Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:13][C:12]([CH2:14]OS(C)(=O)=O)=[N:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.[N+:20]([C:23]1[CH:27]=[N:26][NH:25][N:24]=1)([O-:22])=[O:21].CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC.O>[CH3:3][C:4]1([C:9]2[S:13][C:12]([CH2:14][N:25]3[N:24]=[C:23]([N+:20]([O-:22])=[O:21])[CH:27]=[N:26]3)=[N:11][CH:10]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: O=[N+]([O-])c1cn[nH]n1
Reactant: CC1(c2cnc(COS(C)(=O)=O)s2)OCCO1
Agent: N#N
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC1(c2cnc(Cn3ncc([N+](=O)[O-])n3)s2)OCCO1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of methanesulfonic acid 5-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl ester (445 mg, 1.59 mmol) in DMF (3.0 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (180 mg, 1.58 mmol) in DMF (3.0 mL) pre-treated for 30 min with DIPEA (0.54 mL, 3.16 mmol) and the reaction mixture was stirred for 72 h at 50° C. Water (10 mL), followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over NaSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (5:1 to 2:1 hept-EA) gave the title compound as a pale yellow oil: TLC:rf (1:2 hept-EA)=0.39. LC-MS-conditions 01: tR=0.85 min; [M+H]+=297.91.
Reaction SMILES: [CH:1]([C@H:4]1[NH:7][C:6](=[O:8])[C@H:5]1[O:9][Si:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:11][CH3:12])([CH3:3])[CH3:2].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:17]([N:7]1[C@H:4]([CH:1]([CH3:2])[CH3:3])[C@H:5]([O:9][Si:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:11][CH3:12])[C:6]1=[O:8])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC[Si](CC)(CC)O[C@@H]1C(=O)N[C@@H]1C(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[Si](CC)(CC)O[C@@H]1C(=O)N(C(=O)c2ccccc2)[C@@H]1C(C)C
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A solution of (+)-cis-4-isopropyl-3-triethylsilyloxy-azetidin-2-one (486 mg, 2.00 mmole), benzoyl chloride (0.255 mL, 1.1 equiv), diisopropylethyl amine (0.346 mL, 1.2 equiv) and p-dimethylaminopyridine (244 mg, 1 equiv) in dry DCM (6 mL) was left stirring at 0° C. for 6 hr. The bath was removed and the reaction was left stirring overnight. It was then diluted with DCM and washed with water, aq. HCl solution (0.1 N), saturated aq. NaHCO3 solution, brine and dried (Na2SO4). Removal of the solvent followed by silica gel column chromatography (gradient elution with 0 to 5% EtOAc in hexane) gave the title compound: 1H NMR δ (CDCl3) 0.47-0.94 (m, 21H), 2.09 (m, 1H), 4.07 (m, 1H), 4.75 (m, 1H), 7.24-7.76 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[N:20]1([C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[CH:24]=[CH:23][N:22]=[CH:21]1>>[N:20]1([C:25]2[CH:26]=[CH:27][C:28]([C:29]([NH:19][C:3]3[CH:4]=[CH:5][C:6]([N:8]4[CH2:12][CH2:11][CH:10]([N:13]5[CH2:17][CH2:16][CH2:15][CH:14]5[CH3:18])[CH2:9]4)=[CH:7][C:2]=3[CH3:1])=[O:30])=[CH:32][CH:33]=2)[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1ccc(-n2ccnc2)cc1
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc(-n2ccnc2)cc1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-imidazol-1-yl benzoic acid. MS: 430.5 (M+H).
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[C:4]([Cl:18])[CH:3]=1.[Cl:19][C:20]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:21]=1[NH2:22].C(=O)([O-])[O-].[Na+].[Na+].ClC1C=CC=CC=1Cl>[Cu]I.O.C1(C)C=CC=CC=1.N1C=CC=CC=1>[Cl:19][C:20]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:21]=1[NH:22][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[C:4]([Cl:18])[CH:3]=1
Reactant: O=C1c2ccccc2C(=O)c2c(Cl)cc(Cl)cc21
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)c2c(Nc3ccc([N+](=O)[O-])cc3Cl)cc(Cl)cc21
Reaction time: 5 h

