Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[I:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1>O.C(O)C.[Fe]>[I:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(I)cc2)cc1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccc(I)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
A solution of 6.04 ml (68.4 mmole) of concentrated hydrochloric acid in 25 ml of water and 25 ml of ethanol was added in a dropwise manner over 50 minutes to a mechanically stirred refluxing suspension of 23.34 g (68.4 mmole) of 4-(4'-iodophenoxy) nitrobenzene and 11.46 g (205 mmole, 3.0 equiv) of iron filings in 150 ml of water and 150 ml of ethanol. After 1 hour, the mixture was allowed to cool to room temperature and was evaporated to about 200 ml volume. The mixture was made alkaline to a pH of about 11 using 10% aqueous sodium hydroxide solution before adding 200 ml of water and 250 ml of ethyl acetate. The aqueous fraction was extracted twice with 50 ml of ethyl acetate and the combined organic phase was washed twice with 125 ml of water and 50 ml of brine, dried over MgSO4, filtered and evaporated to obtain 20.25 g of the desired product as a brown semi solid. Flash column chromatography (0-10% EtOAc/CH2Cl2 eluent) yielded 13.40 g (62.9%) of the product as pale brown crystals.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:14]=[C:15]([NH:21][C:22](=[O:34])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4([C:32]#[N:33])[CH2:31][CH2:30]4)[CH:24]=3)[CH:16]=[CH:17][C:18]=2[O:19][CH3:20])=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([O:12][C:13]1[CH:14]=[C:15]([NH:21][C:22](=[O:34])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4([C:32]#[N:33])[CH2:31][CH2:30]4)[CH:24]=3)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[N:10]=2
Reactant: N#C[S-]
Reactant: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc(N)cn1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc2nc(N)sc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
Potassium thiocyanate (4.44 g, 45.7 mmol) was suspended in acetic acid (100 mL), and the mixture was stirred at room temperature for 30 min. A solution of N-{3-[(5-aminopyridin-2-yl)oxy]-4-methoxyphenyl}-3-(1-cyanocyclopropyl)benzamide (4.1 g) in acetic acid (100 mL) was added to the obtained solution, and the mixture was further stirred at room temperature for 30 min. A solution of bromine (2.65 g, 16.6 mmol) in acetic acid (100 mL) was added dropwise to the obtained solution for 30 min or more. After the completion of the dropwise addition, the mixture was stirred at room temperature for 16 hr. The yielded yellow solid was filtered off, and washed with acetic acid, and the filtrate and the washing solution were combined and concentrated under reduced pressure. The residue was suspended in ethyl acetate (300 mL), and the suspension was washed with saturated aqueous sodium hydrogen carbonate solution (100 mL×2) and saturated brine (100 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (2.68 g, total of 2 steps 59%) as a yellow amorphous substance.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11]O)[OH:10])O)O)O.C1(C)C=CC=CC=1.[ClH:20]>O>[Cl:20][CH2:11][C:9]1[O:10][C:3]([CH:2]=[O:1])=[CH:5][CH:7]=1
Reactant: Cl
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(CCl)o1
Reaction time: 5 h

Procedure:
Five grams (0.028 mole) of a commercially available D-glucose was added to a three-necked flask equipped with a condenser and a stirrer, and dissolved in 5 ml of water. Thirty milli-liters of toluene was further added and the mixture was stirred. Thereafter, a molar excess of hydrogen chloride (about 12 g) was passed through the mixture at room temperature for 30 minutes with thorough stirring. Stirring was further continued at 45° C. for 5 hours. The reaction solution containing a small amount of humud was diluted with a little water and filtered through Celite while being washed with a small amount of toluene. The toluene layer was neutralized with an aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and concentrated. Thus, about 1.0 g (theoretical yield 4.01 g) of 5-chloromethylfurfural was obtained as a crude product of pale brown color.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][N:4]=1.C[Li].CN([CH:18]=[O:19])C>C1COCC1.C(NC(C)C)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][N:4]=1)[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: COCOc1ccc(OC)nc1
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COCOc1cnc(OC)cc1C=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
To a mixture of 2-methoxy-5-(methoxymethoxy)pyridine (30 g, 0.178 mol) and diisopropylamine (507 uL, 3.6 mmol) in THF (500 mL) was added methyl lithium (1.6 M/THF, 200 mL, 0.32 mol) at −40° C. Upon the completion of addition, the mixture was warmed to 0° C. and continued to stir at 0° C. for 3 h. The reaction mixture was then cooled back down to −40° C. followed by addition of DMF (24.7 mL, 0.32 mol) slowly. The mixture was then stirred at −40° C. for 1 h and quenched with a mixture of HCl (12 N, 120 mL) and THF (280 mL). Water (200 mL) was added and the pH of the mixture was adjusted to pH 8-9 with solid K2CO3. The mixture was extracted with EtOAc (300 mL) twice. The organic layer was combined, dried over Na2SO4, and concentrated to give 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (33.5 g, 95.7%) as a brown solid, which was used for next step without further purification. 1H NMR (400 MHz; CD3OD) 7.90 (s, 1H), 6.92 (s, 1H), 5.64 (s, 1H), 5.20 (s, 2H), 3.84 (s, 3H), 3.48 (s, 3H); MS (ESI) m/z 198.1 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>>[CH:33]1([C:36]([NH:1][C@@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=5[O:28][CH2:29][CH:30]5[CH2:31][CH2:32]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:37])[CH2:35][CH2:34]1
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c23)c1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)C5CC5)CC4)c[nH]c23)c1

