Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([N:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])[CH3:4])#N.C[Mg]Br>O1CCCC1>[F:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]([N:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]1)([CH3:4])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCN(C(C)(C#N)c2ccccc2F)CC1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(C)(C)c2ccccc2F)CC1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
To a stirred solution of 0.60 g (1.8 mmol) of the title compound from Step A above in 10 mL of anhydrous tetrahydrofuran cooled to 0° C. under a nitrogen atmosphere was added 3.0 mL (9.0 mmol) of a 3.0 M methyl magnesium bromide solution in tetrahydrofuran. The resulting mixture was allowed to warm to ambient temperature over 8 h then quenched with water. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with a 0-100% ethyl acetate in hexanes gradient to afford the title compound as a yellow gum (0.40 g, 69% yield). (500 MHz, CDCl3) δ 7.56 (td, J=8.1, 1.7 Hz, 1H), 7.21-7.16 (m, 1H), 7.06 (t, J=8.1, 1H), 6.97 (dd, J=12.7, 8.1 Hz, 1H), 3.40-3.38 (m, 4H), 2.45 (br s, 4H), 1.44 (s, 9H), 1.43 (s, 3H), 1.42 (s, 3H). LC-MS: m/z (ES) 323.0 (MH)+.
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:4]=1[CH2:5]Cl.CN(C)[CH:14]=[O:15].Cl>C(OCC)C>[Cl:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:4]=1[CH2:5][CH:14]=[O:15]
Reactant: ClCc1c(Cl)cccc1Cl
Reactant: CN(C)C=O
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: O=CCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
A 200-mL three-necked flask equipped with a thermometer, a dropping funnel, a three-way stopcock, and a mechanical stirrer was purged with nitrogen. Thereto, were added 1.85 g (76 mmol) of magnesium, and 30 mL of diethyl ether. The dropping funnel was filled with a solution of 13.5 g (69 mmol) of 2,6-dichlorobenzyl chloride (produced by Tokyo Kasei K.K.) in 40 mL of diethyl ether. The solution was added dropwise into the flask by keeping the temperature of the reaction system at about 30° C. Thereafter, the reaction mixture was aged at room temperature for 30 minutes, and cooled with ice. Thereto, 6 g (82 mmol) of N,N-dimethylformamide was added dropwise. The reaction mixture was aged at room temperature for one hour, cooled with ice, and poured into 50 mL of 3N hydrochloric acid solution. The mixture was allowed to separate into phases, and the separated matter was extracted with diethyl ether. The combined organic phase was dried over anhydrous sodium sulfate. After filtration and concentration, 5 mL of methyl t-butyl ether was added to the concentration residue, and the mixture was heated to dissolve the residue. After cooling of the solution to room temperature, the deposited crystalline matter was collected by filtration to obtain 8.1 g (43 mmol) of crystalline 2,6-dichlorophenylacetaldehyde. (Yield: 62%)
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(O)C.[CH2:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:9]1[O:11][CH2:10]1>>[CH2:13]([O:12][CH2:8][CH:9]([CH2:10][O:1][CH2:2][CH3:3])[OH:11])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CC[O-]
Reactant: CCCCCCCCCCCCCCOCC1CO1
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCCCCOCC(O)COCC
Temperature: 80 °C
Reaction time: 18 h
Yield: 319.6 %