Procedure:
27.7 parts of 1,3-dichloroanthraquinone, 18.15 parts of 2-chloro-4-nitroaniline and 10 parts of sodium carbonate are suspended in 400 parts of o-dichlorobenzene whilst stirring. After adding a solution of 0.4 part of copper-(I) iodide in 5 parts of pyridine and 25 parts of toluene, the mixture is kept at 160°-165° for 5 hours, whilst eliminating the water of reaction. When the mixture has cooled, it is filtered and the precipitate is washed with o-dichlorobenzene, acetone and hot water and extracted by boiling with dilute hydrochloric acid. 29 parts of 1-(2'-chloro-4'-nitroanilino)-3-chloroanthraquinone, which bulk-dyes PES in orange shades of good fastness properties, are obtained.
Reaction SMILES: [CH3:1][CH:2]([N:9]1[CH2:12][CH:11]([O:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-:22].[K+].O>C(O)(C)(C)C>[CH3:1][CH:2]([N:9]1[CH2:10][CH:11]([O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH2:19])=[O:22])=[CH:20][CH:21]=2)[CH2:12]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [OH-]
Reactant: CC(c1ccccc1)N1CC(Oc2ccc(C#N)cc2)C1
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(c1ccccc1)N1CC(Oc2ccc(C(N)=O)cc2)C1

Procedure:
To 45.0 g. (0.16 mole) of 4-[1-(α-methylbenzyl)-3-azetidinyloxy]benzonitrile in 500 ml of t-butyl alcohol was added 45.0 g. of finely ground potassium hydroxide. The mixture was stirred and refluxed for 30 minutes. Ice and water were added and a thick white solid separated. The solid was recrystallized from toluene to give 30.0 g. (63%) of product melting at 174°-178° C.
Reaction SMILES: N1C=CC=CC=1C([O-])=O.[CH2:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)=[N:20][C:21]([C:24]([O:26][CH2:27]C)=[O:25])=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH3:11]>OS(O)(=O)=O.CO>[CH2:10]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[N:20][C:19]=2[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[CH:16][CH:17]=1)[CH3:11]
Reactant: CCOC(=O)c1ccc(-c2ccc(CC)cc2)c(-c2ccncc2)n1
Agent: O=C([O-])c1ccccn1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCc1ccc(-c2ccc(C(=O)OC)nc2-c2ccncc2)cc1

Procedure:
Following General Procedure E, ethyl 5-(4-ethylphenyl)-6-(pyridine-4-yl)phenyl)pyridine-2-carboxylate (Compound 49, 48 mg, 0.14 mmol) and conc. H2SO4 (10 drops) in methanol were reacted to produce the title compound as a light yellow solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[N:10]([CH2:18][CH3:19])[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:20][S:21]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)(=[O:23])=[O:22].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:18]([N:10]1[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:17]=[C:9]1[C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH:29]=2)[N:3]=1)[CH3:19]
Reactant: CCn1c(-c2nc(Br)cnc2N)nc2cnccc21
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(-c2nc(-c3cccc(S(C)(=O)=O)c3)cnc2N)nc2cnccc21
Temperature: 200 °C
Yield: 3 %

