Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:37]=[CH:36][C:5]2[N:6]([C:9]3[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[C:11]([O:18][C@@H:19]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][Si](C(C)(C)C)(C)C)[C:22]=4[Cl:35])[CH3:20])[CH:10]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.O.[N:39]1[CH:44]=[C:43](B(O)O)[CH:42]=[CH:41][C:40]=1[CH3:48].C([O-])([O-])=O.[Na+].[Na+]>CC(N(C)C)=O>[Cl:35][C:22]1[C:23]([OH:27])=[CH:24][CH:25]=[CH:26][C:21]=1[C@H:19]([O:18][C:11]1[CH:10]=[C:9]([N:6]2[C:5]3[CH:36]=[CH:37][C:2]([C:43]4[CH:44]=[N:39][C:40]([CH3:48])=[CH:41][CH:42]=4)=[CH:3][C:4]=3[N:8]=[CH:7]2)[S:13][C:12]=1[C:14]([O:16][CH3:17])=[O:15])[CH3:20]
Reactant: COC(=O)c1sc(-n2cnc3cc(Br)ccc32)cc1O[C@H](C)c1cccc(O[Si](C)(C)C(C)(C)C)c1Cl
Reactant: Cc1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)c1sc(-n2cnc3cc(-c4ccc(C)nc4)ccc32)cc1O[C@H](C)c1cccc(O)c1Cl
Temperature: 80 °C

Procedure:
To a solution of methyl 5-(5-bromo-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}phenyl)ethyl]oxy}-2-thiophenecarboxylate (300 mg, 0.48 mmol) in 4.5 mL of DMA was added 2-picoline-5-boronic acid hydrate (79 mg, 0.58 mmol), 1M Na2CO3 (1.44 ml, 1.44 mmol) and Cl2Pd(dppf) (41 mg, 0.05 mmol), and the reaction was heated to 80° C. The dark reaction was concentrated onto silica gel and purified by flash column chromatography to give the title compound, which was triturated into ether (147 mg, 59%). 1H NMR (400 MHz, d6-DMSO) δ 10.26 (s, 1H), 8.80 (s, 1H), 8.70 (s, 1H), 8.08 (s, 1H), 8.01 (dd, J=8.0 and 2.4 Hz, 1H), 7.68 (m, 2H), 7.34-7.32 (m, 2H), 7.20-7.11 (m, 2H), 6.91 (d, J=8.0 Hz, 1H), 5.93 (m, 1H), 3.70 (s, 3H), 2.49 (s, 3H), 1.60 (d, J=6.0 Hz, 3H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[C:14](=[N:23]O)[CH:13]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:25]([N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH3:39])([CH3:38])[C:30]1=[CH2:40])[CH:26]([CH3:28])[CH3:27]>C(O)C>[CH2:25]([N:29]1[C:30]2([O:22][C:15]3[C:16]4[C:21]([C:12]([C:9]5[CH:10]=[CH:11][C:6]([N:1]6[CH2:5][CH2:4][CH2:3][CH2:2]6)=[CH:7][CH:8]=5)=[CH:13][C:14]=3[N:23]=[CH:40]2)=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:31]([CH3:39])([CH3:38])[C:32]2[C:37]1=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]([CH3:28])[CH3:27]
Reactant: O=C1C(=NO)C=C(c2ccc(N3CCCC3)cc2)c2ccccc21
Reactant: C=C1N(CC(C)C)c2ccccc2C1(C)C
Solvent: CCO
Product: CC(C)CN1c2ccccc2C(C)(C)C12C=Nc1cc(-c3ccc(N4CCCC4)cc3)c3ccccc3c1O2
Yield: 19 %