Procedure:
Under nitrogen stream, 30 g of sodium ethoxide was added to 851.8 g (18.5 mol) of ethanol, and the mixture was heated to 80° C. Then, 500 g (1.85 mol) of tetradecyl glycidyl ether were added dropwise thereto. The mixture was stirred for 18 hours at the same temperature. Thereafter, ethanol was distilled off, and 10.8 g of 85% phosphoric acid was added thereto, followed by washing the resultant mixture with water three times. After water washing, distillation was performed under reduced pressure, to thereby obtain 446 g of 1-tetradecyl-3-ethylglycerol (yield 76.2%).
Reaction SMILES: C(N(CC)CC)C.C(OP(Cl)(OCC)=O)C.[O:17]1[C@@:34]2([CH3:35])[C@@H:18]1[CH2:19][C@@H:20]1[C:25]([C:26]([OH:28])=[O:27])=[CH:24][O:23][C@@H:22]([O:29][C:30](=[O:33])[NH:31][CH3:32])[C@H:21]12.[CH3:36][C:37](=[CH:39][CH2:40][CH2:41]/[C:42](=[CH:44]/[CH2:45]O)/[CH3:43])[CH3:38]>CN(C)C1C=CN=CC=1.CCCCCC.C(OCC)(=O)C.ClCCl>[CH2:45]([O:27][C:26]([C:25]1[C@H:20]2[CH2:19][C@@H:18]3[O:17][C@:34]3([CH3:35])[C@@H:21]2[C@H:22]([O:29][C:30](=[O:33])[NH:31][CH3:32])[O:23][CH:24]=1)=[O:28])/[CH:44]=[C:42](/[CH2:41][CH2:40][CH:39]=[C:37]([CH3:38])[CH3:36])\[CH3:43]
Reactant: CNC(=O)O[C@@H]1OC=C(C(=O)O)[C@H]2C[C@@H]3O[C@]3(C)[C@H]12
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CNC(=O)O[C@@H]1OC=C(C(=O)OC/C=C(\C)CCC=C(C)C)[C@H]2C[C@@H]3O[C@]3(C)[C@H]12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
0.5 ml of triethylamine and 0.45 ml of diethylchlorophosphate were added to a dichloromethane solution containing 331 mg of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy)cyclopenta[c]-pyrane-4-carboxylic acid described in Example 1. After stirring for 30 minutes at room temperature, 0.42 ml of geraniol and 17 mg of 4-dimethylaminopyridine (to be abbreviated as DMAP) were added followed by stirring for 5 hours at room temperature. The reaction mixture was then extracted with dichloromethane. After washing the organic phase with dilute hydrochloric acid, saturated aqueous sodium bicarbonate and brine, it was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a colorless oil from the hexane-ethyl acetate eluate in the form of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy)cyclopenta[c]-pyrane-4-carboxylic acid geranyl ester (280 mg, yield: 50%). The physicochemical properties of this compound are described in Table 2, Compound No. 6.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1Br)[CH3:9].C([Li])CCC.CCCCCC.[CH3:31][C:32]([CH3:34])=[O:33]>>[CH3:1][C:2]([CH3:19])([CH3:18])[C:3]#[C:4][CH:5]=[CH:6][CH2:7][N:8]([CH2:10][C:11]1[CH:16]=[C:15]([C:32]([OH:33])([CH3:34])[CH3:31])[CH:14]=[CH:13][CH:12]=1)[CH3:9]
Reactant: CC(C)=O
Reactant: CN(C/C=C/C#CC(C)(C)C)Cc1ccccc1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CN(CC=CC#CC(C)(C)C)Cc1cccc(C(C)(C)O)c1
Yield: 42.8 %

