C=O)[C:32]=2[OH:39])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCCCCC.C(OCC)(=O)C>CO.[C].[Pd]>[CH:1]1([NH:7][C:8](=[O:24])[C@H:9]([CH:21]([CH3:22])[CH3:23])[N:10]=[CH:11][C:33]2[C:32](=[C:31]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:38]=[CH:37][CH:36]=2)[OH:39])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=Cc1cccc(-c2ccccc2)c1O
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC1CCCCC1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)[C@H](N=Cc1cccc(-c2ccccc2)c1O)C(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.6 %

Procedure:
The carbobenzoxy-(S)-valine cyclohexylamide (0.33 g, 1 mmol) was dissolved in methanol (30 ml) and the solution was stirred at room temperature for 3 hours in the presence of 5% palladium-carbon (30 mg) under a hydrogen gas atmosphere. After the reaction was over, the palladium-carbon catalyst was filtered off to obtain a colorless solution. To this solution was added 3-phenylsalicylaldehyde (0.22 g, 1.1 mmol). This solution was stirred at room temperature for 24 hours and concentrated under reduced pressure to obtain yellow solids. These solids were subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=5:1) to obtain 0.29 g (76%) of the desired N-(3-phenylsalicylidene)-(S)-valine cyclohexylamide which was further recrystallized from ether. m.p. 87.0°-89.5° C. [α]26D +158.3° (c 1.02, CHCl3)
Reaction SMILES: [C:1]([C:9]1([CH3:22])[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.CO>[OH:8][CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1([CH3:22])[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C)(C(=O)c2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(C)(C(O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
tert-Butyl 3-benzoyl-3-methylpiperidine-1-carboxylate (278 mg, 0.92 mmol) was dissolved in 1:1 THF/MeOH (8 mL) and NaBH4 (70 mg, 1.84 mmol, 2 equiv) was added. After stirring 30 min at rt, LC-MS showed the reaction was complete. After concentration, the residue was partitioned between ether and diluted (˜1%) aq HCl. The aqueous layer was separated and extracted twice with ether. The combined organic layers were washed with satd aq NaHCO3, brine, dried over Na2SO4 and evaporated to afford crude product which was purified by chromatography on a 12-g prepacked silica gel cartridge eluted with a 0-35% EtOAc in hexanes gradient to afford tert-butyl 3-(hydroxy(phenyl)methyl)-3-methylpiperidine-1-carboxylate (198 mg, 71%). LC-MS (3 min) tR=1.83 min, m/z 328 (M+Na).
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]([F:20])=[C:11]([CH:16]([OH:19])[CH2:17][CH3:18])[CH:12]=[C:13]([F:15])[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)Cl.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>CCOC(C)=O.CC1(C)N([O])C(C)(C)CCC1>[Si:1]([O:8][C:9]1[C:10]([F:20])=[C:11]([C:16](=[O:19])[CH2:17][CH3:18])[CH:12]=[C:13]([F:15])[CH:14]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(O)c1cc(F)cc(O[Si](C)(C)C(C)(C)C)c1F
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: Ic1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCC(=O)c1cc(F)cc(O[Si](C)(C)C(C)(C)C)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