Procedure:
A solution of 4-(4-pyrrolidinophenyl)-1,2-naphthoquinone-2-oxime (0.005 mol) and 1-isobutyl-3,3-dimethyl-2-methyleneindoline (0.005 mol) in anhydrous ethanol (70 cm3) was refluxed until examination of the reaction mixture by thin layer chromatography indicated that none of the 4-(4-pyrrolidinophenyl)-1,2-naphthoquinone-2-oxime remained. The mixture was cooled, reduced in volume and the precipitated product collected by vacuum filtration washed with a little cold ethanol and dried. Yield=19%, m.p.=242-245° C., λmax=614 nm in PhMe upon irradiation.
Reaction SMILES: C(O[CH:4]1[NH:9][C:7](=[O:8])[CH2:6][CH2:5]1)C.S(=O)(=O)(O)O.[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)(=O)C>[OH:21][C:15]1[CH:20]=[CH:19][C:18]([CH:4]2[NH:9][C:7](=[O:8])[CH2:6][CH2:5]2)=[CH:17][CH:16]=1
Reactant: CCOC1CCC(=O)N1
Reactant: Oc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C1CCC(c2ccc(O)cc2)N1
Temperature: 25 °C
Reaction time: 48 h
Yield: 18.9 %

Procedure:
At 0° C., 12.9 g of γ-ethoxy-γ-butyrolactam, 10 ml of conc. sulphuric acid and 90 ml of glacial acetic acid were initially charged and admixed, a little at a time, with a total of 18.8 g of phenol. After thawing, the mixture was stirred at room temperature for 2 days. For work-up, the mixture was poured onto ice and extracted three times with ethyl acetate, and the combined extracts were washed once each with water and saturated sodium chloride solution, dried and concentrated. After some time, γ-2-hydroxyphenyl-γ-butyrolactam (XI-2b) of melting point 220° C. (6.4 g, 36% of theory) crystallized from the aqueous phase. The residue obtained after concentration was stirred with a 1:1 mixture of cyclohexane/ethyl acetate and gave, after filtration with suction, 4.65 g of γ-4-hydroxyphenyl-γ-butyrolactam (XI-2a) of melting point 183° C. The filtrate was concentrated. A further 3.35 g (total: 45% of theory) of γ-4-hydroxyphenyl-γ-butyrolactam were obtained by recrystallization from dichloromethane/hexane.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:32](=[O:33])[CH2:31][C:30](=[O:34])[NH:29][C:28]3[C:35]4[C:40]([CH:41]=[CH:42][C:27]2=3)=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:22][CH:21]=1>>[CH3:12][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[C:32](=[O:33])[CH2:31][C:30](=[O:34])[NH:29][C:28]4[C:35]5[C:40]([CH:41]=[CH:42][C:27]3=4)=[CH:39][CH:38]=[CH:37][CH:36]=5)=[CH:22][CH:21]=2)=[O:9])=[CH:10][CH:11]=1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Product: CN(C)c1ccc(C(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)cc1
Yield: 25.8 %

Procedure:
4-Dimethylaminobenzoic acid (33 mg, 0.2 mmol) was treated with oxalyl chloride in the same manner as that of Example 40, and then by using the resultant together with 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.1 mmol) obtained in Example 1, (3), the title compound (12 mg, yield 26%) was obtained as pale brown crystals in the same manner as that of Example 1, (4). The structure was confirmed by NMR and MS.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[CH:27]=[C:26]([C:28]([N:30]2[C:38]3[C:33](=[C:34]([F:40])[C:35]([F:39])=[CH:36][CH:37]=3)[CH2:32][CH2:31]2)=[O:29])[CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[F:40][C:34]1[C:35]([F:39])=[CH:36][CH:37]=[C:38]2[C:33]=1[CH2:32][CH2:31][N:30]2[C:28]([C:26]1[CH:27]=[CH:22][N:23]=[C:24]([N:17]2[CH2:18][CH2:19][CH:14]([N:10]3[CH2:9][CH2:8][C:7]4[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[NH:12][C:11]3=[O:13])[CH2:15][CH2:16]2)[CH:25]=1)=[O:29]
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: O=C(c1ccnc(Cl)c1)N1CCc2c1ccc(F)c2F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5c4ccc(F)c5F)ccn3)CC1)C(=O)N2