Procedure:
Starting from cis-4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A154) and cyclopropanecarbonyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [O-2:1].[Al+3].[O-2].[O-2].[Al+3].[CH3:6][CH2:7][C:8]1[CH2:19][N:17]2[CH2:18][C@H:10]([CH2:11][C@:12]([C:60]([O:62][CH3:63])=[O:61])([C:27]3[CH:32]=[C:31]4[C:33]56[C@@H:44]([N:45]([CH3:46])[C:30]4=[CH:29][C:28]=3[O:58][CH3:59])[C@@:43]([OH:51])([C:47]([O:49][CH3:50])=[O:48])[C@H:42]([O:52][C:53]([CH3:55])=[O:54])[C@:38]3([CH2:56][CH3:57])[CH:39]=[CH:40][CH2:41][N:36]([C@H:37]53)[CH2:35][CH2:34]6)[C:13]3[NH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:14]=3[CH2:15][CH2:16]2)[CH:9]=1>>[CH3:6][CH2:7][C@@:8]12[O:1][C@@H:9]1[C@H:10]1[CH2:18][N:17]([CH2:16][CH2:15][C:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[NH:26][C:13]=3[C@@:12]([C:60]([O:62][CH3:63])=[O:61])([C:27]3[CH:32]=[C:31]4[C@:33]56[C@@H:37]7[C@:38]([CH2:56][CH3:57])([C@@H:42]([O:52][C:53]([CH3:55])=[O:54])[C@:43]([OH:51])([C:47]([O:49][CH3:50])=[O:48])[C@@H:44]5[N:45]([CH3:46])[C:30]4=[CH:29][C:28]=3[O:58][CH3:59])[CH:39]=[CH:40][CH2:41][N:36]7[CH2:35][CH2:34]6)[CH2:11]1)[CH2:19]2
Reactant: CCC1=C[C@@H]2CN(CCc3c([nH]c4ccccc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@@H]3C45CCN4CC=C[C@](CC)([C@H]45)[C@@H](OC(C)=O)[C@]3(O)C(=O)OC)C2)C1
Reactant: [O-2]
Agent: [Al+3]
Product: CC[C@]12CN3CCc4c([nH]c5ccccc45)[C@@](C(=O)OC)(c4cc5c(cc4OC)N(C)[C@H]4[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]6(CC)C=CCN7CC[C@]54[C@@H]76)C[C@H](C3)[C@H]1O2

Procedure:
Following the procedure described in the Example 19 but performing the oxidation in the presence of aluminium oxide used in a five-fold amount related to the anhydrovinblastine the title compound is prepared. The quality of the aluminium oxide employed corresponds to the activity grade I or II. The reaction is completed within two hours.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH2:20][C:21]#[N:22]>>[Cl:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]2[C:3]=1[CH:4]=[C:20]([CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[O:12][CH3:11])[C:21]([NH2:22])=[N:1]2
Reactant: Nc1cccc(Cl)c1C=O
Reactant: COc1ccccc1CCC#N
Product: COc1ccccc1Cc1cc2c(Cl)cccc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-6-chlorobenzaldehyde and 3-(2-methoxyphenyl)propionitrile.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][NH:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1([CH3:16])[CH3:15].[C:18](OC(=O)C)(=[O:20])C>C(O)=O>[CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]([CH:18]=[O:20])[CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1([CH3:15])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)CNC1c2ccccc2CC1(C)C
Solvent: O=CO
Product: COC(=O)CN(C=O)C1c2ccccc2CC1(C)C
Reaction time: 18.5 h

