Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[CH:10]([O:12][CH2:13][CH2:14][OH:15])[C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(P(CCCC)CCCC)CCC.[CH2:33]([O:35][C:36](=[O:49])[CH:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1)[CH3:34].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1C=CC=CC=1.CCCCCCC>[CH2:33]([O:35][C:36](=[O:49])[CH:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:15][CH2:14][CH2:13][O:12][CH:10]2[C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=3[CH2:7][S:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]2=3)=[CH:41][CH:40]=1)[CH3:34]
Reactant: OCCOC1c2ccccc2CSc2ccccc21
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCCC
Solvent: c1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCOC2c3ccccc3CSc3ccccc32)cc1)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74.7 %

Procedure:
Under a nitrogen atmosphere, 2-(6,11-dihydrodibenzo[b,e]thiepin-11-yloxy)-ethanol (340 mg, 1.25 mmol), tributylphosphine (280 mg, 1.37 mmol) and 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (330 mg, 1.37 mmol) were successively dissolved in dry benzene (10 mL). Solid azodicarboxylic dipiperidine (ADDP) (350 mg, 1.37 mmol) was added under stirring at 0° C. to the solution. After 10 min, the reaction mixture was brought to room temperature and the stirring was continued for 16 h. Heptane (10 mL) was added to the reaction mixture and dihydro-ADDP separated out was filtered off. After evaporation of the solvent the product was purified chromatography eluting with ethyl acetate/heptane (1:4) to give 460 mg (75%) of the title compound: 1H NMR (300 MHz, CDCl3) δ1.15 (t, 3H), 1.25 (t, 3H), 2.95 (d, 2H), 3.30-3.40 (m, 1H), 3.55-3.65 (m, 1H), 2.85 (t, 2H), 3.95 (t, 1H), 4.10-4.22 (m, 4H), 4.5-5.1 (bs, 1H), 5.60-5.75 (bs, 1H), 6.82 (d, 2H), 7.05-7.50 (m, 10H).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[NH:18][C:17]=2[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Na].[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37](Cl)=[O:38]>CN(C=O)C>[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([N:18]1[C:19]2[C:24](=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:16]([CH2:15][CH2:14][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]2[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:17]1[CH3:27])=[O:38]
Reactant: O=C(Cl)c1ccccn1
Reactant: COc1ccc2[nH]c(C)c(CCN3CCCCC3CC3CCCCC3)c2c1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CCN1CCCCC1CC1CCCCC1)c(C)n2C(=O)c1ccccn1

Procedure:
Reaction of the 3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole described in Example 1 above with sodium hydride in DMF, and reaction of the resulting sodium salt with 2-pyridine carbonyl chloride using the procedure described above in Example 1 affords 1-(2-pyridylcarbonyl)-3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole.
Reaction SMILES: C([O-])(=O)C.[NH4+].[CH2:6]([O:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22](=[O:24])[CH3:23])=[C:16]([N+:25]([O-])=O)[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(C)C=CC=CC=1>[Fe].O>[NH2:25][C:16]1[CH:15]=[C:14]([O:13][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:19]([O:20][CH3:21])=[CH:18][C:17]=1[C:22](=[O:24])[CH3:23]
Reactant: COc1cc(C(C)=O)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: [Fe]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(C(C)=O)c(N)cc1OCc1ccccc1

Procedure:
A Mixture of iron powder (477 mmol, 27 g), ammonium acetate (500 mmol, 31. g), 1-(4-Benzyloxy-5-methoxy-2-nitro-phenyl)-ethanone (120 mmol, 36 g), toluene (500 ml) and water (500 ml) was refluxed overnight, or until completion. The mixture was filtered through celite and washed with EtOAc. The organic layer was washed with water and Sat. NaCl, dried over Na2SO4, and concentrated to afford the product, 90%. 1H NMR (CDCl3): 7.408-7.298 (5H, m), 7.130 (1H, s), 6.155 (2H, br), 6.104 (1H, s), 5.134 (2H, s), 3.834 (3H, s),2.507 (3H, s). LC/MS (M+1=272).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:3][CH:2]=1.C(O)(=O)C>CO.[Pd]>[NH:1]1[CH2:2][CH2:3][CH:4]([CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:6]1
Reactant: COC(=O)C(=Cc1ccncc1)C(=O)OC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C(CC1CCNCC1)C(=O)OC