Procedure:
0.18 g (0.67 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.020 g (0.68 mmol) (2-chloro-pyridin-4-yl)-(4,5-difluoro-2,3-dihydro-indol-1-yl)-methanone and 97 mg (0.70 mmol) potassium carbonate were stirred in 3 mL NMP for 4 h at 130° C., then overnight at RT. The reaction mixture was purified by HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: C1C=C(Cl)C=C([C:8](OO)=[O:9])C=1.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]2[C:24]3[CH2:34][CH2:33][N:32]([C:35]4[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][N:36]=4)[CH2:31][C:25]=3[N:26]=[C:27](SC)[N:28]=2)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].C[O-].[Na+]>C(O)C>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]2[C:24]3[CH2:34][CH2:33][N:32]([C:35]4[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][N:36]=4)[CH2:31][C:25]=3[N:26]=[C:27]([O:9][CH3:8])[N:28]=2)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2c(c(Nc3ccc(C(C)(C)C)cc3)n1)CCN(c1ncccc1Cl)C2
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1nc2c(c(Nc3ccc(C(C)(C)C)cc3)n1)CCN(c1ncccc1Cl)C2
Temperature: 60 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
m-CPBA (148 mg, 0.6 mmol) was added to the solution of N-(4-tert-butylphenyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine from Example 28.C. (88 mg, 0.2 mmol) in ethanol (7 mL) and stirred at room temperature for 1 hr. Solid thus formed was filtered out and dried in vacuo (50 mg). This solid was suspended in methanol (5 mL) and sodium methoxide (9 mg, 0.165 mmol) was added and stirred at 60° C. overnight. Solvent was removed in vacuo and residue was dissolved in ethyl acetate, washed by water, sodium hydrosulfite aqueous solution, brine and dried over sodium sulfate. Purified by column to yield the product as a white solid (33 mg, 39%).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([F:17])[CH:16]=1)[NH:13][C:12](=O)[CH:11]=[CH:10]2>>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([F:17])[CH:16]=1)[N:13]=[C:12]([Cl:3])[CH:11]=[CH:10]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc2cc(Br)cc(F)c2[nH]1
Product: Fc1cc(Br)cc2ccc(Cl)nc12

Procedure:
Using the POCl3 procedure from INTERMEDIATE 4 Step B, 6-bromo-8-fluoroquinolone was converted to the title compound: LC6: 3.42 min. (M+H) 260.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[Br:12]Br.O>C(O)(=O)C>[Br:12][C:7]1[CH:6]=[CH:5][C:4]([O:8][CH3:9])=[CH:3][C:2]=1[C:1]([OH:11])=[O:10]
Reactant: BrBr
Reactant: COc1cccc(C(=O)O)c1
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Br)c(C(=O)O)c1

Procedure:
To m-anisic acid in acetic acid (1 L) was added dropwise bromine (85 ml), followed by water (1 L). The reaction mixture was heated to reflux, cooled in an ice-bath and then the product was collected by filtration, washed with cold water and dried to afford 2-bromo-5-methoxybenzoic acid, m.p. 154°-156° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH:13]1[C:17]3[C:18]([O:22][CH3:23])=[CH:19][CH:20]=[CH:21][C:16]=3[O:15][CH2:14]1)[CH:6]=[CH:5]2.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=1>>[CH3:23][O:22][C:18]1[C:17]2[CH:13]([NH:12][C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([NH:24][C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=5)[CH:3]=4)[N:8]=3)[CH2:14][O:15][C:16]=2[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cccc(N)n1
Reactant: COc1cccc2c1C(Nc1ccc3cc(Br)ccc3n1)CO2
Product: COc1cccc2c1C(Nc1ccc3cc(Nc4cccc(C)n4)ccc3n1)CO2

Procedure:
The title compound, yellow foam, MS: m/e=399.2 (M+H+), was prepared in accordance with the general method of example 66 from rac-(6-bromo-quinolin-2-yl)-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-amine (see example 109, step C) and commercially available 2-amino-6-methyl-pyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[H-].[Na+].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([O:21][C:22](=[O:23])[NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc2cnccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2cnccc2c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 6-aminoisoquinoline in DMF at −40° C. was added NaH and solution was warmed to 0° C. for 30 minutes. Then benzylchloroformate was added and the reaction stirred at 0° C. for 2 hours. The solution was quenched with AcOH, poured into NaHCO3(sat) and extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Flash chromatography (SiO2 90% EtOAc/Hex) gave benzylisoquinolin-6-ylcarbamate. (E87).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][CH2:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH2:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CN)C1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](CNc2nc(Cl)ncc2F)C1
Temperature: 80 °C