Procedure:
The procedure described in Example 17 was repeated, except that Compound 36 (2.35 g; 7.3 mmol), n-butyl lithium in n-hexane (1.56 M: 5.2 ml; 8.1 mmol), and acetone (1 ml) were used, to thereby yield 940 mg of the target compound (yield: 42.8%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:30]2[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=2[C:37]#[N:38])=[CH:4][C:5](=[O:29])[N:6]([CH:8]([CH2:25][CH2:26][O:27][CH3:28])[C:9]([NH:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([O:18]C(C)(C)C)=[O:17])=[CH:14][CH:13]=2)=[O:10])[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[C:3]([C:30]2[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=2[C:37]#[N:38])=[CH:4][C:5](=[O:29])[N:6]([CH:8]([CH2:25][CH2:26][O:27][CH3:28])[C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:23][CH:24]=2)=[O:10])[CH:7]=1
Reactant: COCCC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: COCCC(C(=O)Nc1ccc(C(=O)O)cc1)n1cc(Cl)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
438 mg (0.76 mmol) of tert-butyl 4-({2-[5-chloro-4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]-4-methoxybutanoyl}amino)benzoate (racemate) were hydrolysed with TFA according to General Method 2. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 123 mg (32% of theory)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[NH:9][N:10]=[CH:11][C:3]=12.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:18][C:19]1[C:24]([CH3:25])=[C:23]([O:26][CH3:27])[C:22]([CH3:28])=[C:21]([CH2:29]Cl)[N:20]=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[N:9]([CH2:29][C:21]3[C:22]([CH3:28])=[C:23]([O:26][CH3:27])[C:24]([CH3:25])=[C:19]([Cl:18])[N:20]=3)[N:10]=[CH:11][C:3]=12
Reactant: COc1c(C)c(Cl)nc(CCl)c1C
Reactant: Nc1nc(Cl)c2cn[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(C)c(Cl)nc(Cn2ncc3c(Cl)nc(N)nc32)c1C
Temperature: 80 °C

Procedure:
A mixture of 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (124 mg), Cs2CO3 (392 mg) and crude 2-chloro-6-chloromethyl-4-methoxy-3,5-dimethyl-pyridine (200 mg) in DMF (2 ml) was heated to 80° C. for 1 h, diluted with EtOAc and washed with water. Concentration and purification by preparative TLC (EtOAc) gave the title compound. R.t. 6.43 min. 1H-NMR (CDCl3) δ 7.86 (s, 1H), 5.48 (s, 2H), 5.37 (s, 2H), 3.71 (s, 3H), 2.27 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4](F)[CH:3]=1.[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4]([O:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:3]=1
Reactant: Oc1ccccc1
Reactant: O=C(OCc1ccccc1)c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(Br)cc1Oc1ccccc1
Temperature: 85 °C

Procedure:
Phenylmethyl 4-bromo-2-fluorobenzoate (Example 189, 260 mg, 0.84 mmol) was combined with phenol (160 mg, 1.68 mmol, 2.0 eq.) and solid potassium carbonate (580 mg, 4.21 mmol, 5.0 eq.) in anhydrous N,N-dimethylformamide and was heated at 85° C. for 5 hours. The mixture was cooled and partitioned between diethyl ether and water. The aqueous layer was separated and extracted with fresh ether. The organic layers were combined, washed with brine (4×), dried (MgSO4), and concentrated in vacuo to a crude oil. The crude was purified by flash chromatography on silica gel eluted with 95:5 hexanes/ether to provide the title compound as a colorless oil that crystallized upon standing (110 mg, 34%); 1H NMR (300 MHz, CDCl3) δ 7.84 (d, 1H), 7.39-7.27 (m, 7H), 7.17-7.10 (m, 1H), 6.98-6.91 (m, 2H), 6.85 (d, 2H), 5.30 (s, 2H); Rf 0.51 (4:1 hexanes/diethyl ether).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([CH2:28][OH:29])[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[CH:9][C:8]([O:30][CH3:31])=[CH:7][CH:6]=2.[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>ClCCl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([CH2:28][O:29][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])[CH2:19][CH2:20]1)=[CH:9][C:8]([O:30][CH3:31])=[CH:7][CH:6]=2
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2ncc(Cl)c(CCCC3(CO)CCN(C(=O)OC(C)(C)C)CC3)c2c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc2ncc(Cl)c(CCCC3(COS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 0 °C