Procedure:
5-bromo-3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine (0.032 g, 0.10 mmol) (made in example 2), 3-(methylsulfonyl)phenylboronic acid (0.040 g, 0.20 mmol), Pd(PPh3)2Cl2 (0.0035 g, 0.005 mmol) and K2CO3 (0.050 g, 0.36 mmol) were combined in 0.5 mL of N,N-dimethylformamide and heated to 200° C. in the SmithSynthesizer microwave for 8 minutes. The reaction mixture was concentrated in vacuo and the residue purified by mass directed HPLC to give 0.0012 g of the title compound. MS m/z 395 (M+1)+.
Reaction SMILES: [K].[Cl:2][C:3]1[CH:19]=[CH:18][C:6]2[N:7]=[C:8]([O:10][C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[O:9][C:5]=2[CH:4]=1.[C:20]([CH:22]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[Cl:35])[C:23](=[O:27])[CH:24](Cl)[CH3:25])#[N:21].O>CN(C)C=O>[C:20]([CH:22]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[Cl:35])[C:23](=[O:27])[CH:24]([O:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][C:8]2[O:9][C:5]3[CH:4]=[C:3]([Cl:2])[CH:19]=[CH:18][C:6]=3[N:7]=2)=[CH:16][CH:15]=1)[CH3:25])#[N:21]
Reactant: Oc1ccc(Oc2nc3ccc(Cl)cc3o2)cc1
Reactant: CC(Cl)C(=O)C(C#N)c1ccc(Cl)cc1Cl
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(Oc1ccc(Oc2nc3ccc(Cl)cc3o2)cc1)C(=O)C(C#N)c1ccc(Cl)cc1Cl
Temperature: 100 °C
Yield: 46.9 %

Procedure:
2.70 Grams of a potassium salt of 4-(6-chloro-2-benzoxazolyloxy)phenol and 2.48 g of 1-cyano-1-(2,4-dichlorophenyl)-3-chloro-2-butanone were refluxed in 50 ml of N,N-dimethylformamide under heat at 100° C. for 4 hours. The reaction mixture was added to water, and after the mixture was subjected to extraction with chloroform, the extract was concentrated. The residue was separated and purified by column chromatography to give 2.05 g of a compound No. 176 which was a light yellow solid (melting point 93°-94° C.). The yield was 46.9%. The compound No. 176 was analyzed, and the results are shown in Tables 1 to 23.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:29]=2)O1.Br[C:32]1[CH:43]=[CH:42][C:35]([C:36]([NH:38][CH2:39][CH2:40][OH:41])=[O:37])=[C:34]([F:44])[CH:33]=1>>[F:44][C:34]1[CH:33]=[C:32]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:29]=2)[CH:43]=[CH:42][C:35]=1[C:36](=[O:37])[NH:38][CH2:39][CH2:40][OH:41]
Reactant: O=C(NCCO)c1ccc(Br)cc1F
Reactant: CC(C)OC(=O)N1CCC(c2nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3o2)CC1
Product: CC(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(C(=O)NCCO)c(F)c4)ccc3o2)CC1
Yield: 32.2 %

Procedure:
Following the General Procedure-3, the titled compound (65 mg) was prepared from Intermediate 14 (200 mg, 0.54 mmol) and 4-bromo-2-fluoro-N-(2-hydroxyethyl)benzamide (110 mg, 0.43 mmol) as a brown solid. M.P.: 145-147° C. MS (m/z): 470.4 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:23])=[N:11][C:12]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][CH2:26][CH2:27][CH3:28].[Li]CCCC>C1COCC1.CCCCC>[CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[N:13][C:12]([N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[CH3:22])=[N:11][C:10]=1[CH2:23][CH2:25][CH2:26][CH2:27][CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCBr
Reactant: Cc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCCc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution at −78° C. containing 1.00 g (3.25 mmol) of 5-(Benzyloxy)-2-(2,5-dimethyl-1H-pyrrol-1-yl)-4,6-dimethylpyrimidine and 233 μL (2.16 mmol) of 4-bromobutane in 30 mL of anhydrous THF were added 2.70 mL (4.32 mmol) of a 1.6 M solution of n-BuLi in pentane. The reaction mixture was stirred at 23° C. for 30 min. The reaction was quenched with saturated aqueous ammonium chloride and then poured into 70 mL of water. The mixture was then extracted with two 70-mL portions of diethyl ether. The combined organic layer was then washed with a 100-mL portion of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (15×5 cm). Elution with 4:1 hexanes-diethyl ether afforded the expected product as a colorless oil: yield 533 mg (69%); silica gel TLC Rf 0.50 (4:1 hexanes-diethyl ether); 1H NMR (CDCl3) δ 0.90 (t, 3H, J=7.2 Hz), 1.34 (m, 2H), 1.77 (m, 2H), 2.33 (s, 6H), 2.49 (s, 3H), 2.79 (dd, 2H, J=7.6, 7.6 Hz), 4.91 (s, 62), 5.88 (s, 2H) and 7.40-7.44 m, 5H); 13C NMR (CDCl3) δ 13.95, 14.34, 19.29, 22.47, 27.41, 31.59, 31.73, 75.72, 107.94, 107.94, 128.01, 128.01, 128.22, 128.72, 129.30, 136.22, 147.38, 147.38, 152.60, 161.62, 161.62 and 165.08; mass spectrum (APCI), m/z 364.2394 (M+H)+ (C23H30N3O requires 364.2389).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[C:18]3[CH:17]=[CH:16][C:15](=[O:19])[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].CN(C)C=O.C(O)C>[Fe].O>[O:19]=[C:15]1[NH:14][C:13]2[N:12]=[CH:11][CH:10]=[C:9]([O:8][C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:21][CH:20]=3)[C:18]=2[CH:17]=[CH:16]1
Reactant: O=c1ccc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2[nH]1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(Oc2ccnc3[nH]c(=O)ccc23)cc1