Procedure:
To a solution of 2,4-dichloro-5-fluoropyrimidine (0.43 g, 2.59 mmol) and (R)-tert-butyl 3-(aminomethyl)piperidine-1-carboxylate (0.56 g, 2.59 mmol) in THF (50 mL) was added iPr2NEt (0.45 mL, 2.59 mmol). The reaction mixture was heated at 80° C. at for 8 h. The solvent was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography (5-30% EtOAc/hexanes) to afford the desired product, 11a.
Reaction SMILES: [BH4-].[Na+].[C:3]1([S:9]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O1CCCC1>C(OCC)(=O)C>[C:3]1([S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH2:16][OH:17])=[CH:18][CH:19]=2)(=[O:10])=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccccc1)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.3 %

Procedure:
Sodium borohydride (777 mg, 20.5 mmol) was added slowly in portions to a 0° C. solution of 4-(benzenesulfonyl)-benzaldehyde (4.29 g, 18.6 mmol) and tetrahydrofuran (60 mL). The reaction mixture was allowed to warm to room temperature, then stirred at room temperature for 4 hours. The reaction mixture was then cooled over an ice-water bath, diluted with ethyl acetate (80 mL), then carefully quenched with a saturated aqueous solution of ammonium chloride (10 mL). The mixture was washed with water (80 mL), then the organic phase was dried over MgSO4, filtered, and concentrated to afford 2.83 g (61%) of (4-benzenesulfonyl-phenyl)-methanol as a white solid. This product was used in subsequent steps without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3](/[C:16](/[CH3:34])=[CH:17]/[C:18]2[N:19]=[C:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:21](S(=O)(=O)N(C)C)[CH:22]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.CI.[C:37]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[C:3](/[C:16](/[CH3:34])=[CH:17]/[C:18]2[N:19]=[C:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:21]([CH3:37])[CH:22]=2)=[CH:4][C:5]2[C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CCOC(=O)c1nc(/C=C(\C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)cn1S(=O)(=O)N(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)c1nc(/C=C(\C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)cn1C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
Ethyl (E)-4-[2-(5,6,7,8 -tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)propen-1-yl]-1-N,N-dimethylsulfamoyl-2-imidazolecarboxylate (Compound 4, 70 mg, 0.18 mmol) was dissolved in acetone (10 mL) at room temperature and treated with methyl iodide (0.5 mL) and K2CO3 (350 mg). The suspension was stirred for 30 min, filtered through Celite and concentrated under reduced pressure. The residue was treated with water (5 mL) and the organic material was extracted with ethyl acetate, washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexanes/ethyl acetate=5:1) to give the title compound as a light yellow solid (35 mg, 50%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>ClCCl>[C:26]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1cccc(O)c1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cccc(C=O)c1

Procedure:
3-Hydroxybenzaldehyde (10 g., 81.88 mmol) was dissolved in 150 ml dichloromethane under argon. Triethylamine (17.12 ml, 0.123 mol) and dimethylaminopyridine (5 mg.) were added, and the resulting stirred solution was treated with acetic anhydride (8.5 ml, 90 mmol). After stirring for fifteen hours, the reaction mixture was transferred to a separatory funnel using an additional 50 ml dichloromethane. The organic layer was washed with water (2×100 ml) and concentrated to give a light brown oil weighing 14.85 g. Plug filtration through silica gel using dichloromethane furnished 13.3 g (quant.) of a light orange oil which was shown by NMR and IR to be pure enough for use in subsequent reactions (see Tables 3 and 7). ##STR34##
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][O:19][C:20]2[C:32](Cl)=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:22]([F:34])[CH:21]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:35]1(B(O)O)[CH2:37][CH2:36]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O>[CH:1]([N:14]1[CH2:17][CH:16]([CH2:18][O:19][C:20]2[C:32]([CH:35]3[CH2:37][CH2:36]3)=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:22]([F:34])[CH:21]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Reactant: OB(O)C1CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2CN(C(c3ccccc3)c3ccccc3)C2)cc1F
Temperature: 90 °C
Yield: 54.6 %

