Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:8][CH:9]([OH:13])[C:10](=[N+:11]=[N-:12])[C:4]2=[CH:3][CH:2]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[OH:28].C(=O)(O)[O-].[Na+].Cl>O>[OH:13][C:9]1[CH:8]=[C:7]([S:14]([OH:17])(=[O:15])=[O:16])[C:5]2[C:4]([C:10]=1[N:11]=[N:12][C:18]1[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:19]=1[OH:28])=[CH:3][CH:2]=[CH:1][CH:6]=2
Reactant: [N-]=[N+]=C1c2ccccc2C(S(=O)(=O)O)=CC1O
Reactant: Oc1ccc2ccccc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)c1cc(O)c(N=Nc2c(O)ccc3ccccc23)c2ccccc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
To a stirring solution of 1-diazo-2-naphthol-4-sulfonic acid (1.49 g, 5.95 mmol) and 2-naphthol (0.858 g, 5.95 mmol) in water (20 mL), sodium bicarbonate (1.50 g, 17.85 mmol) was added slowly. The resulting solution was heated at 60° C. with stirring overnight. The solution was cooled to room temperature, and was adjusted to pH=1 with 3 N hydrochloride solution. The purple precipitate was isolated by filtration and washed with water to provide the title compound (1.35 g, 58%) MS(ES) m/z 393 [M−H].
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)=[C:10]([C:25]#[N:26])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O[Li].O>O1CCOCC1.Cl.C(Cl)Cl>[C:1]([O:5][C:6](=[O:27])[CH2:7][C:8]1[CH:24]=[CH:23][C:11]([O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)=[C:10]([C:25]#[N:26])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(Oc2ccc(CC(=O)OC(C)(C)C)cc2C#N)cc1
Agent: Cl
Agent: [Li]O
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)O)cc2)c(C#N)c1
Temperature: 10 °C
Reaction time: 5 h
Yield: 65.3 %

Procedure:
Methyl 4-(4-(2-tert-butoxy-2-oxoethyl)-2-cyanophenoxy)benzoate (11.60 g, 31.57 mmol) was dissolved in dioxane (160 mL) and the solution was cooled to 10° C. in an ice bath. LiOH—H2O, 1M (37.89 ml, 37.89 mmol) was added to the solution and the mixture was stirred at ambient temperature for 5 hours. The mixture was diluted with 2N HCl (100 mL) and CH2Cl2 (200 mL). Layers were separated and aqueous layer was extracted with CH2Cl2. The combined extracts were washed with brine (100 mL), dried over MgSO4, filtered through a Celite pad and concentrated under reduced pressure. The crude material was purified by silica gel chromatography to provide 4-(4-(2-tert-butoxy-2-oxoethyl)-2-cyanophenoxy)benzoic acid (7.29 g) as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][NH:7]2.[H-].[Na+].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>CS(C)=O.CCCCCC.O>[CH3:1][NH:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1
Reactant: CNc1ncnc2[nH]cnc12
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: O
Product: CNc1ncnc2c1ncn2-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
In 120 mL of dimethyl sulfoxide, 10.78 g (80 mmol) of methyl-(9H-purin-6-yl)amine was dissolved, and 1.98 g (82.5 mmol) of sodium hydride (60%) after washing with hexane was added thereto and the mixture solution was stirred at room temperature for one hour. To the reaction solution, 13.0 g (92 mmol) of 4-fluoronitrobenzene was added dropwise and the resulting solution was stirred at 80° C. for two hours. The reaction solution was diluted with 300 mL of water, and the crystal deposited was collected on a filter, then washed with 100 mL of water and subsequently with 500 mL of ethanol, and vacuum dried to obtain 16.14 g (83%) of a target product as a yellow solid.
Reaction SMILES: [Br:1]Br.[Br:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClC1C=CC=CC=1Cl>[Br:1][C:13]([CH3:14])([CH3:15])[C:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][Br:3])=[CH:7][CH:8]=1)=[O:16]
Reactant: BrBr
Reactant: CC(C)C(=O)c1ccc(CCBr)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: Clc1ccccc1Cl
Product: CC(C)(Br)C(=O)c1ccc(CCBr)cc1
Reaction time: 8 h
Yield: 44.1 %