Procedure:
936 g of N-(2,2-dimethyl-indan-1-yl)glycine methyl ester are added dropwise with cooling to 5° C. to 1817 ml of formic acid. Additionally 664 ml of acetic anhydride are added, and the mixture is kept at room temperature for 18.5 hours. Destillation under vacuum affords 1015 g of N-formyl-N-(2,2-dimethyl-indan-1-yl)glycine methyl ester.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.[C:6]([O:10][C:11]([N:13]1[CH2:16][CH:15]([C:17]([OH:19])=O)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:6]([O:10][C:11]([N:13]1[CH2:14][CH:15]([C:17]([N:2]2[CH2:5][CH2:4][CH2:3]2)=[O:19])[CH2:16]1)=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(C(=O)N2CCC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Azetidine hydrochloride salt (515 mg, 5.50 mmol) was added to a solution of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (1.0 g, 4.97 mmol), HATU (2.09 g, 5.50 mmol) and DIPEA (2.18 mL, 12.52 mmol) in DMF (100 mL) and the resulting mixture stirred at ambient temperature for 1 h, then concentrated in vacuo. The resulting oil was partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, then dried (MgSO4) and concentrated in vacuo to give 3-(azetidine-1-carbonyl)azetidine-1-carboxylic acid tert-butyl ester as a colourless oil. TFA (3 mL) was added to a solution of 3-(azetidine-1-carbonyl)-azetidine-1-carboxylic acid tert-butyl ester in DCM (15 mL) and the mixture stirred at ambient temperature for 1 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a colourless oil (260 mg, 37%). 1H NMR (CD3OD, 400 MHz) δ 4.19-4.08 (m, 2H); 4.07-3.92 (m, 2H); 3.91-3.78 (m, 2H); 3.72-3.52 (m, 3H) and 2.36-2.21 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:10]2=[O:38])=[N:4]1)[CH3:2].[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>C(Cl)Cl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[CH2:1]([N:3]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]3)[C:10]2=[O:38])=[N:4]1)[CH3:2]
Reactant: CCn1ccc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1ccc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-{1-[(1-ethyl-1H-pyrazol-3-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (665 mg; compound B19) in DCM (5 ml) is added trifluoroacetic acid (5 ml). The reaction mixture is stirred for 3 h at RT. All volatile materials are removed in vacuo and the residue is taken up in diethyl ether. The resulting suspension is stirred at RT, then all solids are filtered off and dried in vacuo. The procedure is repeated a second time to afford the title compound as a solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[O-]CC.[Na+].Cl>C(O)C>[F:18][C:15]1[CH:14]=[CH:13][C:12]([C:7]2[C:6]([C:4]([OH:3])=[O:5])=[C:10](/[CH:11]=[CH:19]/[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:9][N:8]=2)=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)noc1C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1c(-c2ccc(F)cc2)noc1/C=C/c1ccccc1
Yield: 77 %

Procedure:
To a solution of 3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (20.0 g, 80.2 mmol) and benzaldehyde (8.19 mL, 80.2 mmol) in ethanol (113 mL) was added sodium ethoxide (2.71 M, 32.5 mL, 88.3 mmol) and the reaction mixture was heated under reflux for 1 h. Hydrochloric acid (1 N, 96.3 mL) was added and the resulting mixture was extracted with toluene. The solvent was then distilled off to afford the title compound (19.1 g, 77%) as a light yellow solid. MS: m/e=308.0 [M−H]−.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[CH2:20][OH:21])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([O:21][CH2:20][C:5]2[CH:6]=[C:7]([CH:18]=[CH:19][C:4]=2[O:3][CH2:1][CH3:2])[CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[O:31])=[CH:25][CH:24]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1CO
Product: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1COC(=O)Nc1ccc(Cl)cc1

Procedure:
Using dimethyl 2-[4-ethoxy-3-(hydroxymethyl)benzyl]-malonate and 4-chlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2].[N:16]([O-:18])=[O:17].[Na+].O>C(O)(C(F)(F)F)=O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=2)[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)C[C@H](C)N2C(C)=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(C)=O)[C@@H](C)C2
Yield: 90.5 %