A 200 mL round bottom flask was charged with 90.C (0.48 g, 1.6 mmol), DCM (15 mL), iodobenzene diacetate (0.56 g, 1.7 mmol), and TEMPO (0.012 g, 0.079 mmol). The mixture was stirred overnight at room temperature and diluted with EtOAc. The organics were washed with saturated aqueous sodium thiosulfate, saturated aqueous sodium bicarbonate, and brine, dried (MgSO4), and concentrated. The crude product was purified by silica gel flash chromatography (0-5% EtOAc/hexane) to afford 90.D (0.45 g, 94% yield) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[N:6][CH:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][C:19]=1[C:28]([F:31])([F:30])[F:29]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:16][C:4]2[C:5]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:25])=[O:26])=[CH:20][C:19]=1[C:28]([F:31])([F:29])[F:30]
Reactant: Nc1cc(Cl)cnc1Oc1ccccc1F
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)cnc1Oc1ccccc1F)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
A solution of 5-chloro-2-(2-fluoro-phenoxy)-pyridin-3-ylamine (75 mg, 0.31 mmol), 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (103 mg, 0.36 mmol), DMAP (20 mg, 0.16 mmol) in anhydrous pyridine (1 mL) was stirred at room temperature for 2 days. The reaction product was separated by preparative HPLC using acetonitrile-water solvent mixture and pure product fractions were lyophilized to provide pure product as a solid. 1H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.96 (s, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.79 (s, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.15-7.13 (m, 3H), 7.00-6.96 (m, 1H). MS m/z: 481.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5](O)=[O:6].B.C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[C:9]([CH3:11])[N:10]=1
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Agent: B
Solvent: C1CCOC1
Product: Cc1cc(CO)cc(Cl)n1
Temperature: 0 °C

Procedure:
2-Chloro-6-methyl-isonicotinic acid (13-1, 2.00 g, 11.7 mmol) was dissolved in 10 mL of anhydrous THF under N2. The solution was cooled to 0° C., and borane-THF (1 M solution in THF, 14.0 mL, 14.0 mmol) was added slowly. The reaction was heated to reflux. After 3 hours the reaction was cooled to room temperature and quenched slowly with 1M HCl (aq) until cessation of bubbling. The pH of the solution was adjusted to 7 with saturated NaHCO3 (aq). The mixture was extracted 3× with EtOAc and the extracts dried over Na2SO4, filtered and concentrated to afford (2-chloro-6-methyl-pyridin-4-yl)-methanol. 1H NMR (CDCl3) δ 7.16 (s, 1H), 7.06 (s, 1H), 4.70 (d, 2H, J=5.8 Hz), 2.53 (s, 3H), 1.95 (t, 1H, J=5.8 hz).
Reaction SMILES: [OH:1][CH:2]1[C:6]([CH3:8])([CH3:7])[CH2:5][O:4][C:3]1=O.[C:10]1([CH2:16][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C>[CH2:16]([N:17]1[CH2:5][C:6]([CH3:8])([CH3:7])[CH:2]([OH:1])[C:3]1=[O:4])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC1(C)COC(=O)C1O
Reactant: NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: CC1(C)CN(Cc2ccccc2)C(=O)C1O
Temperature: 210 °C
Yield: 44.8 %

Procedure:
A mixture of 3-hydroxy-4,4-dimethyldihydrofuran-2(3H)-one (4.5 g, 34.6 mmol), phenylmethanamine (5.66 mL, 51.9 mmol) and p-toluenesulfonic acid (0.595 g, 3.46 mmol) was sealed in a reaction vial and heated in microwave at 210° C. for 3 h. The mixture was diluted with ethyl acetate (300 mL). The organic layer was washed with 1N HCl (30 mL) three times, brine (20 mL), dried and concentrated. The residue was purified via silica gel chromatography, eluting with 20-50% ethyl acetate in hexanes, to give the title compound as a yellow oil (3.4 g, 45% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.37-7.29 (m, 3H), 7.26-7.22 (m, 2H), 4.55-4.36 (m, 2H), 4.02 (s, 1H), 3.37 (br. s., 1H), 3.00-2.83 (m, 2H), 1.18 (s, 3H), 0.96 (s, 3H); MS (ES+) m/z: 219.1, 220.1 (M+H); LC retention time: 2.83 min (analytical HPLC Method I).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([N:10]([CH3:12])[CH3:11])[CH2:7][N:6]1C(OCC1C=CC=CC=1)=O)=[O:4]>[Pd].CO>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([N:10]([CH3:11])[CH3:12])[CH2:7][NH:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](N(C)C)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](N(C)C)CN1