Procedure:
4-(4-Nitrophenoxy)-7-oxo-7,8-dihydro[1,8]naphthyridine (156 mg), iron powder (300 mg), ammonium chloride (600 mg), dimethylformamide (2 ml), ethanol (1 ml) and water (1 ml) were stirred at 100° C. for 20 minutes. The mixture was filtered with celite, and then water and ethyl acetate were added for extraction. The organic layer was washed 4 times with ammonium chloride water and then dried over magnesium sulfate. The drying agent was filtered off and the solvent was distilled off under reduced pressure to obtain 30 mg of the target substance as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](C=NO)[CH:5]=[CH:4][N:3]=1.CO.[CH2:13]([N:15](CC)CC)C>>[CH3:1][C:2]1[N:7]=[C:6]([NH:15][CH3:13])[CH:5]=[CH:4][N:3]=1
Reactant: CCN(CC)CC
Reactant: Cc1nccc(C=NO)n1
Solvent: CO
Product: CNc1ccnc(C)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
An autoclave was charged with 2-methyl-pyrimidine-4-carbaldehyde oxime (13 g) from I.1.2, 150 ml of methanol and 70 ml of triethylamine. The autoclave was purged with nitrogen. To this mixture was added 3 g of a 10% palladium-on-carbon catalyst. The autoclave was sealed and purged twice with hydrogen gas. The hydrogenation was run for 2 h. In doing this, the reaction mixture was warmed up to 40° C. in the meantime. The precipitate was filtered off, washed with methanol to yield the title compound as light red solid (11 g, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:29][C:30]1([CH3:39])[O:34][C@@H:33]([CH:35](O)[CH:36]=[CH2:37])[CH2:32][O:31]1>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:35]([C@H:33]1[CH2:32][O:31][C:30]([CH3:39])([CH3:29])[O:34]1)[CH:36]=[CH2:37]
Reactant: C=CC(O)[C@H]1COC(C)(C)O1
Reactant: Oc1ccc(F)cc1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC(Oc1ccc(F)cc1Br)[C@H]1COC(C)(C)O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
On a stirred solution composed by 2-bromo-4-fluoro-phenol (12.07 g, 0.063 mol) and triphenylphosphine (16.18 g, 0.063 mol) in THF (85 ml) under nitrogen at 18° C., 1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-prop-2-en-1-ol (10.0 g, 0.054 mol) was added as a crude product. The reaction miture was then cooled to 0° C. and diisopropyl-aza-dicarboxylate (12.78 g, 0.063 mol) was added dropwise over a period of 30 min. At the end of the addition the temperature was raised gradually to 18° C. and the mixture left to stir for further 1 h. The crude reaction was then concentrated under reduced pressure and then MTBE (31 g) added. After 15 min agitation, the slurry was filtered and the panel washed with MTBE (2×10 g). The mother liquors were then concentrated in vacuo and heptane (23 g) added. After 30 min stirring, the slurry was filtered and the cake washed with heptane (11 g). The mother liquors were then concentrated in vacuo and purified by column chomatography on silica using a mixture heptan:ethyl acetate:triethylamine 9.5:0.5:0.01, as eluent. 14.28 g of (R)-4-(1-(2-bromo-4-fluorophenoxy)allyl)-2,2-dimethyl-1,3-dioxolane were isolated as a mixture of diastereoisomers (80% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:14]2([CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)[CH:13]([CH3:20])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:22]1[C:23]2[CH:30]=[CH:29][NH:28][C:24]=2[N:25]=[CH:26][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:1]([O:8][C:9]([N:11]1[C:14]2([CH2:19][CH2:18][CH2:17][N:16]([C:22]3[C:23]4[CH:30]=[CH:29][NH:28][C:24]=4[N:25]=[CH:26][N:27]=3)[CH2:15]2)[CH:13]([CH3:20])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(C(=O)OCc2ccccc2)C12CCCNC2
Reactant: Clc1ncnc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC1CN(C(=O)OCc2ccccc2)C12CCCN(c1ncnc3[nH]ccc13)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.2 %