Procedure:
A mixture of tert-butyl 4-((1-benzhydrylazetidin-3-yl)methoxy)-5-chloro-2-fluorobenzoate (500 mg), cyclopropylboronic acid (188 mg), potassium phosphate (1.12 g) in toluene (6.2 mL) and water (0.31 mL) was purge with nitrogen. Tricyclohexylphosphine tetrafluoroborate (79 mg) and palladium acetate (24 mg) were added. The mixture was heated at 90° C. for 16 hours. The mixture was diluted with EtOAc and filtered. The filtrate was concentrated. The residue was purified with flash chromatography (0-30% EtOAc/heptane) to give the product (276 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][C:13]([C:17](Cl)=[O:18])=[C:14]([CH3:16])[N:15]=3)[S:10][C:3]=12.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][C:13]([C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[O:18])=[C:14]([CH3:16])[N:15]=3)[S:10][C:3]=12
Reactant: Cc1nc(-c2cc3nccc(Cl)c3s2)sc1C(=O)Cl
Reactant: C1COCCN1
Product: Cc1nc(-c2cc3nccc(Cl)c3s2)sc1C(=O)N1CCOCC1
Yield: 82 %

Procedure:
[2-(7-Chloro-thieno[3,2-b]pyridin-2-yl) -4-methyl-thiazol-5-yl]-morpholin-4-yl-methanone (532 mg, 82%) was prepared from 2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazole-5-carbonyl chloride and morpholine in a procedure analogous to Example 20. C16H14ClN3O2S2: APCI m/z 380.0/382.1 (pos.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[OH:13])[CH:6]=[CH:7][CH:8]=O.[C:16]([CH2:18][C:19]([NH2:21])=[S:20])#[N:17]>>[NH2:21][C:19](/[C:18](=[CH:8]/[CH:7]=[CH:6]/[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]([OH:13])=[C:11]([O:14][CH3:15])[CH:10]=1)/[C:16]#[N:17])=[S:20]
Reactant: COc1cc(C=CC=O)cc(OC)c1O
Reactant: N#CCC(N)=S
Product: COc1cc(/C=C/C=C(\C#N)C(N)=S)cc(OC)c1O
Yield: 47.8 %

Procedure:
The compound was prepared as described in Example 3 by adding 3,5-dimethoxy-4-hydroxycinnamaldehyde (0.15 g, 0.72 mmol) to 2-cyanothioacetamide (0.073 g, 0.72 mmol). After refluxing for 1 h the residue was purified on a TLC-plate in hexane-ethyl acetate, 1:1 to give a red solid (0.10 g, 52%). The product gave the following analytical data:
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11](=[O:17])[N:12]([CH2:14][CH2:15][OH:16])[CH3:13])[N:10]=2)[CH2:3]1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>CN(C)C=O>[Si:18]([O:16][CH2:15][CH2:14][N:12]([CH3:13])[C:11]([C:9]1[N:10]=[C:6]([N:4]2[CH2:5][CH:2]([OH:1])[CH2:3]2)[S:7][CH:8]=1)=[O:17])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(CCO)C(=O)c1csc(N2CC(O)C2)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1csc(N2CC(O)C2)n1
Temperature: 0 °C
Yield: 58.8 %