Procedure:
A mixture of 24.8 g of tert-butyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-4-hydroxymethylpiperidine-1-carboxylate in 400 cm3 of dichloromethane and 12.9 cm3 of triethylamine was cooled to about 0° C. with stirring and under an inert atmosphere. Methanesulfonyl chloride, dissolved beforehand in 125 cm3 of dichloromethane, was added dropwise and the reaction mixture was then stirred for 18 hours at a temperature in the region of 20° C. 200 cm3 of water were added to the reaction mass, followed by a further addition of 3 000 cm3 of water. The phases were separated by settling and the aqueous phase was extracted with 200 cm3 of dichloromethane. The organic extracts were washed with 300 cm3 of aqueous sodium chloride solution, dried over sodium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 45° C. 30.6 g of tert-butyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-4-methanesulfonyloxymethylpiperidine-1-carboxylate were obtained in the form of an orange-colored oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:17](O)[CH:18]=[CH2:19]>>[F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:19][CH:18]=[CH2:17])=[O:5]
Reactant: C=CCO
Reactant: O=C(O)c1ccc(O)cc1F
Agent: O=S(=O)(O)O
Product: C=CCOC(=O)c1ccc(O)cc1F
Yield: 69 %

Procedure:
In a manner analogous to Example 1(a), starting with 8.3 g 53 mmoles) of 2-fluoro-4-hydroxybenzoic acid treated for 2 hours at 100° C. with 60 ml of allyl alcohol and 1.5 ml of concentrated sulfuric acid, 7.2 g (69% yield) of the expected ester having a melting point of 80°-81° C. are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]([CH3:16])([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([S:25]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([CH3:15])([CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:17][CH:18]=2)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCNS(=O)(=O)c2ccccc2)cc1

Procedure:
from ethyl 2-[4-(2-aminoethyl)-phenoxy]-2-methylpropionate and benzenesulphonyl chloride;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:16])([CH3:15])[C:10]([O:12]CC)=[O:11])[CH:6]=[CH:5][C:4]=1[C:17]1[CH:22]=[C:21]([CH2:23][O:24][CH3:25])[CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>CCO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:16])([CH3:15])[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][C:4]=1[C:17]1[CH:22]=[C:21]([CH2:23][O:24][CH3:25])[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(C)(C)c1ccc(-c2cccc(COC)c2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCc1cccc(-c2ccc(C(C)(C)C(=O)O)cc2OC)c1
Yield: 99.4 %

Procedure:
Ethyl 2-(2-methoxy-5′-(methoxymethyl)biphenyl-4-yl)-2-methylpropanoate (example 27b) (986 mg, 2.88 mmol) was suspended in EtOH (10 mL) and 1M aq. NaOH (15 mL) and stirred at 100° C. for 3 h. EtOH was removed under reduced pressure and the residue was diluted with water (10 mL) and acidified with 6N aq. HCl to pH 2-3. The product was extracted with EtOAc, washed with water and brine, dried over MgSO4, filtered and evaporated to give 900 mg (99%) of 2-(2-Methoxy-5′-(methoxymethyl)biphenyl-4-yl)-2-methylpropanoic acid. 1H NMR(400 MHz, DMSO): δ 1.48 (s, 6H), 3.29 (s, 3H), 4.45 (s, 2H), 7.40-7.61 (m, 8H), 12.44 (s, 1H).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].[Na+].[N+:11]([CH2:14][CH3:15])([O-:13])=[O:12]>CN(C)C=O>[N+:11]([CH:14]([CH:2]([CH2:3][C:4]([OH:6])=[O:5])[C:1]([O:8][CH3:9])=[O:7])[CH3:15])([O-:13])=[O:12]
Reactant: COC(=O)/C=C\C(=O)[O-]
Reactant: CC[N+](=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CC(=O)O)C(C)[N+](=O)[O-]
Temperature: 60 °C

Procedure:
Into a 100 ml, one neck flask is placed 10 grams of sodium methyl maleate, 60 mls N,N-dimethyl formamide (DMF) and 40 grams nitroethane. The solution is heated at 60° C. for two hours and then partially distilled in vacuo to remove the DMF and nitroethane. The residue, by NMR analysis (D2O), has the following structure: ##STR39## CH2 (b) multiplet, 2.5-2.72δ
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][N:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[NH3:12]>>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][N:7]=[N:8]2)=[C:4]([NH2:12])[N:3]=1
Reactant: N
Reactant: Nc1nc(Cl)c2[nH]nnc2n1
Product: Nc1nc(N)c2[nH]nnc2n1