Procedure:
An optically-active compound of 3-methyl-1,6-diazaspiro[3,5]nonane-1-carboxylic acid 1-benzyl ester (2.20 g) was mixed with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.17 g), potassium carbonate (3.17 g) and water (12 ml), and the mixture was stirred for 4 hours with refluxing. The mixture was cooled to room temperature, and extracted with chloroform twice. The combined organic layer was washed with water, 10% aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/ethyl acetate=1/0 to 1/3, followed by chloroform/methanol=95/5) to give the titled compound (2.84 g).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:6][N:5]=[C:4]2[NH:16][N:17]=[CH:18][C:3]=12.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO.C([O-])(O)=O.[Na+]>[C:20]1([CH2:19][O:1][C:2]2[C:7]([C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:9])=[CH:6][N:5]=[C:4]3[NH:16][N:17]=[CH:18][C:3]=23)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C(c1ccccc1)c1cnc2[nH]ncc2c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C(c1ccccc1)c1cnc2[nH]ncc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.8 %

Procedure:
To a solution of [4-hydroxy-1H-pyrazolo[3,4-b]pyridin-5-yl]phenylmethanone (50 mg, 0.21 mmol) in methanol (1 mL) and saturated aqueous NaHCO3 solution (10 mL) was added benzyl bromide (0.027 mL, 0.23 mmol). The reaction mixture was stirred at room temperature for 16 h and extracted with CH2Cl2 (3×10 mL). The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give an oil. The crude material was purified by flash chromatography (SiO2, 230-400 mesh, eluted with 1:19 MEOH/CH2Cl2) to afford the title compound (13 mg, 20%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:18][CH3:19])[CH:6]=[CH:7][CH:8]=1)#[N:2]>C1COCC1.ClCCl>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:18][CH3:19])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1cccc(C#N)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])cc1-c1cccc(CN)c1
Temperature: 25 °C

Procedure:
2-(3-cyanophenyl)-4-nitroanisole (8.0 g) from Example 111, part a, was dissolved in THF (200 mL) and purged with nitrogen. A 11.0M solution of borane in THF (135 mL) was then added, and the reaction was heated at reflux for 4 hours. When the reaction was complete, the mixture was cooled to room temperature and 4.0N HCl in dioxane (25 mL) was added dropwise over 30 minutes. Methanol (200 mL) was slowly added to the acidified solution, and the solvent was removed in vacuo. The resulting gum was redissolved in methanol (150 mL) and concentrated in vacuo to give a solid. The product was dissolved in dichloromethane (150 mL) and cooled to −20° C. to give 2-(3-aminomethylphenyl)-4-nitroanisole which was collected on a filter and dried in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:32])=[C:16]([N:19]4[CH2:23][CH2:22][CH:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]4)[CH:17]=3)[C:12](=[O:33])[N:11]([O:34]CC3C=CC=CC=3)[C:10]2=[O:42])=[CH:5][CH:4]=1>[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:32])=[C:16]([N:19]4[CH2:23][CH2:22][CH:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])[CH2:20]4)[CH:17]=3)[C:12](=[O:33])[N:11]([OH:34])[C:10]2=[O:42])=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(N4CCC(NC(=O)OC(C)(C)C)C4)cc32)cc1
Agent: [Pd]
Product: COc1ccc(-n2c(=O)n(O)c(=O)c3cc(F)c(N4CCC(NC(=O)OC(C)(C)C)C4)cc32)cc1
Yield: 100.1 %