Procedure:
To a solution of 3-hydroxy-1-{4-[N-(2-hydroxyethyl)-N-methyl-carbamoyl]-1,3-thiazol-2-yl}azetidine (576 mg, 2.24 mmol) (obtained as described in Reference Example 40(3)) in dimethylformamide (29 ml) were added t-butyldimethylsilyl chloride (354 mg, 2.35 mmol) and imidazole (160 mg, 2.35 mmol) in an ice bath, and then the reaction mixture was stirred in the ice bath for 2 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (3:1)→ethyl acetate as the eluant to afford 1-(4-{N-[2-(t-butyldimethylsilyloxy)-ethyl]-N-methyl-carbamoyl}-1,3-thiazol-2-yl)-3-hydroxyazetidine (489 mg, yield 60%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=[O:5].[Cl:20][CH2:21][C:22](Cl)=O>C(O)(=O)C>[Cl:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:2]2[C:3]=1[C:4](=[O:5])[N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[C:22]([CH2:21][Cl:20])=[N:1]2
Reactant: O=C(Cl)CCl
Reactant: COc1ccccc1NC(=O)c1c(N)cccc1Cl
Solvent: CC(=O)O
Product: COc1ccccc1-n1c(CCl)nc2cccc(Cl)c2c1=O
Yield: 27.7 %

Procedure:
Prepared according to Procedure B with 1l (2.6 g, 9.41 mmol) and chloroacetyl chloride (2.2 mL, 28.2 mmol) in acetic acid (40 mL). Purified by chromatography in CH2Cl2, followed by recrystallization from isopropanol to afford 874 mg of a pale yellow solid (28%). 1H NMR (CDCl3) δ: 7.55-7.74 (m, 2H); 7.47-7.54 (m, 2H); 7.34 (dd, J=1.7, 7.8 Hz, 1H); 7.13 (dt, J=1.2, 7.7 Hz, 1H); 7.08 (dd, J=1.0, 8.4 Hz, 1H); 4.29 (d, J=12 Hz, 1H); 4.11 (d, J=12 Hz, 1H); 3.80 (s, 3H). MS (ES): m/z 335.0 (M+).
Reaction SMILES: Br[CH2:2][N:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[N-:20]=[N+:21]=[N-:22].[Na+].CC(C)=O>[I-].[K+].O>[N:20]([CH2:2][N:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N+:21]=[N-:22]
Reactant: CCOC(=O)CC1c2ccccc2C(=O)NN1CBr
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)CC1c2ccccc2C(=O)NN1CN=[N+]=[N-]
Yield: 96.1 %

Procedure:
A mixture of ethyl 2-bromomethyl-4-oxo-3H-phthalazine-1-yl-acetate (2.0 g), sodium azide (0.4 g), acetone (20 ml), water (2 ml) and a catalytic amount of potassium iodide (10 mg) was stirred at room temperature for 4 hours. The mixture was concentrated under vacuum to remove the solvents and obtain the title product as a white solid (1.7 g).
Reaction SMILES: [O:1]1[CH:5]([CH2:6][NH:7]C(=O)OCC2C=CC=CC=2)[CH2:4][C:3]2[CH:18]=[C:19]3[C:24](=[CH:25][C:2]1=2)[CH2:23][CH2:22][CH2:21][CH2:20]3>[Pd]>[O:1]1[CH:5]([CH2:6][NH2:7])[CH2:4][C:3]2[CH:18]=[C:19]3[C:24](=[CH:25][C:2]1=2)[CH2:23][CH2:22][CH2:21][CH2:20]3
Reactant: O=C(NCC1Cc2cc3c(cc2O1)CCCC3)OCc1ccccc1
Agent: [Pd]
Product: NCC1Cc2cc3c(cc2O1)CCCC3
Yield: 106.9 %

Procedure:
Treatment of (±)-benzyl 2,3,5,6,7,8-hexahydronaphtho[2,3-b]furan-2-ylmethylcarbamate (1.00 g, 2.96 mmol) with palladium on carbon (10 wt. %, 0.100 g) generally according to the procedure described for Example 2 provided 0.643 g (91%) of (±)-1-(2,3,5,6,7,8-hexahydronaphtho[2,3-b]furan-2-yl)methanamine as a white solid, hydrochloride salt. mp>225° C.; Anal. calcd. for C13H17NOHCl: C, 65.13; H, 7.57; N, 5.84. Found: C, 65.0; H, 7.87; N, 5.77.