Procedure:
A solution of 428 mg. of the 2-amino-6-chloro-8-azapurine of Example 8 in 25 ml. of liquid ammonia was heated for 18 hours at 60° C. in a stainless steel bomb containing a glass liner. The bomb was chilled and opened, and ammonia was evaporated with a current of nitrogen. The residual solid was triturated with water (12 ml.), collected by filtration, washed with cold water, and dried in vacuo at 56° C.: yield, 359 mg. (90%); m.p. 245°-247° C. dec. (inserted at 200° C., 3° C./min.). A second crop of the carbocyclic analog of 2,6-diamino-8-azapurine 2'-deoxyribofuranoside was isolated in the same way from the concentrated filtrate: weight 31 mg. (total yield, 98%); m.p. 244°-246° C. dec. (inserted at 200° C., 3° C./min.). A solution of the two portions in boiling water (35 ml.) was treated with a small amount of activated charcoal, concentrated to about one-half of the original volume, and refrigerated. The white crystalline compound (Formula VII, X=NH2) was separated by filtration, washed with cold water, and dried in vacuo at 56° C.: weight, 350 mg. (92% recovery); m.p. 246°-248° C. dec. (inserted at 200° C., 3° C./min.); TLC, 1 spot (40 mcg., 2:1 chloroform-methanol as developing solvent); UV max 285 nm (ε7700), 255 (ε9800), 214 (ε26,000) at pH 1; 287 (ε10,600), 258 (ε5800), 223 (ε25,800) at pH 7; 287 (ε10,700), 258 (ε5800), 223 (ε26,000) at pH 13; MS (direct-probe temperature, 220° C.), m/e 265 (M), 248 (M-OH), 235, 234 (M-CH2OH), 218 (M-OH-CH2OH+H), 206 (M-CH2OH-N2), 190 (M-75), 178 (P+C2H4), 152 (P+2H), 151 (P+H); IR (strong bands; 1800-600 cm-1 region) 1670, 1630, 1600, 1585 vs, 1480 vs, 1420, 1020, 785, 670.
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)=O)(C)(C)C.B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)(=O)C>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]([NH:15][C:10]2[C:9]([NH2:8])=[CH:14][CH:13]=[CH:12][N:11]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: COc1ccc(C(=O)Nc2ncccc2NC(=O)OC(C)(C)C)cc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2ncccc2N)cc1
Reaction time: 2 h
Yield: 49.2 %

Procedure:
A solution of N3-(tert-butoxycarbonyl)-N2-(4-methoxy-benzoyl)-2,3-pyridinediamine (350 mg, 1.02 mmol) in acetic acid (2 mL) at 0° C. was treated with boron trifluoride etherate (0.50 mL, 4.1 mmol). After 2 h, the mixture was poured into aqueous sodium bicarbonate and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate and the combined extracts were dried (magnesium sulfate), filtered, and concentrated in vacuo. Purification of the residue by chromatography (silica gel, ethyl acetate/methylene chloride) yielded 122 mg (49%) of the title compound.
Reaction SMILES: CO[CH:3](OC)[CH2:4]Br.Br.O.[NH2:10][C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1>CN(C)C=O>[N:12]1[CH:13]=[CH:14][N:10]2[CH:4]=[CH:3][N:15]=[CH:16][C:11]=12
Reactant: Nc1cnccn1
Reactant: COC(CBr)OC
Agent: Br
Solvent: CN(C)C=O
Solvent: O
Product: c1cn2ccnc2cn1
Reaction time: 12 h