Procedure:
A 0° C. orange solution of (2S)-1-acetyl-2-methyl-5-(methyloxy)-2,3-dihydro-1H-indole (5.19 g, 25.3 mmol) in TFA (30 mL) was treated with NaNO2 (1.745 g, 25.3 mmol) portion wise. After 2 h more NaNO2 (800 mg, 11.6 mmol) was added. After 1 h the resulting mixture was poured into water (450 mL). The resulting slurry was filtered and the solids were washed with water. The solids were dissolved in CH2Cl2. The layers were separated, the organic layer was dried (Na2SO4) and concentrated to afford (2S)-1-acetyl-2-methyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole as a green solid (5.73 g, 91%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (d, J=6.23 Hz, 3H), 2.22 (s, 3H), 2.76 (d, J=17.21 Hz, 1H), 3.45 (dd, J=17.03, 8.97 Hz, 1H), 3.89 (s, 3H), 4.58-4.78 (m, 1H), 7.35 (s, 1H), 8.41 (s, 1H); ESIMS (M+H)+=251.02.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[NH:10][CH:9]([C:11]([OH:13])=[O:12])[CH2:8][S:7]1)=[O:5].[C:14](Cl)(=[O:16])[CH3:15].C(N(CC)CC)C>>[CH3:1][CH2:2][O:3][C:4]([CH:6]1[N:10]([C:14](=[O:16])[CH3:15])[CH:9]([C:11]([OH:13])=[O:12])[CH2:8][S:7]1)=[O:5]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C1NC(C(=O)O)CS1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1SCC(C(=O)O)N1C(C)=O

Procedure:
Thiazolidine-2,4-dicarboxylic acid 2-ethyl ester (1.0 g, 4.89 mmol) was subjected to acylation with acetyl chloride (0.52 ml, 7.31 mmol) in the presence of triethylamine (1.02 ml, 7.33 mmol) to give N-acetylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (with the ratio of two kinds of stereoisomers of about 37:63 as confirmed by NMR) as an amorphous solid (1.19 g).
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[CH:18]3[CH:21]([CH2:22][C:23]=2[S:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]([CH:31]([OH:33])[CH3:32])[C:19]3=[O:34])=[O:16])C2C=CC=CC=2)C=CC=CC=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[C:25]1([S:24][C:23]2[CH2:22][CH:21]3[CH:18]([C:19](=[O:34])[CH:20]3[CH:31]([OH:33])[CH3:32])[C:17]=2[C:15]([OH:16])=[O:14])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(O)C1C(=O)C2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Sc3ccccc3)CC21
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(O)C1C(=O)C2C(C(=O)O)=C(Sc3ccccc3)CC21
Yield: 80.4 %

Procedure:
A solution of 50 mg of 3-phenylthio-6-(1-hydroxyethyl)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid diphenylmethyl ester, and 50 mg of anisole in 1 mL of trifluoroacetic acid was stirred for 5 min at room temperature after which time the solvent was removed by evaporation. Trituration of the residue with ether-petroleum ether afforded 26 mg (80%) of 3-phenylthio-6-(1-hydroxyethyl)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid as colorless crystals. IR (Nujol mull): 1765, 1650, 1535 cm-1 ; NMR (220 MHz; CDCl3 /DMSO-D6): δ 1.18 (3H, d, J=6.5), 2.32 (1H, dd, J=19, 3.5), 2.67 (1H, m), 2.85 (1H, dd, J=19, 8), 3.07 (1H, m), 3.92 (1H, dq, J=6.5, 6.5), 4.41 (1H, m), and 7.3-7.6 (5H, m).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH3:17])=[C:10]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:9]=2)[C:6]2[CH:24]=[CH:25][CH:26]=[CH:27][C:5]=2[N:4]=1)[CH3:2].CN(CCN(C)C)C.[Li]CCCC.[C:41]([O:45][C:46]([N:48]1[CH2:51][C:50](=[O:52])[CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42]>C1COCC1>[C:41]([O:45][C:46]([N:48]1[CH2:51][C:50]([C:13]2[N:14]([CH3:17])[C:15]3[C:11]([N:12]=2)=[C:10]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:9]=[C:8]([N:7]2[C:6]4[CH:24]=[CH:25][CH:26]=[CH:27][C:5]=4[N:4]=[C:3]2[CH2:1][CH3:2])[N:16]=3)([OH:52])[CH2:49]1)=[O:47])([CH3:44])([CH3:42])[CH3:43]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2ncn(C)c2n1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CN(C(=O)OC(C)(C)C)C3)n(C)c2n1
Temperature: -40 °C
Yield: 65.3 %