Reaction time: 16 h

Procedure:
A mixture of (2S,4R)-4-dimethylamino-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (420 mg), 10% palladium on carbon (80 mg) and methanol (10 ml) is stirred for 16 hours under an atmosphere of hydrogen. Filtration and evaporation gives the title compound which is used without purification in the following steps.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=1)(=O)=O.[CH3:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[C:25]([CH3:38])[C:24]=1[OH:39].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.ClCCl>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[OH:39][C:24]1[C:25]([CH3:38])=[CH:26][C:27]([C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=2)=[CH:28][C:23]=1[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc(C)c1O
Yield: 82.1 %

Procedure:
Nitrogen was bubbled through a mixture of tert-butyl 4-[(trifluoromethyl)sulfonyl]oxy-3,6-dihydropyridine-1(2H)-carboxylate (5.80 g, 0.0175 mol), 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (4.82 g, 0.0194 mol) and potassium carbonate (7.26 g, 0.0525 mol) in N,N-dimethylformamide (50.0 mL, 0.646 mol) for 10 min. To the reaction mixture was then added [1,1′-Bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (1:1) (0.8 g, 0.001 mol). The resultant mixture was heated at 80 Celsius overnight. After quenched with water, the mixture was neutralized with 1N HCl, extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried and evaporated to dry. The residue was applied on column, eluting with 0 to 50% EtOAc in hexane, to yield the desired product (4.36 g, 82.09%). MS (ESI): (M-Boc+2) 204.0.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[N:13]=[C:14]([N:21]4[CH2:31][CH2:30][C@H:24]5[CH2:25][NH:26]C(=O)[O:28][C@@H:23]5[CH2:22]4)[C:15]4[O:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:8][CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.NC[C@@H]1CCN(CC2C=CC=CC=2)C[C@H]1O.ClC1N=C(Cl)C2OC=CC=2N=1.[OH-].[Na+]>CO>[NH2:26][CH2:25][C@@H:24]1[CH2:30][CH2:31][N:21]([C:14]2[C:15]3[O:20][CH:19]=[CH:18][C:16]=3[N:17]=[C:12]([NH:11][C:7]3[CH:6]=[C:5]4[C:10]([C:2]([CH3:1])=[N:3][NH:4]4)=[CH:9][CH:8]=3)[N:13]=2)[CH2:22][C@H:23]1[OH:28]
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2cc(Nc3nc(N4CC[C@H]5CNC(=O)O[C@@H]5C4)c4occc4n3)ccc12
Agent: Clc1nc(Cl)c2occc2n1
Agent: NC[C@@H]1CCN(Cc2ccccc2)C[C@H]1O
Agent: [Na+]
Solvent: CO
Product: Cc1n[nH]c2cc(Nc3nc(N4CC[C@@H](CN)[C@H](O)C4)c4occc4n3)ccc12
Temperature: 80 °C
Yield: 50 %

Procedure:
To a vial was added tert-butyl 3-methyl-6-(4-((4aS,8aS)-2-oxotetrahydro-2H-pyrido[4,3-e][1,3]oxazin-7(3H,8H,8aH)-yl)furo[3,2-d]pyrimidin-2-ylamino)-1H-indazole-1-carboxylate (0.367 g, 0.706 mmol, prepared using AL from (3S,4S)-4-(aminomethyl)-1-benzylpiperidin-3-ol [Sunshine Labs], G, A with 2,4-dichlorofuro[3,2-d]pyrimidine [ArkPharm] and B with Example#3, Step B) in MeOH (5 mL). An aqueous solution of NaOH (5 M, 2.83 mL, 14.1 mmol) was added. The mixture was heated at about 80° C. for about 3 h. The resulting suspension was filtered. The precipitate obtained was discarded. Precipitation was observed in the filtrate, the precipitate was collected by filtration and dried to give (3S,4S)-4-(aminomethyl)-1-(2-(3-methyl-1H-indazol-6-ylamino)furo[3,2-d]pyrimidin-4-yl)piperidin-3-ol (0.14 g, 50%): LC/MS (Table 2, Method n) Rt=1.16 min.; MS m/z: 394 (M+H)+. Syk IC50=A