Procedure:
Using the General Method 6A, the reaction of 10% Pd/C (0.074 g) with 1-(4-methoxy phenyl)-6-fluoro-3-benzyloxy-7-(3-t-butoxycarbonylamino-pyrrolidin-1-yl)-1H-quinazoline-2,4-dione (Example Q-1, 0.222 g, 0.38 mmol) afforded 0.185 g of 1-(4-methoxyphenyl)-6-fluoro-3-hydroxy-7-(3-t-butoxycarbonylamino-pyrrolidin-1-yl)-1H-quinazoline-2,4-dione as a solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:17]([F:20])([F:19])[F:18])=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])C.ClCCl>[OH-].[Na+]>[OH:16][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([C:17]([F:20])([F:18])[F:19])[C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc2ccccc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(O)c1c(C(F)(F)F)nc2ccccc2c1O

Procedure:
A suspension of 4-hydroxy-2-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (5 g, 17.5 mmol) in 10% aqueous NaOH solution was heated at reflux for 2 h. After cooling, dichloromethane was added and the aqueous phase was separated and acidified with concentrated HCl to pH 4. The resulting precipitate was collected via filtration, washed with water and Et2O to provide 4-hydroxy-2-trifluoromethyl-quinoline-3-carboxylic acid (A-15) (3.6 g, 80%). 1H NMR (DMSO-d6) δ 8.18-8.21 (d, J=7.8 Hz, 1H), 7.92-7.94 (d, J=8.4 Hz, 1H), 7.79-7.83 (t, J=14.4 Hz, 1H), 7.50-7.53 (t, J=15 Hz, 1H); ESI-MS 257.0 m/z (MH+).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:33])=[C:10]([N:14]3[CH2:18][CH2:17][CH:16]([NH:19][S:20]([C:23]4[CH:28]=[CH:27][C:26]([NH:29]C(=O)C)=[CH:25][CH:24]=4)(=[O:22])=[O:21])[CH2:15]3)[C:11]=2[F:13])[C:6](=[O:34])[C:5]([C:35]([OH:37])=[O:36])=[CH:4]1)[CH3:2].Cl.[OH-].[Na+]>C(O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:33])=[C:10]([N:14]3[CH2:18][CH2:17][CH:16]([NH:19][S:20]([C:23]4[CH:24]=[CH:25][C:26]([NH2:29])=[CH:27][CH:28]=4)(=[O:22])=[O:21])[CH2:15]3)[C:11]=2[F:13])[C:6](=[O:34])[C:5]([C:35]([OH:37])=[O:36])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(NS(=O)(=O)c4ccc(NC(C)=O)cc4)C3)c(F)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(NS(=O)(=O)c4ccc(N)cc4)C3)c(F)c21

Procedure:
To the compound obtained in Example 14 is added a mixture solution made up of 100 ml of 2N hydrochloric acid and 10 ml of ethanol, and the resulting mixture is refluxed for 4 hours while heating. After cooling, the reaction mixture is neutralized with 2N sodium hydroxide solution and concentrated under reduced pressure. The residue is added to water which is then adjusted to pH 13 with 2N sodium hydroxide solution to dissolve, and any undissolved matter, if present, is removed. The solution is adjusted to pH 7 with acetic acid. Precipitating crystals are collected by filtration and washed. To the washed crystals is added water, pH adjusted to 3 to dissolve, and any undissolved matter, if present, is removed. The solution is then adjusted to pH 7 with 2N sodium hydroxide solution and precipitating crystals are collected by filtration and washed with water. Recrystallization from DMF-methanol gives 1.07 g of the titled compound. Melting point 214°-216° C.