Procedure:
A solution of dimethyl (4-pyridylmethylene)malonate [XXVIIIa] (925 g) in methanol (9 L) was hydrogenated in the presence of glacial acetic acid (360 mL) and 10% palladium on activated carbon catalyst (92.5 g) at 60° C. and 200 psi. The catalyst was filtered off and the resulting solution of the title compound in the form of acetic acid salt was used directly in the next step.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH3:14])=[CH:10]/[C:11]([OH:13])=O)=[CH:5][CH:4]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:22][C@@H:18]2[CH2:19][CH2:20][CH2:21][N:17]2[C:11](=[O:13])/[CH:10]=[C:9](/[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:15])=[CH:8][CH:7]=2)\[CH3:14])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCN(C[C@@H]2CCCN2)CC1
Reactant: C/C(=C\C(=O)O)c1ccc(C(F)(F)F)cc1
Product: C/C(=C\C(=O)N1CCC[C@H]1CN1CCCCC1)c1ccc(C(F)(F)F)cc1

Procedure:
110 mg of the title compound were synthesized as described for (E)-3-(4-bromophenyl)-1-((S)-2-((pyrrolidin-1-yl)methyl)pyrrolidin-1-yl)propenone, using (E)-3-(4-(trifluoromethyl)phenyl)but-2-enoic acid instead of (E)-4-bromocinnamic acid and 1-(((S)-pyrrolidin-2-yl)methyl)piperidine instead of (S)-2-((pyrrolidin-1-yl)methyl)pyrrolidine.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:12]([C:14]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17])[CH3:13]>>[CH2:12]([C:14]1[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:19][C:15]=1[C:16]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:17])[CH3:13]
Reactant: CCc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Product: CCc1cc(C(F)(F)F)ccc1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, white solid, MS: m/e=355.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-ethyl-4-(trifluoromethyl)-benzoic acid (CAS 854531-63-8).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[C:21]([O:25][C:26](=[O:34])[NH:27][CH2:28][C@H:29]1[CH2:32][C@H:31]([OH:33])[CH2:30]1)([CH3:24])([CH3:23])[CH3:22].C[Si](C)(C)N[Si](C)(C)C.[K]>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:33][C@H:31]2[CH2:32][C@H:29]([CH2:28][NH:27][C:26](=[O:34])[O:25][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:30]2)[C:5]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)nc(Cl)nc21
Reactant: CC(C)(C)OC(=O)NC[C@H]1C[C@H](O)C1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@H]1C[C@H](Oc2nc(Cl)nc3c2c(I)cn3COCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2,4-dichloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (416 mg, 0.94 mmol), as prepared in Example 5, step 1, in THF (10 mL) was added tert-butyl(trans-3-hydroxycyclobutyl)methylcarbamate (175 mg, 0.94 mmol) and potassium hexamethyldisilazane (560 mg, 2.8 mmol, 3.0 mol eq) and the reaction was stirred at ambient temperature for 20 hrs. The reaction was then quenched with brine (3 mL) and stirred for 10 min, and diluted with ethyl acetate (60 mL) and water (10 mL). The organic layer was separated, washed with brine (10 mL), dried over Na2SO4, filtered and evaporated to give an oil which was purified via flash chromatography (eluting with a gradient of 0 iodobenzene diacetate 100% EtOAc in heptanes) to give the title compound (452 mg, 80% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.80 (s, 1H) 5.48 (s, 2H) 5.38 (t, J=6.54 Hz, 1H) 4.86 (br. s., 1H) 3.44-3.59 (m, 2H) 2.81 (s, 3H) 2.61-2.74 (m, 2H) 2.27-2.43 (m, 2H) 1.40 (s, 9H) 0.71-0.97 (m, 2H) −0.08 (s, 9H). m/z (APCI+) for C22H34ClIN4O4Si 509.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14]CC)=[O:13])[NH:6]2.C1COCC1.O[Li].O.Cl>O>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[NH:6]2
Reactant: CCOC(=O)c1cc2c(Cl)cc(Cl)cc2[nH]1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc2c(Cl)cc(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.5 %