Reaction SMILES: O[C@@H:2]1[C:11]2[C:6](=[C:7]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.P([N:46]=[N+:47]=[N-:48])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:46]([C@H:2]1[C:11]2[C:6](=[C:7]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1)=[N+:47]=[N-:48]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC[C@@H]2O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](Oc1cccc2c1CCC[C@H]2N=[N+]=[N-])(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of (1S)-1-hydroxy-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.0 g) and diphenyl phosphorazidate (0.65 ml) was dissolved in toluene (10 ml). The mixture was cooled to 0° C. under N2, and neat 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) (0.45 ml) was added. The reaction mixture was stirred for 2 hours at 0° C. then at 20° C. for 16 hours. The resulting mixture was washed with water and 1N-HCl. The organic layer was concentrated in vacuo and purified by silica gel chromatography to give (1R)-1-azido-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (950 mg).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][O:12][CH2:13][C@@H:14]1[O:18][C:17]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[O:16][C@H:15]1[CH2:24][OH:25].C(N(CC)CC)C>C(Cl)Cl.O>[CH3:11][O:12][CH2:13][C@@H:14]1[O:18][C:17]2([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[O:16][C@H:15]1[CH:24]=[O:25]
Reactant: COC[C@@H]1OC2(CCCCC2)O[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC[C@@H]1OC2(CCCCC2)O[C@H]1C=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 110.4 %

Procedure:
A solution of methylsulfinylmethane (20.6 ml, 289 mmol) in CH2Cl2 (260 mL) at −60° C., was added dropwise to a 2M solution of oxalyl dichloride (15.2 ml, 174 mmol) in CH2Cl2 (80 mL). The mixture was stirred for 20 minutes and then a solution of ((2S,3S)-3-(methoxymethyl)-1,4-dioxaspiro[4.5]decan-2-yl)methanol (31.3 g, 145 mmol) in CH2Cl2 (80 mL) was added dropwise. The mixture was stirred for 10 minutes and then triethylamine (101 ml, 724 mmol) was slowly added. The reaction mixture was warmed to ambient temperature and water was added. When the mixture became clear, it was extracted with CH2Cl2, dried over sodium sulfate, filtered and concentrated to afford crude (2R,3S)-3-(methoxymethyl)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde (34.3 g, 96.2% yield, 87% pure) which was taken on to next reaction without further purification.
Reaction SMILES: [S:1]1[CH:9]2[C:4]([CH2:5][NH:6][CH2:7][CH2:8]2)=[CH:3][C:2]1=[O:10].[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:16][CH:17]=1.[CH:22]([Si:25]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])Cl)([CH3:24])[CH3:23].C(N(CC)CC)C>C(Cl)Cl>[CH:22]([Si:25]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[O:10][C:2]1[S:1][C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=1)([CH3:24])[CH3:23].