Procedure:
A solution of 10 g of bromine in 25 ml of 1,2-dichlorobenzene is added drop wise at room temperature to 13.0 g (0.0509 mol) of crude 1-[4-(2-bromoethyl)phenyl]-2-methylpropan-1-one that is dissolved in 100 ml of 1,2-dichlorobenzene. The reaction mixture is stirred overnight, and then poured into a 5% sodium thiosulfate solution. The mixture is stirred for 30 minutes, and the organic layer is washed with 5% sodium thiosulfate solution, sodium bicarbonate solution, and distilled water. The organic layer is passed through a pad of silica gel and eluted with 9:1 heptane:ethyl acetate to give, after concentration, 7.5 g (55% yield) of 2-bromo-1-[4-(2-bromoethyl)phenyl]-2-methylpropan-1-one.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21](O)=[O:22])=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:24][C:25]([CH3:44])([Si:27]([CH3:43])([CH3:42])[O:28][CH2:29][C:30]([CH3:41])([NH2:40])[CH2:31][O:32][Si:33]([CH3:39])([CH3:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[CH3:26].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.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21]([NH:40][C:30]([CH3:41])([CH2:29][O:28][Si:27]([CH3:43])([CH3:42])[C:25]([CH3:44])([CH3:26])[CH3:24])[CH2:31][O:32][Si:33]([CH3:38])([CH3:39])[C:34]([CH3:37])([CH3:36])[CH3:35])=[O:22])=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(N)(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.1 %

Procedure:
A mixture of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (70 mg, 0.225 mmol), 2,2,3,3,6,9,9,10,10-nonamethyl-4,8-dioxa-3,9-disilaundecan-6-amine (112 mg, 0.338 mmol), HATU (171 mg, 0.45 mmol) and DIPEA (58 mg, 0.45 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. The mixture was poured into water (5 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography on silica gel eluting with petroleum ether/EtOAc (1:1, v/v) to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-(2,2,3,3,6,9,9,10,10-nonamethyl-4,8-dioxa-3,9-disilaundecan-6-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (65 mg, 46%) as a white solid. 1H NMR (300 MHz, DMSO): δ 9.00 (s, 1H), 8.44-8.40 (m, 1H), 8.38 (s, 1H), 7.91 (s, 1H), 7.87 (dd, J=10.2, 2.7 Hz, 1H), 7.06-7.05 (m, 1H), 4.13 (s, 3H), 3.92-3.84 (m, 1H), 1.43 (s, 3H), 0.64 (s, 18H), 0.01 (s, 12H).
Reaction SMILES: [C:1]([Si:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:6][CH2:7][CH2:8][C:9]([NH2:11])=[NH:10])([CH3:4])([CH3:3])[CH3:2].CN([CH:27]=[C:28]1[C:33](=[O:34])[CH2:32][CH2:31][CH2:30][C:29]1=O)C>CCO>[C:1]([Si:5]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:6][CH2:7][CH2:8][C:9]1[N:11]=[CH:27][C:28]2[C:33](=[O:34])[CH2:32][CH2:31][CH2:30][C:29]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=C1C(=O)CCCC1=O
Reactant: CC(C)(C)[Si](OCCC(=N)N)(c1ccccc1)c1ccccc1
Solvent: CCO
Product: CC(C)(C)[Si](OCCc1ncc2c(n1)CCCC2=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 3-(tert-butyl-diphenyl-silanyloxy)-propionamidine (25 g, 77 mmol) and 2-dimethylaminomethylene-cyclohexane-1,3-dione (12.8 g, 77 mmol) in 400 mL of dry EtOH was heated at 80° C. for 3 h. After cooling to RT, the solvent was evaporated. Flash chromatography (SiO2, EtOAc/hexane=1:1) gave the desired compound as a white solid.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Na].[N+:7]([C:10](=[C:15]1[NH:20][CH2:19][CH2:18][CH2:17][S:16]1)[C:11]([O:13][CH3:14])=[O:12])([O-:9])=[O:8]>C1COCC1>[CH3:14][O:13][C:11](=[O:12])[C:10](=[C:15]1[N:20]([C:2]([O:4][CH3:5])=[O:3])[CH2:19][CH2:18][CH2:17][S:16]1)[N+:7]([O-:9])=[O:8]
Reactant: COC(=O)C(=C1NCCCS1)[N+](=O)[O-]
Reactant: COC(=O)Cl
Agent: [Na]
Solvent: C1CCOC1
Product: COC(=O)C(=C1SCCCN1C(=O)OC)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° a solution of 16.0 g of methyl chloroformate in THF was added dropwise to a solution of the sodium derivative of 32.7 g of methyl nitro(tetrahydro-2H-1,3-thiazin-2-ylidene)acetate (3A; Example 2, Ser. No. 554,371) in THF. The stirred solution was then allowed to warm to room temperature and stirred overnight. The solvent was evaporated under reduced pressure and the residue was poured into ether. The ether phase was washed with water, dried (MgSO4) and the solvent evaporated under reduced pressure. The resulting oil was mixed with pentane to give 3, as yellow crystals, m.p.: 71°-2°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:16])[CH:12]=[CH:13][C:14]=1[Br:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[C@@H:18]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)S([O-])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CCOCC.O>[Br:15][C:14]1[CH:13]=[CH:12][C:11]([O:16][C@H:23]([CH3:18])[CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Br)c(OCc2ccccc2)c1
Reactant: C[C@@H](CCCCc1ccccc1)S(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C[C@H](CCCc1ccccc1)Oc1ccc(Br)c(OCc2ccccc2)c1
Yield: 72 %