Procedure:
To a solution of ethyl 4,6-dichloro-1H-indole-2-carboxylate (I-1c: 50 g, 193.72 mmol) in a solvent mixture consisting of THF & water (1:1) (900 mL) was added LiOH.H2O (24.41 g, 581.7 mmol) and the reaction mixture stirred at room temperature for 18h. The solvent (THF) was distilled-off, the residue was diluted with water (400 mL) and acidified with 2N aqueous HCl to pH 6.0. The residue was extracted in to ethyl acetate (4×150 mL), combined organic layer washed with brine (350 ml), dried on anhydrous Na2SO4 and concentrated under reduced pressure to obtain 39 g (87.5%) of 4,6-dichloro-1H-indole-2-carboxylic acid (I-1d) as light brown solid.
Reaction SMILES: [CH3:1][C:2]([CH3:20])=[CH:3][CH2:4][C@H:5]1[O:7][C@@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([OH:17])[C@H:10]1[O:18][CH3:19])[CH3:8].[CH3:21][S-:22].O>CN(C=O)C>[O:7]1[CH:5]([CH2:4][CH:3]=[C:2]([CH3:20])[CH3:1])[C:6]1([CH:9]1[CH:10]([O:18][CH3:19])[CH:11]([OH:17])[CH2:12][CH2:13][C:14]1([CH2:15][S:22][CH3:21])[OH:16])[CH3:8]
Reactant: C[S-]
Reactant: CO[C@@H]1[C@H](O)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC1C(O)CCC(O)(CSC)C1C1(C)OC1CC=C(C)C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
Fumagillol (3.00 g) was dissolved in DMF (6 ml), to which was added thiomethoxide (2.23 g). The mixture was stirred for 30 minutes, to which was added water to suspend the reaction. The product was extracted with isopropylether. The extract solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, then the residue was purified by means of a silica gel column chromatography (carrier 150 g, developing solvent : ethyl acetate - hexane=1:2), followed by recrystallization from hexane to afford 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (2.43 g:yield 69%) as colorless powder, m.p. 52° to 53° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19]Cl)=[CH:7]2.Cl.[NH2:22][C:23]1[CH:28]=[C:27]([NH2:29])[N:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][NH:22][C:23]1[CH:28]=[C:27]([NH2:29])[N:26]=[CH:25][N:24]=1)=[CH:7]2
Reactant: ClCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Reactant: Nc1cc(N)ncn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1cc(NCc2cc3cccc(Cl)c3nc2-c2ccccc2Cl)ncn1

Procedure:
Prepared according to Procedure H using 8-chloro-3-(chloromethyl)-2-(2-chloro-phenyl)quinoline (0.035 g, 0.11 mmol), 4,6-diaminopyrimidine hydrochloride (0.032 g, 0.22 mmol, 2 eq) and DIEA (0.55 mL, 2.2 mmol, 20 eq) in ethanol (1 mL). N4-((8-Chloro-2-(2-chlorophenyl)quinolin-3-yl)methyl)pyrimidine-4,6-diamine [PI3Kδ IC50=6868 nM] was obtained after purification as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.32 (1H, s), 8.05 (1H, dd, J=8.4, 1.0 Hz), 7.95 (1H, dd, J=7.4, 1. Hz), 7.84 (1H, s), 7.51-7.67 (5H, m), 7.24 (1H, s), 6.19 (2H, s), 5.32 (1H, s), 4.33 (1H, s) Mass Spectrum (ESI) m/e=396.1 and 398.0 (M+1)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N.[CH:26](OCC)(OCC)OCC>C(O)(=O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([N:17]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH:26]=[N:16][C:14]2=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)C1(Nc2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Reactant: CCOC(OCC)OCC
Agent: N
Solvent: CC(=O)O
Solvent: O
Product: O=C1N=CN(c2ccc(F)cc2)C12CCN(Cc1ccccc1)CC2
Reaction time: 0.17 h