Procedure:
To a mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (2.5 g, 6.88 mmol) and TMEDA (1.6 mL, 10.33 mmol) in THF (40 mL) at −78° C. was added n-BuLi (4.1 mL, 2.5 M in hexanes, 10.33 mmol). The resulting mixture was allowed to warm to −40° C. over 30 min then cooled back to −78° C. before the addition of a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (1.8 g, 10.33 mmol) in THF (10 mL). The reaction mixture was warmed to −10° C. over 2 h then quenched with sat, aq. NH4Cl and extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-5%) then recrystallised from iPrOAc and pentane affording 3-[2-(2-Ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester as a cream solid (2.4 g, 64%). LCMS (method A): RT 2.83 min [M+H]+ 535.4
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.[B:20](OC)([O:23]C)[O:21]C.O.Cl>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([B:20]([OH:23])[OH:21])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2ccc(Br)cc2)cc1
Temperature: -80 °C
Yield: 41 %

Procedure:
10.0 g (0.032 mol) of 4,4′-dibromobiphenyl was put in a 500 mL three neck flask, and nitrogen was substituted for air in the flask, and then 200 mL of tetrahydrofuran was added and stirred at −80° C. 20 mL (0.032 mol) of n-butyllithium (1.60 M hexane solution) was dropped into a reaction solution, and stirred for 1 hour at −80° C., and 40 mL (0.060 mol) of trimethyl borate was added and stirred for 1 hour while returning to room temperature. After 200 mL (1.0 mol/L) of hydrochloric acid water was added to the reaction solution, and stirred for about 12 hours, an organic layer was washed with a saturated sodium hydrogen carbonate solution and saturated saline, and then dried with magnesium sulfate. After the reaction solution was naturally filtered, a solid which was obtained by concentrating a filtrate, was recrystallized with a mixture of ethyl acetate and hexane. 3.7 g of 4-(4-bromophenyl)phenylboronic acid that was a target substance and was a white solid was obtained in a yield of 41% (Synthesis Scheme (e-1)).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=1.Cl[C:15]1[C:16]2[CH2:26][CH2:25][CH2:24][C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[C:17]=2[N:18]=[C:19]([NH2:21])[N:20]=1>COCCO.[OH-].[Na+]>[NH2:13][C:9]1[N:8]=[C:7]([NH:6][CH2:5][CH2:4][NH:3][C:15]2[C:16]3[CH2:26][CH2:25][CH2:24][C:23]4[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=4[C:17]=3[N:18]=[C:19]([NH2:21])[N:20]=2)[CH:12]=[CH:11][N:10]=1
Reactant: Nc1nc(Cl)c2c(n1)-c1ccccc1CCC2
Reactant: NCCNc1ccnc(N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: Nc1nccc(NCCNc2nc(N)nc3c2CCCc2ccccc2-3)n1
Temperature: 130 °C

Procedure:
The product of Example 1E (155 mg, 0.686 mmol) and the product of Example 1C (140 mg, 0.571 mmol) were combined in 2-methoxyethanol (0.8 mL) and heated to 130° C. for three hours. The mixture was diluted with 1 N aqueous sodium hydroxide and extracted twice with methylene chloride. The organic layers were combined and dried over sodium sulfate and the mixture was absorbed on silica gel and purified using silica gel chromatography, eluting with a gradient of 7 N ammonia in methanol in methylene chloride (5-15%) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.62 (d, J=4.41 Hz, 1H) 7.50-7.56 (m, 1H) 7.26-7.34 (m, 2H) 7.19-7.26 (m, 1H) 6.67-6.75 (m, 1H) 5.85 (s, 2H) 5.70-5.81 (m, 4H) 3.37-3.52 (m, 4H) 2.44 (t, J=6.78 Hz, 2H) 2.08-2.18 (m, J=6.78, 6.78 Hz, 2H) 1.92-2.04 (m, 2H); MS (ESI+) m/z 363.9 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9])=[O:2].S(=O)(=O)(O)O.[CH2:18](OCC)C.O>CO>[CH3:18][O:9][C:8](=[O:10])[C:7]1[CH:11]=[C:3]([CH:1]=[O:2])[CH:4]=[CH:5][C:6]=1[OH:12]
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Reactant: CCOCC
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(C=O)ccc1O
Reaction time: 0.25 h

Procedure:
5-Formyl-2-hydroxy-benzoic acid (11.3 g) was dissolved in methanol (35 ml) and conc. sulfuric acid (3 ml). The mixture was heated at reflux for 40 h. Diethyl ether was added, and the mixture was poured into water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in a mixture of dioxane (80 ml) and water (50 ml) and treated with 6N hydrochloric acid (2.5 ml). After 15 min., dioxane was removed in vacuo. The mixture was extracted with ethyl acetate. The organic layer was dried (MgSO4), filtered and concentrated in vacuo.