Procedure:
A mixture of 21.8 g. (78 mmole) of 3-benzyloxy-4-bromophenol, 20.0 g. (82.6 mmole) of (S)-1-methyl-4-phenylbutylmethane sulfonate and 25.2 g. (200 mmole) of potassium carbonate in 100 ml. dimethylformamide was heated at 85° C. for 13.5 hours. The reaction was cooled and added to 500 ml. water-500 ml. ether. The organic extract was washed with two 250 ml. portions of water, dried over magnesium sulfate and evaporated to an oil. The crude oil was purified via column chromatography on 750 g. of silica gel eluted with 10% ether-hexane to yield 23.9 g. (72%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]=C)=[C:10]([F:14])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=[O:24].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[C:11]([CH:12]=[O:24])=[C:10]([F:14])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: C=Cc1c(F)cc2ncccc2c1F
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1cccc(C)n1
Solvent: O
Product: O=Cc1c(F)cc2ncccc2c1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5,7-Difluoro-6-vinyl-quinoline (iv) (614 mg, 3.21 mmol) was dissolved in dioxane (1.7 mL) and water (0.6 mL). 2,6-lutidine (0.761 mL, 6.42 mmol), sodium periodate (2.75 g, 12.85 mmol) and osmium tetroxide (653 mg, 0.064 mmol) were added to the previous solution. The RM was stirred at rt for 15 min. A precipitate was formed. Water was added to the RM and it was extracted twice with EtOAc. The organics were joined and washed with brine, dried over Na2SO4 and the solvent was removed. The residue was purified by MPLC with Hexane and EtOAc to give the title compound as a white solid (tR 1.2 min (conditions 2), MH+=244, 1H-NMR in DMSO-d6: 10.36 (s, 1H); 9.15 (s, 1H); 8.65 (d, 1H); 7.79 (d, 1H); 7.69 (dd, 1H)).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N:28]=[CH:27][C:26]([CH2:29][O:30][CH3:31])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[CH:7][C:6]=1[F:32].CO.[OH-].[Li+].Cl>O1CCCC1.O>[F:32][C:6]1[CH:7]=[C:8]([O:11][CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N:24]=[CH:25][C:26]([CH2:29][O:30][CH3:31])=[CH:27][N:28]=3)[CH2:19][CH2:18]2)[CH:9]=[CH:10][C:5]=1[CH2:4][C:3]([OH:33])=[O:2]
Reactant: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)OC)c(F)c3)CC2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl{2-fluoro-4-[2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethoxy]phenyl}acetate (1.50 g, 3.28 mmol) in 21 ml of tetrahydrofuran was added 14 ml of methanol and 14 ml of water. Lithium hydroxide (0.393 g, 16.4 mmol) was added to the mixture, and stirred at RT overnight. 1 M hydrochloric acid was added to adjust the pH to 4. The volatiles were removed in vacuo, and the remaining aqueous layer extracted with dichloromethane (3×30 ml). The organic fractions were combined, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (50 g silica gel) using a gradient eluent of 0-70% ethyl acetate in hexanes (1000 ml) to afford the title compound. LC/MS (m/z) 444.4 (M+H)+.
Reaction SMILES: [OH-:1].[Na+].[OH2:3].C([CH:7]1[CH:12]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)[CH:11]([C:21](=[O:23])C)C(O)(C)C[C:8]1=[O:26])(=O)C>C(O)C>[F:19][C:17]1[CH:18]=[C:13]([CH:12]([CH2:7][C:8]([OH:26])=[O:3])[CH2:11][C:21]([OH:23])=[O:1])[CH:14]=[C:15]([F:20])[CH:16]=1
Reactant: O
Reactant: [OH-]
Reactant: CC(=O)C1C(=O)CC(C)(O)C(C(C)=O)C1c1cc(F)cc(F)c1
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CC(CC(=O)O)c1cc(F)cc(F)c1
Yield: 33 %

Procedure:
To a hot (95° C.) solution prepared from sodium hydroxide (322 g, 8.1 mol) and deionized water (322 ml) was added a mixture of 2,4-diacetyl-3-(3,5-difluorophenyl)-5-hydroxy-5-methyl-1-cyclohexanone (43 g, 0.112 mol) in ethanol (322 ml) with rapid stirring. The resulting mixture was refluxed for 4 hrs using an oil bath at 140° C. The ethanol was removed by spin evaporation in vacuo and the resulting slurry was cooled with an ice bath, and concentrated hydrochloric acid (12N) was added to adjust the pH to approximately 1. The precipitate was dissolved by the addition of water, and this aqueous solution was extracted with ethyl acetate (total volume 1500 ml). The ethyl acetate extracts were combined, washed with water, dried with MgSO4, and the volatiles were removed by spin evaporation in vacuo. Recrystallization of the residue from dichloromethane and hexanes gave 9.10 g (33%) of 3-(3,5-difluorophenyl)glutaric acid: m.p., 170-172° C.;
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][OH:15])=[C:4](N)[N:3]=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:19]>O.S([O-])([O-])(=O)=O.[NH4+].[NH4+].CO>[OH:15][CH2:14][CH2:13][O:12][CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:19])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: Nc1nc(N)c2ncn(COCCO)c2n1
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1nc2c(ncn2COCCO)c(=O)[nH]1

Procedure:
To a solution of 2-amino-9-(2-hydroxyethoxymethyl)adenine (0.22 g) in water (30 ml) was added a suspension of adenosine deaminase in aqueous ammonium sulfate (0.44 ml, containing 4.4 mg of the enzyme). The reaction mixture, which initially had a pH of 7.0, was heated at 37° C. for 18 hours, at which time the pH was 8.5 and TLC (silica gel plates developed in 15% methanol-85% chloroform) indicated a single product different from starting material. The reaction mixture was thoroughly chilled in an ice bath and the resulting white solid removed by filtration and thoroughly washed with cold water. The product was dried at 100° C./0.1 mm Hg for 16 hours to give 0.20 g of 9-(2-hydroxyethoxymethyl)guanine. 1/4 H2O, the structure of which was confirmed by m.p., TLC, U.V., NMR and mass spectroscopy analysis. Recrystallization from methanol gave the anhydrous 9-(2-hydroxyethoxymethyl)guanine.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[CH3:31][C:32](O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[O:16]1[CH2:17][CH2:18][N:13]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:28]4[CH2:29][CH2:30][N:25]([C:20]5[N:21]=[CH:22][CH:23]=[CH:24][N:19]=5)[CH2:26][CH2:27]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:31]3[CH:32]=[N:21][C:20]([NH2:25])=[N:19][CH:24]=3)[N:3]=2)[CH2:14][CH2:15]1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(c5ncccn5)CC4)cc3n2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde (150 mg, 0.5 mmol) in 1,2-dichloroethane (2.5 mL) was added 1-(2-pyrimidyl)piperazine (110 μL, 0.7 mmol) and AcOH (30 μL, 0.5 mmol). After stirring 10 min at room temperature, Na(OAc)3BH (130 mg, 0.6 mmol) was added and the resulting mixture stirred overnight. The reaction was quenched by the addition of saturated aqueous NaHCO3 and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 and the combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude mixture was coupled using General Procedure A with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin2-amine to provide 138 after reverse phase HPLC purification (5 mg). MS (Q1) 491 (M)+.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:33]Br>>[C:1]([O:5][C@@H:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:33][C:32]3[CH:35]=[CH:36][C:37]([F:38])=[C:30]([F:29])[CH:31]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2cc[nH]c2c(=O)n1C
Reactant: Fc1ccc(CBr)cc1F
Product: Cn1c([C@H](OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccn(Cc3ccc(F)c(F)c3)c2c1=O