Procedure:
A solution of 155 g (473 mmol) 1-benzyl-4-(4-fluoro-phenylamino)-piperidine-4-carboxylic acid amide in 200 ml triethyl orthoformate and 100 ml acetic acid was irradiated by microwaves in a sealed reactor to 150° C. for 10 min. and then to 200° C. for further 10 min. The reaction mixture was diluted with water, made alkaline with conc. ammonia, and extracted with dichloromethane. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was crystallised from Et2O: 85 g 8-benzyl-1-(4-fluoro-phenyl)-1,3,8-triaza-spiro[4.5]dec-2-en-4-one: light brown crystals.
Reaction SMILES: [Na].[CH3:2][OH:3].C[O-].[Na+].O.[C:8]1([CH3:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:2][O:3][CH2:14][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:10][CH2:9]1
Reactant: CO
Reactant: Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: COC[C@H]1CC[C@H](c2ccccc2)CC1
Temperature: 25 °C

Procedure:
Slices of metal sodium (17.4 g, 0.755 mol) were added in small portions to methyl alcohol (250 ml) agitated at room temperature, to prepare sodium methoxide. After metal sodium pieces disappeared, a solution obtained by dissolving compound (C) (200.0 g, 0.581 mol) previously obtained, in dry toluene (600 ml) was gradually added through a dropping funnel so that the inner temperature was kept in the range of 50°~60° C. After the dropwise addition, the mixture was refluxed for 4 hours and then cooled, followed by adding water (20 ml), transfering the mixture into a separating funnel, washing separated toluene layer with water till the aqueous layer became neutral, distilling off toluene under reduced pressure, distilling the residuce under reduced pressure, and collecting a fraction having a boiling point of 105°~108° C./1.5 mmHg to obtain trans-4-methyloxymethyl-1-phenylcyclohexane (D) (100.0 g).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([NH:14][NH2:15])=O)=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:17](N)(=[NH:19])[CH3:18].C1(C)C(C)=CC=CC=1>>[CH3:18][C:17]1[NH:15][N:14]=[C:12]([C:10]2[O:11][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:8][N:9]=2)[N:19]=1
Reactant: NNC(=O)c1nnc(-c2ccccc2)o1
Reactant: CC(=N)N
Agent: Cl
Solvent: Cc1ccccc1C
Product: Cc1nc(-c2nnc(-c3ccccc3)o2)n[nH]1
Temperature: 170 °C
Reaction time: 36 h
Yield: 22.5 %

Procedure:
To a solution of 5-phenyl-1,3,4-oxadiazole-2-carbohydrazide (400 mg, 1.96 mmol) and acetamidine hydrochloride (573 mg, 6.07 mmol) in xylene (20 mL) NaOH (243 mg, 6.07 mmol) was added. The mixture was stirred at 170° C. for 36 h, and then the reaction was cooled to RT, washed with H2O (20 mL), extracted with 4:1 CHCl3:i-PrOH (5×50 mL), dried with MgSO4 and concentrated. The crude product was purified on a Biotage pre-packed silica gel column (MeOH:DCM 2% to 20% MeOH) to afford 2-(5-methyl-1H-1,2,4-triazol-3-yl)-5-phenyl-1,3,4-oxadiazole (100 mg, 22%) as a white powder. MS (ES+) C11H9N5O requires: 227 found: 228 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:7](=[O:19])[NH:6][C:5]2=[O:20].[H-].[Na+].[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[C:26]([F:32])[CH:25]=1.O>CN(C)C=O>[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:6]2[C:5](=[O:20])[C:4]3[C:9](=[CH:10][C:11]([Cl:12])=[C:2]([Cl:1])[CH:3]=3)[N:8]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:7]2=[O:19])=[C:26]([F:32])[CH:25]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: CCOC(=O)Cn1c(=O)[nH]c(=O)c2cc(Cl)c(Cl)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)n(Cc2ccc(Br)cc2F)c(=O)c2cc(Cl)c(Cl)cc21
Yield: 92.5 %