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: O=C1C=C2CNCCC2S1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[Si](Oc1cc2c(s1)CCNC2)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2.00 g of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one-p-toluenesulfonate, 1.29 g of triisopropylchlorosilane, 0.66 g of triethylamine and 7 ml of methylene chloride was stirred at room temperature for 3 hours. The produced 2-triisopropylsilyloxy-4,5,6,7-tetrahydrothieno-[3,2-c]pyridine-p-toluenesulfonate was not isolated, 0.96 g of 2-chlorobenzyl chloride and 1.21 g of triethylamine were added thereto, and the mixture was allowed to react under further stirring at 40° C. for 10 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[O:12]1[CH2:17][CH2:16][N:15]([S:18]([C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=2)[C:24]([NH:26][NH2:27])=[O:25])(=[O:20])=[O:19])[CH2:14][CH2:13]1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](/[C:8](=[N:27]/[NH:26][C:24](=[O:25])[C:23]2[CH:28]=[CH:29][CH:30]=[C:21]([S:18]([N:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)(=[O:19])=[O:20])[CH:22]=2)/[CH3:9])[CH:7]=1
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 31.2 %

Procedure:
1-(5-Chloro-2-hydroxyphenyl)ethanone (20 mg, 0.117 mmol) and 3-(morpholinosulfonyl)benzohydrazide (33.5 mg, 0.117 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound (16 mg) as a solid. 1H NMR (400 MHz, CD3OD): δ 8.26 (m, 1H), 8.17 (d, 1H, J=8.0 Hz), 7.92 (d, 1H, J=8.0 Hz), 7.72 (t, 1H, J=8.0 Hz), 7.48 (d, 1H, J=2.0 Hz), 7.22 (m, 1H), 6.91 (d, 1H, J=8.8 Hz), 3.72 (m, 4H), 3.01 (m, 4H), 2.43 (s, 3H). ESI-MS: 438.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[NH2:21][CH2:22][C:23]1[NH:28][C:27](=[O:29])[C:26]([CH3:30])=[C:25]([CH3:31])[N:24]=1>>[CH3:31][C:25]1[N:24]=[C:23]([CH2:22][NH:21][C:16](=[O:18])[CH2:15][N:12]2[CH2:11][CH2:10][CH:9]([C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[NH:28][C:27](=[O:29])[C:26]=1[CH3:30]
Reactant: Cc1nc(CN)[nH]c(=O)c1C
Reactant: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Product: COc1ccc(C(=O)C2CCN(CC(=O)NCc3nc(C)c(C)c(=O)[nH]3)CC2)cc1
Yield: 49.3 %

Procedure:
The title compound (183 mg) was prepared following the general procedure of Example 1 from 2-(4-(4-methoxybenzoyl)piperidin-1-yl)acetic acid (357 mg, 0.90 mmol, 70% purity) and 2-(aminomethyl)-5,6-dimethylpyrimidin-4(3H)-one (138 mg, 0.90 mmol). 1H NMR (400 MHz, DMSO-d6) δ 12.21 (br. s., 1H), 8.20 (s, 1H), 7.96 (d, J=9.1 Hz, 2H), 7.02-7.06 (m, 2H), 4.14 (d, J=5.6 Hz, 2H), 3.84 (s, 3H), 2.86-3.08 (m, 4H), 2.25-2.39 (m, 2H), 2.22 (s, 1H), 2.16 (s, 3H), 1.88 (s, 3H), 1.63-1.82 (m, 4H). HRMS calculated for C22H28N4O4 413.2189. found (ESI, [M+H]+), 413.2195. Retention time=4.44 min.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([C:12]([OH:14])=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:15]([N:17]1[CH:21]=[C:20]([CH2:22][NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[CH:19]=[N:18]1)[CH3:16]>>[CH2:15]([N:17]1[CH:21]=[C:20]([CH2:22][N:23]([C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:29]=2)[C:12]([CH:11]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:6]=3[CH2:7][CH2:8][CH2:9][CH2:10]2)=[O:14])[CH:19]=[N:18]1)[CH3:16]
Reactant: O=C(O)C1CCCCc2ccccc21
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Product: CCn1cc(CN(C(=O)C2CCCCc3ccccc32)c2ccc(C(C)C)cc2)cn1
Yield: 57 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 6,7,8,9-tetrahydro-5H-benzocycloheptene-5-carboxylic acid (0.29 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-5-carboxamide (0.36 g) was obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:5][CH:4]([CH2:6][CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.C([O:23]O)(C)(C)C>C(O)(=O)C.[Na+].[Na+].Cl[Pd+2](Cl)(Cl)Cl>[O:23]=[C:7]([CH2:6][CH:4]1[CH2:3][C:2](=[O:1])[NH:5]1)[CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10]
Reactant: O=C1CC(CC=CC(=O)OCc2ccccc2)N1
Reactant: CC(C)(C)OO
Agent: Cl[Pd]Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(CC(=O)OCc1ccccc1)CC1CC(=O)N1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
A mixture of benzyl 4-[(2RS)-4-oxoazetidin-2-yl]but-2-enoate (167 mg), tert-butylhydroperoxide (0.3 ml), and sodium tetrachloropalladate (80 mg) in 67% aqueous acetic acid (2.7 ml) was heated at 50° C. for 8.5 hours. Additional tert-butylhydroperoxide (0.5 ml) and sodium tetrachloropalladate (40 mg) were added. The reaction mixture was stirred at room temperature for three days and heated at 50° C. for 14 hours. After evaporation of the solvent in vacuo, the residue was taken up into ethyl acetate (20 ml) and washed with dilute aqueous sodium chloride. Drying over magnesium sulfate and evaporation left an oil (200 mg), which was chromatographed on silica gel plate (developing solvent: 20% acetone in dichloromethane) afforded benzyl 3-oxo-4-[(2RS)-4-oxoazetidin-2-yl]butanoate (66 mg).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:19]=[C:18]([O:20]CC2C=CC=CC=2)[C:11]2[CH2:12][CH:13]([CH2:15][O:16][CH3:17])[O:14][C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(C1C=C(O[C:47]2[CH:52]=[CH:51][C:50]([C:53](=[O:57])[N:54]([CH3:56])[CH3:55])=[CH:49][CH:48]=2)C2CC(CO)OC=2C=1)=O)(C)(C)C.CI>>[C:1]([O:5][C:6]([C:8]1[CH:19]=[C:18]([O:20][C:47]2[CH:52]=[CH:51][C:50]([C:53](=[O:57])[N:54]([CH3:55])[CH3:56])=[CH:49][CH:48]=2)[C:11]2[CH2:12][CH:13]([CH2:15][O:16][CH3:17])[O:14][C:10]=2[CH:9]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C)C(=O)c1ccc(Oc2cc(C(=O)OC(C)(C)C)cc3c2CC(CO)O3)cc1
Reactant: COCC1Cc2c(OCc3ccccc3)cc(C(=O)OC(C)(C)C)cc2O1
Solvent: CI
Product: COCC1Cc2c(Oc3ccc(C(=O)N(C)C)cc3)cc(C(=O)OC(C)(C)C)cc2O1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 204b, from 4-(4-dimethylcarbamoyl-phenoxy)-2-hydroxymethyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (211a) and methyl iodide. 1H NMR (400 MHz, CDCl3) δ 7.40-7.43 (m, 2 H) 7.24 (d, J=1.26 Hz, 1 H) 7.17 (d, J=1.26 Hz, 1 H) 6.92-7.01 (m, 2 H) 4.92-5.05 (m, 1 H) 3.51-3.59 (m, 2 H) 3.41 (s, 3 H) 2.99-3.15 (m, 7 H) 2.81-2.90 (m, 1 H) 1.54 (s, 9 H); LCMS for C24H29NO6 m/z 428.20 (M+H+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@@H:5]([CH3:7])[NH2:6].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([BH3-])#N.[Na+]>CO>[CH3:2][O:3][C:4](=[O:8])[C@@H:5]([CH3:7])[NH:6][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)[C@@H](C)N
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](C)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of D-alanine methyl ester hydrochloride (3.0 g, 21.5 mmol) in methanol (10 mL) is added benzaldehyde (2.3 mL, 22.6 mmol). The reaction mixture is stirred at room temperature for 3 hours. The solvent is then evaporated. To the resultant residue is added acetic acid (15 mL) and methanol (1 mL) followed by portionwise addition of sodium cyanoborohydride (1.35 g, 21.5 mmol) at room temperature. The mixture is stirred overnight, and then the solvent is evaporated. The remaining residue is diluted with water (75 mL) and basified with Na2CO3. The mixture is extracted with ethyl acetate (3x75 mL). The combined organic extracts are washed with brine (50 mL), dried (Na2SO4), and the solvent is evaporated to give N-benzyl-D-alanine methyl ester.