Procedure:
The title compound was prepared in a manner similar to that described in Example 2 from methyl 2-(tert-butoxy)-2-(4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate and 3,4-difluorobenzyl bromide. The crude racemic mixture was purified by chiral chromatography to give (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-1-(3,4-difluorobenzyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetic acid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.68-7.59 (m, 1H), 7.52-7.45 (m, 1H), 7.46-7.39 (m, 1H), 7.17-6.98 (m, 4H), 6.06-5.99 (m, 1H), 5.86-5.71 (m, 1H), 5.38-5.32 (s, 1H), 3.64 (s, 3H), 1.02 (s, 9H); LCMS (m/z) ES+=515 (M+1).
Reaction SMILES: C(OC(=O)C)(=O)C.[NH2:8][C:9]1[C:18]([CH3:19])=[CH:17][C:16]([Br:20])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].C([O-])(=O)C.[K+].[N+:26]([O-])(OCCC(C)C)=O>C(Cl)(Cl)Cl>[Br:20][C:16]1[CH:17]=[C:18]2[C:9](=[C:10]([C:11]([O:13][CH3:14])=[O:12])[CH:15]=1)[NH:8][N:26]=[CH:19]2
Reactant: CC(C)CCO[N+](=O)[O-]
Reactant: COC(=O)c1cc(Br)cc(C)c1N
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Br)cc2cn[nH]c12
Temperature: 90 °C
Reaction time: 1 h
Yield: 43.3 %

Procedure:
Acetic anhydride (4.5 g, 4.1 mL, 44 mmol) was added dropwise to the homogenous solution of methyl 2-amino-5-bromo-3-methylbenzoate (4.72 g, 19 mmol) in chloroform (55 mL) over a period of 20 min at room temperature and allowed to stir for 1 h. Potassium acetate (5.7 g, 58 mmol) and isoamyl nitrate (6.6 g, 7.6 mL, 57 mmol) were added at once to the reaction mixture under nitrogen. The clear reaction mixture turned to dark upon heating at 90° C. The reaction mixture was cooled to room temperature after overnight reflux, concentrated, diluted with water and stirred. The beige solid formed was collected by filtration and dried to obtain methyl 5-bromo-1H-indazole-7-carboxylate (2.1 g, 42%). 1H NMR (DMSO-d6): δ 13.44 (s, 1H), 8.33 (s, 1H), 8.21 (s, 1H), 7.99 (s, 1H), 3.95 (s, 3H).LCMS: rt 6.86 min (A), purity 99%, MS (m/e) 255 (MH+).
Reaction SMILES: C([N:3](CC)CC)C.[OH:8][CH:9]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)/[CH:10]=[CH:11]/[C@H:12]1[CH2:17][CH2:16][CH2:15][C:14](=[O:18])[N:13]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26].ClC(OCC)=O.N>C(Cl)Cl.CCOC(C)=O>[OH:8][CH:9]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)/[CH:10]=[CH:11]/[C@H:12]1[CH2:17][CH2:16][CH2:15][C:14](=[O:18])[N:13]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH2:3])=[O:26]
Reactant: CCN(CC)CC
Reactant: O=C(O)CCCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Agent: CCOC(=O)Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)CCCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
Triethylamine (9 μL, 0.065 mmol) was added to a solution of 7-[(R)-2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acid (11.3 mg, 0.030 mmol) in CH2Cl2 (0.3 mL) at rt. After cooling to 0° C., ethyl chloroformate (3.2 μL, 0.033 mmol) was added. After 1 h at 0° C., a solution of ammonia (0.5 M in 1,4-dioxane, 0.3 mL, 0.15 mmol) was added and the reaction mixture was allowed to warm to rt. After 18 h at rt, the reaction mixture was diluted with EtOAc (10 mL) and washed with aqueous HCl (0.5 M, 3 mL), saturated aqueous NaHCO3 (5 mL) and brine (5 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→3% MeOH/CH2Cl2, gradient) afforded 3.5 mg (31%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:26]=[C:25]4[C:20]([CH:21]=[CH:22][CH:23]=[N:24]4)=[C:19](Cl)[N:18]=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:26]=[C:25]4[C:20]([CH:21]=[CH:22][CH:23]=[N:24]4)=[C:19]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[N:18]=3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(-c2cccc3c2ccn3Cc2ccccc2)cc2ncccc12
Reactant: C1COCCN1
Product: c1ccc(Cn2ccc3c(-c4cc5ncccc5c(N5CCOCC5)n4)cccc32)cc1
Yield: 91 %

Procedure:
A flask charged with 7-(1-benzyl-1H-indol-4-yl)-5-chloro-1,6-naphthyridine, 3 (94 mg, 0.25 mmol, 1 eq) and morpholine (1.6 mL, 18 mmol, 70 eq) was heated at 100° C. overnight under Ar(g). Once cooled down, the solvent was removed in vacuo, and the residue was purified by silica gel column chromatography with hexane/EtOAc (3:2-0:1) to yield the product as pale yellow solid (96 mg, 91%).