Procedure:
To a suspension of ethyl 2-(6,7-dichloro-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl)acetate (2.0 g) in N,N-dimethylformamide (50 ml) was added sodium hydride (60% in mineral oil, 288 mg) at room temperature with stirring and the mixture was stirred at the same temperature for 1 hour. To this mixture was added 4-bromo-2-fluorobenzyl bromide (1.93 g) at room temperature with stirring and the mixture was stirred at the same temperature for 2 hours. The solvent was removed to give a residue, which was poured into water. The resulting precipitates were collected by filtration and washed with n-hexane to give ethyl 2-[3-(4-bromo-2-fluorobenzyl)-6,7-dichloro-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl]acetate (2.94 g).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:23][CH2:24][CH3:25])=[CH:11][C:6]=2[O:5][C:4]([C:26]([O:28]CC)=[O:27])=[CH:3]1.C(=O)(O)[O-].[Na+]>C(O)C>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:23][CH2:24][CH3:25])=[CH:11][C:6]=2[O:5][C:4]([C:26]([OH:28])=[O:27])=[CH:3]1
Reactant: CCCc1ccccc1OCCCOc1ccc2c(=O)cc(C(=O)OCC)oc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCc1ccccc1OCCCOc1ccc2c(=O)cc(C(=O)O)oc2c1

Procedure:
A solution of 2.05 parts of ethyl 4-oxo-7-(3-[2-propylphenoxy]-propoxy)-4H-1-benzopyran-2-carboxylate and 0.46 parts of sodium bicarbonate in 100 parts of 50% v /v aqueous ethanol was stirred on a steam bath for three hours, then cooled and extracted with ether. The aqueous extract was acidified with excess 2N hydrochloric acid to give a white precipitate which was collected, washed with water and dried. Crystallisation of this solid from acetone gave 1.01 parts of 4-oxo-7-(3-[2-propylphenoxy]propoxy)-4H-1-benzopyran-2-carboxylic acid, m.pt. 168°-171°.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21]C)[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][C:25]([N:27]3[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]3)=[O:26])=[CH:5][C:4]=2[N:3]=1>ClCCl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][OH:21])[N:14]([CH2:15][C:16]([CH3:17])([OH:18])[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][C:25]([N:27]3[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]3)=[O:26])=[CH:5][C:4]=2[N:3]=1
Reactant: COCc1nc2c(N)nc3cc(CCC(=O)N4CCS(=O)(=O)CC4)ccc3c2n1CC(C)(C)O
Solvent: ClCCl
Product: CC(C)(O)Cn1c(CO)nc2c(N)nc3cc(CCC(=O)N4CCS(=O)(=O)CC4)ccc3c21
Reaction time: 18 h
Yield: 51 %

Procedure:
To a stirring solution of 1-[4-amino-7-[3-(1,1-dioxidothiomorpholin-4-yl)-3-oxopropyl]-2-(methoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (655 mg, 1.34 mmol) in dichloromethane (125 mL), sealed with a septum and purged with nitrogen gas, was added a 1.0 M solution of boron tribromide in dichloromethane (6.6 mL) via syringe. The resulting mixture was stirred for 18 hours. Methanol (50 mL) was added and the solution was concentrated under reduced pressure. The resulting solid was dissolved in a 2.0 M solution of ammonia in methanol (75 mL) and then concentrated under reduced pressure to a solid. This step was repeated two more times with silica gel (1 tbsp) being added prior to the final concentration. The crude product absorbed on silica was purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient; 0-25% CMA over 1200 mL, followed by 25-40% CMA over 1300 mL). The recovered solid was washed with 1% aqueous sodium carbonate and filtered to provide 325 mg of 1-[4-amino-7-[3-(1,1-dioxidothiomorpholin-4-yl)-3-oxopropyl]-2-(hydroxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as an off white semi-solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:23]=[C:11]3[NH:12][C:13]([CH:16]4[CH2:21][CH2:20][NH:19][CH:18]([CH3:22])[CH2:17]4)=[N:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:4][C:3]=1[O:24]C.B(Br)(Br)Br.CCN(CC)CC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:23]=[C:11]3[NH:12][C:13]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=4)=[N:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:4][C:3]=1[OH:24]
Reactant: COc1ccc(-c2cc3[nH]c(C4CCNC(C)C4)ncc-3n2)cc1F
Agent: BrB(Br)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(-c2ncc3nc(-c4ccc(O)c(F)c4)cc-3[nH]2)ccn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.2 %