Procedure:
A mixture of 34 g (0.2 mol) of bromoacetaldehyde dimethyl acetal, 6,6 ml of concentrated aqueous HBr solution and 28 ml of distilled water is brought to reflux for one hour. After reaction, the mixture is alkalinized and extracted with ether. This organic phase is added to a solution of 19 g (0.2 mol) of aminopyrazine in 50 ml of dimethylformamide (DMF). The ether is removed by distillation and the mixture is maintained with stirring and under a stream of nitrogen for 12 hours. After reaction, the DMF is distilled off; the reaction medium is dissolved in 150 ml of anhydrous ethanol, and then brought to reflux for one hour. The alcohol is then removed by distillation; the residue is dissolved in water, alkalinized with Na2CO3 and extracted using dichloromethane. After chromatography on a neutral alumina column (eluant =anhydrous ether), 10.7 g (Yld=45%) of imidazo[1,2-a]pyrazine (m.p. 84° C.). are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18](Br)[CH:17]=1)[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])[CH3:2].[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:27].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:17]=[C:18]([C:31]3[CH:32]=[CH:33][C:28]([C:26]#[N:27])=[CH:29][CH:30]=3)[CH:19]=[C:20]([F:22])[CH:21]=1)[C:10]([CH3:25])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(Br)c1)N2
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(-c3ccc(C#N)cc3)c1)N2
Temperature: 120 °C
Yield: 35 %

Procedure:
A mixture of 2-(3-bromo-5-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.41 g, 1.0 mmol), 4-cyanobenzeneboronic acid (0.29 g, 2.0 mmol), bis(triphenylphosphine)palladium (II) chloride (70.2 mg, 0.1 mmol) and 2 M sodium carbonate (1.5 mL, 3.0 mmol) in dioxane (4 mL) was heated for 3 hours at 120° C. After cooling to room temperature, the mixture was treated with ethyl acetate (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(10% ethyl acetate/hexanes) to afford 2-(4′-cyano-5-fluoro-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.15 g, 35%) as a white solid: LC/MS m/e calcd for C27H25FN2O2 (M+H)+: 429.5, observed: 429.3.
Reaction SMILES: C([O:5][C:6]([CH2:8][NH:9][C@H:10]([CH3:33])[C@@H:11]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:7])(C)(C)C.C1(C([O-])=O)CC1(C(OCC)=O)C(OCC)=O.[O:50]1[CH2:54][C@@H:53]([C:55]([O-:57])=O)[O:52][C:51]1([C:63]([O:65][CH2:66][CH3:67])=[O:64])[C:58]([O:60][CH2:61][CH3:62])=[O:59]>>[C:6]([CH2:8][N:9]([C@H:10]([CH3:33])[C@@H:11]([C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:24][CH:25]=1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:55]([C@@H:53]1[CH2:54][O:50][C:51]([C:63]([O:65][CH2:66][CH3:67])=[O:64])([C:58]([O:60][CH2:61][CH3:62])=[O:59])[O:52]1)=[O:57])([OH:7])=[O:5]
Reactant: CCOC(=O)C1(C(=O)OCC)OC[C@@H](C(=O)[O-])O1
Reactant: C[C@@H](NCC(=O)OC(C)(C)C)[C@H](CCc1ccccc1)c1ccc(Oc2ccccc2)cc1
Agent: CCOC(=O)C1(C(=O)OCC)CC1C(=O)[O-]
Product: CCOC(=O)C1(C(=O)OCC)OC[C@@H](C(=O)N(CC(=O)O)[C@H](C)[C@H](CCc2ccccc2)c2ccc(Oc3ccccc3)cc2)O1

Procedure:
The above identified compound was obtained by the same method as in Example 1 except that instead of N-(tert-butoxycarbonylmethyl)-{(1R,2R)-2-(2-fluoro-4-biphenylyl)-1-methyl-4-phenylbutyl}amine used as the starting material in Example 1, N-(tert-butoxycarbonylmethyl)-{(1R,2R)-1-methyl-2-(4-phenoxyphenyl)-4-phenylbutyl}amine obtained in Example 50, was used, and instead of 2,2-diethyl 1,2,2-cyclopropanetricarboxylate, 2,2,-diethyl (4S)-1,3-dioxolane-2,2,4-tricarboxylate obtained in Example 56, was used.