Procedure:
To a −78° C. solution of 2-fluoro-1-methoxy-4-[2-methyl-4-piperidylpyrrolo[4,5-d]pyrimidin-6-yl]benzene (Example 119) (0.80 g, 2.35 mmol) in CH2Cl2 (40 mL) under a N2 atmosphere was added 1 M BBr3 (4.7 mL, 4.70 mmol). The reaction mixture was allowed to warm to room temperature. The mixture was stirred at room temperature for an additional 20 h. The reaction mixture was then poured onto ice-water (200 mL) and the pH of the aqueous solution was adjusted to pH 9 with the addition of NEt3 (4 mL). The resulting mixture was stirred at room temperature for 2 h. The solid which formed was removed by filtration and dicarded. The remaining solution was transferred to a separatory funnel. The organic solution was separated, washed with H2O (100 mL), saturated NaCl (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure to afford 483 mg (62%) of 2-fluoro-4-(2-methyl-4-pyridylpyrrolo[4,5-d]pyrimidin-6-yl)phenol as a pale yellow colored solid. This compound (481 mg, 1.50 mmol) was dissolved in 4:2:1 EtOAc/MeOH/CH2Cl2 (50 mL) and heated to boiling. To the hot solution was added 1 M ethereal HCl (1.50 mL, 1.50 mmol). The solution was allowed to cool to room temperature. The resulting solid was collected by filtration, washed with EtOAc (2×10 mL), Et2O (3×15 mL) and dried under vacuum at 60° C. to give 315 mg (37%) of the title compound as a pale yellow colored solid. Mp: >280° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.63 (br s, 6), 2.49 (s, 3), 3.96 (br s, 4), 6.76 (s, 1), 7.06 (dt, 1, J=1.9, 8.7), 7.58 (d, 1, J=8.5), 7.83 (dd, 1, J=1.9, 12.5), 10.47 (s, 1), 11.79 (s, 1), 14.12 (s, 1). MS m/z: 327 (M+1 for free base). Anal. Calcd for C18H19FN4O.HCl.1.5H2O: C, 55.45; H, 5.95; N, 14.37; Cl, 9.09. Found: C, 55.49; H, 5.87; N, 14.07; Cl, 9.03.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[C:9]1[CH3:28])(C)(C)C.Br[CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1>>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([O:33][CH2:32][CH2:31][N:18]2[CH:17]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=4)[N:8]([CH2:7][C:6]([OH:5])=[O:29])[C:9]=3[CH3:28])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19]2(=[O:27])=[O:26])=[CH:35][CH:36]=1
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Reactant: Clc1ccc(OCCBr)cc1
Product: Cc1c(C2c3ccccc3S(=O)(=O)N2CCOc2ccc(Cl)cc2)c2ccccc2n1CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 3, step c) and 1-(2-bromo-ethoxy)-4-chloro-benzene. MS: ESI (negative): 509 (M−H).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[S:11]([O-:15])([O-:14])(=[O:13])=[S:12]>>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([N:2]([CH3:10])[CH3:1])=[CH:4][C:5]=1[S:12][S:11](=[O:14])(=[O:13])[OH:15]
Reactant: CN(C)c1ccc(N)cc1
Reactant: O=S([O-])([O-])=S
Product: CN(C)c1ccc(N)c(SS(=O)(=O)O)c1

Procedure:
In one embodiment, an N,N-dimethyl-1,4-diamino-benzene, 3′, is oxidized in the presence of a thiosulfate to give a thiosulfuric acid S-{2-(amino)-5-(dimethylamino)-phenyl}ester, 4′, as illustrated in the following scheme: